Built from Reproduction Module 05-06 (LOs 1–6). Close notes. Fill from memory. Reveal only after a genuine attempt.

LO 1

ON EXAM — 6-TIER CASCADE: Chromosomal → Gonadal → Hormonal → Morphological → Secondary sex → Brain/behavior. DEFAULT is FEMALE at every tier — male anatomy needs active testis-secreted hormones (T + AMH). SRY (not the Y chromosome itself) determines sex → SOX9 → Sertoli commitment → testis. Sertoli FIRST (AMH), Leydig SECOND (T). Estrogen closes epiphyses in BOTH sexes. Male brain masculinization is actually estradiol (T aromatized locally; α-fetoprotein protects female fetus). Karyotype variants: Turner (45,X), Klinefelter (47,XXY), de la Chapelle (46,XX SRY+ → male), Swyer (46,XY SRY− → female)

The 6 levels of sexual differentiation (LO 1)

Level	Female-typical	Male-typical	Controls next tier via…
1. Chromosomal
2. Gonadal
3. Hormonal
4. Morphological
5. Secondary sex
6. Brain & behavior

Chromosomal level & SRY (LO 1)

What does SRY stand for, and where on the Y chromosome?

What transcription factor does SRY activate → testis fate?

Without SRY, which default ovarian pathway takes over (3 genes)?

45,X karyotype — name, gonad, and 3 classic features

47,XXY karyotype — name, phenotype, fertility

46,XX SRY+ — name and phenotype

46,XY SRY− — name, phenotype, and why gonads must be removed

Gonadal differentiation — bipotential ridge (LO 1)

Where does the germinal ridge form, and when?

Testis fate: which cell forms FIRST? Which SECOND? Why does order matter?

Ovary fate cells + what stays quiet in the fetal ovary

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

Testosterone (fetal Leydig) — what does it do?

AMH (fetal Sertoli) — what does it do?

DHT (peripheral 5α-RD2) — what does it do?

Secondary sex + brain/behavior tiers (LO 1)

Estrogen and epiphyseal closure — effect in BOTH sexes

Aromatase paradox — what actually masculinizes the male brain?

Why is the female fetal brain protected from maternal/fetal estrogen?

AVPV kisspeptin fate in males — consequence for LH surge ability

Organizational vs activational brain effects — distinguish

LO 2

ON EXAM — T for TUBES (Wolffian/internal), DHT for DONG/PROSTATE/PATTERN HAIR (external), AMH MURDERS MOM (Müllerian regression). SEED = Wolffian (Seminal vesicles, Epididymis, Ejaculatory duct, Ductus deferens). FUTV = Müllerian (Fallopian tubes, Uterus, Top 1/3 vagina, cerVix). Lower 2/3 vagina = urogenital SINUS (endoderm, NOT Müllerian). Fused hypo/failed: hypospadias = urogenital fold fusion failure. CAIS = high T + no uterus + female external + testes inguinal. 5α-RD = normal internal male, female-appearing external, virilize at puberty

Unified hormone requirement (LO 2)

Structure	Hormone required	Source	If missing…
Testis formation
Ovary formation
Müllerian regression
Wolffian stabilization
External virilization
Testis descent

Müllerian vs Wolffian derivatives (LO 2)

Müllerian (paramesonephric) derivatives — mnemonic + 4 structures

Origin of lower 2/3 of vagina (NOT Müllerian)

Wolffian (mesonephric) derivatives — mnemonic + 4 structures

Why does T act paracrine (not systemic) on Wolffian?

External genitalia — bipotential primordia (LO 2)

Primordium	Female (no DHT)	Male (DHT present)	Failure state
Genital tubercle
Urogenital (urethral) folds
Labioscrotal swellings
Urogenital sinus

T vs DHT territories (LO 2)

T controls which tissues/processes? (4)

DHT controls which tissues/processes? (3)

Why does 5α-RD2 matter — what does it add to T (+ where expressed)?

