crushing the creogs rapid primer. high yield amenorrhea abnormal puberty (delayed and precocious)...

Crushing the CreogsCrushing the Creogs

Rapid PrimerRapid Primer

High YieldHigh Yield

AmenorrheaAmenorrhea

Abnormal puberty (delayed and Abnormal puberty (delayed and precocious)precocious)

EmbryologyEmbryology

Embryonic Sexual Embryonic Sexual DeterminationDetermination

Embryo bipotent at 5 Embryo bipotent at 5 wkswks

KaryotypeKaryotype– XY vs XXXY vs XX– SRY Gene (TDF)SRY Gene (TDF)

XX

No SRY

Normal female

Normal Male

XY

SRY

Embryonic Sexual Embryonic Sexual DeterminationDeterminationXX

XY (with SRY)

Ovary Testes at 6 weeks

Sertoli Leydig

Anti Mullerian Hormone

Testosterone DHT

Dev Ext Male

Ispilateral regressesionDev. Int. Male, ipsilaterally

““Default” pathwayDefault” pathway

MullerianDuct

UterineSeptum

Caudal tip ofMullerian Ducts

SinovaginalBulbs

(Vaginal plate)Urogenital Sinus

Lumen of uterus

Cervix

Fornix

Vagina

Hymen

Ovaries develop separately

Summary of Sex DeterminationSummary of Sex Determination

Embryo is bipotent at 5 weeks.Embryo is bipotent at 5 weeks.

If male (SRY, AMH, Testosterone/DHT) If male (SRY, AMH, Testosterone/DHT) starts male differentiation at 6 weeks.starts male differentiation at 6 weeks.

If no male differentiation If no male differentiation female is female is default pathway.default pathway.

Age

Gonadotropin

Prepubertal PhysiologyPrepubertal Physiology

+

-

Increasing weight, fat mass

Normal Puberty - Normal Puberty - GonadarcheGonadarche

Normal Puberty - Normal Puberty - GonadarcheGonadarche

Suppression of the gonadostat decreases.*Suppression of the gonadostat decreases.*

Nocturnal pulses in GnRH lead to:Nocturnal pulses in GnRH lead to:

Increasing FSH (then increasing LH) levels Increasing FSH (then increasing LH) levels lead to:lead to:

Increasing androgens and estrogen, leading Increasing androgens and estrogen, leading to:to:

– Everything we associate with puberty.Everything we associate with puberty.

Timing of puberty is largely geneticTiming of puberty is largely genetic

Estrogen Estrogen Breast Development and Breast Development and

Androgens Androgens Pubic Hair Pubic Hair

Bone Growth

Measurement of Puberty: Tanner Measurement of Puberty: Tanner StagesStages

Measurement of Puberty: Tanner Measurement of Puberty: Tanner StagesStages

Breast Pubic Hair

Stage 1 Elevation of papilla No pubic hair

Stage 2 Breast bud, areola enlarged

median age - 9.8 yrs

Sparse long pigmented hair, mostly labial

median age - 10.5 yrs (resident could count)

Stage 3 Further enlargement


Dark,coarse,curled hair, spread to mons

median age - 11.4 yrs (student could count)

Stage 4 Secondary mounding of areola


Adult type hair, abundant, limited to mons

median age - 12.0 yrs (to numerous to count)

Stage 5 Recession of 2° mound


Adult-type spread (thighs and abd)


There is NO stage Zero!

Order of Pubertal EventsOrder of Pubertal Events

Growth spurt / BreastsGrowth spurt / Breasts

Pubic hairPubic hair

Maximum growth velocityMaximum growth velocity

MensesMenses

aka “Boobs, pubes/pits and pads”aka “Boobs, pubes/pits and pads”

Normal Puberty - AdrenarcheNormal Puberty - AdrenarcheNormal Puberty - AdrenarcheNormal Puberty - Adrenarche

Independent of HPO axis. Independent of HPO axis.

Trigger unclearTrigger unclear

Generally precedes Generally precedes changes associated with changes associated with puberty.puberty.

Increase adrenal Increase adrenal androgens: DHEAS and androgens: DHEAS and A.A.

Mechanism: increased Mechanism: increased 17,20 lyase activity.17,20 lyase activity.

Appearance of Pubic Hair

The Menstrual CycleThe Menstrual CycleThe Menstrual CycleThe Menstrual Cycle

0

100

200

300

400

500

0

2

4

6

8

10

12

14

16

18

20

FSHFSHLHLHIU/LIU/L

2 4 6 8 10 2812 14 16 18 2420 22 260

1

2

3

4

5

6

7

8

9

10

PPng/mlng/ml

LHLH

FSHFSH

EE22

PP

OvulationMenses

EndocrinologyEndocrinologyEndocrinologyEndocrinology

Inh-BInh-BInh-AInh-A

Inh-Inh-AA//BBEEpg/mlpg/ml

22

ContinuousContinuous process process

Occurs in “waves”Occurs in “waves”

Stimulus/mechanism unknownStimulus/mechanism unknown

Independent of gonadotropinsIndependent of gonadotropins– Occurs in prepubertal ovaryOccurs in prepubertal ovary– Uninterupted by pregnancy, OCPUninterupted by pregnancy, OCP

Ends with follicular depletionEnds with follicular depletion

Preantral FolliclePreantral FollicleInitiation of Follicular GrowthInitiation of Follicular Growth

Preantral FolliclePreantral FollicleInitiation of Follicular GrowthInitiation of Follicular Growth

0

100

200

300

400

500

0

2

4

6

8

10

12

14

16

18

20

FSHFSHLHLHIU/LIU/L

EE22

pg/mlpg/ml

2 4 6 8 10 2812 14 16 18 2420 22 260

1

2

3

4

5

6

7

8

9

10

PPng/mlng/ml

LHLH

FSHFSH

EE22

PP

OvulationOvulationMensesMenses

GrowthGrowth AtresiaAtresia

Timely gonadotropin stimulation Timely gonadotropin stimulation can promote further growthcan promote further growth– Intercycle rise in FSH crucial Intercycle rise in FSH crucial

for continued development for continued development

Without gonadotropin support, Without gonadotropin support, doomed to atresiadoomed to atresia

Preantral FolliclePreantral FollicleIn Delicate BalanceIn Delicate BalancePreantral FolliclePreantral FollicleIn Delicate BalanceIn Delicate Balance

The “Two Cell, Two The “Two Cell, Two Gonadotropin Concept”Gonadotropin Concept”

The “Two Cell, Two The “Two Cell, Two Gonadotropin Concept”Gonadotropin Concept”

LH

LH Receptor

THECA CELLTHECA CELL

ATP cAMP

Androstenedione Testosterone

Cholesterol

Pregnenolone

GRANULOSA CELLGRANULOSA CELL

ATP

cAMP

Androstenedione Testosterone

FSH

Estrone Estradiol

Basement MembraneBasement Membrane

P450sccP450scc

P450c17P450c17

P450aromP450arom<< >>

Dominant FollicleDominant FollicleSelection MechanismsSelection MechanismsDominant FollicleDominant Follicle

Selection MechanismsSelection MechanismsNormal ovulatory quota = 1Normal ovulatory quota = 1

