steroid hormones. objectives recall the overall role of steroids in human body. understand the...

Steroid HormonesSteroid Hormones

Objectives Objectives

Recall the overall role of steroids in human body.Recall the overall role of steroids in human body. Understand the physiological roles of cholesterol especially in synthesis Understand the physiological roles of cholesterol especially in synthesis

of steroid hormones.of steroid hormones. Recall the biochemical and clinical aspects of all types of adrenal Recall the biochemical and clinical aspects of all types of adrenal

steroids.steroids. Explain with appropriate details the biochemical and physiological Explain with appropriate details the biochemical and physiological

aspects of steroids from the testis and ovariesaspects of steroids from the testis and ovaries Recognize the biochemical and clinical relations of congenital adrenal Recognize the biochemical and clinical relations of congenital adrenal

hyperplasia and testicular feminization syndromehyperplasia and testicular feminization syndrome

Types of steroid hormones:Types of steroid hormones: GlucocorticoidsGlucocorticoids: cortisol cortisol is the major representative in most mammals

MineralocorticoidsMineralocorticoids: aldosteronealdosterone being most prominent

Sex hormonesSex hormones: : Androgens:Androgens: such as testosterone testosterone

Estrogens: Estrogens: including estradiolestradiol & estrone estrone

Progestogens: Progestogens: also known a progestins such as progesterone progesterone


Steroid HormonesSteroid HormonesAll steroid hormones are:All steroid hormones are:Derived from cholesterolcholesterol & differ only in the ring structure & side chains attached to it.Lipid soluble Lipid soluble & thus are freely permeable to membranesfreely permeable to membranes so are notnot stored in cells

Steroid hormones are synthesized in:Steroid hormones are synthesized in: Adrenal cortex: Adrenal cortex: cortisol, aldosterone & androgens (androstendione) cortisol, aldosterone & androgens (androstendione) Testis: Testis: testosteronetestosterone OvariesOvaries: estrogens & progesterone: estrogens & progesterone PlacentaPlacenta: progesterone: progesterone Some peripheral tissues Some peripheral tissues (as adipose tissue adipose tissue & the brain)


Cholesterol Cholesterol is the precursor of is the precursor of steroid hormonessteroid hormones

Steroid hormones have to be carried in the blood complexed to specific binding plasma proteins (globulins).

CortisolCortisol: by corticosteroid binding globulin (transcortin)corticosteroid binding globulin (transcortin)Sex steroids Sex steroids (testosterone & estradiol): by sex hormone-binding protein (SHBG)sex hormone-binding protein (SHBG)AldosteroneAldosterone: by the plasma protein albuminalbumin

Transport of Steroid Hormones in Transport of Steroid Hormones in BloodBlood

General Functions of Steroid General Functions of Steroid HormonesHormones

Steroid hormones play important roles in:Steroid hormones play important roles in:Metabolic regulation (glucocorticoids Metabolic regulation (glucocorticoids i.e. cortisoli.e. cortisol))Electrolyte balance (mineralocorticoids Electrolyte balance (mineralocorticoids i.e. aldosteronei.e. aldosterone))Reproductive functions (gonadal steroids Reproductive functions (gonadal steroids i.e. testosterone & estrogensi.e. testosterone & estrogens))

Steroids Steroids alsoalso play roles in: play roles in:Inflammatory responsesInflammatory responsesStress responsesStress responsesBone metabolismBone metabolismCardiovascular fitnessCardiovascular fitnessBehavior, cognition & moodBehavior, cognition & mood

Steroid Hormone Steroid Hormone SynthesisSynthesis

A series of enzymatic steps in the mitochondria & ER of steroidogenic tissues steroidogenic tissues convert cholesterol into all of the other steroid hormones & intermediates.

An important control point this process is the transport of free cholesterol from the cytoplasm into mitochondria.

