Reproduction Module 05-06 Endocrinology of the Ovary & Female Reproductive Tract

1 · Chromosomal sex & SRY

• SRY = Sex-determining Region of the Y chromosome:
  • Encoded on the short arm of Y (Yp).FA 2024 Repro
  • Encodes the testis-determining factor (TDF), a transcription factor that activates SOX9.
  • SOX9 pushes the bipotential germinal ridge toward testis fate (Sertoli-cell commitment).
• Without SRY:
  • Germinal ridge adopts the default ovarian pathway (WNT4, RSPO1, FOXL2).
  • This is why the default is female at every downstream tier.

• 45,X (Turner):
  • One X missing → streak gonads → no hormones.Pathoma Ch 15
  • Female phenotype, short stature, webbed neck, bicuspid aortic valve.
• 47,XXY (Klinefelter):
  • SRY present → male phenotype; extra X impairs seminiferous tubules → infertility + tall stature.
• 46,XX SRY+ (de la Chapelle): Y→X translocation of SRY → male phenotype.
• 46,XY SRY− (Swyer): loss-of-function SRY → streak gonads, female phenotype. Must remove Y-bearing gonads (gonadoblastoma risk).

2 · Gonadal differentiation — the bipotential germinal ridge

• Week-5 germinal ridge:
  • Mesodermal tissue on the medial side of the mesonephros (proto-kidney).Costanzo 6e ch 10
  • Equally capable of becoming ovary or testis — a true bipotential primordium.
• The two fates:
  • Testis: SRY → SOX9 → Sertoli cells form first; Leydig cells second.
  • Ovary: default; granulosa + theca cells form around primordial germ cells.

• Sertoli first, then Leydig:
  • Sertoli cells secrete AMH early → Müllerian ducts begin regressing before testosterone peaks.
  • Leydig cells secrete T slightly later → Wolffian ducts stabilize.
  • This order explains why a Sertoli-only defect can leave a 46,XY with a persistent uterus (LO 6).

3 · Hormonal tier — T vs AMH vs DHT

• Testosterone (fetal Leydig):
  • Stabilizes Wolffian ducts into epididymis, vas deferens, seminal vesicles, ejaculatory duct.
  • Acts paracrine — each testis masculinizes its ipsilateral duct.
  • Drives male brain patterning after local aromatization to estradiol.
• AMH (fetal Sertoli):
  • Regresses Müllerian ducts → no uterus, tubes, or upper vagina in males.
  • Loss → persistent Müllerian duct syndrome (46,XY with uterus at hernia repair).
• DHT (peripheral, via 5α-reductase type 2):
  • Virilizes external genitalia (penis, scrotum), prostate, and pattern hair.
  • Loss → normal internal male + female-appearing external at birth (\"guevedoces\" phenotype at puberty).

4 · Morphological tier (hand-off to LO 2)

• Müllerian vs Wolffian:
  • Both duct systems exist side-by-side at week 6. Survival depends on what hormones reach them.
  • Default (no hormones): Müllerian persists, Wolffian regresses → female internal anatomy.
  • With T + AMH: Wolffian persists, Müllerian regresses → male internal anatomy.

5 · Secondary sex & brain-behavior tier

• Driven by gonadal & adrenal steroids once HPG axis reactivates:
  • Females: breast development (E2), gluteofemoral fat (E2), pubic/axillary hair (adrenal DHEA → androgens).
  • Males: facial/body hair (DHT), muscle mass (T), laryngeal growth / voice deepening (T), androgenic alopecia (DHT).
  • Estrogen closes epiphyses in BOTH sexes — aromatase-deficient patients (XX or XY) grow extremely tall.

• Organizational (perinatal, permanent):
  • Androgen → local aromatization to estradiol in hypothalamus → apoptosis of AVPV kisspeptin neurons in males.
  • Consequence: males retain negative feedback only; females keep both negative and positive → females can mount an LH surge, males cannot.
• Activational (adult, reversible):
  • Libido tracks current T/E2. Mood and migraine pattern track menstrual E2. Postpartum drop in placental steroids can precipitate mood disorders.
• Aromatase paradox:
  • T masculinizes the male brain only after local conversion to estradiol. Fetal α-fetoprotein binds maternal/fetal E2 and keeps it out of the female fetal brain, so female brain is protected.