Drugs that block 5α-RD + their clinical uses

Clinical mutations — side-by-side (LO 2)

Condition	Karyotype	Fetal state / labs	External	Internal
Complete AIS
5α-RD type 2 deficiency
21-OH CAH
Persistent Müllerian duct syndrome

KEY RULE: Female phenotype requires ZERO hormones in utero. Male phenotype requires BOTH T/DHT (masculinization) AND AMH (defeminization). A defect anywhere — enzyme, receptor, or hormone — creates a predictable mix-and-match DSD phenotype.

LO 3

ON EXAM — Pulsatile GnRH only (continuous = shutdown, basis of leuprolide depot). Two-cell/two-gonadotropin model: LH→THECA→androgens; FSH→GRANULOSA→aromatase→estradiol. Granulosa LACKS 17α-hydroxylase — can't finish estradiol alone. Feedback: moderate E₂ = NEGATIVE; sustained E₂ >200 pg/mL x 48 h = POSITIVE → LH surge (AVPV kisspeptin). Progesterone BLOCKS positive feedback (no second surge in luteal phase). Kisspeptin: AVPV (positive) + arcuate (negative) — AVPV apoptoses in males. LH/FSH/TSH/hCG share α-subunit → hCG can trigger ovulation and cross-stimulate TSHR

HPG pipeline (LO 3)

Hypothalamus — hormone + pulse frequency + nucleus

Pituitary — which hormones + shared subunit

Ovary — which cells + hormones produced

GnRH details (LO 3)

GnRH size (amino acids) + where released

Pulse frequency in females + who drives it

Slow vs fast GnRH pulse effect on FSH:LH ratio

Continuous GnRH effect + clinical application

Which α-subunit does LH share with 3 other hormones? Consequence?

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

Cell	Tropic hormone	Key enzymes present	Key enzymes MISSING	Secretes
Thecal cell
Granulosa cell

How does androstenedione get from theca to granulosa?

Late-follicular phase change on granulosa (which receptor appears)?

Why does this late receptor change matter at ovulation?

Feedback rules (LO 3)

Signal	Target	Effect	Dominant when…
Moderate estradiol
High sustained E₂ (threshold?)
Progesterone
Inhibin A / B

Kisspeptin — the two populations (LO 3)

AVPV kisspeptin — where, stimulated by what, function

Arcuate kisspeptin — where, regulated by what, function

KISS1R loss-of-function → what clinical syndrome?

KISS1R gain-of-function → what clinical syndrome?

Modulators of the GnRH neuron (LO 3)

Kisspeptin + norepinephrine — effect on GnRH

β-endorphins + GnIH + dopamine — effect on GnRH (when would each dominate?)

Leptin — how it signals energy availability to axis

Glucocorticoid (stress) — 3 levels of inhibition

Prolactin mechanism in amenorrhea-galactorrhea + treatment

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. Theca has LH-R from secondary stage; granulosa has FSH-R throughout + LH-R LATE (Graafian) — this enables surge to trigger ovulation. CL hormones: PEI (Progesterone, Estradiol, Inhibin A). CL LIFESPAN = 12 days without hCG rescue. AMH tracks antral pool — HIGH in PCOS, LOW in POI/menopause. Peak oocyte count ~6–7 million at 20 wk gestation → ~1-2M at birth → ~400K at puberty → ~400-500 ovulated

Primordial pool across lifespan (LO 4)

Time point	Approximate oocyte count
20 weeks gestation
Birth
Puberty / menarche
Lifetime ovulations
Menopause

Meiotic arrest — two pauses (LO 4)

First arrest — stage, when starts, when resolves

Second arrest — stage, when resolves, by what event

Why does advanced maternal age ↑ aneuploidy risk?

Follicle stages — histology + hormones (LO 4)

Stage	Histology	Endocrine cells	Hormones secreted
Primordial
Primary
Secondary (preantral)
Antral (tertiary)
Graafian (preovulatory)
Corpus luteum
Corpus albicans

Dominant follicle selection (LO 4)

What triggers the rising FSH at the start of the cycle?

