Built from Reproduction Module 05-06 (LOs 1–6). Use this to check your work after the active recall sheet.

LO 1

ON EXAM — 6 TIERS: Chromosomal → Gonadal → Hormonal → Morphological → Secondary sex → Brain/behavior. DEFAULT = FEMALE. SRY (not Y itself) determines sex. Sertoli FIRST (AMH), Leydig SECOND (T). Estrogen closes epiphyses in BOTH sexes. Aromatase paradox — male brain masculinized by E₂; α-fetoprotein protects female fetus

The 6 levels of sexual differentiation (LO 1)

Level	Female-typical	Male-typical	Controls next tier via…
1. Chromosomal	XX (homogametic)	XY (heterogametic)	Presence/absence of the SRY gene on Yp
2. Gonadal	Ovary (default; WNT4/RSPO1/FOXL2 pathway)	Testis (SRY → SOX9 → Sertoli commitment)	Fetal testis secretes T + AMH; fetal ovary is endocrinologically quiet
3. Hormonal	Low T, no AMH, no DHT	High T (Leydig), AMH (Sertoli), peripheral DHT (5α-RD2)	Target-tissue receptors respond (AR) or enzymes act (5α-RD2) — or not
4. Morphological	Müllerian ducts persist → uterus/tubes/upper 1/3 vagina; feminized external	Wolffian ducts persist → SEED; Müllerian regressed by AMH; virilized external by DHT	Organs remodel at puberty under sex steroids
5. Secondary sex	Breasts (E₂), gluteofemoral fat (E₂), pubic/axillary hair (adrenal DHEA)	Facial/body hair (DHT), muscle (T), voice deepening (T), sperm (T)	Hormonal milieu patterns the CNS
6. Brain & behavior	AVPV kisspeptin preserved → can mount LH surge (positive feedback intact)	AVPV kisspeptin apoptosed perinatally → no surge; negative feedback only	Terminal tier — behavior, libido, mood track current steroid milieu

Chromosomal level & SRY (LO 1)

SRY meaning

Sex-determining Region of the Y chromosome. Encoded on the SHORT ARM (Yp). Encodes testis-determining factor (TDF), a transcription factor

SRY downstream

SOX9 — pushes the bipotential germinal ridge toward testis fate (Sertoli-cell commitment)

No SRY pathway

WNT4, RSPO1, FOXL2 — default ovarian pathway. Why "default is female" at every downstream tier

45,X

TURNER syndrome. Streak gonads (accelerated follicular atresia) → no hormones. Female phenotype with short stature, webbed neck, bicuspid AV, horseshoe kidney, lymphedema at birth

47,XXY

KLINEFELTER syndrome. SRY present → male phenotype. Extra X impairs seminiferous tubules → infertility, small firm testes, tall stature, gynecomastia, learning difficulties

46,XX SRY+

DE LA CHAPELLE syndrome (46,XX male). Y→X SRY translocation during paternal meiosis → phenotypic male with testes. Typically infertile

46,XY SRY−

SWYER syndrome. Loss-of-function SRY mutation → streak gonads (no testis). Female phenotype. Y-bearing gonads carry GONADOBLASTOMA risk → must be surgically removed

Gonadal differentiation (LO 1)

Ridge origin

Mesodermal tissue on the MEDIAL side of the mesonephros (proto-kidney). Forms around week 5. Truly bipotential

Sertoli vs Leydig order

Sertoli FIRST (secretes AMH; Müllerian regression begins early). Leydig SECOND (secretes T; stabilizes Wolffian). Order matters — a Sertoli-only defect can leave 46,XY with a persistent uterus (PMDS)

Ovary cells

Granulosa + theca cells form around primordial germ cells. Fetal ovary is ENDOCRINOLOGICALLY QUIET — no AMH, no T

Hormonal tier — T vs AMH vs DHT (LO 1)

T (fetal Leydig)

(1) Stabilizes Wolffian → SEED (epididymis, vas, seminal vesicles, ejaculatory duct). (2) Paracrine — each testis masculinizes IPSILATERAL duct. (3) Drives male brain patterning AFTER local aromatization to E₂

AMH (fetal Sertoli)

Regresses Müllerian ducts → no uterus, tubes, or upper 1/3 vagina in males. Loss → PMDS (46,XY with uterus at hernia repair)

DHT (peripheral 5α-RD2)

Virilizes EXTERNAL genitalia (penis, scrotum, prostate) + pattern hair. Made from T in genital skin, prostate, hair follicles

Secondary sex + brain/behavior tiers (LO 1)

Estrogen and epiphyses

Drives epiphyseal CLOSURE in BOTH sexes. Without estrogen (aromatase deficiency XX or XY; ER mutations) → long bones keep growing → tall stature + osteoporosis

Aromatase paradox

T masculinizes the male brain only AFTER local conversion to ESTRADIOL in hypothalamus. Estrogen is the actual masculinizing signal — counterintuitive but consistent

Female fetus protection

α-fetoprotein binds maternal and fetal estrogens → keeps them out of the female fetal brain. Prevents inadvertent masculinization

Male AVPV fate

Perinatal androgen (aromatized locally to E₂) triggers APOPTOSIS of AVPV kisspeptin neurons in males. AVPV mediates positive feedback → males cannot mount an LH surge. Arcuate (negative feedback) preserved