This step is carried out by the Steroidogenic Acute Regulatory Protein (STAR)Steroidogenic Acute Regulatory Protein (STAR)

cholesterolcholesterol

CholesterolCholesterolpoolpool

LHLH

ATP

cAMPProtein Kinase

PregnenolonePregnenolone

ALL STEROID HORMONES

Sources of Sources of Cholesterol for Cholesterol for

Steroid SynthesisSteroid Synthesis

Acetyl CoAAcetyl CoA

LipoproteinLipoproteins in Bloods in Blood

mitochondriamitochondriaDesmolaseDesmolase

PregnenolonePregnenolone

STAR

In:In:Adrenal Adrenal CortexCortexTestisTestisOvaryOvary

The first enzymatic step is the conversion of cholesterolcholesterol to pregnenolonepregnenolone

which occurs in the mitochondriamitochondria.

This reaction is carried out by the enzyme desmolasedesmolase

This is a rate limiting, nonreversible step rate limiting, nonreversible step in the initiation of steroid biosynthesis.

This step occurs in This step occurs in Adrenal CortexAdrenal Cortex, , OvaryOvary & & TestisTestis

Steroid Hormone Steroid Hormone SynthesisSynthesis

Steroid hormone synthesis Steroid hormone synthesis in the in the Adrenal CortexAdrenal Cortex

1- The adrenal cortexadrenal cortex::

The zona glomerulosa: secretes The zona glomerulosa: secretes aldosteronealdosterone

The zona fasciculata: secretes The zona fasciculata: secretes cortisol cortisol

The zona reticularis: secretes the adrenal The zona reticularis: secretes the adrenal androgensandrogens

2- The adrenal medullaadrenal medulla:

Secretes adrenaline (epinephrineepinephrine)

Organization of the Adrenal Organization of the Adrenal GlandGland

The adrenal gland is composed of the The adrenal gland is composed of the adrenal cortex adrenal cortex & & adrenal medullaadrenal medulla

Steroid Steroid Hormone Hormone

SynthesisSynthesis

In In Adrenal Adrenal Cortex Cortex

Steroid Steroid Hormone Hormone

SynthesisSynthesis

In In Adrenal Adrenal Cortex Cortex

CholesterolCholesterol

Pregnenolone Pregnenolone 3-ββ-Hydroxysteroid dehydrogenase-Hydroxysteroid dehydrogenase

ProgesteroneProgesterone

17-17-αα-Hydroxylase-Hydroxylase

17-17-αα-Hydroxyprogesterone-Hydroxyprogesterone

AndrostenedioAndrostenedione ne

Testosterone Testosterone

Estradiol Estradiol

11-Deoxycortisol11-Deoxycortisol

11-Deoxycorticosterone11-Deoxycorticosterone

Cortisol Cortisol

21-21-αα-Hydroxylase-Hydroxylase

11- 11- ββ -Hydroxylase-Hydroxylase

Corticosterone Corticosterone

Aldosterone Aldosterone

Peripheral Peripheral TissuesTissues

DesmolaseDesmolase

NOTNOT IN IN

ADRENAL ADRENAL CORTEXCORTEX

androgenandrogen21-21-αα-Hydroxylase-Hydroxylase

Negative feedback control: Negative feedback control:

ACTHACTH release from the anterior pituitary is stimulated by hypothalamic secretion of corticotrophin releasing hormone (CRHCRH).

CRH ACTH Cortisol

Cortisol Cortisol (or synthetic steroids)

Suppress CRH & ACTH CRH & ACTH secretion

PituitaryPituitary

HypothalamusHypothalamus

AdrenalAdrenal

Regulation of Regulation of CortisolCortisol Secretion Secretion from the Adrenal Cortexfrom the Adrenal Cortex

Testosterone Production Testosterone Production in the in the TestisTestis

The production of androgens from cholesterol is identical to that in the adrenal, except that it continues from androstenedione to testosteroneandrostenedione to testosterone.