How does the winner kill off the loser follicles?

Clomiphene / letrozole break this loop how → clinical consequence?

PCOS — why does the string-of-pearls appearance happen?

AMH as ovarian reserve marker (LO 4)

Source of AMH — which cells, which follicle size?

Low AMH — which clinical states (2)?

High AMH — which clinical state + why?

AMH use in IVF workup

Corpus luteum → corpus albicans (LO 4)

What triggers luteinization? What do the cells physically become?

3 main hormones of the CL (mnemonic PEI)

CL lifespan WITHOUT hCG rescue

CL rescue mechanism by hCG (which receptor?)

Luteoplacental shift — when does placenta take over?

LO 5

ON EXAM — Day 1 = 1st day of bleeding. Ovulation day 14 (~36 h after LH begins rising). Luteal phase = FIXED 14 days; cycle variability lives in FOLLICULAR phase. Ovarian cycle (follicular→ovulation→luteal) drives uterine cycle (menses→proliferative→secretory). Day-21 progesterone >5–10 ng/mL confirms ovulation. BBT rises 0.3–0.5°C after ovulation (progesterone thermogenic). Estrogen = GROW (endometrium, breasts); Progesterone = PROTECT (thickens cervical mucus, quiets myometrium, builds glycogen). Unopposed estrogen → endometrial hyperplasia/cancer

Master cycle figure (LO 5)

Day	Ovarian phase	Uterine phase	Dominant hormone(s)
1–5
6–13
14
15–28
28+

Follicular phase details (LO 5)

What triggers the rise in FSH at the start of the cycle?

Late-follicular hormone shift — dominant follicle + E₂ threshold

Proliferative phase endometrium — histologic features

When does the LH surge begin + how long until ovulation?

Mechanism of follicle rupture (local progesterone + enzymes)

Luteal phase details (LO 5)

Day of peak progesterone

Day-21 progesterone threshold that confirms ovulation

Secretory phase endometrium — histology (subnuclear vacuoles when?)

Why no 2nd LH surge despite high E₂ during luteal phase?

What causes menses if no pregnancy? (sequence)

Estrogen vs progesterone tissue effects (LO 5)

Target	Estrogen	Progesterone
Endometrium
Myometrium
Cervical mucus
Vagina
Breast
Bone
Basal body temperature
Water / Na balance
Clotting
HPG feedback

Pregnancy & luteoplacental shift (LO 5)

When is β-hCG first detectable + doubling time

When does placenta take over progesterone production?

Source of fetal-placental estriol (2 organs)

Why does maternal SHBG rise in pregnancy?

Two mechanisms by which combined OCPs prevent pregnancy

Why does unopposed estrogen cause endometrial cancer (e.g., PCOS)?

LO 6

ON EXAM — Hi-Lo (primary) / Lo-Lo (secondary) / Hi-Hi (receptor defect) decoder. Primary: Turner (45,X), Swyer (46,XY SRY−), POI (<40). Secondary: Kallmann (anosmia + hypogonadotropic), FHA (low leptin → low GnRH), prolactinoma. PCOS: LH:FSH > 2, hyperandrogenism, anovulation, insulin resistance, string of pearls. CAIS: 46,XY phenotypic female with testes inguinal, no uterus. 5α-RD: normal internal male, female-appearing at birth, virilize at puberty. 21-OH CAH: virilized 46,XX + salt-wasting. Menopause: FSH > LH (inhibin lost). HRT with uterus MUST include progestin

The primary-vs-secondary decoder (LO 6)

Pattern	LH / FSH	E₂ or T	Where's the lesion?
Primary hypogonadism (Hi-Lo)
Secondary (hypogonadotropic) (Lo-Lo)
Overproduction
Receptor/enzyme defect