Rising estrogen levels Rising estrogen levels – positive feedback locallypositive feedback locally– negative feedback centrallynegative feedback centrally

Rising inhibin levels Rising inhibin levels – further negative feedback further negative feedback

Declining FSH levelsDeclining FSH levels– withdraw growth support withdraw growth support – Atresia in lesser follicles atresiaAtresia in lesser follicles atresia

Dominant Follicle SelectionDominant Follicle Selection“Survival of the Fittest”“Survival of the Fittest”

Dominant Follicle SelectionDominant Follicle Selection“Survival of the Fittest”“Survival of the Fittest”

Selected follicleSelected follicle– More and larger cellsMore and larger cells

– more FSH receptor and greater sensitivity to falling more FSH receptor and greater sensitivity to falling FSHFSH

– more aromatasemore aromatase

Advanced vascular development provides Advanced vascular development provides preferential delivery of FSH and LDL substratepreferential delivery of FSH and LDL substrate

LHLH

FSHFSH

P Plasmin

Collagenase

PG

PB

Smooth MuscleSmooth MuscleFibersFibers

OvulationOvulation

OMI

PG

LI LH

LH stimulates meiosis, luteinization, and LH stimulates meiosis, luteinization, and PG productionPG production

P enhances proteolytic enzymes P enhances proteolytic enzymes

FSH stimulates expansion of cumulus and FSH stimulates expansion of cumulus and plasmin to stimulate collagenaseplasmin to stimulate collagenase

EstradiolEstradiol

ProgesteroneProgesterone

Corpus LuteumCorpus LuteumCorpus LuteumCorpus LuteumFollicle wall becomes convolutedFollicle wall becomes convoluted

Luteal cells enlarge, acquire lutein Luteal cells enlarge, acquire lutein pigment and lipidpigment and lipid

Capillary network penetrates granulosaCapillary network penetrates granulosa

Production of large amounts of both E & Production of large amounts of both E & PP

E & P act centrally and locally to E & P act centrally and locally to suppresses new follicular growthsuppresses new follicular growth

Corpus Luteum Corpus Luteum Requirements for Normal Luteal Requirements for Normal Luteal

FunctionFunction

Corpus Luteum Corpus Luteum Requirements for Normal Luteal Requirements for Normal Luteal

FunctionFunction

Optimal preovulatory follicular development - luteal cell massOptimal preovulatory follicular development - luteal cell mass– Adequate follicular phase FSHAdequate follicular phase FSH

Tonic LH stimulationTonic LH stimulation

LDL cholesterol substrateLDL cholesterol substrate

0

100

200

300

400

500

0

2

4

6

8

10

12

14

16

18

20

FSHFSHLHLHIU/LIU/L

EE22

pg/mlpg/ml

2 4 6 8 10 2812 14 16 18 2420 22 260

1

2

3

4

5

6

7

8

9

10

PPng/mlng/ml

LHLH

FSHFSH

EE22

PP

OvulationOvulationMensesMenses

Ovarian CycleOvarian CycleConceptionConception

Ovarian CycleOvarian CycleConceptionConception

hCGhCG

Normal mensesNormal menses

24-35 days24-35 days

2-7 days of flow2-7 days of flow

35ml (mean) <80 cc of non-clotting debris.35ml (mean) <80 cc of non-clotting debris.

Abnormal PubertyAbnormal Puberty

Terminology of Precocious PubertyTerminology of Precocious PubertyTerminology of Precocious PubertyTerminology of Precocious Puberty

GnRH - Dependent GnRH - Dependent aka aka True Precocious True Precocious Puberty Puberty aka Central Precocious Pubertyaka Central Precocious Puberty

GnRH - Independent GnRH - Independent aka aka Precocious Precocious Pseudopuberty Pseudopuberty aka Peripheral Precocious aka Peripheral Precocious PubertyPuberty

Isolated Precocious DevelopmentIsolated Precocious Development

Precocious PubertyPrecocious Puberty

Bone Age guides therapy.Bone Age guides therapy.

Bone age, bone age, bone ageBone age, bone age, bone age

Typically, once menses have started, Typically, once menses have started, growth is limited to 6 cm more. growth is limited to 6 cm more.

Mature Axis: GnRH stim test LH > FSH rise.

Prepubertal: GnRH stim test FSH > LH rise.

GnRH Dependent GnRH Dependent femalefemale male maleIdiopathicIdiopathic 74%74% 41%41%

CNS problemCNS problem 7%7% 26%26%

GnRH IndependentGnRH Independent Ovarian (cyst or tumor)Ovarian (cyst or tumor) 11%11% n/a n/a

TesticularTesticular n/an/a 10%10%

McCune-AlbrightMcCune-Albright 5%5% 1% 1%

Adrenal feminizingAdrenal feminizing 1%1% 0% 0%

Adrenal masculinizingAdrenal masculinizing 1%1% 22%22%

Ectopic gonadotropinEctopic gonadotropin 0.5%0.5% 0.5%0.5%

HypothyroidismHypothyroidism

Exogenous SteroidsExogenous Steroids

Etiologies of Precocious PubertyEtiologies of Precocious PubertyEtiologies of Precocious PubertyEtiologies of Precocious Puberty

1° Gonadotropin Elevation1° Gonadotropin ElevationCNS CausesCNS Causes– Hypothalamic TumorHypothalamic Tumor

Hamartoma (secretes GnRH), Hamartoma (secretes GnRH), Craniopharyngioma, Glioma, Ependymomas, Craniopharyngioma, Glioma, Ependymomas, NeurofibromaNeurofibroma

– Congenital malformation Congenital malformation Hydrocephalus, Rickett’s (skull malformation)Hydrocephalus, Rickett’s (skull malformation)

– Pineal tumorPineal tumor– Trauma (brain injury stims TGFTrauma (brain injury stims TGF which stims which stims

GnRH)GnRH)– EncephalitisEncephalitis

1° Steroid Elevation1° Steroid Elevation1° Steroid Elevation1° Steroid Elevation

TumorTumor– OvaryOvary

may produce estrogens, androgens, hCG - may produce estrogens, androgens, hCG - typically causing heavy irreg. bleedingtypically causing heavy irreg. bleeding

80% have palpable mass80% have palpable mass

granulosa, theca, gonadoblastomas, granulosa, theca, gonadoblastomas, teratomas, lipoid cell, cystadenomas, teratomas, lipoid cell, cystadenomas, epithelial cancerepithelial cancer

– Feminizing Adrenal TumorFeminizing Adrenal Tumorvery rare, usu. associated with very rare, usu. associated with DHA-S DHA-S

McCune Albright SyndromeMcCune Albright SyndromeMcCune Albright SyndromeMcCune Albright Syndromeaka polyostic fibrous dysplasiaaka polyostic fibrous dysplasiaMechanismMechanism:: – Activating mutation of GActivating mutation of Gss

resulting in unregulated cAMP resulting in unregulated cAMP formation.formation.

– Somatic mosaicSomatic mosaic mutation, therefore mutation, therefore not lethal and variable phenotype.not lethal and variable phenotype.