Organizational vs activational

ORGANIZATIONAL = perinatal, PERMANENT (brain structure, AVPV apoptosis). ACTIVATIONAL = adult, REVERSIBLE (libido tracks current T/E₂; mood tracks menstrual E₂; postpartum mood disorders from steroid withdrawal)

LO 2

ON EXAM — T for TUBES, DHT for DONG/PROSTATE/PATTERN HAIR, AMH MURDERS MüLLERIAN. SEED = Wolffian. FUTV = Müllerian. Lower 2/3 vagina = UROGENITAL SINUS (endoderm). CAIS = 46,XY with testes + no uterus + female external. 5α-RD = normal internal male + female external at birth + virilize at puberty. 21-OH CAH = virilized 46,XX + salt-wasting. PMDS = 46,XY male + uterus (AMH failed)

Unified hormone requirement (LO 2)

Structure	Hormone required	Source	If missing…
Testis formation	SRY → SOX9 (genetic, not hormonal)	Genetic	Streak gonad → Swyer syndrome (46,XY with SRY mutation)
Ovary formation	None (default)	—	Streak gonad only if chromosomal defect (Turner 45,X)
Müllerian regression	AMH	Fetal Sertoli cells	Persistent Müllerian duct syndrome — 46,XY male with uterus at hernia repair. T intact → normal external male + Wolffian
Wolffian stabilization	Testosterone	Fetal Leydig cells (paracrine)	Wolffian regresses → NO male internal ducts (SEED)
External virilization	DHT (from T by 5α-RD2)	Peripheral tissues (genital skin, prostate, hair follicles)	Female-appearing external in 5α-RD deficiency; or AR loss (AIS)
Testis descent	T + INSL3	Fetal Leydig cells	Cryptorchidism → infertility + testicular cancer risk

Müllerian vs Wolffian derivatives (LO 2)

FUTV (Müllerian)

FUTV mnemonic — Fallopian tubes, Uterus, Top 1/3 vagina, cerVix. All from paramesonephric (Müllerian) ducts

Lower vagina origin

Lower 2/3 of vagina comes from UROGENITAL SINUS (endoderm), NOT Müllerian. Meets Müllerian-derived upper 1/3 at sinovaginal bulb

SEED (Wolffian)

SEED mnemonic — Seminal vesicles, Epididymis, Ejaculatory duct, Ductus (vas) deferens. All from mesonephric (Wolffian) ducts

T paracrine

Wolffian ducts need very HIGH local T concentrations that only the ipsilateral testis can provide (diffusion across short distance). Systemic T (maternal or even fetal adrenal) isn't enough. Each testis masculinizes its own side

External genitalia — bipotential primordia (LO 2)

Primordium	Female (no DHT)	Male (DHT present)	Failure state
Genital tubercle	Clitoris	Glans penis	Micropenis (if T/DHT insufficient); clitoromegaly (if androgen exposure in 46,XX)
Urogenital folds	Labia minora	Penile (spongy) shaft + penile urethra (midline fusion over urethra)	HYPOSPADIAS — failed fusion → urethra opens on ventral surface. Sign of in-utero androgen insufficiency or EDC exposure
Labioscrotal swellings	Labia majora	Scrotum (midline raphe = fusion scar)	Bifid scrotum (failed fusion) in severe androgen insufficiency
Urogenital sinus	Lower 2/3 vagina, urethra, Skene glands, Bartholin glands	Prostate, bulbourethral (Cowper) glands, prostatic + membranous urethra	Persistent urogenital sinus in 21-OH CAH (single opening in virilized 46,XX)

T vs DHT territories (LO 2)

T territory (4)

T for TUBES (internal Wolffian/SEED), axial musculature, brain patterning (after aromatization), deep voice. T is the systemic hormone

DHT territory (3)

DHT for DONG + PROSTATE + PATTERN HAIR (external virilization + prostate growth + scalp/body hair). Also sebaceous gland activity (acne, seborrhea)

5α-RD2 role

Expressed in GENITAL SKIN, prostate, hair follicles. Converts T → DHT (much higher AR affinity, ~2-5× T). Type 1 is in scalp + sebaceous glands

5α-RD drugs

Finasteride (type 2 selective) — BPH + baldness. Dutasteride (types 1 + 2, more complete DHT drop). Both TERATOGENIC in male fetus (pregnancy warning)

Clinical mutations (LO 2)

Condition	Karyotype	Fetal state / labs	External	Internal
Complete AIS	46,XY	Testes descend partially (often inguinal). T + DHT produced but can't signal. ↑ T, ↑ LH (no feedback), ↑ E₂ (aromatization)	Female-appearing. Breasts at puberty (aromatase). No pubic/axillary hair (AR-dependent)	NO uterus (AMH worked). NO Wolffian (AR broken). Blind vagina. Testes inguinal (remove after puberty)
5α-RD type 2 deficiency	46,XY	Normal T, LOW DHT, elevated T:DHT ratio. Normal testes + AMH	Female-appearing at birth. Virilizes at puberty (“guevedoces”)	Normal internal male (T-dependent Wolffian preserved)
21-OH CAH	46,XX	Can't make cortisol or aldosterone → shunt to androgens. Elevated 17-OH-progesterone on NBS. Salt-wasting, hyperkalemia, hypotension	VIRILIZED by in-utero adrenal androgens — fused labia, clitoromegaly	NORMAL ovaries + uterus + upper vagina. Fertility preserved with treatment
PMDS	46,XY	AMH or AMH receptor loss-of-function. T intact	NORMAL male external (T and DHT work)	Normal Wolffian (T) PLUS persistent uterus + tubes. Often found at inguinal hernia repair

KEY RULE: Female phenotype requires ZERO hormones in utero. Male phenotype requires BOTH T/DHT (masculinization) AND AMH (defeminization).