Disorder exam table — lock these patterns (LO 6)

Condition	LH / FSH	E₂ / T	Key clue
Turner (45,X)
Swyer (46,XY SRY−)
POI
Kallmann
Functional hypothalamic amenorrhea
Prolactinoma
PCOS
Complete AIS
5α-RD deficiency
21-OH CAH (46,XX)
Menopause

PCOS deep dive (LO 6)

Rotterdam criteria (2 of 3)

Why LH:FSH > 2? (mechanism)

Source of unopposed estrogen → endometrial cancer risk

Insulin resistance feedback on SHBG + theca

First-line ovulation induction drug + mechanism

AR antagonist for hirsutism + caution

Menopause & HRT (LO 6)

Earliest perimenopausal hormone change + why

Why does FSH rise MORE than LH in menopause?

Main remaining estrogen + source after menopause

Menopause symptoms mnemonic (HAVOCS)

HRT rule for uterus intact vs post-hysterectomy

Timing hypothesis for HRT benefit/risk

2 main HRT risks to counsel patient about

Other clinical patterns (LO 6)

POI treatment goal + duration

Kallmann single distinguishing symptom

Female athlete triad — components + management

Prolactinoma first-line treatment + drug name

Hypothyroidism mechanism for menstrual irregularity

LO 1–6 · USMLE Step 1 Style

10 vignettes weighted across LOs.

Q1. A 16-year-old phenotypically female patient presents with primary amenorrhea. Exam shows normal breast development, sparse axillary/pubic hair, and a blind-ending vagina. Karyotype is 46,XY. Bilateral inguinal masses are palpable. Labs: elevated testosterone, elevated LH, elevated estradiol. No uterus on imaging. Which BEST explains this presentation?

A. Swyer syndrome (SRY mutation)
B. 5α-reductase type 2 deficiency
C. Complete androgen insensitivity syndrome (CAIS) — X-linked AR loss-of-function
D. Persistent Müllerian duct syndrome
E. 21-hydroxylase deficiency

C — Complete AIS.
46,XY with functional Sertoli cells makes AMH → Müllerian regression (no uterus, blind vagina). Leydig cells make T but AR is non-functional → Wolffian regresses, external defaults female, no pubic/axillary hair (AR-dependent). Peripheral aromatase converts circulating T → E₂ → ERα drives breast development. AR on the X chromosome → X-linked recessive inheritance. Testes are usually in the inguinal canal.

Q2. A 3-day-old 46,XX infant presents with ambiguous genitalia (clitoromegaly, partial labial fusion), vomiting, hypotension, hyponatremia, and hyperkalemia. Newborn screen returns elevated 17-hydroxyprogesterone. The MOST likely diagnosis is:

A. Turner syndrome
B. 21-hydroxylase deficiency CAH
C. 5α-reductase deficiency
D. Complete AIS
E. Aromatase deficiency

B — 21-OH deficiency CAH.
Can't make cortisol or aldosterone → substrate shunts to androgens (DHEA, androstenedione, T) in a 46,XX fetus → in-utero virilization of external genitalia. Normal uterus and ovaries (gonadal T not required). Aldosterone deficiency → salt-wasting crisis (hypotension, hyponatremia, hyperkalemia). Elevated 17-OH-progesterone is diagnostic. Medical emergency — IV hydrocortisone + fluids + electrolyte correction + later fludrocortisone.

Q3. A 46,XY infant is born with female-appearing external genitalia. Internal exam reveals normal testes, vasa deferentia, and epididymides, but no uterus. At puberty, the patient develops phallic growth, muscle mass, and deepening voice. Labs: normal testosterone, LOW DHT, elevated testosterone-to-DHT ratio. Enzyme deficient?