Classic TriadClassic Triad::– cystic bone lesions causing easy cystic bone lesions causing easy

fracture - Tc bone scanfracture - Tc bone scan– cafe au lait spotscafe au lait spots– sexual precocitysexual precocity

Findings in Various DisordersFindings in Various Disorders

Gonadal Gonadal SizeSize

Basal FSH Basal FSH & LH& LH

E or T E or T LevelsLevels

DHEASDHEAS GnRH GnRH ResponseResponse

IdiopathicIdiopathic IncreasedIncreased IncreasedIncreased IncreasedIncreased IncreasedIncreased Pubertal Pubertal LH>FSHLH>FSH

CerebralCerebral IncreasedIncreased IncreasedIncreased IncreasedIncreased IncreasedIncreased Pubertal Pubertal LH>FSHLH>FSH

GonadalGonadal Unilat Unilat enlargedenlarged

DecreasedDecreased IncreasedIncreased IncreasedIncreased Flat*Flat*

McCune- McCune- AlbrightAlbright

IncreasedIncreased DecreasedDecreased IncreasedIncreased IncreasedIncreased Flat*Flat*

AdrenalAdrenal SmallSmall DecreasedDecreased IncreasedIncreased IncreasedIncreased Flat*Flat*

Isolated Premature Isolated Premature DevelopmentDevelopment

Isolated ThelarcheIsolated Thelarche– May be unilateral, may wax and waneMay be unilateral, may wax and wane– Normal growthNormal growth

Isolated Premature MenarcheIsolated Premature Menarche– VERY rare: suspect trauma or foreign body, VERY rare: suspect trauma or foreign body,

tumor.tumor.

Isolated Premature AdrenarcheIsolated Premature Adrenarche– Rule out CAHRule out CAH

Treatment ObjectivesTreatment ObjectivesTreatment ObjectivesTreatment Objectives

Dx and Rx any intracranial diseaseDx and Rx any intracranial diseaseDx and surgically treat peripheral Dx and surgically treat peripheral tumorstumorsArrest maturation until appropriate ageArrest maturation until appropriate ageLessen established precocious Lessen established precocious characteristicscharacteristicsMaximize adult heightMaximize adult heightAvoidance of abuse, treat emotional Avoidance of abuse, treat emotional problems, and consider contraceptionproblems, and consider contraception

Treatment of Central Precocious PubertyTreatment of Central Precocious PubertyTreatment of Central Precocious PubertyTreatment of Central Precocious Puberty

GnRHa therapy – GnRHa therapy – – monitor growth, 2° sexual characteristics, monitor growth, 2° sexual characteristics,

bone age, and keep E2 < 10 or maintain bone age, and keep E2 < 10 or maintain negative GnRH stim testnegative GnRH stim test

– GnRH may be used in the case of hamartomaGnRH may be used in the case of hamartoma

Delayed PubertyDelayed PubertyDelayed PubertyDelayed Puberty

Most girls in USA enter puberty by age 13Most girls in USA enter puberty by age 13

Workup whenWorkup when– no 2° sex characteristics by age 13no 2° sex characteristics by age 13– absence of menarche by age 16absence of menarche by age 16– 5 years between onset thelarche and 5 years between onset thelarche and

menarchemenarche

Delayed puberty is rare in girls and is Delayed puberty is rare in girls and is commonly associated with pathologycommonly associated with pathology

Delayed PubertyDelayed Puberty

Hypergonadotropic HypogonadismHypergonadotropic Hypogonadism 43%43%– Ovarian failure – abnormal karyotype (26%)Ovarian failure – abnormal karyotype (26%)

Turner’s SyndromeTurner’s Syndrome– Ovarian failure – normal karyotypeOvarian failure – normal karyotype

46XX (15%)46XX (15%)

46XY ( 2%)46XY ( 2%)– Other (rare)Other (rare)

1717 hydroxylase deficiency hydroxylase deficiency (HTN, sexual infantilism, (HTN, sexual infantilism, high P)high P)

Sickle Cells Disease, Torsion, Resistant Ovary Sickle Cells Disease, Torsion, Resistant Ovary SyndromeSyndrome

Frequency of Delayed Puberty Frequency of Delayed Puberty EtiologiesEtiologies


Hypogonadotropic HypogonadismHypogonadotropic Hypogonadism31%31% – Reversible (18%)Reversible (18%)

Physiologic delayPhysiologic delay 10%10%

Weight loss/anorexiaWeight loss/anorexia 3% 3%

ProlactinomaProlactinoma 1.5% 1.5%

1° hypothyroidism1° hypothyroidism 1% 1%

CAHCAH 1% 1%

Cushing’sCushing’s 0.5% 0.5%



Hypogonadotropic Hypogonadism Hypogonadotropic Hypogonadism 31%31%– Irreversible (13%)Irreversible (13%)

GnRH deficiencyGnRH deficiency 7%7%– Kallman’s, Prader WilliKallman’s, Prader Willi– GP54R, Leptin Receptor deficiencyGP54R, Leptin Receptor deficiency– Irradiation, infiltrating diseaseIrradiation, infiltrating disease

HypopituitarismHypopituitarism 3%3%CraniopharyngiomasCraniopharyngiomas 1%1%Congenital CNS defectsCongenital CNS defects 0.5% 0.5%pituitary adenomaspituitary adenomas 0.5% 0.5%Malignant pituitary tumorMalignant pituitary tumor 0.5% 0.5%



Eugonadism Eugonadism 26%26%

– Mullerian agenesisMullerian agenesis 14%14%– Inappropriate + feedback 7%Inappropriate + feedback 7%

(PCOS)(PCOS)– Vaginal septumVaginal septum 3% 3%– Androgen insensitivityAndrogen insensitivity 1% 1%– Imperforate hymenImperforate hymen 0.5% 0.5%

Three Cases of Amenorrhea Three Cases of Amenorrhea and Blind Pouchand Blind Pouch

MRKHMRKH– Normal pubic hair & breasts. No cyclic pain. Normal pubic hair & breasts. No cyclic pain.

AISAIS– Scant pubic hair, normal breast. No pain.Scant pubic hair, normal breast. No pain.– Androgen Receptor Defect (can’t respond to Androgen Receptor Defect (can’t respond to

Androgens, develop breasts because unopposed E, Androgens, develop breasts because unopposed E, have testes/AMH therefore don’t develop uterus.)have testes/AMH therefore don’t develop uterus.)

Transverse SeptumTransverse Septum– Normal pubic hair & breasts. Normal pubic hair & breasts. Cyclic Pain!Cyclic Pain!

Idiopathic Precocious PubertyIdiopathic Precocious Puberty

Spontaneous increase in GnRH.Spontaneous increase in GnRH.

Diagnosis of exclusion.Diagnosis of exclusion.

Treat with GnRH-agonist.Treat with GnRH-agonist.

Know for CREOGSKnow for CREOGSOrder of pubertal stages.Order of pubertal stages.

Genetics = #1 determinant of timing.Genetics = #1 determinant of timing.