6 · When the cascade breaks — intersex & EDCs

• Break types & results:
  • Chromosomal (Turner 45,X): streak ovary → no hormones → female-appearing with short stature + cardiac findings.
  • Gonadal (Swyer 46,XY SRY−): no testis → no T + no AMH → female external & internal; Y-gonads need removal.
  • Hormonal excess (21-OH CAH, 46,XX): adrenal androgens in utero → virilized external but normal uterus/ovary.
  • Receptor (AIS 46,XY): testes + T + DHT all there, but AR non-functional → female external, no uterus (AMH still works).
  • Enzyme (5α-RD 46,XY): normal T, low DHT → internal male + female-appearing external at birth; virilizes at puberty.

• Categories & windows:
  • Plasticizers (BPA, phthalates), pesticides (DDT), PCBs, and historic DES exposure can mimic or block sex-steroid signaling.
  • Critical windows: perinatal organizational effects can be lifelong.
  • Rodent 2-M female (flanked by 2 male fetuses) is a classic example of intrauterine androgen exposure altering adult reproductive behavior.

1 · The default-is-female rule

• Feminization & demasculinization:
  • Default developmental programs — do not require a hormonal signal.
  • This is why an early-gonadectomized fetus of any karyotype develops female anatomy.Costanzo 6e ch 10
• Masculinization & defeminization:
  • Masculinization requires testosterone (+ DHT peripherally).
  • Defeminization requires AMH.
  • Both must occur for complete male morphology.

• α-fetoprotein:
  • Binds maternal and fetal estrogens → keeps them out of the fetal brain and reproductive tract.
  • This is why maternal estrogens don't feminize or masculinize (via aromatization) a female fetus.

2 · Internal ducts — Müllerian vs Wolffian

• Müllerian (paramesonephric) ducts:
  • Default: persist → fallopian tubes, uterus, cervix, upper ⅓ of vagina.
  • In males: regressed by AMH.
  • Lower ⅔ of vagina comes from the urogenital sinus (endoderm), NOT Müllerian.
• Wolffian (mesonephric) ducts:
  • Default: regress in the absence of testosterone.
  • In males: stabilized by T into epididymis, vas deferens, seminal vesicles, ejaculatory duct.
  • T acts paracrine — high local concentration from the adjacent testis is required.FA 2024 Repro; B&B Repro

• Weeks 6–7:
  • Sertoli cells form first → AMH secretion begins → Müllerian regression begins.
• Weeks 8–12:
  • Leydig cells appear → T rises → Wolffian stabilization.
  • This order is why a defect in AMH can leave a male with a uterus (PMDS) but otherwise normal male anatomy.

3 · External genitalia — tubercle, folds, swellings, sinus

• Genital tubercle:
  • Female (default, no DHT): clitoris.
  • Male (DHT present): glans penis.
• Urogenital folds:
  • Female: labia minora.
  • Male: penile shaft; fuse in the midline → penile (spongy) urethra. Failure to fuse → hypospadias.
• Labioscrotal swellings:
  • Female: labia majora.
  • Male: scrotum (midline raphe = fusion scar).
• Urogenital sinus:
  • Female: lower ⅔ vagina, urethra, Skene & Bartholin glands.
  • Male: prostate, bulbourethral (Cowper) glands, prostatic/membranous urethra.

• 5α-reductase type 2:
  • Expressed in genital skin, prostate, hair follicles.
  • Converts T → DHT with much higher AR affinity.
  • Finasteride / dutasteride block this enzyme (BPH, alopecia).Lippincott Pharm 7e
• T vs DHT territory:
  • T = Tubes (internal Wolffian structures), axial musculature, brain patterning, deep voice.
  • DHT = Dick + Prostate + Pattern hair (external + prostate + scalp/body).

