FEMALE FEMALE REPRODUCTIVErsquos REPRODUCTIVErsquos

HORMONESHORMONES

BIOCHEMISTRY DEPARTMENTBIOCHEMISTRY DEPARTMENT

Molecular medicine case studies Molecular medicine case studies Mutations of the FSH and LH Mutations of the FSH and LH receptors (which have similar receptors (which have similar structure)structure)

Primary ovarian failure caused by a Primary ovarian failure caused by a point mutation in the FSH receptor point mutation in the FSH receptor genegene

Chromosome 2p C to T in nucleotide Chromosome 2p C to T in nucleotide 566 of exon 7 of the FSH receptor 566 of exon 7 of the FSH receptor gene Alanine to Valine substitution gene Alanine to Valine substitution at residue 189 of the protein at residue 189 of the protein

Pituitary HormonesPituitary Hormones

Posterior pituitaryPosterior pituitary

Stores and releases 2 hormones that areStores and releases 2 hormones that are

produced in the hypothalamusproduced in the hypothalamus

o Antidiuretic hormone Antidiuretic hormone (ADHvasopressin)(ADHvasopressin)

o OxytocinOxytocin

OxytocinOxytocin

9 amino acid peptide produced primarily 9 amino acid peptide produced primarily by paraventricular nucleus and small by paraventricular nucleus and small amount by supraoptic nucleusamount by supraoptic nucleusTargets Uterus and mammary glandsTargets Uterus and mammary glandsContraction of pregnant uterusContraction of pregnant uterusStimulates contractions of the mammary Stimulates contractions of the mammary gland alveoligland alveoli Milk-ejection reflexMilk-ejection reflex

Pituitary HormonesPituitary Hormones

Anterior pituitaryAnterior pituitary

Prolactin Prolactin Growth Hormone (GH)Growth Hormone (GH) Thyroid Stimulating Hormone (TSH)Thyroid Stimulating Hormone (TSH) Adrenocorticotropic Hormone (ACTH) Adrenocorticotropic Hormone (ACTH) Follicle-stimulating Hormone (FSH) Follicle-stimulating Hormone (FSH) Luteinizing Hormone (LH)Luteinizing Hormone (LH)

PROLACTINPROLACTIN

Protein consist of 199 amino acidsProtein consist of 199 amino acidsIn females stimulates milk production in the In females stimulates milk production in the mammary glandsmammary glandsRelease inhibited at non-pregnant women Release inhibited at non-pregnant women As estrogen and progesterone levels rise As estrogen and progesterone levels rise late in pregnancy it stimulates prolactin late in pregnancy it stimulates prolactin releasereleaseHyperprolactinaemia can cause menstrual Hyperprolactinaemia can cause menstrual problems in females and breast problems in females and breast enlargement in malesenlargement in males

Hypo-Pit-Gonadal AxesHypo-Pit-Gonadal Axes

An Overview

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

Hypothalamus(synthesizesGonadotropin releasinghormone)

GnRH

Anterior pituitary(synthesizes Gonadotropinsluteinizing hormonefollicle stimulating hormone)

LH+FSH

Gonads -synthesizegonadal hormones

estrogens

androgens

RESEPTOR RESEPTOR

Reseptor Hormon umumnya di Reseptor Hormon umumnya di membran plasma atau didalam membran plasma atau didalam sitoplasmasitoplasma

Interaksi H-R Interaksi H-R signal transduction signal transduction kedalam selkedalam sel

Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulation

Reseptor Angiotensin II terlihat akan Reseptor Angiotensin II terlihat akan meningkat atau menurun bergantung meningkat atau menurun bergantung pada tipe sel yang dipengaruhinyapada tipe sel yang dipengaruhinya

TRHTSH dan T3-T4 regulasi melalui TRHTSH dan T3-T4 regulasi melalui reseptor masing-masing dalam reseptor masing-masing dalam mekanisme negative feedback mekanisme negative feedback

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Molecular medicine case studies Molecular medicine case studies Mutations of the FSH and LH Mutations of the FSH and LH receptors (which have similar receptors (which have similar structure)structure)

Primary ovarian failure caused by a Primary ovarian failure caused by a point mutation in the FSH receptor point mutation in the FSH receptor genegene