Average age of menarche is 12.8Average age of menarche is 12.8

Precocious puberty: prior to age 8Precocious puberty: prior to age 8

Delayed puberty: absence of 2Delayed puberty: absence of 2ndary ndary chars by age chars by age 1313

McCune-Albright SyndromeMcCune-Albright Syndrome

Clinical Differences between AIS, Transverse Clinical Differences between AIS, Transverse Septum and Mullerian AgenesisSeptum and Mullerian Agenesis

AmenorrheaAmenorrhea

Primary: Primary: – No menses by 16 in the presence normal No menses by 16 in the presence normal

growth and secondary sex characteristicsgrowth and secondary sex characteristics– No menses by 14 without secondary sex No menses by 14 without secondary sex

characteristicscharacteristics

Secondary:Secondary:– H/o previous menses. H/o previous menses. – No menses in for past three expected cycles No menses in for past three expected cycles

or past 6 months. or past 6 months.

Primary Amenorrhea PearlsPrimary Amenorrhea Pearls

Physical Exam is essential.Physical Exam is essential.– Breasts = Estrogen exposure.Breasts = Estrogen exposure.– Normal height = Estrogen exposure.Normal height = Estrogen exposure.– Uterus = Eliminates AIS, MRKH, Transverse Uterus = Eliminates AIS, MRKH, Transverse

Septum.Septum.

Broad DDxBroad DDx– Hypergonadotropic (ovarian failure)Hypergonadotropic (ovarian failure)– Hypogonadotropic (CNS, Pituitary issue)Hypogonadotropic (CNS, Pituitary issue)– Eugonadal (Secondary amenorrhea w/u)Eugonadal (Secondary amenorrhea w/u)

Primary AmenorrheaPrimary AmenorrheaIncreased FSHIncreased FSH

Gonadal FailureGonadal FailureMost common cause is Most common cause is geneticgenetic: XO or mosaic : XO or mosaic (XO/XX), or XY(XO/XX), or XY– Turners: Short stature, webbed neck, wide spaced Turners: Short stature, webbed neck, wide spaced

nipples, increased arm carrying angle, coarctation, nipples, increased arm carrying angle, coarctation, low posterior hair line, renal abnormalities, streak low posterior hair line, renal abnormalities, streak gonads.gonads.

GalactosemiaGalactosemia: failure to thrive, abnormal FSH : failure to thrive, abnormal FSH and LH and failure of germ cells to migrate to and LH and failure of germ cells to migrate to ovary.ovary.1717 hydroxylase deficiency hydroxylase deficiency (HTN, hypokalemia) (HTN, hypokalemia) with high 17-OHPwith high 17-OHP

Steroid SynthesisSteroid Synthesis

Start with cholesterol (27C)Start with cholesterol (27C)Rate limiting reaction is side chain cleavage 27C Rate limiting reaction is side chain cleavage 27C 21C 21C PregnenolonePregnenolone

21 Carbons21 Carbons: progestins, glucocorticoids, : progestins, glucocorticoids, mineralocorticoidsmineralocorticoids

19 Carbons19 Carbons: Androgens: Androgens

18 Carbons18 Carbons: Estrogens: Estrogens

Cortisol levels are Cortisol levels are regulated tightly, regulated tightly, others are not. others are not. – if cortisol synthesis is if cortisol synthesis is

limited, ACTH limited, ACTH increases to overcome increases to overcome blockage. blockage.

– precursors build upprecursors build up

Adrenal Steroid DisordersAdrenal Steroid Disorders

CAH (CAH ( nomal genitalia vs nomal genitalia vs ambiguous) ambiguous)– 21 hydroxylase deficiency (90% of cases)21 hydroxylase deficiency (90% of cases)– 1111 hydroxylase deficiency (5% of cases) hydroxylase deficiency (5% of cases)– 33 dehydrogenase deficiency (rare) dehydrogenase deficiency (rare)

Pubertal Disorders (Pubertal Disorders ()) vs Ambiguous vs Ambiguous Genitalia (Genitalia ())– 1717 hydroxylase deficiency hydroxylase deficiency – 1717 dehydrogenase deficiency dehydrogenase deficiency

CAH -- 21 Hydroxlase CAH -- 21 Hydroxlase

Most common enzyme deficiency leading Most common enzyme deficiency leading to congenital adrenal hyperplasia.to congenital adrenal hyperplasia.

Name is confusing: (named backwards)Name is confusing: (named backwards)– It adds on –OH group to C21It adds on –OH group to C21– Named this way because, scientists were Named this way because, scientists were

working back from cortisol and aldosterone. working back from cortisol and aldosterone.

The product names confuse people, for The product names confuse people, for the same reasons.the same reasons.

CAH – 11CAH – 11 hydroxylase hydroxylase deficiencydeficiency

Presentation more Presentation more variablevariable

HypertensionHypertension– Incr 11DOCIncr 11DOC

NaNa++ overload overload

Hypo KHypo K++

Female masculinizedFemale masculinized

Addisons possible Addisons possible with stresswith stress

1717 Hydroxylase Deficiency Hydroxylase Deficiency

Female pubertal delayFemale pubertal delayMale ambiguous genitaliaMale ambiguous genitaliaHTNHTN due to mineralocorticoid due to mineralocorticoid affect of 11-DOCaffect of 11-DOCHypokalemiaHypokalemia17-OHP is low.17-OHP is low.Renin low due to Na retension Renin low due to Na retension and water expansion.and water expansion.Aldosterone is also lowAldosterone is also lowLow urinary 17 keto-steroidsLow urinary 17 keto-steroids

CAH DiagnosisCAH Diagnosis

Screening Test is 17-Screening Test is 17-OHPOHP

Diagnosis made with Diagnosis made with ACTH stimulation ACTH stimulation test. test.

Measure cortisol and Measure cortisol and precursors before and precursors before and after. after.

CAH SummaryCAH Summary

The Cortisol, Aldo The Cortisol, Aldo enzymes are named enzymes are named backwards.backwards.21-hydroxylase def. is 21-hydroxylase def. is most common cause most common cause of CAH.of CAH.11-hydroxylase is 211-hydroxylase is 2ndnd Blockages lead to Blockages lead to buildup of precursors buildup of precursors and androgens.and androgens.

PCOSPCOS

Rotterdam Diagnostic CriteriaRotterdam Diagnostic CriteriaNeed two of threeNeed two of three

Chronic Oligo-Anovulation

Hyperandrogenism Polycystic Ovaries

Rule out other causes

Differential DiagnosisDifferential Diagnosis

Late-onset congenital adrenal hyperplasiaLate-onset congenital adrenal hyperplasia

Idiopathic (constitutional) hirsutismIdiopathic (constitutional) hirsutism

Hypothalamic amenorrheaHypothalamic amenorrhea

Premature ovarian failurePremature ovarian failure

ProlactinProlactin

ThyroidThyroid

Differential DiagnosisDifferential Diagnosis

Cushing’s SyndromeCushing’s Syndrome

Androgen producing tumorsAndrogen producing tumors

AcromegalyAcromegaly

Anabolic drugsAnabolic drugs

PathogenesisPathogenesis

Anovulation

Increasedandrogens

Acyclic, elevatedestrogen

Increased LHPCOS

Hirsutism

Amenorrhea

Polycystic ovaries

Insulinresistance& obesity

SHBG

FSH

Converted to DHT

‘‘Metabolic Syndrome’Metabolic Syndrome’

Insulin ResistanceAbdominal Obesity

Diabetesmellitus

Hypertension DyslipidemiaHigh triglycerides

Low HDL

Atherosclerosis PCOS

PCOS TreatmentPCOS Treatment

Management of mensesManagement of menses– OCP (35mcg EE), Mirena, Cyclic POCP (35mcg EE), Mirena, Cyclic P

Management of hirsuitismManagement of hirsuitism– OCP, Spironolactone, Finasteride, Vaniqa, LaserOCP, Spironolactone, Finasteride, Vaniqa, Laser

Management of insulin resistanceManagement of insulin resistance– Weight loss, metformin, exercise.Weight loss, metformin, exercise.– Metformin most useful if patient overweight.Metformin most useful if patient overweight.