LO 3

ON EXAM — Pulsatile GnRH only. Two-cell model: LH→THECA→androgens; FSH→GRANULOSA→aromatase→E₂. Granulosa LACKS 17α-hydroxylase. Moderate E₂ = negative; sustained E₂ >200 pg/mL × 48 h = positive (AVPV kisspeptin). P BLOCKS positive. α-subunit shared LH/FSH/TSH/hCG

HPG pipeline (LO 3)

Hypothalamus

GnRH (decapeptide) released in PULSES every 60-90 min. Cell bodies in MEDIAL PREOPTIC AREA + arcuate nucleus

Pituitary

LH + FSH (glycoprotein heterodimers). α-subunit SHARED with TSH and hCG

Ovary

Theca + granulosa cells (two-cell unit) → E₂, progesterone, inhibin A (luteal) or inhibin B (follicular)

GnRH details (LO 3)

GnRH size + release site

10 amino acids (decapeptide). Released from median eminence axon terminals into hypophyseal portal system

Pulse frequency

Every 60-90 min in females. ARCUATE kisspeptin drives tonic pulses; AVPV drives pre-ovulatory surge

Slow vs fast pulses

SLOW pulses → FSH-dominant. FAST pulses → LH-dominant. Part of why PCOS has LH > FSH

Continuous GnRH

Gonadotropes DOWNREGULATE GnRH receptors and desensitize → axis shutdown after initial "flare". LEUPROLIDE depot for prostate CA, endometriosis, precocious puberty, IVF. Flare covered with anti-androgen in prostate CA

α-subunit sharing

LH/FSH/TSH/hCG all share α-subunit. hCG cross-reacts at LH-R (IVF trigger + CL rescue) AND TSH-R (gestational thyrotoxicosis)

Two-cell, two-gonadotropin model (LO 3)

Cell	Tropic hormone	Enzymes present	Enzymes MISSING	Secretes
Thecal cell	LH (Gs-cAMP)	Cholesterol desmolase, 17α-hydroxylase, 17,20-lyase, 3β-HSD	AROMATASE — cannot finish E₂ alone	Androstenedione + T (hand off to granulosa)
Granulosa cell	FSH (Gs-cAMP)	AROMATASE (CYP19A1), 17β-HSD1	17α-hydroxylase + 17,20-lyase — cannot make own androgens	E₂, inhibin B (follicular), P (after LH surge once LH-R upregulated)

Androstenedione handoff

Androstenedione (and some T) diffuses across basement membrane from theca to granulosa. Granulosa aromatizes to estrone → 17β-HSD1 → estradiol

Late-follicular granulosa change

Granulosa UPREGULATE LH receptors late in follicular phase (Graafian stage). Only the dominant follicle does this

Late LH-R importance

Enables MID-CYCLE LH SURGE to trigger (1) ovulation via local progesterone + proteolytic enzymes, AND (2) luteinization after ovulation

Feedback rules (LO 3)

Signal	Target	Effect	Dominant when…
Moderate E₂	Hypothalamus + pituitary	NEGATIVE feedback (↓ GnRH pulses + ↓ LH/FSH)	Most of the cycle (early/late follicular + throughout luteal)
High sustained E₂	Hypothalamus (AVPV kisspeptin) + pituitary. Threshold >200 pg/mL for ~48 h	POSITIVE feedback → LH surge (10× baseline) + smaller FSH surge	Late follicular phase (days 12-14)
Progesterone	Hypothalamus + pituitary	Strong NEGATIVE. BLOCKS positive feedback at AVPV even if E₂ high	Luteal phase (from CL)
Inhibin A / B	Pituitary gonadotropes	Selectively suppresses FSH (not LH)	Inhibin B = early follicular. Inhibin A = luteal

Kisspeptin (LO 3)

AVPV kisspeptin

Anteroventral periventricular nucleus (within medial POA). STIMULATED by sustained high E₂ → positive feedback → LH surge. Apoptosed perinatally in males from local T→E₂ conversion → males can't mount surge

Arcuate kisspeptin

Arcuate nucleus. INHIBITED by E₂ → mediates negative feedback + tonic GnRH pulse generation. PRESERVED in males

KISS1R loss-of-function

Hypogonadotropic hypogonadism (no puberty). Inability to activate GnRH neurons → low LH/FSH → low gonadal steroids

KISS1R gain-of-function

Central precocious puberty — premature GnRH pulse generator activation

Modulators (LO 3)

Activators

Kisspeptin (PRIMARY activator). Norepinephrine (stimulates GnRH release)