Chromosome 2p C to T in nucleotide Chromosome 2p C to T in nucleotide 566 of exon 7 of the FSH receptor 566 of exon 7 of the FSH receptor gene Alanine to Valine substitution gene Alanine to Valine substitution at residue 189 of the protein at residue 189 of the protein

Pituitary HormonesPituitary Hormones

Posterior pituitaryPosterior pituitary

Stores and releases 2 hormones that areStores and releases 2 hormones that are

produced in the hypothalamusproduced in the hypothalamus

o Antidiuretic hormone Antidiuretic hormone (ADHvasopressin)(ADHvasopressin)

o OxytocinOxytocin

OxytocinOxytocin

9 amino acid peptide produced primarily 9 amino acid peptide produced primarily by paraventricular nucleus and small by paraventricular nucleus and small amount by supraoptic nucleusamount by supraoptic nucleusTargets Uterus and mammary glandsTargets Uterus and mammary glandsContraction of pregnant uterusContraction of pregnant uterusStimulates contractions of the mammary Stimulates contractions of the mammary gland alveoligland alveoli Milk-ejection reflexMilk-ejection reflex

Pituitary HormonesPituitary Hormones

Anterior pituitaryAnterior pituitary

Prolactin Prolactin Growth Hormone (GH)Growth Hormone (GH) Thyroid Stimulating Hormone (TSH)Thyroid Stimulating Hormone (TSH) Adrenocorticotropic Hormone (ACTH) Adrenocorticotropic Hormone (ACTH) Follicle-stimulating Hormone (FSH) Follicle-stimulating Hormone (FSH) Luteinizing Hormone (LH)Luteinizing Hormone (LH)

PROLACTINPROLACTIN

Protein consist of 199 amino acidsProtein consist of 199 amino acidsIn females stimulates milk production in the In females stimulates milk production in the mammary glandsmammary glandsRelease inhibited at non-pregnant women Release inhibited at non-pregnant women As estrogen and progesterone levels rise As estrogen and progesterone levels rise late in pregnancy it stimulates prolactin late in pregnancy it stimulates prolactin releasereleaseHyperprolactinaemia can cause menstrual Hyperprolactinaemia can cause menstrual problems in females and breast problems in females and breast enlargement in malesenlargement in males

Hypo-Pit-Gonadal AxesHypo-Pit-Gonadal Axes

An Overview

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

Hypothalamus(synthesizesGonadotropin releasinghormone)

GnRH

Anterior pituitary(synthesizes Gonadotropinsluteinizing hormonefollicle stimulating hormone)

LH+FSH

Gonads -synthesizegonadal hormones

estrogens

androgens

RESEPTOR RESEPTOR

Reseptor Hormon umumnya di Reseptor Hormon umumnya di membran plasma atau didalam membran plasma atau didalam sitoplasmasitoplasma

Interaksi H-R Interaksi H-R signal transduction signal transduction kedalam selkedalam sel

Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulation

Reseptor Angiotensin II terlihat akan Reseptor Angiotensin II terlihat akan meningkat atau menurun bergantung meningkat atau menurun bergantung pada tipe sel yang dipengaruhinyapada tipe sel yang dipengaruhinya

TRHTSH dan T3-T4 regulasi melalui TRHTSH dan T3-T4 regulasi melalui reseptor masing-masing dalam reseptor masing-masing dalam mekanisme negative feedback mekanisme negative feedback

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Pituitary HormonesPituitary Hormones

Posterior pituitaryPosterior pituitary

Stores and releases 2 hormones that areStores and releases 2 hormones that are

produced in the hypothalamusproduced in the hypothalamus

o Antidiuretic hormone Antidiuretic hormone (ADHvasopressin)(ADHvasopressin)

o OxytocinOxytocin

OxytocinOxytocin

9 amino acid peptide produced primarily 9 amino acid peptide produced primarily by paraventricular nucleus and small by paraventricular nucleus and small amount by supraoptic nucleusamount by supraoptic nucleusTargets Uterus and mammary glandsTargets Uterus and mammary glandsContraction of pregnant uterusContraction of pregnant uterusStimulates contractions of the mammary Stimulates contractions of the mammary gland alveoligland alveoli Milk-ejection reflexMilk-ejection reflex