FertilityFertility– Ovulation induction: clomid, letrozole, metforminOvulation induction: clomid, letrozole, metformin

Clomid = anti estrogen (increases FSH)Clomid = anti estrogen (increases FSH)Letrozole = aromatase inhibitor (increases FSH)Letrozole = aromatase inhibitor (increases FSH)Require functioning hypothalmus/pituitary!!!Require functioning hypothalmus/pituitary!!!

HirsuitismHirsuitism

HirsuitimHirsuitim– Excess terminal hair in male pattern.Excess terminal hair in male pattern.

Midline chest, face, back, lower midline Midline chest, face, back, lower midline abdomen. Arm and leg hair get darker.abdomen. Arm and leg hair get darker.

VirilizationVirilization– Deepening voice, clitoromegally, breast Deepening voice, clitoromegally, breast

atrophy and loss of feminine contour. atrophy and loss of feminine contour.

Causes of HirsuitismCauses of Hirsuitism

EthnicityEthnicityIdiopathic (intrinsic 5a reductase activity)Idiopathic (intrinsic 5a reductase activity)Insulin stimulates pilosebaceous unit, ovarian Insulin stimulates pilosebaceous unit, ovarian androgen production and decreases SHBGandrogen production and decreases SHBGPCOSPCOSCAHCAHOvarian tumorOvarian tumorAdrenal tumorAdrenal tumorCushings, hyperprolactinemiaCushings, hyperprolactinemia

Hirsuitism WorkupHirsuitism Workup

Androgen assays not very reliable in women.Androgen assays not very reliable in women.

Rapid change associated with pathologyRapid change associated with pathology– Free T – most sensitive, rarely neededFree T – most sensitive, rarely needed..– Total T – used to rule out ovarian tumor, or follow Total T – used to rule out ovarian tumor, or follow

treatmenttreatment– DHEAS – used to rule out adrenal tumor DHEAS – used to rule out adrenal tumor – 17-OHP – screen for CAH17-OHP – screen for CAH– PRL – can lead to increased DHEASPRL – can lead to increased DHEAS

Consider Insulin Resistance, Cortisol, GHConsider Insulin Resistance, Cortisol, GH

Hirsuitism TreatmentsHirsuitism Treatments

Takes 6 months to arrest new hair growth. Takes 6 months to arrest new hair growth.

Lifestyle changes, as neededLifestyle changes, as needed

Cosmetic treatments:Cosmetic treatments:

Laser, ElectrolysisLaser, Electrolysis

Eflornithine (Vaniqa) – arrests new hair Eflornithine (Vaniqa) – arrests new hair growth – twice a day x 4 hours. 58% had growth – twice a day x 4 hours. 58% had overall improvement.overall improvement.

Hirsuitism TreatmentsHirsuitism Treatments

OCPs are off-label and no studies of adequate power to OCPs are off-label and no studies of adequate power to show benefit.show benefit.– Decrease LH (decrease androgens)Decrease LH (decrease androgens)– Increase SHBGIncrease SHBG

Spironolactone (Spironolactone (need contraceptionneed contraception))– Directly blocks androgen receptor and mildly inhibits 5a Directly blocks androgen receptor and mildly inhibits 5a

reductasereductase– Cheap and more affective than finasteride.Cheap and more affective than finasteride.– More side effects: polyuria, hypotension, fatique, hyperKMore side effects: polyuria, hypotension, fatique, hyperK

Finasteride (Finasteride (need contraceptionneed contraception))– 5a reductase inhibitor5a reductase inhibitor– Non-toxicNon-toxic

Flutamide (Flutamide (need contraceptionneed contraception))– Androgen receptor blocker, but Androgen receptor blocker, but liver toxliver tox limits use. limits use.

HyperprolactinemiaHyperprolactinemia

Elevated prolactin: Elevated prolactin:

May interfere with GnRH secretion to cause:May interfere with GnRH secretion to cause:– Short luteal phaseShort luteal phase– OligomenorrheaOligomenorrhea– AmenorrheaAmenorrhea

GalactorrheaGalactorrhea

HirsuitismHirsuitism

Bone lossBone loss

Decreased libido in menDecreased libido in men


InhibitorsInhibitors– Dopamine (primary Dopamine (primary

regulator via portal regulator via portal system)system)

– ProlactinProlactin

StimulatorsStimulators– TRHTRH– EstrogenEstrogen– VIP (food)VIP (food)– Oxytocin (sex, nipple Oxytocin (sex, nipple

stimulation)stimulation)– Many drugsMany drugs


Galactorrhea is bilateral and white. Galactorrhea is bilateral and white. May be seen with normal prolactin levels. May be seen with normal prolactin levels. – Assay does not reflect biologic activity.Assay does not reflect biologic activity.– May not detect nocturnal PRL secretion. May not detect nocturnal PRL secretion.

Fat seen on smear.Fat seen on smear.#1 cause of hyperprolactinemia is idiopathic. #1 cause of hyperprolactinemia is idiopathic. The higher the prolactin, the greater the chance The higher the prolactin, the greater the chance of having an adenoma. of having an adenoma. Renally and hepatically cleared, so increased Renally and hepatically cleared, so increased with renal failure and liver disease. with renal failure and liver disease.

HyperPRL – CNS IssuesHyperPRL – CNS Issues

Microadenoma <10mm, usually does not Microadenoma <10mm, usually does not grow.grow.Macroadenoma Macroadenoma >> 10mm (may secrete 10mm (may secrete GH, ACTH, TSH, FSH or nothing)GH, ACTH, TSH, FSH or nothing)Infiltrating disorders (sarcoid, TB)Infiltrating disorders (sarcoid, TB)RadiationRadiationEmpty Sella Syndrome (herniation of CNS Empty Sella Syndrome (herniation of CNS fluid into sella and compresses stalk)fluid into sella and compresses stalk)Rathke’s cyst or other stalk tumors.Rathke’s cyst or other stalk tumors.