Inhibitors

β-endorphins (runner's amenorrhea); GnIH (induced by glucocorticoids); dopamine (indirectly — low dopamine = high PRL = GnRH suppression)

Leptin

Signals ENERGY AVAILABILITY to kisspeptin neurons. LOW leptin (anorexia, over-training) → LOW kisspeptin → LOW GnRH → hypothalamic amenorrhea. Basis of female athlete triad

Cortisol inhibition

(1) ↓ GnRH from hypothalamus (↑ GnIH), (2) ↓ LH/FSH from pituitary, (3) ↓ ovarian steroidogenesis. Clinical: FHA, ICU illness, female athlete triad

Prolactin

Inhibits GnRH directly. Hyperprolactinemia (prolactinoma, antipsychotics, hypothyroidism) → amenorrhea-galactorrhea. Treatment: DOPAMINE AGONIST (cabergoline, bromocriptine)

LO 4

ON EXAM — Oocytes arrest PROPHASE I from fetal life → LH SURGE completes meiosis I → arrest METAPHASE II → fertilization completes meiosis II. Stage parade: Primordial → Primary → Secondary → Antral → Graafian → CL → Albicans. CL hormones PEI (Progesterone/E₂/Inhibin A). CL LIFESPAN = 12 days without hCG rescue. AMH HIGH in PCOS, LOW in POI/menopause

Primordial pool across lifespan (LO 4)

Time point	Approximate oocyte count
20 weeks gestation	~6-7 million (PEAK)
Birth	~1-2 million
Puberty / menarche	~300,000-400,000
Lifetime ovulations	~400-500 total
Menopause	~1,000 (below cycling threshold)

Meiotic arrest (LO 4)

First arrest

Prophase I (DIPLOTENE stage). Begins in fetal life (~20 weeks gestation). Resolves only at LH surge → completes meiosis I → secondary oocyte + first polar body

Second arrest

Metaphase II. Arrests immediately after ovulation. Resolves at FERTILIZATION → completes meiosis II → second polar body + haploid egg

Maternal age aneuploidy

Longer meiosis I arrest (decades in older mothers) → cumulative damage → ↑ non-disjunction at meiotic resumption → aneuploidies (trisomy 21 most common, also 18, 13). Declining AMH reflects shrinking antral pool

Follicle stages (LO 4)

Stage	Histology	Endocrine cells	Hormones
Primordial	Oocyte + SINGLE layer SQUAMOUS granulosa	Minimal activity	None (silent)
Primary	CUBOIDAL unilaminar granulosa; zona pellucida begins	Granulosa ACTIVATED (partly FSH-independent)	Low estrogen
Secondary	MULTILAMINAR granulosa + THECA forms	Theca interna + granulosa (gonadotropin-DEPENDENT)	Low androgens + low E₂
Antral	Fluid-filled ANTRUM; theca interna + externa	Mature two-cell unit	↑ E₂, inhibin B, androgens (escalating)
Graafian	~20 mm; oocyte on cumulus stalk	LH-responsive granulosa + theca (late LH-R expression)	PEAK E₂ + inhibin B; some local P late (primes for ovulation)
Corpus luteum	Luteinized theca + granulosa with LIPID DROPLETS (yellow); vascularized	Large luteal (granulosa-derived) + small luteal (theca-derived)	PROGESTERONE (dominant), E₂, inhibin A
Corpus albicans	Fibrous scar — remnant of involuted CL	None (connective tissue only)	None

Dominant follicle selection (LO 4)

FSH rise trigger

Luteal-phase DROP in inhibin A (from involuted CL) removes FSH brake → FSH rises → recruits next cohort of antral follicles

Winner take all

Winner secretes rising E₂ + inhibin B → these suppress FSH → weaker follicles (less FSH-sensitive) lose FSH → undergo ATRESIA

Clomiphene / letrozole

Clomiphene (SERM) blocks hypothalamic ER → removes negative feedback → FSH stays HIGH → multiple follicles escape atresia. Letrozole (AI) lowers E₂ → same FSH rise. Explains ↑ DIZYGOTIC TWINS

PCOS string of pearls

Relatively LOW FSH + excess theca androgens → multiple follicles arrested at antral stage → NO dominant follicle → chronic anovulation → “string of pearls” (>12 small antral follicles on US)

AMH as ovarian reserve (LO 4)

AMH source

SMALL ANTRAL granulosa cells (primary + secondary + early antral). Serum AMH correlates with antral pool size

Low AMH states

(1) Diminished ovarian reserve / POI. (2) Menopause approaching. Also: chemo/radiation damage

High AMH state

PCOS — many arrested small antral follicles. AMH is high despite anovulation

AMH in IVF

Predicts ovarian RESPONSE to stimulation and doses gonadotropins. Also helps with fertility counseling for delayed childbearing

Corpus luteum (LO 4)

Luteinization trigger

LH SURGE triggers it. Granulosa + theca cells HYPERTROPHY, acquire LIPID DROPLETS, become yellow. Blood vessels invade previously avascular follicle → high hormone output