Pituitary HormonesPituitary Hormones

Anterior pituitaryAnterior pituitary

Prolactin Prolactin Growth Hormone (GH)Growth Hormone (GH) Thyroid Stimulating Hormone (TSH)Thyroid Stimulating Hormone (TSH) Adrenocorticotropic Hormone (ACTH) Adrenocorticotropic Hormone (ACTH) Follicle-stimulating Hormone (FSH) Follicle-stimulating Hormone (FSH) Luteinizing Hormone (LH)Luteinizing Hormone (LH)

PROLACTINPROLACTIN

Protein consist of 199 amino acidsProtein consist of 199 amino acidsIn females stimulates milk production in the In females stimulates milk production in the mammary glandsmammary glandsRelease inhibited at non-pregnant women Release inhibited at non-pregnant women As estrogen and progesterone levels rise As estrogen and progesterone levels rise late in pregnancy it stimulates prolactin late in pregnancy it stimulates prolactin releasereleaseHyperprolactinaemia can cause menstrual Hyperprolactinaemia can cause menstrual problems in females and breast problems in females and breast enlargement in malesenlargement in males

Hypo-Pit-Gonadal AxesHypo-Pit-Gonadal Axes

An Overview

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

Hypothalamus(synthesizesGonadotropin releasinghormone)

GnRH

Anterior pituitary(synthesizes Gonadotropinsluteinizing hormonefollicle stimulating hormone)

LH+FSH

Gonads -synthesizegonadal hormones

estrogens

androgens

RESEPTOR RESEPTOR

Reseptor Hormon umumnya di Reseptor Hormon umumnya di membran plasma atau didalam membran plasma atau didalam sitoplasmasitoplasma

Interaksi H-R Interaksi H-R signal transduction signal transduction kedalam selkedalam sel

Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulation

Reseptor Angiotensin II terlihat akan Reseptor Angiotensin II terlihat akan meningkat atau menurun bergantung meningkat atau menurun bergantung pada tipe sel yang dipengaruhinyapada tipe sel yang dipengaruhinya

TRHTSH dan T3-T4 regulasi melalui TRHTSH dan T3-T4 regulasi melalui reseptor masing-masing dalam reseptor masing-masing dalam mekanisme negative feedback mekanisme negative feedback

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

OxytocinOxytocin

9 amino acid peptide produced primarily 9 amino acid peptide produced primarily by paraventricular nucleus and small by paraventricular nucleus and small amount by supraoptic nucleusamount by supraoptic nucleusTargets Uterus and mammary glandsTargets Uterus and mammary glandsContraction of pregnant uterusContraction of pregnant uterusStimulates contractions of the mammary Stimulates contractions of the mammary gland alveoligland alveoli Milk-ejection reflexMilk-ejection reflex

Pituitary HormonesPituitary Hormones

Anterior pituitaryAnterior pituitary

Prolactin Prolactin Growth Hormone (GH)Growth Hormone (GH) Thyroid Stimulating Hormone (TSH)Thyroid Stimulating Hormone (TSH) Adrenocorticotropic Hormone (ACTH) Adrenocorticotropic Hormone (ACTH) Follicle-stimulating Hormone (FSH) Follicle-stimulating Hormone (FSH) Luteinizing Hormone (LH)Luteinizing Hormone (LH)

PROLACTINPROLACTIN

Protein consist of 199 amino acidsProtein consist of 199 amino acidsIn females stimulates milk production in the In females stimulates milk production in the mammary glandsmammary glandsRelease inhibited at non-pregnant women Release inhibited at non-pregnant women As estrogen and progesterone levels rise As estrogen and progesterone levels rise late in pregnancy it stimulates prolactin late in pregnancy it stimulates prolactin releasereleaseHyperprolactinaemia can cause menstrual Hyperprolactinaemia can cause menstrual problems in females and breast problems in females and breast enlargement in malesenlargement in males

Hypo-Pit-Gonadal AxesHypo-Pit-Gonadal Axes

An Overview

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

Hypothalamus(synthesizesGonadotropin releasinghormone)

GnRH

Anterior pituitary(synthesizes Gonadotropinsluteinizing hormonefollicle stimulating hormone)

LH+FSH

Gonads -synthesizegonadal hormones

estrogens

androgens

RESEPTOR RESEPTOR

Reseptor Hormon umumnya di Reseptor Hormon umumnya di membran plasma atau didalam membran plasma atau didalam sitoplasmasitoplasma

Interaksi H-R Interaksi H-R signal transduction signal transduction kedalam selkedalam sel

Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulation

Reseptor Angiotensin II terlihat akan Reseptor Angiotensin II terlihat akan meningkat atau menurun bergantung meningkat atau menurun bergantung pada tipe sel yang dipengaruhinyapada tipe sel yang dipengaruhinya

TRHTSH dan T3-T4 regulasi melalui TRHTSH dan T3-T4 regulasi melalui reseptor masing-masing dalam reseptor masing-masing dalam mekanisme negative feedback mekanisme negative feedback

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Pituitary HormonesPituitary Hormones

Anterior pituitaryAnterior pituitary

Prolactin Prolactin Growth Hormone (GH)Growth Hormone (GH) Thyroid Stimulating Hormone (TSH)Thyroid Stimulating Hormone (TSH) Adrenocorticotropic Hormone (ACTH) Adrenocorticotropic Hormone (ACTH) Follicle-stimulating Hormone (FSH) Follicle-stimulating Hormone (FSH) Luteinizing Hormone (LH)Luteinizing Hormone (LH)

PROLACTINPROLACTIN

Protein consist of 199 amino acidsProtein consist of 199 amino acidsIn females stimulates milk production in the In females stimulates milk production in the mammary glandsmammary glandsRelease inhibited at non-pregnant women Release inhibited at non-pregnant women As estrogen and progesterone levels rise As estrogen and progesterone levels rise late in pregnancy it stimulates prolactin late in pregnancy it stimulates prolactin releasereleaseHyperprolactinaemia can cause menstrual Hyperprolactinaemia can cause menstrual problems in females and breast problems in females and breast enlargement in malesenlargement in males

Hypo-Pit-Gonadal AxesHypo-Pit-Gonadal Axes

An Overview

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

Hypothalamus(synthesizesGonadotropin releasinghormone)

GnRH

Anterior pituitary(synthesizes Gonadotropinsluteinizing hormonefollicle stimulating hormone)

LH+FSH

Gonads -synthesizegonadal hormones

estrogens

androgens

RESEPTOR RESEPTOR

Reseptor Hormon umumnya di Reseptor Hormon umumnya di membran plasma atau didalam membran plasma atau didalam sitoplasmasitoplasma

Interaksi H-R Interaksi H-R signal transduction signal transduction kedalam selkedalam sel

Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulation

Reseptor Angiotensin II terlihat akan Reseptor Angiotensin II terlihat akan meningkat atau menurun bergantung meningkat atau menurun bergantung pada tipe sel yang dipengaruhinyapada tipe sel yang dipengaruhinya

TRHTSH dan T3-T4 regulasi melalui TRHTSH dan T3-T4 regulasi melalui reseptor masing-masing dalam reseptor masing-masing dalam mekanisme negative feedback mekanisme negative feedback

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

PROLACTINPROLACTIN

Protein consist of 199 amino acidsProtein consist of 199 amino acidsIn females stimulates milk production in the In females stimulates milk production in the mammary glandsmammary glandsRelease inhibited at non-pregnant women Release inhibited at non-pregnant women As estrogen and progesterone levels rise As estrogen and progesterone levels rise late in pregnancy it stimulates prolactin late in pregnancy it stimulates prolactin releasereleaseHyperprolactinaemia can cause menstrual Hyperprolactinaemia can cause menstrual problems in females and breast problems in females and breast enlargement in malesenlargement in males

Hypo-Pit-Gonadal AxesHypo-Pit-Gonadal Axes

An Overview

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

Hypothalamus(synthesizesGonadotropin releasinghormone)

GnRH

Anterior pituitary(synthesizes Gonadotropinsluteinizing hormonefollicle stimulating hormone)

LH+FSH

Gonads -synthesizegonadal hormones

estrogens

androgens

RESEPTOR RESEPTOR

Reseptor Hormon umumnya di Reseptor Hormon umumnya di membran plasma atau didalam membran plasma atau didalam sitoplasmasitoplasma

Interaksi H-R Interaksi H-R signal transduction signal transduction kedalam selkedalam sel

Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulation

Reseptor Angiotensin II terlihat akan Reseptor Angiotensin II terlihat akan meningkat atau menurun bergantung meningkat atau menurun bergantung pada tipe sel yang dipengaruhinyapada tipe sel yang dipengaruhinya

TRHTSH dan T3-T4 regulasi melalui TRHTSH dan T3-T4 regulasi melalui reseptor masing-masing dalam reseptor masing-masing dalam mekanisme negative feedback mekanisme negative feedback