4 · Clinical mutations side-by-side

• Fetal state:
  • Testes descend partially (often inguinal). T + DHT produced but cannot signal.
  • Wolffian fails (no T signal). Müllerian regressed (AMH still works). No uterus.
  • External: female-appearing (no DHT effect).
• Puberty & labs:
  • Breast development from peripheral aromatization of T to E2.
  • No pubic/axillary hair (AR required). Primary amenorrhea.
  • Labs: ↑ T, ↑ LH (no negative feedback), elevated E2.

• Internal male normal (T + AMH intact).
• External female-appearing at birth (no DHT in utero).
• Pubertal T surge partially virilizes externally → \"guevedoces\" / \"penis at 12\".
• Labs: normal T, elevated T:DHT ratio.

• Can't make cortisol or aldosterone → substrate shunts to androgens (DHEA, androstenedione, T).
• Ovaries + uterus + upper vagina all normal (no gonadal T, no AMH).
• External: virilized by androgens in utero → fused labia, clitoromegaly, ambiguous genitalia.
• Systemic: salt-wasting, hyperkalemia, hypotension; elevated 17-OH-progesterone on newborn screen.Pathoma Ch 15

• Loss-of-function of AMH or AMH receptor.
• T intact → normal external male + Wolffian.
• AMH failed → persistent uterus and fallopian tubes (often discovered at inguinal hernia repair).

1 · GnRH → LH/FSH pathway

• GnRH neurons:
  • Cell bodies in the medial preoptic area (POA) and arcuate nucleus.Costanzo 6e ch 10
  • Axons project to the median eminence → release GnRH into the hypophyseal portal system.
  • GnRH = 10-amino-acid peptide (decapeptide).
• Pulse generator:
  • GnRH is released in pulses every 60–90 min.
  • Kisspeptin (arcuate) drives tonic pulses; AVPV kisspeptin drives the pre-ovulatory surge.

• LH & FSH structure:
  • α + β heterodimer glycoproteins.
  • α-subunit is shared with TSH and hCG — this is why hCG can cross-react at LH receptors (trigger shots in IVF; gestational thyrotoxicosis at TSHR).FA 2024 Endo
• Pulse frequency bias:
  • Slow GnRH pulses → FSH-dominant release.
  • Fast GnRH pulses → LH-dominant release (part of why PCOS has LH > FSH).
• Continuous GnRH = shutdown:
  • Gonadotropes down-regulate GnRH receptors when signal is continuous.
  • Leuprolide depot exploits this (prostate CA, precocious puberty, endometriosis). Initial \"flare\" before suppression.

2 · Two-cell, two-gonadotropin model — the test favorite

• Theca cells:
  • Have LH receptors.
  • Have cholesterol desmolase + 17α-hydroxylase + 17,20-lyase → can make androgens.
  • Do NOT express aromatase → cannot finish estradiol synthesis alone.
• Granulosa cells:
  • Have FSH receptors.
  • Express aromatase (CYP19A1).
  • Lack 17α-hydroxylase/17,20-lyase → depend on theca-derived androgens as aromatase substrate.
• Cell-cell handoff:
  • Androstenedione / T diffuse across the basement membrane from theca to granulosa.
  • Granulosa aromatizes them to estrogen.

• Granulosa gain LH receptors:
  • Only the dominant follicle upregulates LH-R on granulosa late in the follicular phase.
  • Enables the LH surge to trigger ovulation and local progesterone secretion.

3 · Negative vs positive feedback — the concentration/duration rule

• Moderate E2:
  • Inhibits GnRH at the arcuate nucleus and the gonadotropes.
  • Combined OCPs exploit this by holding E2 steady below the surge threshold.
• Progesterone (luteal):
  • Powerful negative feedback; slows pulse generator → slow, low-amplitude LH pulses.
  • Blocks positive feedback at AVPV even if E2 is high → no second surge in luteal phase.
• Inhibin B / A:
  • Selectively suppress FSH at the pituitary.
  • Inhibin B = early follicular; Inhibin A = luteal.