PRL and RxPRL and Rx

AntipsychoticsAntipsychotics

AntidepressantsAntidepressants

Opiates & CocaineOpiates & Cocaine

VerapamilVerapamil

MethyldopaMethyldopa

MetoclopramideMetoclopramide

H2 blockers ranitidine H2 blockers ranitidine and cimetidineand cimetidine

EstrogenEstrogen

DilantinDilantin

PRL levels usually return to normal within 2-4 days of stopping Rx

Prolactin VariantsProlactin Variants

PRL = normal bioactive formPRL = normal bioactive form

Big PRL (macro-PRL dimers which are Big PRL (macro-PRL dimers which are connected, can lyse and become connected, can lyse and become bioactive)bioactive)

Big-Big PRL (little bioactivity, but cross Big-Big PRL (little bioactivity, but cross react with assay)react with assay)

When to image for PRL?When to image for PRL?

Debatable. No clear answer.Debatable. No clear answer.– Some say any elevation is indication. Some say any elevation is indication. – Levels > Levels > 100 ng/ml100 ng/ml in absence of drug is in absence of drug is

universally accepted.universally accepted.– Antipsychotics my raise PRL into 300 range. Antipsychotics my raise PRL into 300 range.

(Still no one would fault you for imaging.) (Still no one would fault you for imaging.)

MRIMRI with and without contrast is image of with and without contrast is image of choice. choice.

HyperPRL TxHyperPRL Tx

Remove offending agentRemove offending agentBromocriptine (DA agonist) (FDA+)Bromocriptine (DA agonist) (FDA+)– Ergot deriv. Usually req 2-3x/day doseErgot deriv. Usually req 2-3x/day dose– 12% nausea, headache, syncope, dizziness and orthostatic 12% nausea, headache, syncope, dizziness and orthostatic

hypotensionhypotension– PO or PV route good. PO or PV route good.

Cabergoline (DA agonist) (Off label)Cabergoline (DA agonist) (Off label)– Long t 1/2 , give 2 x per weekLong t 1/2 , give 2 x per week– Few side effectsFew side effects

Both lead to tumor shrinkage.Both lead to tumor shrinkage.Except in cases of neurologic emergency, Rx therapy is Except in cases of neurologic emergency, Rx therapy is always first choice. always first choice.

MenopauseMenopause

Menopause DefinitionsMenopause Definitions

MenopauseMenopause: cessation of menses for 12 months due to : cessation of menses for 12 months due to loss of ovarian function.loss of ovarian function.– Average age 51Average age 51– Younger if smoker, Hispanic, African American.Younger if smoker, Hispanic, African American.

ClimactericClimacteric (perimenopause begins 5-6 years prior) (perimenopause begins 5-6 years prior) symptoms appear (vasomotor and irregular cycles.)symptoms appear (vasomotor and irregular cycles.)– Natural menopause: gradual decline, characterized by Natural menopause: gradual decline, characterized by

fluctuating E and FSH. fluctuating E and FSH. – Increase FSH due to loss of inhibin!Increase FSH due to loss of inhibin!

Premature ovarian failurePremature ovarian failure/menopause /menopause <<4040– Under 30 should get karyotypeUnder 30 should get karyotype to look for Y chromosome. to look for Y chromosome.– Consider Fragile X gene mutation testing (FMR1)Consider Fragile X gene mutation testing (FMR1)

Surgical menopauseSurgical menopause: sudden drop in E.: sudden drop in E.

Managing PerimenopauseManaging Perimenopause

Standard HRT doses Standard HRT doses will not prevent will not prevent pregnancypregnancy and should not be used as first and should not be used as first line agents unless a patient is surgically line agents unless a patient is surgically sterile or cannot take OCP.sterile or cannot take OCP. The patch:The patch:– Low dose patch 0.025 mg will reduce hot Low dose patch 0.025 mg will reduce hot

flashes by 85%. flashes by 85%. – If the patient has a uterus, you must give If the patient has a uterus, you must give

progestin therapyprogestin therapy for 14 days q monthfor 14 days q month..

Hot Flash Alternative ApproachesHot Flash Alternative Approaches

Lifestyle changes, cool environment Lifestyle changes, cool environment

BiofeedbackBiofeedback

Vitamin E, dong quai, and black cohoshVitamin E, dong quai, and black cohosh——no no difference compared with placebodifference compared with placebo

PhytoestrogensPhytoestrogens

Clonidine (patch or pill)Clonidine (patch or pill)

MegestrolMegestrol

SSRI/SNRI therapySSRI/SNRI therapy

Menopausal ChangesMenopausal Changes

SymptomsSymptoms: hot flashes (catecholamine : hot flashes (catecholamine mediated) hot and cold, night sweats, mood mediated) hot and cold, night sweats, mood changes, insomnia, vaginal atrophy, possibly changes, insomnia, vaginal atrophy, possibly skin changes.skin changes.

Bone lossBone loss (most in first 5 years), especially (most in first 5 years), especially trabecular bone. trabecular bone.

Increased Increased central obesitycentral obesity..

Lipid abnormalitiesLipid abnormalities..– Latter two increase Latter two increase HTN, CADHTN, CAD risk. risk.

ManagementManagement

Protect bone.Protect bone.

Protect against hyperplasia.Protect against hyperplasia.

Alleviate symptoms.Alleviate symptoms.

Promote healthy living.Promote healthy living.

Bone Mass by Age and SexBone Mass by Age and Sex

10 20 30 40 50 60 70 80

Bo

ne

Mas

s

Age (years)

Men Women

Menopause-AssociatedBone Loss

Adapted from Finkelstein JS. Cecil Textbook of Medicine. 21st ed. 1999;1366-73.Riggs BL, Melton LJ III. N Engl J Med. 1986;314:1676-86.

OsteoporosisOsteoporosisDEXA scan = gold standard DEXA scan = gold standard (Dual Energy Xray Absorptiometry)(Dual Energy Xray Absorptiometry)

T scoreT score = StDev from healthy 30yo woman. = StDev from healthy 30yo woman.– Osteopenia = T -1 to -2.5Osteopenia = T -1 to -2.5– Osteoporosis = T < -2.5Osteoporosis = T < -2.5

Z scoreZ score = StDev from same age woman. = StDev from same age woman.– Used in premenopausal women.Used in premenopausal women.

T & Z scores correlate with fracture risk.T & Z scores correlate with fracture risk.– DEXA less reliable in Obese (artificially low T score) and DEXA less reliable in Obese (artificially low T score) and

osteoarthritis (artificially high T score) osteoarthritis (artificially high T score) Error range of DEXA = ~7% and repeat test not valid at <1 year, Error range of DEXA = ~7% and repeat test not valid at <1 year, more valid at 2 years.more valid at 2 years.Urinary and serum markers of bone turnover measure Urinary and serum markers of bone turnover measure cancellous bone. cancellous bone. (Telopeptides most commonly used, if at all)(Telopeptides most commonly used, if at all)

When to Measure BMD in When to Measure BMD in Postmenopausal WomenPostmenopausal Women

Non-ModifiableNon-ModifiableAge Age >> 65 65

Caucasian RaceCaucasian Race

FemaleFemale

Family historyFamily history

History of fractureHistory of fracture

History of fallsHistory of falls

Bad EyesightBad Eyesight

ModifiableModifiableSmoking CigarettesSmoking Cigarettes

Low Body WeightLow Body Weight

ETOHETOH

Not on HRT (low E)Not on HRT (low E)

HypothyroidismHypothyroidism

Immobility*Immobility*

Poor nutritionPoor nutrition

Medications (steroids Medications (steroids and heparin)and heparin)