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Hypo-Pit-Gonadal AxesHypo-Pit-Gonadal Axes

An Overview

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

Hypothalamus(synthesizesGonadotropin releasinghormone)

GnRH

Anterior pituitary(synthesizes Gonadotropinsluteinizing hormonefollicle stimulating hormone)

LH+FSH

Gonads -synthesizegonadal hormones

estrogens

androgens

RESEPTOR RESEPTOR

Reseptor Hormon umumnya di Reseptor Hormon umumnya di membran plasma atau didalam membran plasma atau didalam sitoplasmasitoplasma

Interaksi H-R Interaksi H-R signal transduction signal transduction kedalam selkedalam sel

Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulation

Reseptor Angiotensin II terlihat akan Reseptor Angiotensin II terlihat akan meningkat atau menurun bergantung meningkat atau menurun bergantung pada tipe sel yang dipengaruhinyapada tipe sel yang dipengaruhinya

TRHTSH dan T3-T4 regulasi melalui TRHTSH dan T3-T4 regulasi melalui reseptor masing-masing dalam reseptor masing-masing dalam mekanisme negative feedback mekanisme negative feedback

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

An Overview

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

Hypothalamus(synthesizesGonadotropin releasinghormone)

GnRH

Anterior pituitary(synthesizes Gonadotropinsluteinizing hormonefollicle stimulating hormone)

LH+FSH

Gonads -synthesizegonadal hormones

estrogens

androgens

RESEPTOR RESEPTOR

Reseptor Hormon umumnya di Reseptor Hormon umumnya di membran plasma atau didalam membran plasma atau didalam sitoplasmasitoplasma

Interaksi H-R Interaksi H-R signal transduction signal transduction kedalam selkedalam sel

Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulation

Reseptor Angiotensin II terlihat akan Reseptor Angiotensin II terlihat akan meningkat atau menurun bergantung meningkat atau menurun bergantung pada tipe sel yang dipengaruhinyapada tipe sel yang dipengaruhinya

TRHTSH dan T3-T4 regulasi melalui TRHTSH dan T3-T4 regulasi melalui reseptor masing-masing dalam reseptor masing-masing dalam mekanisme negative feedback mekanisme negative feedback

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

RESEPTOR RESEPTOR

Reseptor Hormon umumnya di Reseptor Hormon umumnya di membran plasma atau didalam membran plasma atau didalam sitoplasmasitoplasma

Interaksi H-R Interaksi H-R signal transduction signal transduction kedalam selkedalam sel

Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulation

Reseptor Angiotensin II terlihat akan Reseptor Angiotensin II terlihat akan meningkat atau menurun bergantung meningkat atau menurun bergantung pada tipe sel yang dipengaruhinyapada tipe sel yang dipengaruhinya

TRHTSH dan T3-T4 regulasi melalui TRHTSH dan T3-T4 regulasi melalui reseptor masing-masing dalam reseptor masing-masing dalam mekanisme negative feedback mekanisme negative feedback

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

RESEPTOR RESEPTOR

Hal ini dipengaruhi oleh alHal ini dipengaruhi oleh al

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang disekresikan misalnya disekresikan misalnya

reseptor reseptor Insulin akan up Insulin akan up regulate bila regulate bila Insulin sedikit Insulin sedikit

2 pengaruh dari hormon 2 pengaruh dari hormon lainmisalnya lainmisalnya

reseptor LH akan meningkat reseptor LH akan meningkat oleh oleh sekresi FSH sekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH hCG sel luteal dan TSH reseptor FSH hCG sel luteal dan TSH

Reseptor-reseptor tersebut dapat Reseptor-reseptor tersebut dapat bermutasi bermutasi timbul kelainan timbul kelainan

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi Beberapa obat dapat berinteraksi dengan reseptor tersebutdengan reseptor tersebut

Efek yang timbul agonist Efek yang timbul agonist (menyerupai efek ligand yang (menyerupai efek ligand yang sebenarnya) atau antagonist sebenarnya) atau antagonist (berlawanan dengan efek ligand (berlawanan dengan efek ligand nya misalnya menghambat nya misalnya menghambat transduksi signal)transduksi signal)

Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain seperti Interleukin molekul lain seperti Interleukin Interferon Antigen Interferon Antigen Neurotransmiter LDL dllNeurotransmiter LDL dll