• Threshold:
  • E2 must be > ~200 pg/mL for ≥ 48 h — intensity AND duration matter.Guyton 14e ch 75
• Mechanism:
  • AVPV kisspeptin neurons sense high E2 → burst of GnRH → pituitary LH spike (10× baseline).
  • Smaller FSH surge, limited by inhibin B.
  • Ovulation ~36 h after the surge begins.

4 · Kisspeptin — the master activator, two populations

• AVPV kisspeptin:
  • Anteroventral periventricular nucleus (within POA).
  • Stimulated by sustained high E2 → positive feedback → LH surge.
  • Apoptoses in males perinatally from aromatized androgen → why males cannot mount an LH surge.
• Arcuate kisspeptin:
  • Inhibited by E2 → negative feedback and tonic pulse generation.
  • Preserved in males.

• Disorders:
  • KISS1R loss-of-function → hypogonadotropic hypogonadism (no puberty).
  • KISS1R gain-of-function → central precocious puberty.
  • Kisspeptin analogs: under study as alternative ovulation triggers in IVF.

5 · Stress, metabolic, and neural inputs to GnRH

• Activators:
  • Kisspeptin (primary activator).
  • Norepinephrine.
• Inhibitors:
  • β-endorphins (runner's amenorrhea).
  • GnIH (gonadotropin-inhibiting hormone) — induced by glucocorticoids.
  • Dopamine (indirect via prolactin when dopamine is low).
• Permissive factors:
  • Leptin — signals energy availability to kisspeptin neurons. Low leptin → low kisspeptin → low GnRH → hypothalamic amenorrhea.
• Glucocorticoids (stress):
  • Inhibit every tier: ↓ GnRH, ↑ GnIH, ↓ LH/FSH release, ↓ ovarian steroidogenesis.
  • Clinical: functional hypothalamic amenorrhea, ICU illness, female athlete triad.
• Prolactin:
  • Inhibits GnRH → hyperprolactinemia → amenorrhea-galactorrhea. Prolactinoma → treat with dopamine agonist (cabergoline).

1 · The primordial pool & meiotic arrest

• Prophase I arrest (in utero until ovulation):
  • All primordial oocytes pause in the diplotene stage of prophase I from fetal life.FA 2024 Repro
  • LH surge resumes meiosis I → secondary oocyte + first polar body.
• Metaphase II arrest (until fertilization):
  • After ovulation, the secondary oocyte arrests at metaphase II.
  • Fertilization triggers completion → 2nd polar body + haploid egg.

• Aging egg pool:
  • Longer MI arrest → ↑ risk of non-disjunction → aneuploidies with advanced maternal age (trisomy 21, 18, 13).
  • Declining AMH reflects shrinking antral pool → counseled in fertility care.

2 · Follicle stages — who expresses what receptor

• Theca cells:
  • Express LH receptors from the secondary stage onward.
  • Keep making androgens for granulosa throughout antral/Graafian stages.
• Granulosa cells:
  • Express FSH receptors throughout.
  • LH receptors appear late (Graafian stage).
  • This late LH-R expression is what enables the surge to trigger ovulation + luteinization.Costanzo 6e ch 10; B&B Repro

• Primordial + primary:
  • Essentially no measurable endocrine output.
  • Their development is partly FSH-independent (gonadotropin-independent phase).
• Secondary → antral:
  • Now gonadotropin-dependent.
  • Theca androgens + granulosa aromatase → escalating estradiol.
  • Granulosa also makes inhibin B.
• Graafian:
  • Peak estradiol, peak inhibin B.
  • Late in the stage, granulosa begins making some progesterone locally (primes for ovulation).

3 · Dominant follicle selection — winner take all

• FSH rises after CL regression (loss of inhibin A).
• A cohort of ~15–20 antral follicles begins to grow together in response to rising FSH.
• The most FSH-sensitive follicle grows fastest → the \"dominant\" follicle.
• Its own escalating E2 + inhibin B suppress FSH → weaker follicles undergo atresia.Guyton 14e ch 82

• Clomiphene / letrozole:
  • Clomiphene (SERM) blocks hypothalamic ER → removes negative feedback → FSH stays high → multiple follicles escape atresia.
  • Letrozole (aromatase inhibitor) lowers E2 production → same FSH rise.
  • Explains increased dizygotic twins with ovulation induction.
• PCOS:
  • Relatively low FSH + excess theca androgens → multiple follicles arrested at antral stage → \"string of pearls\" on ultrasound.
  • No dominant follicle selected → chronic anovulation.