One or more risk factors

Treatment OptionsTreatment Options

CalciumCalcium– 1500-2000mg daily1500-2000mg daily

Vit D supplementationVit D supplementation– SunshineSunshine– 400-800 IU/daily400-800 IU/daily

SERMs (raloxifene)SERMs (raloxifene)HRT (oral or patch)HRT (oral or patch)Bisphosphonates (Etidronate, Alendronate)Bisphosphonates (Etidronate, Alendronate)Weight bearing exerciseWeight bearing exercise

Affects of Various TreatmentsAffects of Various Treatments

Increases in Increases in BMD (%)BMD (%)††

Decreases Decreases Vertebral Vertebral Fracture Fracture RatesRates

ERT/HRT

Alendronate||

Risedronate||

Raloxifene||

Calcitonin

Yes§

Yes¶

Yes

No

No

5 - 6

5 - 8

5 - 6

1 - 2

1 - 2

Yes‡

Yes‡

Yes

Yes

Yes

MostMostCommon Common Side EffectSide Effect

Breakthrough bleeding

Gastric ulceration

Upper GI symptoms

Hot flushes

Nasal irritation

Decreases Hip Fracture Rates

WHI ResultsWHI Results

Absolute and Relative Risk or Benefit of HRT

Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.

Heart attacks

Strokes

Breast cancer

VTEs

Colorectal cancer

Hip fractures

Relative Riskvs Placeboat 5. Years

Increased Absolute Riskper 10,000Women/YrHealth Event

1.29

1.41

1.26

2.11

0.63

0.66

7

8

8

18

6

5

Increased Absolute Benefitper 10,000Women/Yr

WHI E-only ArmWHI E-only Arm

What’s differentWhat’s different– No increased CVD risk.No increased CVD risk.– No increased breast cancer risk.No increased breast cancer risk.

What’s the similarWhat’s the similar– Increased risk of DVTIncreased risk of DVT– Small increase risk of strokeSmall increase risk of stroke– Bone protection.Bone protection.

WHIWHI

Use HRT for shortest period of time needed, to Use HRT for shortest period of time needed, to treat symptoms.treat symptoms.HRT should not be continued or started to prevent HRT should not be continued or started to prevent heart diseaseheart diseaseDiscuss other methods of CVD prevention:Discuss other methods of CVD prevention:– lifestyle changeslifestyle changes– cholesterol- and blood pressure-lowering drugscholesterol- and blood pressure-lowering drugs

For osteoporosis prevention:For osteoporosis prevention:– weigh the benefits against their personal risks for heart weigh the benefits against their personal risks for heart

attack, stroke, blood clots, and breast cancer; alternate attack, stroke, blood clots, and breast cancer; alternate treatments are available to prevent osteoporosis and treatments are available to prevent osteoporosis and fractures.fractures.

NIH Recommendations

Endometriosis/AdenomyosisEndometriosis/Adenomyosis

Endometriosis = endometrial tissue outside the uterus.Endometriosis = endometrial tissue outside the uterus.Adenomyosis = endometrium within muscle.Adenomyosis = endometrium within muscle.Endometriosis Incidence: Endometriosis Incidence: – 3-10% of general population3-10% of general population– 30% of infertile population30% of infertile population– 50% of pelvic pain50% of pelvic pain– 70% of pelvic pain and infertility70% of pelvic pain and infertility

LEFTLEFT ovary is most common site of endometrioma. ovary is most common site of endometrioma. Disease stage correlates with ~fertility, but not pain.Disease stage correlates with ~fertility, but not pain.Genetic (7% of first degree relatives)Genetic (7% of first degree relatives)Etiology: genetic, environmental, autoimmune.Etiology: genetic, environmental, autoimmune.Tissue has abnormal regulation (altered responsiveness to Tissue has abnormal regulation (altered responsiveness to progesterone: resistant to apoptosis; excess aromatase.)progesterone: resistant to apoptosis; excess aromatase.)Also assoc with: premenstrual spotting, poor egg qualityAlso assoc with: premenstrual spotting, poor egg quality

Endometriosis TreatmentEndometriosis Treatment

InfertilityInfertilitySurgery benefits stage I-II disease.Surgery benefits stage I-II disease.– NNT = 12NNT = 12– More advanced disease, role of surgery mainly limited More advanced disease, role of surgery mainly limited

to diagnosis.to diagnosis.

GnRH-agonistGnRH-agonist– Modest benefit, if any for fertilityModest benefit, if any for fertility

All forms of fertility have decreased efficacy with All forms of fertility have decreased efficacy with endometriosis (IVF, COH/IUI)endometriosis (IVF, COH/IUI)– Likely related to poorer egg quality. Likely related to poorer egg quality.

Endometriosis TreatmentEndometriosis Treatment(pregnancy, pseudopregnancy or pseudomenopause)(pregnancy, pseudopregnancy or pseudomenopause)

OCPs (60-90% get relief in first year)OCPs (60-90% get relief in first year)– Promote decidualization (progestin effect), pseudopregnancyPromote decidualization (progestin effect), pseudopregnancy– 10% recurrence risk/year10% recurrence risk/year

Depo Provera/ProgestinsDepo Provera/Progestins– Promote decidualization (pseudopregnancy)Promote decidualization (pseudopregnancy)

Depot Lupron (75-90% get relief in first year)Depot Lupron (75-90% get relief in first year)– Decapeptide, long-acting GnRH promotes pseudomenopause by Decapeptide, long-acting GnRH promotes pseudomenopause by

decreasing ovarian E.decreasing ovarian E.– 50% recurrence upon stopping. 50% recurrence upon stopping. – Bone loss at 6 monthsBone loss at 6 months

Addback regimens: 25 ug E patch q week, 0.625 mg CEE QD, or Addback regimens: 25 ug E patch q week, 0.625 mg CEE QD, or norethindrone acetate 5mg QD.norethindrone acetate 5mg QD.

Levonorgestrel IUDLevonorgestrel IUD– Decrease severity of symptoms (pseudopregnancy).Decrease severity of symptoms (pseudopregnancy).

Danazol (95% relief)Danazol (95% relief)– Androgen side effects: hirsuitism, loss of female contour, liver toxAndrogen side effects: hirsuitism, loss of female contour, liver tox

Endometriosis SurgeryEndometriosis Surgery

Hysterectomy/BSOHysterectomy/BSO: 90% cure. : 90% cure.

Presacral neurectomyPresacral neurectomy: risks constipation, : risks constipation, helps midline pain.helps midline pain.

Laparoscopic Uterosacral Nerve AblationLaparoscopic Uterosacral Nerve Ablation (LUNA): no proven benefit. (LUNA): no proven benefit.

Cystectomy vs ablation of cyst wallCystectomy vs ablation of cyst wall– Both superior to simple drainage. Both superior to simple drainage.

InfertilityInfertility

No pregnancy after 1 year of adequate, No pregnancy after 1 year of adequate, unprotected intercourse. unprotected intercourse.

15% of all couples.15% of all couples.

Increases with age. Increases with age.

Roughly equal between male and female Roughly equal between male and female causes. causes.