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Action of GnRHAction of GnRH

GnRH action GnRH action rarr rarr A system stimulation of A system stimulation of phosphatidylinositol phosphatidylinositol

GnRH binds to receptors at the cell membrane of the GnRH binds to receptors at the cell membrane of the gonadotropegonadotrope

Phospholipase C is activated catalyzes the hidrolysis of Phospholipase C is activated catalyzes the hidrolysis of PIPPIP2 2 to DAG and to DAG and IPIP3 3

DAG activates protein kinase C (PKC) which DAG activates protein kinase C (PKC) which phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exterior

IPIP3 3 stimulates Castimulates Ca2+ 2+ from calcium stroge particle and from calcium stroge particle and

cause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from the cellparticipates in exocytosis of LH and FSH from the cell

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Action of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

GONADOTROPINSGONADOTROPINS

Follicle-stimulating hormone (FSHFollicle-stimulating hormone (FSH))

Target Ovaries and TestisTarget Ovaries and TestisStimulates the maturation of sperm and Stimulates the maturation of sperm and eggeggIn the females causes the release of In the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

GONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

Target Ovaries and TestisMale Production of testosterone

In the females LH and FSH caused In the females LH and FSH caused follicle development and then LH follicle development and then LH independently is responsible for independently is responsible for ovulation ovulation

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Sex HormonesSex Hormones

Gonad and AdrenalGonad and Adrenal

EstrogenEstrogen

ProgesteroneProgesterone

DihydrotestosteroneDihydrotestosterone

TestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Ovarian hormonesOvarian hormones

SteroidsSteroids

o EstrogensEstrogens

o AndrogensAndrogens

o ProgesteroneProgesterone

PeptidesPeptides

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

Produced in both interstitial andProduced in both interstitial and

follicular cellsfollicular cells

Derivatives of cholesterol (LDL- Derivatives of cholesterol (LDL-

lipoproteins and de novo synthesis)lipoproteins and de novo synthesis)

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

SYNTHESISSYNTHESIS

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Chemical structure C18Chemical structure C18 SourceSource

o follicular cellsfollicular cellso corpus luteumcorpus luteumo placentaplacentao adrenal cortexadrenal cortexo adipose tissue (DHEA rarr androstenedione adipose tissue (DHEA rarr androstenedione rarr rarr E1)E1)

ESTROGENESTROGEN

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

SYNTHESISSYNTHESIS

First step in mitochondriaFirst step in mitochondria

The rest in smooth ERThe rest in smooth ER

Reduction in number of carbon atomsReduction in number of carbon atoms

Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells

Androgens are primarily synthesized in Androgens are primarily synthesized in

thecal cellsthecal cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Ovarian Steroid HormonesOvarian Steroid Hormones

Three types of steroid hormones Three types of steroid hormones Progestogens Androgens and Progestogens Androgens and EstrogensEstrogens

Estrogen biosynthesisEstrogen biosynthesis

1 C19 Androgens (thecal cells) will be 1 C19 Androgens (thecal cells) will be aromatized (granulosa cells) to obtain aromatized (granulosa cells) to obtain EstrogensEstrogens

2 LH stimulates Androgen production 2 LH stimulates Androgen production and aromatized within the thecal cellsand aromatized within the thecal cells

Also are available for aromatization in Also are available for aromatization in the granulosa cellsthe granulosa cells

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Ovarian Steroid HormonesOvarian Steroid Hormones

Estrogen produced by thecal cells Estrogen produced by thecal cells the major steroid in the circulationthe major steroid in the circulation

Estrogen synthesized by granulosa Estrogen synthesized by granulosa cells a local role possibly related cells a local role possibly related to ovum maturation to ovum maturation

FSH regulate production and FSH regulate production and subsequent induction and subsequent induction and activation of Aromatase in the activation of Aromatase in the granulosa cellsgranulosa cells

Estradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone within the liver and Estrone hydrated to Estriol (E3)hydrated to Estriol (E3)

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Ovarian Steroid HormonesOvarian Steroid Hormones

These three estrogens are excreted These three estrogens are excreted in the urine as glucuronides and in the urine as glucuronides and sulfatessulfates

Placenta Adrenals Adipose tissue Placenta Adrenals Adipose tissue can produce significant quantities can produce significant quantities of Estrogens from steroid of Estrogens from steroid precursorsprecursors