• Small antral follicles make AMH:
  • Serum AMH correlates with the size of the antral pool.
  • Low AMH: diminished ovarian reserve, primary ovarian insufficiency, menopause approaching.
  • High AMH: PCOS (lots of arrested small antral follicles).

4 · Corpus luteum → corpus albicans

• LH surge triggers luteinization:
  • Granulosa & theca cells hypertrophy, acquire lipid droplets, look yellow (→ \"luteum\").
  • Granulosa-derived cells become \"large luteal cells\"; theca-derived become \"small luteal cells\".
• Vascularization:
  • Blood vessels invade the previously avascular follicle → CL can reach higher hormone output than the Graafian follicle.
• Corpus hemorrhagicum → CL:
  • Immediately after ovulation the follicle bleeds (corpus hemorrhagicum) before becoming yellow CL.
  • Pelvic ultrasound in early luteal phase may show a hemorrhagic cyst — usually physiologic.

• Progesterone (dominant):
  • Drives secretory endometrium, thickens cervical mucus, inhibits myometrium, raises basal body temperature.
• Estradiol:
  • Maintains endometrium; reinforces negative feedback (blocks another surge).
• Inhibin A:
  • Selectively suppresses FSH → prevents new follicle recruitment during the luteal phase.
• Relaxin (late pregnancy):
  • Softens cervix, loosens ligaments — contributes to pregnancy accommodation.

• No pregnancy:
  • CL lifespan is ~12 days without hCG rescue.
  • Involution → fibrous scar = corpus albicans.
  • Progesterone & estradiol fall → endometrium sloughs → menses.
• Pregnancy:
  • Trophoblast hCG cross-reacts with LH-R on CL → rescues it.
  • CL makes progesterone until ~8–10 weeks; placenta takes over (luteoplacental shift).
  • After the shift, oophorectomy is tolerated without miscarriage.

1 · Follicular phase — early and late

• FSH rises:
  • Driven by the luteal-phase drop in inhibin A (from involuted CL).Costanzo 6e ch 10
  • Recruits a cohort of antral follicles.
• LH:
  • Low and steady (normal tonic GnRH pulses).
• Estradiol & inhibin B:
  • Low initially; rise as granulosa cells proliferate.
• Uterus:
  • Days 1–5 = menses (spiral artery constriction after prior CL drop in P/E2).
  • Days 6–13 = proliferative phase — glands grow under estradiol.

• Dominant follicle:
  • Secretes escalating estradiol + inhibin B → suppress FSH → atresia of competing follicles.
• Estradiol crosses the surge threshold:
  • ~200 pg/mL for ~48 h → positive feedback imminent.
• Endometrium:
  • Proliferative — straight tubular glands, lengthening spiral arteries.

2 · LH surge & ovulation — mechanics in detail

• AVPV kisspeptin:
  • Sustained high E2 activates AVPV → burst GnRH release → LH spike (~10× baseline).
  • Smaller FSH surge (limited by inhibin B).
• Timing:
  • Surge lasts ~24–48 h.
  • Ovulation occurs ~36 h after LH begins rising, ~10–12 h after LH peak.FA 2024 Repro

• Granulosa cells (LH-R positive):
  • Make local progesterone that activates proteolytic enzymes (collagenase, plasminogen activators).
  • Follicle wall weakens; antral fluid pressure rises.
• Stigma → rupture:
  • A thin-walled bulge (stigma) forms on the follicle surface, ruptures, and the ovum + cumulus are released into the fimbriated tube.

• Before surge: primary oocyte arrested prophase I.
• LH surge → completes meiosis I → secondary oocyte + 1st polar body.
• Post-ovulation: arrests at metaphase II until fertilization.
• Fertilization completes meiosis II → 2nd polar body.