Pathway of Testosterone Production Pathway of Testosterone Production

in the in the TestisTestis

AndrostenedioneAndrostenedione TestosteroneTestosterone1717-hydroxysteroid-hydroxysteroid

OxidoreductaseOxidoreductase

CholesterolCholesterol

N.B. In the adrenal cortexthe adrenal cortex, androstendione androstendione (adrenal androgen) is formed.They are released to blood & converted in the testis (& peripheral tissues)the testis (& peripheral tissues)to testosteronetestosterone

In the TestisIn the Testis

The main steroid produced in the male is testosteronetestosterone produced from the testis. .

- In the maleIn the male, there is peripheral conversion of testosterone peripheral conversion of testosterone to:

DihydrotestosteroneDihydrotestosterone:: in androgen target tissues, like musclesmuscles by 5 5 reductasereductase

Or to Or to - EstradiolEstradiol : : mostly in adiposeadipose tissue by enzyme cytochrome P450 aromatasearomatase

Pathway of Testosterone Production Pathway of Testosterone Production in the Testisin the Testis

Control of Testicular Function by Control of Testicular Function by the the Pituitary Gonadotrophins (LH & Pituitary Gonadotrophins (LH &

FSH)FSH)

HypothalamuHypothalamuss

Anterior Anterior PituitaryPituitary

TestiTestiss

+

FSHFSH LHLH

TestosteroneTestosterone

--

SpermatogenesisSpermatogenesis

GnRHGnRHLH LH ++ testosterone synthesis in testis++ testosterone synthesis in testis

FSHFSH++ spermatogenesis in testis++ spermatogenesis in testis

TestosteroneTestosterone++ Spermatogenesis++ Spermatogenesis++ Development of secondary ++ Development of secondary male sex charactersmale sex characters++ Anabolism++ Anabolism

+

+

+

Synthesis of Steroid Hormones Synthesis of Steroid Hormones in the in the OvaryOvary

Synthesis of Steroid Hormones Synthesis of Steroid Hormones

in the in the OvaryOvary

In the ovary:In the ovary: EstradiolEstradiol is formed from the conversion of androgensandrogens (testosteronetestosterone) into

estradiolestradiol by the enzyme cytochrome P450 cytochrome P450 aromatasearomatase (in granulosa cells). The androgens required for conversion come from the neighboring theca cells. Cholesterol Cholesterol

Theca CellsTheca Cells

Androstendione Testosterone Androstendione Testosterone EstradiolEstradiol

AromataseAromatase

Granulosa Cells of the OvaryGranulosa Cells of the Ovary

Stimulated by Stimulated by FSHFSHStimulated Stimulated by by LHLH

Theca Theca cellscells

Granulosa Granulosa cellscells

LHLH

LH receptor

cholesterolcholesterol

AndrostendioneAndrostendione AndrostendioneAndrostendione TestosteroneTestosterone

FSHFSH

aromatasearomatase

EstradiolEstradiol

Synthesis of steroid Hormones in the Synthesis of steroid Hormones in the OvaryOvary

LHLH++ estrogen secretion++ estrogen secretion++ ++ ovulation

FSHFSH++ secretion of estrogen++ secretion of estrogenRegulates growth of ovarian follicle

LH & FSH stimulates LH & FSH stimulates estrogenestrogen secretion secretionFSH regulates growth of FSH regulates growth of ovarian folliclesovarian folliclesLH stimulates LH stimulates ovulationovulation

FSH receptors

Cytosolic Cytosolic ReceptorsReceptors

HRE HRE of genesof genes

Hormone Receptor Hormone Receptor ComplexComplex

Transcription Transcription of genes of genes

is increasedis increased

Mechanism of Action of Steroid Mechanism of Action of Steroid HormonesHormones

Mechanism of Action of Steroid Mechanism of Action of Steroid HormonesHormones

It is the result of an inherited enzyme defect in steroid hormones biosynthesis inherited enzyme defect in steroid hormones biosynthesis in the in the adrenal cortexadrenal cortex..