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

C — 5α-reductase type 2 deficiency.
5α-RD2 converts T → DHT in peripheral tissues (genital skin, prostate, hair follicles). Without DHT, external genital masculinization fails in utero → female-appearing external at birth. Wolffian ducts (T-dependent, not DHT) develop normally → normal internal male. At PUBERTY, rising testosterone partially overcomes the DHT block → late virilization (“guevedoces” — “penis at 12”). Labs: normal T, LOW DHT, elevated T:DHT ratio.

Q4. In the ovarian two-cell / two-gonadotropin model, which statement is CORRECT?

A. Thecal cells express aromatase and produce estradiol
B. Granulosa cells express 17α-hydroxylase and produce androgens
C. LH stimulates thecal cells to produce androstenedione; FSH stimulates granulosa cells, which aromatize androstenedione to estrone → 17β-HSD1 → estradiol
D. FSH stimulates theca; LH stimulates granulosa
E. Both cells make estradiol independently

C — LH/theca & FSH/granulosa.
Thecal cells have 17α-hydroxylase + 17,20-lyase → produce androstenedione under LH. They LACK aromatase. Granulosa cells have FSH-driven aromatase (CYP19A1) but lack 17α-hydroxylase. Androstenedione diffuses from theca to granulosa → aromatized to estrone → 17β-HSD1 converts to 17β-estradiol. Mnemonic: LAT (LH-Androgens-Theca) / FAG (FSH-Aromatase-Granulosa).

Q5. During the normal menstrual cycle, sustained elevation of estradiol above ~200 pg/mL for approximately 48 hours triggers an LH surge. Which hypothalamic population mediates this positive feedback, and why can't adult males mount an LH surge?

A. Arcuate kisspeptin; males have apoptosed arcuate neurons
B. AVPV kisspeptin (positive feedback); in males, perinatal androgens are aromatized to estradiol locally, which triggers APOPTOSIS of AVPV kisspeptin neurons
C. Paraventricular GnRH; males lack PVN neurons
D. SON vasopressin; suppressed in males
E. No hypothalamic mediator — surge is pituitary-intrinsic

B — AVPV kisspeptin; apoptosed perinatally in males.
Two kisspeptin populations: AVPV (anteroventral periventricular, within the POA) mediates POSITIVE feedback; sustained high E₂ activates it → GnRH burst → LH surge. Arcuate kisspeptin mediates NEGATIVE feedback and tonic pulses. In males, perinatal androgens are locally aromatized to estradiol in the hypothalamus → triggers apoptosis of AVPV kisspeptin neurons. Arcuate population preserved. Males retain negative feedback but cannot produce a surge. This is the “aromatase paradox.”

Q6. A 29-year-old woman with normal cycles until 3 months ago presents with oligomenorrhea, hirsutism, acne, and a BMI of 34. Labs: LH:FSH ratio 2.8, elevated free testosterone, mildly elevated DHEA-S, and transvaginal ultrasound shows bilateral “string of pearls” follicles. Which mechanism BEST explains her elevated FREE testosterone despite normal total?

A. Exogenous anabolic steroids
B. Adrenal androgen-secreting tumor
C. Hyperinsulinemia and obesity suppress hepatic SHBG synthesis → raise free T
D. 21-hydroxylase deficiency
E. Pregnancy

C — Hyperinsulinemia suppresses SHBG.
PCOS hyperandrogenism has two drivers: (1) ovarian thecal overproduction of androgens (LH:FSH > 2 + insulin co-stimulation of theca); (2) hyperinsulinemia + obesity SUPPRESS hepatic SHBG synthesis → higher free testosterone fraction for the same total. Metformin and weight loss raise SHBG and reduce clinical hyperandrogenism. Classic Rotterdam criteria met: oligomenorrhea + hyperandrogenism + polycystic ovaries.

Q7. A 22-year-old elite distance runner with BMI 17 presents with secondary amenorrhea of 10 months duration, frequent stress fractures, and low bone mineral density. Labs: LH 1.2, FSH 2.8, estradiol 18 pg/mL. Prolactin and TSH normal. Pregnancy test negative. MOST likely diagnosis and mechanism?