Aromatization of Androstenedione Aromatization of Androstenedione and Testosterone within tissue is a and Testosterone within tissue is a major source of Estrogens in the major source of Estrogens in the male and post menopausal femalemale and post menopausal female

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Estrogens in circulation

Estradiol (E2)

1048708 Secreted by the ovary

Estrone (E1)

1048708 Derived from peripheral conversion of

estradiol and androstenedione

Estriol (E3)

1048708 Liver metabolite of estrone

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

ESTROGENSESTROGENS

Transport in bloodTransport in blood Mostly carrier-bound (albumin sexMostly carrier-bound (albumin sex hormone-binding globulin)hormone-binding globulin) Two peaksTwo peaks

o Before ovulationBefore ovulationo Mid-luteal peakMid-luteal peak

Levels much higher in the follicularLevels much higher in the follicular fluid than in the plasmafluid than in the plasma

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Cytoplasmic receptor binds to steroid Cytoplasmic receptor binds to steroid hormonehormone

Translocates to nucleusTranslocates to nucleus

DNA-binding domain binds to specific HRE DNA-binding domain binds to specific HRE of the DNAof the DNA

Dimerization occursDimerization occurs Process of 2 receptor units coming Process of 2 receptor units coming

together at the 2 half-sitestogether at the 2 half-sites

Stimulates transcription of particular Stimulates transcription of particular genesgenes

Mechanisms of ActionMechanisms of Action

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Mechanisms of ActionMechanisms of Action

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic andor nuclear protein cytoplasmic andor nuclear protein receptorsreceptors

Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from association with a heat-shock proteinassociation with a heat-shock protein

Either identical subunits singly or Either identical subunits singly or possibly together interact directly possibly together interact directly with the DNA hormone responsive with the DNA hormone responsive element to activate transcriptional element to activate transcriptional events leading to translation of a cell-events leading to translation of a cell-specific protein specific protein

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Protein A

nucleus

mRNA A

HREs

steroidthyroid hormoneretinoic acid receptor

Steroidthyroid hormone

retinoic acidPeptide or peptidergic

Gene A

mRNA A

Transcription factor(TF)

PO4-TF

second-messengerregulated kinase orreceptor kinase

cytoplasm

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides and

sulfatessulfates

Recycled in enterohepatic circulationRecycled in enterohepatic circulation

Excreted in the urineExcreted in the urine

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Physiological Physiological

Reproductive systemReproductive system

o Development and maintenance of uterus Development and maintenance of uterus uterine tubesvagina external genitalia uterine tubesvagina external genitalia and breastsand breasts

o Cyclic changes in the endometrium Cyclic changes in the endometrium cervix vaginacervix vagina

o Growth of the ovarian folliclesGrowth of the ovarian follicleso Motility of the uterine tubes uarrMotility of the uterine tubes uarr

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Physiological Physiological

Reproductive systemReproductive system

o Pregnancy uterine muscle mass uarr Pregnancy uterine muscle mass uarr excitability uarr breasts uarrexcitability uarr breasts uarr

o Female secondary sex characteristics Female secondary sex characteristics (fat deposits etc)(fat deposits etc)

o Estrous behavior in animals increased Estrous behavior in animals increased libido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone between males and femalesmales and females

Chemical structure C21Chemical structure C21 SourceSource

1048708 1048708 c luteumc luteum 1048708 1048708 placentaplacenta 1048708 1048708 follicles (small amount)follicles (small amount) 1048708 1048708 adrenal cortexadrenal cortex

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

ProgesteronProgesteron

Progesterone biosynthesis Progesterone biosynthesis FSH promotes the growth of the FSH promotes the growth of the follicle by acting through receptors follicle by acting through receptors on the granulosa cells and inducing on the granulosa cells and inducing the Aromatase enzyme to convert the Aromatase enzyme to convert Androgens to EstrogensAndrogens to EstrogensThe Androgens originate from the The Androgens originate from the theca which is stimulated by LH theca which is stimulated by LH through its receptors initially on through its receptors initially on theca cells and appear in the theca cells and appear in the granulosa cells and are probably granulosa cells and are probably coupled to the same second coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

ProgesteronProgesteronProgesterone biosynthesis Progesterone biosynthesis

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal celland estrogen within the thecal cellBut circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteum

Androgens Androgens Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning of Pubertyof PubertyDevelopment of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogens

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Ovarian Steroid HormonesOvarian Steroid Hormones

Androgens Androgens

Androgens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a puberty

Acne results from sebaceous gland Acne results from sebaceous gland activation by ovarian androgensactivation by ovarian androgens

Pubic and axillary hair growth are Pubic and axillary hair growth are also attributed to androgens of also attributed to androgens of ovarian andor adrenal originovarian andor adrenal origin

Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid dehydrogenase 1-hydroxysteroid dehydrogenase 1-hydroxylase and 1720-desmolase) hydroxylase and 1720-desmolase) activity increased production of activity increased production of adrenal androgensadrenal androgens

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

TransportTransport

2 free2 free

80 albumin-bound80 albumin-bound

18 corticosteroid-binding protein18 corticosteroid-binding protein

(transcortin) -bound(transcortin) -bound

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Cyclic changes in the endometrium cervix and vagina

Breasts supports the secretory function during lactation

Inhibits LH secretion

Responsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Physiological Physiological

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Physiological Physiological

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

RelaxinRelaxin 1048708 1048708 Relaxes pelvic jointsRelaxes pelvic joints 1048708 1048708 Softens and dilates cervixSoftens and dilates cervix 1048708 1048708 Sperm mobility - in malesSperm mobility - in males

InhibinInhibin 1048708 1048708 Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivin 1048708 1048708 Selective stimulaton of FSHSelective stimulaton of FSH 1048708 1048708 Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatins

1048708 1048708 Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factor

1048708 1048708 Prevents premature LH surgePrevents premature LH surge

POMC hormonesPOMC hormones

1048708 1048708 Vasopressin and oxytocin (in Vasopressin and oxytocin (in luteal cells) luteal cells)

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

Several peptides have been Several peptides have been isolated from ovarian follicles isolated from ovarian follicles and regulate oocyte maturation and regulate oocyte maturation

1 Oocyte Maturation Factor 1 Oocyte Maturation Factor

2 Ovarian Growth Factors2 Ovarian Growth Factors

3 Inhibins3 Inhibins

4 Activins4 Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

1 Oocyte Maturation Inhibitor 1 Oocyte Maturation Inhibitor Low molecular weight-peptideLow molecular weight-peptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesGap junctions present between cells of Gap junctions present between cells of the corona radiata and the oocytethe corona radiata and the oocyte structural pathway for cell-to-cell structural pathway for cell-to-cell communicationcommunicationCumulus cell extensions project through Cumulus cell extensions project through the zona pellucida to the oocytethe zona pellucida to the oocyteOMI may exert its action indirectly through OMI may exert its action indirectly through an action on cumulus cells an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

2 Ovarian Growth Factors 2 Ovarian Growth Factors

Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell aspect of granulosa cell differentiation and ovarian follicular differentiation and ovarian follicular development development

Pituitary FSH functions as the Pituitary FSH functions as the inducer of granulosa cell LH receptor inducer of granulosa cell LH receptor acquisition acquisition

This FSH-dependent LH receptor This FSH-dependent LH receptor induction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin is present in follicular fluid Inhibin is present in follicular fluid ovarian and granulosa cell extracts ovarian and granulosa cell extracts Inhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRH-stimulated both basal and GnRH-stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are inversely related to plasma FSH levelsinversely related to plasma FSH levelsInhibin can be detected in the plasma Inhibin can be detected in the plasma of women given FSH but not in of women given FSH but not in castrated subjects castrated subjects

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

3 Inhibin 3 Inhibin Inhibin composed of two subunits Inhibin composed of two subunits that are linked by disulfide bridges that are linked by disulfide bridges The two subunits (The two subunits (αα ββ) encoded by ) encoded by separated genesseparated genesAntibodies to inhibin confirm its Antibodies to inhibin confirm its presence in the plasma of men and presence in the plasma of men and womenwomenThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription at the level of transcription

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory Factors

4 Activin 4 Activin Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries invitroinvitroββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF (TGFββ) were similar) were similarDimers of the Dimers of the ββ subunits of inhibin subunits of inhibin ββAAββBB ββAAββAA and and ββBB ββBB were named Activin were named Activin Activin A and Activin BActivin A and Activin BActivin can enhance basal secretion of Activin can enhance basal secretion of FSH in a dose-dependent manner in vitro FSH in a dose-dependent manner in vitro without affecting the secretion of LHwithout affecting the secretion of LH