The Adrenal Cortex The Adrenal Cortex : CannotCannot secrete cortisol secrete cortisol absent negative feedback to the pituitary)

ACTH continues to drive steroid biosynthesis adrenal hyperplasia adrenal hyperplasia & accumulation of cortisol precursors accumulation of cortisol precursors (depending on which enzyme is lacking)

CannotCannot secrete aldosterone secrete aldosterone electrolyte disturbances

The condition might be fatal unless diagnosed earlyThe condition might be fatal unless diagnosed early

Congenital Adrenal Hyperplasia Congenital Adrenal Hyperplasia (CAH)(CAH)

ProgesteroneProgesterone

11-deoxycorticosterone11-deoxycorticosterone

1717-hydroxy--hydroxy-progesteroneprogesterone AndrostenedioneAndrostenedione

21 21 -Hydroxylase -Hydroxylase Deficiency Deficiency

TestosteroneTestosteroneVirilisation Virilisation

of ♀of ♀

PrecociousPrecocious sexual development sexual development

in ♂in ♂

AldosteroneAldosterone

11-deoxycortisol11-deoxycortisol

CortisolCortisol

InInPeripherPeripher

al al TissuesTissues

21 21 --hydroxylasehydroxylase

Accounts for ~ 95% of all cases of CAH Autosomal recessive condition

Low or absent synthesis of Cortisol & AldosteroneLow or absent synthesis of Cortisol & Aldosterone

Cortisol ACTH secretion Adrenal Gland hyperplasiaAdrenal Gland hyperplasia

Some of the accumulated precursors are diverted to the biosynthesis of sex hormones Signs of Androgen ExcessSigns of Androgen Excess::

stimulation of adrenal androgen production virilisation in baby girlsgirls & precocious puberty in boysboys

In severe cases, Aldosterone Deficiency Aldosterone Deficiency is evident salt & water loss hypovolaemia & shock neonatal adrenal crisis neonatal adrenal crisis


DiagnosisDiagnosis:

1- Prenatal Diagnosis (Intrauterine, before birth)1- Prenatal Diagnosis (Intrauterine, before birth) DNA testing and detection of mutations in the CYP21 gene DNA testing and detection of mutations in the CYP21 gene can be helpful for prenatal diagnosis &

confirmation of diagnosis

2- Neonatal Diagnosis (after birth)2- Neonatal Diagnosis (after birth) Serum sample Serum sample taken at least 2 days after birth at least 2 days after birth (earlier samples may contain

maternally derived 17-hydroxyprogesterone)Classic 21-hydroxylase deficiency is characterized by markedly elevated serum levels of 17-hydroxyprogesterone

3- 3- Late-onset (in adult life)Late-onset (in adult life) May require corticotropin stimulation testcorticotropin stimulation test:

Injecting a 0.125-mg or 0.25-mg bolus of corticotropin Measuring base-line and stimulated levels of 17-hydroxyprogesterone. High level after stimulation is diagnostic ( 2x upper reference range)


Disorders of Male Sexual Disorders of Male Sexual DifferentiationDifferentiation

They are rarerare group of disorders The defect may be in:The defect may be in:

Impaired Testosterone production Impaired Testosterone production Inactive androgen receptors Inactive androgen receptors target tissues cannot respond to

stimulation by circulating testosterone e.g. Testicular Feminization SyndromeTesticular Feminization Syndrome

Testicular Feminization SyndromeTesticular Feminization Syndrome

46, XY karyotypeX-linked recessive disorder

Androgen receptor resistance Androgen receptor resistance high testosterone blood level

In peripheral tissue, testosterone will be converted by aromatase into estradiolestradiol feminization

steroid hormones. objectives recall the overall role of steroids in human body. understand the...

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