20% of cases are isolated male factor.20% of cases are isolated male factor.

10% are unexplained.10% are unexplained.

InfertilityInfertilityBasic workupBasic workupOvulation?Ovulation?– Tests of ovulation: history, BBT (.5 degree rise), urinary LH detection, timed Tests of ovulation: history, BBT (.5 degree rise), urinary LH detection, timed

serum P.serum P.Sperm?Sperm?– Volume 2ml, concentration 20m/ml, motility 40%, morphology 14% (30% WHO Volume 2ml, concentration 20m/ml, motility 40%, morphology 14% (30% WHO

III)III)Anatomy?Anatomy?– HSG (pretty reliable if says tubes are patent 85% specific, only fair if tubes are HSG (pretty reliable if says tubes are patent 85% specific, only fair if tubes are

blocked 54% sensitive)blocked 54% sensitive)– Not the greatest test for endometriosis.Not the greatest test for endometriosis.

Ovarian reserve?Ovarian reserve?– Elevated CD3 FSH ( abnormal if >10 IUm/L)Elevated CD3 FSH ( abnormal if >10 IUm/L)– Elevated CD3 Estradiol (abnormal if >75 pg/ml)Elevated CD3 Estradiol (abnormal if >75 pg/ml)– Predicts outcomes with IVF, reliability not established for general public.Predicts outcomes with IVF, reliability not established for general public.

Post coital test.Post coital test.– Not predictive. Not predictive.

FertilityFertility

Septate uteri do not cause infertility.Septate uteri do not cause infertility.

Fibroids involving the cavity decrease Fibroids involving the cavity decrease fertility.fertility.

Polyps >2cm decrease fertilityPolyps >2cm decrease fertility

Endometriosis decreases fertility via egg Endometriosis decreases fertility via egg quality. quality.

Obesity and cigarette smoking decrease Obesity and cigarette smoking decrease fertility.fertility.

Normal fertilityNormal fertility

FecundityFecundity– approximately 20% per cycle during 20s and approximately 20% per cycle during 20s and

early 30s. early 30s. – Approximately 10% at age 40.Approximately 10% at age 40.– Most couples infertile by age 45.Most couples infertile by age 45.

– At age 44-45, age is more predictive of fertility At age 44-45, age is more predictive of fertility than is ovarian reserve. than is ovarian reserve.

RPLRPL

3 consecutive losses with same partner3 consecutive losses with same partner

If no prior livebirths:If no prior livebirths:– 70% chance of livebirth in next pregnancy.70% chance of livebirth in next pregnancy.– 40% livebirth after 4 losses.40% livebirth after 4 losses.

If prior livebirths:If prior livebirths:– 70% livebirth until 6 losses. 70% livebirth until 6 losses.

Increases risk of ectopic, neural tube Increases risk of ectopic, neural tube defectsdefects

RPL: GEISHARPL: GEISHA

GGenetic enetic 5% 5%

EEndocrinendocrine 20%20%

IInfectionsnfections 5% (controversial) 5% (controversial)

IImmunemmune 20%20%

SStructuraltructural 20%20%

AAnybody’s guess (unknown) 30%nybody’s guess (unknown) 30%

RPLRPL

ThrombophiliaThrombophilia

ACOG says the only definitive ones are ACOG says the only definitive ones are immune mediated:immune mediated:– Anticardiolipin antibodies and Lupus Anticardiolipin antibodies and Lupus

anticoagulant.anticoagulant.– These two are the best characterized.These two are the best characterized.

These are the only two, for which These are the only two, for which treatment has been demonstrated. treatment has been demonstrated.

RPL -- GeneticRPL -- Genetic

NormalNormal


Robertsonian balanced Robertsonian balanced translocation account translocation account for 2/3 genetic for 2/3 genetic etiologies.etiologies.

6 possible gametes, only two can produce unaffected offspring.


Balanced Balanced recipricol recipricol translocationtranslocation

Normal Abnormal Balanced Abnormal

Four possible combinations with two unaffected gametes

Endocrinology of PregnancyEndocrinology of Pregnancy

Maternal Recognition of PregnancyMaternal Recognition of Pregnancy– Progesterone is secreted by CL exclusively for 5-7 Progesterone is secreted by CL exclusively for 5-7

weeks, due to hCGweeks, due to hCG– After 6-7 weeks, placenta produces large amounts. After 6-7 weeks, placenta produces large amounts. – After 9th week, removal of ovaries has no effect on After 9th week, removal of ovaries has no effect on

pregnancypregnancy. . – Progesterone production peaks at termProgesterone production peaks at term. . – hCG quits doubling at 6-7 weeks gestation or at about hCG quits doubling at 6-7 weeks gestation or at about

10K10K– hCG peaks at 10 weekshCG peaks at 10 weeks


Function of P4 (summary)Function of P4 (summary)– Pregnancy maintenance.Pregnancy maintenance.– Uterine quiescenceUterine quiescence– Immune modulationImmune modulation

Is a fall in P associated with partuition?Is a fall in P associated with partuition?– No.No.

Does P have a role in partuition?Does P have a role in partuition?– YesYes

Explain:Explain:– Receptor changes cause decreased function of P.Receptor changes cause decreased function of P.


Placenta and steroid hormone productionPlacenta and steroid hormone productionWhat does the mother contribute to placental steroid What does the mother contribute to placental steroid production?production?– Cholesterol from LDL.Cholesterol from LDL.

What does the baby contribute? What does the baby contribute? – DHEASDHEAS

Which enzymes does placenta lack?Which enzymes does placenta lack?– 17hydroxylase/17,20lyase and 21 hydroxylase17hydroxylase/17,20lyase and 21 hydroxylase

ConsequenceConsequence– Placental steroid production stops at Placental steroid production stops at PP (No androgens or (No androgens or

cortisol)cortisol)– E3 is produced by conversion of DHEASE3 is produced by conversion of DHEAS


What is primary precursor for E?What is primary precursor for E? DHEAS from fetal adrenal.DHEAS from fetal adrenal.Primary E of pregnancy?Primary E of pregnancy? Estriol aka E3 (90%)Estriol aka E3 (90%)What organ makes E3?What organ makes E3? Placenta converts fetal Placenta converts fetal

precursors to E3precursors to E3Role of placental estrogens?Role of placental estrogens? Increase uteroplacental Increase uteroplacental

bloodflow.bloodflow.Are Es required for pregnancy maint?Are Es required for pregnancy maint? Does not seem so. E is Does not seem so. E is

mainly a sink to preventmainly a sink to preventexcess androgens.excess androgens.

Conditions associated with low E?Conditions associated with low E? AnencephallyAnencephallyCongenital adrenal lipoid Congenital adrenal lipoid

hyperplasiahyperplasiaAromatase and sulfatase Aromatase and sulfatase

deficienciesdeficienciesWhy has estriol been used as aWhy has estriol been used as a Indicates HPA axis in fetus.Indicates HPA axis in fetus.

marker of fetal well being?marker of fetal well being? b/c DHEAS b/c DHEAS Estriol Estriol

crushing the creogs rapid primer. high yield amenorrhea abnormal puberty (delayed and precocious)...

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