PEI hormones

P = Progesterone (DOMINANT). E = Estradiol. I = Inhibin A. Main 3 CL products

CL lifespan

~12 days without hCG rescue. Then involutes → corpus albicans → P/E₂ fall → endometrium sloughs → MENSES

hCG rescue

Trophoblast-secreted β-hCG binds LH RECEPTOR on CL (shares α with LH + near-identical β). Keeps P output sustained. hCG detectable 8-10 days post-ovulation, doubles every 48 h

Luteoplacental shift

~8-10 weeks gestation. Placental syncytiotrophoblast makes enough P to maintain pregnancy. After this, OOPHORECTOMY tolerated without miscarriage. hCG peaks ~10 weeks then declines

LO 5

ON EXAM — Day 1 = 1st day of bleeding. Ovulation day 14 (~36 h after LH begins). Luteal phase FIXED 14 days. Day-21 P >5-10 ng/mL = ovulatory cycle. BBT rises 0.3-0.5°C after ovulation (P thermogenic). E = GROW; P = PROTECT. Unopposed E → endometrial cancer. Luteoplacental shift 8-10 weeks. OCPs suppress positive feedback

Master cycle figure (LO 5)

Day	Ovarian phase	Uterine phase	Dominant hormone(s)
1-5	Early follicular	Menses (endometrial shedding)	Rising FSH; low everything else
6-13	Late follicular (dominant follicle develops)	Proliferative (endometrium re-grows)	Estradiol (rising); FSH declining
14	OVULATION	Transition (proliferative to secretory)	LH SURGE (~10× baseline) + smaller FSH surge. ~36 h after LH rise
15-28	Luteal phase (CL active)	Secretory (glandular, decidualized)	PROGESTERONE > E₂. Inhibin A rising
28+	CL involution → corpus albicans	Menses again	P + E₂ fall. Inhibin A falls → FSH rises for next cycle

Follicular phase details (LO 5)

FSH rise trigger

Loss of inhibin A from involuted CL (luteal → early follicular) removes FSH brake → FSH rises → recruits new cohort

Late-follicular shift

Dominant follicle secretes escalating E₂ + inhibin B → suppress FSH (atresia of competitors). E₂ crosses surge threshold (~200 pg/mL × 48 h) → imminent positive feedback

Proliferative histology

Straight tubular glands; lengthening spiral arteries; mitotic activity; stratum functionalis re-growth driven by estradiol

LH surge timing

Surge lasts ~24-48 h. OVULATION occurs ~36 h after LH begins rising, ~10-12 h after LH PEAK

Follicle rupture mechanism

Granulosa (LH-R positive) make LOCAL PROGESTERONE → activates proteolytic enzymes (collagenase, plasminogen activators) → wall weakens. Thin-walled “stigma” bulges on surface → ruptures → ovum + cumulus released

Luteal phase details (LO 5)

Peak P day

Day 21-22 (mid-luteal). ~7 days after ovulation

Day-21 P threshold

Day-21 serum P >5-10 ng/mL = CONFIRMS an ovulatory cycle

Secretory histology

Tortuous + sacculated GLANDS; glycogen-rich cells; SUBNUCLEAR VACUOLES appear days 16-18 (“early secretory”); spiral arteries coil; stroma DECIDUALIZES

No 2nd LH surge

PROGESTERONE BLOCKS positive feedback at AVPV hypothalamus + pituitary — even though E₂ still high during luteal phase, P prevents a second surge. Ensures one-ovulation-per-cycle

Menses cause sequence

No pregnancy → CL lacks sustained LH → involutes after ~12 days → P + E₂ FALL → spiral arteries CONSTRICT → endometrial ischemia + cell death → sloughing + menses. Loss of inhibin A allows FSH to rise → next cycle

Estrogen vs progesterone tissue effects (LO 5)

Target	Estrogen	Progesterone
Endometrium	Proliferation (stratum functionalis re-growth)	Secretory differentiation; decidualization; glycogen storage
Myometrium	↑ contractility + ↑ oxytocin receptors	↓ contractility (quiescence) — maintains pregnancy
Cervical mucus	Thin, watery, clear, ferning — sperm-friendly around ovulation	Thick, scant, sticky — sperm-hostile; cervical plug in pregnancy
Vagina	Proliferation; glycogenated; acidic pH via Lactobacillus	Less proliferative; reduced lactobacilli
Breast	DUCTAL growth	ALVEOLAR / lobular development
Bone	Inhibits osteoclasts; closes epiphyses	Minor direct effect
BBT	No significant change	↑ 0.3-0.5°C (thermogenic)
Water / Na	Mild retention (ADH-like)	Diuretic (antagonizes aldo at MR)
Clotting	↑ factors II, VII, IX, X → PROTHROMBOTIC (OCP VTE)	Minor
HPG feedback	BIPHASIC (negative + positive at surge threshold)	NEGATIVE only; BLOCKS positive feedback

Pregnancy & luteoplacental shift (LO 5)

hCG detectability

Detectable ~8-10 days post-ovulation. Doubles every 48 h in normal early pregnancy

Placenta takeover

~8-10 weeks gestation (luteoplacental shift). Placental syncytiotrophoblast makes enough P. After this, oophorectomy tolerated

Estriol source

Fetal adrenal DHEA-S → placental aromatization → ESTRIOL (E₃). Requires both fetus and placenta. Falling estriol = fetal/placental distress