3 · Luteal phase — the \"waiting for implantation\" phase

• Progesterone rises sharply:
  • Peaks ~day 21–22 (mid-luteal).
  • Day-21 serum P > 5–10 ng/mL = ovulatory cycle confirmation.
• Estradiol stays elevated (CL source).
• Inhibin A rises → selectively suppresses FSH → prevents new follicle recruitment.

• Glands become tortuous & sacculated; glycogen-rich; subnuclear vacuoles appear ~day 16–18 (\"early secretory\").
• Spiral arteries coil.
• Stroma decidualizes in preparation for implantation.
• Cervical mucus thickens (blocks sperm + microbes).
• Myometrium quiescent (progesterone effect).

• CL lacks sustained LH support → involutes after ~12 days.
• P & E2 fall → spiral arteries constrict → endometrial ischemia → menses.
• Fall in inhibin A removes FSH brake → FSH rises → next cycle starts.

4 · Pregnancy & the luteoplacental shift

• Trophoblast secretes β-hCG:
  • Detectable in serum ~8–10 days post-ovulation.
  • Doubles every 48 h in normal early pregnancy.
  • Binds LH-R on CL → CL keeps making progesterone.
• hCG peaks ~10 weeks, then declines.

• Placenta takes over:
  • Placental syncytiotrophoblast makes sufficient progesterone to maintain pregnancy.
  • Oophorectomy after this point is tolerated without miscarriage.

• SHBG rises:
  • Driven by placental estrogens; buffers steroid bioavailability.
• Fetal-placental estriol:
  • Fetal adrenal DHEA-S → placenta → estriol. Maternal serum estriol used in prenatal screening.

1 · Primary hypogonadism — the gonad failed

• Ovary:
  • Accelerated follicular atresia → streak ovaries by birth or early childhood.
• Phenotype:
  • Female external anatomy, short stature, webbed neck (cystic hygroma remnant).
  • Cardiac: bicuspid aortic valve, coarctation of aorta.
  • Renal: horseshoe kidney. Newborns: hand/foot lymphedema.Pathoma Ch 15
• Labs & treatment:
  • ↑ FSH/LH, ↓ E2, ↓ AMH.
  • Growth hormone in childhood; exogenous estrogen then E2 + progestin to induce puberty.
  • Ongoing cardiac & renal surveillance.

• Definition & causes:
  • Menopausal labs (FSH > 40) + amenorrhea before age 40.
  • Causes: Fragile X premutation, Turner mosaic, autoimmune oophoritis, chemo/radiation, galactosemia, idiopathic.
• Management:
  • HRT until average age of menopause (~51) to protect bone + cardiovascular health.
  • Fertility counseling — spontaneous conception possible but rare.

2 · Secondary hypogonadism — the brain failed

• Mechanism:
  • Failure of GnRH neuron migration from the olfactory placode to the hypothalamus.
  • Genes: ANOS1/KAL1, FGFR1, PROK2.
• Phenotype:
  • Delayed/absent puberty + anosmia (no olfactory bulbs — shared embryology).FA 2024 Endo
  • Normal gonadal anatomy.
• Labs & treatment:
  • ↓ LH/FSH, ↓ E2 (or ↓ T).
  • Pulsatile GnRH restores fertility; or exogenous gonadotropins + sex steroids.

• Trigger:
  • Low energy availability (anorexia, over-exercise) + chronic stress.
  • Low leptin → low kisspeptin → low GnRH.
• Female athlete triad:
  • Low energy availability + menstrual dysfunction + low bone mineral density.
• Treatment:
  • Behavioral first: restore weight, reduce training, manage stress.
  • HRT/OCP for bone protection if amenorrhea persists.

• Hyperprolactinemia:
  • Prolactinoma, antipsychotics. Prolactin inhibits GnRH → amenorrhea-galactorrhea.
  • Treatment: dopamine agonist (cabergoline).
• Pituitary dysfunction:
  • Sheehan syndrome (post-partum pituitary necrosis), apoplexy, panhypopituitarism.
• Hypothyroidism:
  • ↑ TRH → ↑ prolactin → ↓ GnRH → menstrual irregularities.