A. Primary ovarian insufficiency (POI)
B. Prolactinoma
C. Functional hypothalamic amenorrhea (FHA) — low leptin → low kisspeptin → low GnRH
D. Polycystic ovary syndrome
E. Kallmann syndrome

C — FHA (female athlete triad).
Low energy availability (BMI 17 + excessive training) → low leptin → reduced kisspeptin drive → reduced GnRH pulse frequency/amplitude → Lo-Lo pattern (low LH/FSH + low E₂). Female athlete triad = low energy availability + menstrual dysfunction + low bone mineral density. POI would show HIGH FSH/LH; prolactinoma would elevate prolactin; PCOS would have high LH + androgens; Kallmann would include anosmia and congenital delayed puberty. Treat with behavioral intervention first (restore energy + reduce training); HRT/OCP for bone if persists.

Q8. A 37-year-old woman presents with 9 months of secondary amenorrhea, hot flashes, and vaginal dryness. Labs: FSH 68, LH 42, estradiol 12 pg/mL, normal TSH, normal prolactin, negative pregnancy test. Karyotype shows 45,X/46,XX mosaicism. Fragile X premutation positive. What is the diagnosis and mechanism?

A. Menopause (too young to matter)
B. Primary ovarian insufficiency (POI) — accelerated follicular atresia
C. Kallmann syndrome
D. Turner syndrome classic (45,X)
E. Complete AIS

B — Primary Ovarian Insufficiency.
POI = menopausal labs (FSH > 40) + amenorrhea before age 40. Causes include Fragile X premutation, Turner mosaic, autoimmune oophoritis, chemo/radiation, galactosemia, idiopathic. Hi-Lo pattern: loss of ovarian inhibin + estradiol → negative feedback gone → FSH/LH rise. Treatment: HRT until average age of menopause (~51) to protect bone + cardiovascular health. Fertility counseling: spontaneous conception rare but possible. Work up karyotype, fragile X, autoimmune screen.

Q9. A healthy 29-year-old woman undergoes endometrial biopsy on day 22 of her menstrual cycle for evaluation of infertility. The specimen shows tortuous sacculated glands, glycogen-rich cells, and subnuclear vacuoles with decidualized stroma. The dominant hormone driving this appearance is:

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

C — Progesterone from the corpus luteum.
Day 22 = mid-luteal phase. The secretory phase endometrium (glandular, tortuous, glycogen-rich, decidualized stroma) is driven by progesterone from the CL. Subnuclear vacuoles classically appear days 16–18 (“early secretory”). This biopsy finding CONFIRMS that the patient ovulated (she has a functioning CL). Endometrial biopsy is one way to confirm ovulation in an infertility workup; serum day-21 progesterone >5-10 ng/mL is the standard test.

Q10. A 58-year-old postmenopausal woman with an intact uterus is considering HRT for persistent vasomotor symptoms. Her physician recommends combined estrogen-progestin rather than estrogen alone. The BEST reason is:

A. Progestin amplifies estrogen's vasomotor relief
B. Progestin prevents estrogen-induced VTE
C. Progestin opposes estrogen's proliferative effect on the ENDOMETRIUM — reducing endometrial hyperplasia and adenocarcinoma risk
D. Progestin is required for bone preservation
E. Estrogen alone causes hot flashes

C — Progestin protects the endometrium.
Unopposed estrogen drives endometrial proliferation → hyperplasia → adenocarcinoma. In a woman with a uterus, HRT MUST include a progestin. Post-hysterectomy patients can use estrogen alone. Timing hypothesis: HRT risk-benefit most favorable when started <60 years old or within 10 years of menopause. VTE and breast CA risks are intrinsic to estrogen (not mitigated by progestin). Same principle underlies endometrial cancer risk in PCOS (unopposed low-level estrone from adipose aromatase without progesterone).

Endocrinology of the Ovary & Female Reproductive Tract — Active Recall