SHBG rise

Driven by high placental ESTROGEN → hepatic SHBG synthesis up. Total T + E₂ rise but free fractions stay normal. Same for CBG + TBG

OCP mechanisms

(1) Steady moderate E₂ + progestin keeps feedback NEGATIVE-ONLY → no surge → no ovulation. (2) Progestin thickens cervical mucus + atrophies endometrium (backup)

Unopposed estrogen cancer

PCOS: chronic anovulation → no CL → no P. Peripheral aromatization makes chronic low-level estrone. Without P to oppose → hyperplasia → adenocarcinoma. Also in obesity, HRT without progestin, estrogen-secreting tumors

LO 6

ON EXAM — Hi-Lo = primary (gonad failed). Lo-Lo = secondary (brain quiet). Hi-Hi (high T ineffective) = receptor defect (AIS). PCOS: LH:FSH >2, string of pearls, IR. Kallmann: hypogonadotropic + anosmia. POI: menopausal labs <40. Menopause: FSH > LH (inhibin loss); estrone dominant. HRT with uterus MUST include progestin

Primary-vs-secondary decoder (LO 6)

Pattern	LH / FSH	E₂ or T	Where's the lesion?
Primary (Hi-Lo)	↑↑ (no negative feedback)	↓ (gonad failed)	Gonad failed — Turner, POI, chemo/radiation, autoimmune, Swyer
Secondary (Lo-Lo)	↓ or inappropriately normal	↓	Hypothalamus/pituitary — Kallmann, FHA, prolactinoma, Sheehan, adenoma
Overproduction	Variable	↑ (or wrong hormone)	Ovary/adrenal tumor, PCOS, CAH
Receptor/enzyme defect	↑ LH (loss of AR feedback)	High but ineffective (high T/E₂, ineffective at target)	End-organ — AIS, 5α-RD

Disorder exam table (LO 6)

Condition	LH / FSH	E₂ / T	Key clue
Turner (45,X)	↑↑ (primary)	↓↓	Short stature, webbed neck, bicuspid AV/coarctation, streak ovaries, horseshoe kidney
Swyer (46,XY SRY−)	↑ (primary)	↓ E₂ AND ↓ T	46,XY female phenotype, streak Y-gonads (remove, gonadoblastoma risk)
POI	↑↑ (primary; FSH >40)	↓	Menopausal labs + amenorrhea BEFORE age 40. Workup: karyotype, fragile X, autoimmune. HRT until ~51
Kallmann	↓ (secondary)	↓	Delayed puberty + ANOSMIA (GnRH + olfactory neurons share embryology)
FHA	↓ (secondary)	↓	Low BMI, stress, over-training. Low leptin → low kisspeptin → low GnRH. Female athlete triad
Prolactinoma	↓ (secondary)	↓	Amenorrhea-galactorrhea + bitemporal hemianopia. PRL very high. Cabergoline
PCOS	LH:FSH >2	↑ free T, ↑ estrone (peripheral aromatization)	Hirsutism, anovulation, string of pearls, IR. Rotterdam 2 of 3
Complete AIS	↑ LH (loss of AR feedback)	↑ T + ↑ E₂ (aromatization)	46,XY phenotypic female, testes inguinal, NO uterus, breasts, sparse hair
5α-RD	Normal or ↑ LH	Normal T, ↓ DHT, ↑ T:DHT	46,XY raised female at birth; virilizes at puberty (“guevedoces”)
21-OH CAH	Normal	↑ 17-OHP, ↑ androgens	46,XX ambiguous external + salt-wasting + normal ovaries/uterus. Newborn screen
Menopause	↑↑ FSH > LH (inhibin loss)	↓↓	Age ~51. Hot flashes, atrophic vagina, osteoporosis. Estrone now dominant

PCOS deep dive (LO 6)

Rotterdam criteria

2 of 3: (1) Oligo/anovulation (oligomenorrhea or amenorrhea). (2) Clinical or biochemical HYPERANDROGENISM (hirsutism, acne, ↑ free T). (3) POLYCYSTIC OVARIES on US (≥12 small antral follicles, “string of pearls”)

LH:FSH >2 mechanism

Fast GnRH pulses favor LH > FSH. High LH stimulates thecal androgens; relatively low FSH means granulosa aromatase underactive → follicles arrest at antral stage → no dominant follicle

Unopposed estrogen source

Peripheral ADIPOSE TISSUE aromatizes androstenedione → estrone. Chronic anovulation means NO CL = NO PROGESTERONE. Chronic low-level E without P → endometrial hyperplasia → cancer

Insulin resistance feedback

Hyperinsulinemia stimulates theca androgen production AND lowers hepatic SHBG → more free T. Self-reinforcing loop. Metformin addresses IR

Ovulation induction drug

LETROZOLE (aromatase inhibitor) — now first-line. Blocks peripheral aromatization → lower E₂ → more FSH. Clomiphene (SERM) is the traditional alternative

Hirsutism drug

SPIRONOLACTONE — AR antagonist (off-target). TERATOGENIC to male fetus → use reliable contraception (combined OCP)

Menopause & HRT (LO 6)

Earliest perimenopause change

Inhibin B falls first (declining follicle pool). Then FSH rises (loss of inhibin). Eventually ovary can't make E₂ → full menopause