3 · PCOS — the metabolic anovulation syndrome

• Fast GnRH pulses → LH:FSH > 2–3:1:
  • High LH stimulates theca → excess androgens (androstenedione, T).
  • Relatively low FSH → granulosa aromatase underactive → follicles arrested at antral stage.
• Peripheral aromatization:
  • Adipose tissue converts androstenedione → estrone (E1).
  • Chronic low-level estrone without progesterone = unopposed estrogen → endometrial hyperplasia → cancer risk.
• Insulin resistance:
  • Hyperinsulinemia stimulates theca androgen production and lowers SHBG (more free T).
  • Creates a self-reinforcing loop.B&B Repro; Pathoma Ch 16

• Oligo/anovulation (oligomenorrhea or amenorrhea).
• Clinical or biochemical hyperandrogenism (hirsutism, acne, ↑ free T).
• Polycystic ovaries on ultrasound (≥ 12 small antral follicles).
• Associated: obesity, insulin resistance/T2DM, acanthosis nigricans, metabolic syndrome, OSA.

• Lifestyle: weight loss can restore ovulation.
• Combined OCPs: cycle regulation + reduce free T (↑ SHBG) + protect endometrium.
• Metformin: addresses insulin resistance.
• Clomiphene / letrozole: ovulation induction (letrozole now first-line).
• Spironolactone: AR antagonist for hirsutism (teratogenic — use contraception).
• Cyclic progestin or OCP protects endometrium.

4 · Menopause & HRT

• Sequence:
  • Declining follicle pool → ↓ inhibin B first (earliest perimenopausal change).
  • FSH rises next (inhibin loss).
  • Eventually ovary can't make estradiol → ↑↑ FSH/LH, ↓↓ E2.
  • FSH rises more than LH because inhibin is also gone.
• Remaining estrogen source:
  • Peripheral aromatization of adrenal androgens to estrone (E1) in adipose tissue.

• H — Hot flashes / vasomotor symptoms (LH pulses → cutaneous vasodilation).
• A — Atrophy of vagina → dyspareunia, recurrent UTIs.
• V — Vaginal dryness (genitourinary syndrome of menopause).
• O — Osteoporosis (estrogen inhibits osteoclasts).
• C — Coronary artery disease risk rises.
• S — Sleep disturbance, mood changes, cognitive fuzziness.

• Benefits:
  • Symptom relief (vasomotor, GSM), bone density preservation.
• Risks:
  • VTE / stroke (estrogen prothrombotic).
  • Breast cancer (long-term combined HRT).
  • Endometrial cancer if estrogen is unopposed in a patient with a uterus.
• Rules:
  • Uterus intact → estrogen + progestin.
  • Post-hysterectomy → estrogen alone.
  • Timing hypothesis: risk-benefit most favorable when started < 60 or within 10 years of menopause.
• Alternatives for vasomotor symptoms: SSRIs/SNRIs, gabapentin, clonidine, lifestyle.

5 · Stress, EDCs, and intersex summary

• Glucocorticoids inhibit every level of the HPG axis (GnRH, LH/FSH, gonadal steroidogenesis) and facilitate GnIH.
• Clinical: FHA, reduced libido, impaired spermatogenesis under chronic stress.
• Severe acute illness (ICU) → transient HPG suppression that typically recovers.

• Examples: BPA, phthalates, DES, PCBs, certain pesticides.
• Population trends associated with exposure: earlier puberty, altered sperm counts, hypospadias.
• Developmental windows matter — organizational effects can be lifelong.

• 46,XX DSD: CAH is the most common cause of ambiguous newborn genitalia.
• 46,XY DSD: AIS, 5α-RD, Swyer, persistent Müllerian duct syndrome.
• Sex chromosome DSD: Turner, Klinefelter, mosaics.
• Multidisciplinary care; long-term concerns include bone health, cardiovascular risk, and cancer risk in retained Y-gonads.