FSH > LH mechanism

Loss of ovarian INHIBIN (which selectively suppresses FSH) adds to loss of E₂ negative feedback. Both rise, but FSH rises MORE (lost both brakes)

Postmenopausal estrogen

Peripheral aromatization of adrenal ANDROSTENEDIONE → ESTRONE (E₁) in adipose tissue + bone. Only source. Obesity → more aromatase → ↑ endometrial/breast cancer

HAVOCS

H = Hot flashes / vasomotor. A = Atrophy of vagina. V = Vaginal dryness. O = Osteoporosis. C = Coronary artery disease risk. S = Sleep disturbance, mood, cognitive fuzziness

HRT rule

Uterus INTACT → estrogen + progestin (protects endometrium from unopposed-E hyperplasia/cancer). Post-HYSTERECTOMY → estrogen alone

Timing hypothesis

HRT risk-benefit most favorable when STARTED <60 years OR within 10 years of menopause. Starting late (10+ years post) has increased CV + stroke risk

HRT risks

(1) VTE/stroke (estrogen prothrombotic — ↑ factors II, VII, IX, X). (2) Breast cancer (long-term combined HRT). Also: endometrial cancer if unopposed E in uterus-intact patient

Other clinical patterns (LO 6)

POI treatment

HRT until AVERAGE AGE OF MENOPAUSE (~51) to protect bone + cardiovascular. Higher doses than standard menopause HRT. Fertility counseling

Kallmann symptom

ANOSMIA (or hyposmia). GnRH + olfactory neurons share embryologic migration from olfactory placode. Genes: ANOS1/KAL1, FGFR1, PROK2. Tx: pulsatile GnRH OR exogenous gonadotropins + sex steroids

Female athlete triad

Low energy availability + menstrual dysfunction + low bone mineral density. Management: BEHAVIORAL FIRST (restore weight, reduce training, manage stress). HRT/OCP for bone if persists. Stress fractures at unusual sites = red flag

Prolactinoma treatment

Dopamine agonist — CABERGOLINE (first-line) or bromocriptine. Restores dopamine tone → suppresses PRL. Surgery only for drug resistance or acute mass effect

Hypothyroid menstrual

↑ TRH (low T₄ feedback removal) → TRH stimulates prolactin at pituitary → hyperprolactinemia → inhibits GnRH → menstrual irregularities, galactorrhea. Treat with levothyroxine

LO 1–6 · USMLE Step 1 Style

10 vignettes — answers pre-revealed.

Q1. 16-year-old phenotypically female with primary amenorrhea, normal breasts, sparse axillary/pubic hair, blind-ending vagina. 46,XY. Bilateral inguinal masses. ↑ T, ↑ LH, ↑ E₂. No uterus. Diagnosis?

A. Swyer syndrome
B. 5α-RD deficiency
C. Complete AIS — X-linked AR loss-of-function
D. PMDS
E. 21-OH deficiency

C — Complete AIS.
46,XY with functional Sertoli makes AMH → Müllerian regression (no uterus, blind vagina). Leydig makes T but AR nonfunctional → Wolffian regresses, external defaults female, no pubic hair (AR-dependent). Peripheral AROMATASE converts T → E₂ → ERα drives breast development. AR on X chromosome → X-linked recessive.

Q2. 3-day-old 46,XX infant with ambiguous genitalia, vomiting, hypotension, hyponatremia, hyperkalemia. Elevated 17-OH-progesterone. Diagnosis?

A. Turner
B. 21-OH deficiency CAH
C. 5α-RD
D. CAIS
E. Aromatase deficiency

B — 21-OH deficiency CAH.
Can't make cortisol or aldosterone → substrate shunts to androgens in 46,XX → in-utero virilization. Normal uterus + ovaries. Aldo deficiency → salt-wasting crisis. Elevated 17-OH-progesterone is diagnostic. Emergency: IV hydrocortisone + fluids + electrolytes + later fludrocortisone.

Q3. 46,XY infant born with female-appearing external. Normal testes, vasa deferentia, epididymides, NO uterus. At puberty: phallic growth, muscle, voice deepening. Normal T, LOW DHT, ↑ T:DHT ratio. Enzyme?

A. 17,20-lyase
B. Aromatase
C. 5α-reductase type 2
D. 21-OH
E. 17β-HSD3

C — 5α-RD2 deficiency.
5α-RD2 converts T → DHT in peripheral tissues (genital skin, prostate, hair follicles). No DHT → external masculinization fails in utero → female-appearing at birth. Wolffian (T-dependent, not DHT) preserved. Puberty: rising T partially virilizes externally → “guevedoces.” Labs: normal T, LOW DHT, ↑ T:DHT.

Q4. Two-cell / two-gonadotropin model — correct pairing?

A. Theca expresses aromatase
B. Granulosa expresses 17α-hydroxylase
C. LH → theca → androstenedione; FSH → granulosa → aromatize androstenedione → estrone → 17β-HSD1 → estradiol
D. FSH → theca; LH → granulosa
E. Both cells make E₂ independently

C — LH/theca + FSH/granulosa.
Thecal cells have 17α-OH + 17,20-lyase → androstenedione under LH. LACK aromatase. Granulosa has FSH-driven aromatase but lacks 17α-OH. Androstenedione diffuses theca → granulosa → aromatized to estrone → 17β-HSD1 → estradiol. Mnemonic LAT/FAG.

Q5. Sustained elevation of E₂ >200 pg/mL for ~48 h triggers LH surge. Which population mediates positive feedback, and why can't males mount a surge?

A. Arcuate kisspeptin; males have apoptosed arcuate
B. AVPV kisspeptin; in males, perinatal androgens aromatized to E₂ trigger APOPTOSIS of AVPV neurons
C. PVN GnRH; males lack PVN
D. SON vasopressin; suppressed in males
E. No hypothalamic mediator

B — AVPV kisspeptin; apoptosed perinatally in males.
AVPV (in POA) mediates POSITIVE feedback; sustained high E₂ activates it → GnRH burst → LH surge. Arcuate kisspeptin mediates NEGATIVE feedback + tonic pulses. In males, perinatal androgens aromatized to E₂ in hypothalamus trigger apoptosis of AVPV. Arcuate preserved. Aromatase paradox — actual masculinizing signal is E₂.

Q6. 29-year-old with oligomenorrhea, hirsutism, acne, BMI 34. LH:FSH 2.8, ↑ free T, mildly ↑ DHEA-S, “string of pearls” on US. Why is FREE T elevated despite normal total?

A. Anabolic steroids
B. Adrenal androgen tumor
C. Hyperinsulinemia + obesity suppress hepatic SHBG → raise free T
D. 21-OH deficiency
E. Pregnancy

C — Hyperinsulinemia suppresses SHBG.
PCOS hyperandrogenism has two drivers: (1) ovarian thecal overproduction (LH:FSH >2 + insulin co-stim of theca); (2) hyperinsulinemia + obesity SUPPRESS hepatic SHBG → higher free T fraction. Metformin and weight loss raise SHBG. Rotterdam criteria met.

Q7. 22-year-old distance runner, BMI 17, 10 months amenorrhea, stress fractures, low BMD. LH 1.2, FSH 2.8, E₂ 18 pg/mL. Normal PRL, TSH. Diagnosis + mechanism?

A. POI
B. Prolactinoma
C. FHA — low leptin → low kisspeptin → low GnRH
D. PCOS
E. Kallmann

C — FHA (female athlete triad).
Low energy availability (BMI 17 + training) → LOW LEPTIN → reduced kisspeptin drive → reduced GnRH → Lo-Lo pattern. Triad = low energy + menstrual dysfunction + low BMD. POI would show HIGH FSH/LH; prolactinoma ↑ PRL; PCOS has high LH + androgens; Kallmann has anosmia. Treat with behavioral intervention first.

Q8. 37-year-old woman, 9 months amenorrhea, hot flashes, vaginal dryness. FSH 68, LH 42, E₂ 12, normal TSH/PRL. 45,X/46,XX mosaic. Fragile X premutation positive. Diagnosis + mechanism?

A. Menopause (too young to matter)
B. POI — accelerated follicular atresia
C. Kallmann
D. Turner classic (45,X)
E. CAIS

B — POI.
POI = menopausal labs (FSH >40) + amenorrhea before age 40. Causes include fragile X premutation, Turner mosaic, autoimmune, chemo/radiation, galactosemia, idiopathic. Hi-Lo pattern: loss of ovarian inhibin + E₂ → FSH/LH rise. TX: HRT until ~51 to protect bone + CV. Fertility counseling. Workup: karyotype, fragile X, autoimmune.

Q9. 29-year-old undergoes endometrial biopsy day 22 for infertility. Shows tortuous sacculated glands, glycogen-rich cells, subnuclear vacuoles, decidualized stroma. Dominant hormone?

A. Estradiol
B. FSH
C. Progesterone from the corpus luteum
D. Prolactin
E. hCG

C — Progesterone from the CL.
Day 22 = mid-luteal. SECRETORY phase endometrium (glandular, tortuous, glycogen-rich, decidualized) driven by P from CL. Subnuclear vacuoles days 16-18 (“early secretory”). This biopsy CONFIRMS ovulation (functioning CL). Endometrial biopsy is one way to confirm ovulation; serum day-21 P >5-10 ng/mL is the standard test.

Q10. 58-year-old postmenopausal woman, intact uterus, considering HRT for vasomotor symptoms. Why combined estrogen-progestin rather than estrogen alone?

A. Progestin amplifies vasomotor relief
B. Progestin prevents estrogen VTE
C. Progestin opposes estrogen's proliferative effect on ENDOMETRIUM — reduces hyperplasia + adenocarcinoma risk
D. Progestin required for bone
E. Estrogen alone causes hot flashes

C — Progestin protects endometrium.
Unopposed estrogen drives endometrial proliferation → hyperplasia → adenocarcinoma. Uterus-intact → HRT MUST include progestin. Post-hysterectomy can use estrogen alone. Timing hypothesis: HRT risk-benefit best when started <60 or within 10 years of menopause. VTE + breast CA risks intrinsic to estrogen. Same principle in PCOS (unopposed estrone from aromatase without P).

Endocrinology of the Ovary & Female Reproductive Tract — Answer Key