Built from Endocrine Lecture 05 (LOs 1–6). Close notes. Fill from memory. Reveal only after a genuine attempt.

LO 1

ON EXAM — C21 (pregnanes): progestins + corticoids — retain full 2-carbon side chain. C19 (androstanes): 17,20-LYASE drops the C20+C21 side chain. C18 (estranes): AROMATASE (CYP19) removes C19 methyl + aromatizes A-ring → unique aromatic phenolic A-ring. Key bridges: 17,20-lyase (C21 → C19, the sex steroid fork) and aromatase (C19 → C18, androgen to estrogen)

Steroid classes by carbon count (LO 1)

Carbons	Class name	Examples	Key structural feature / conversion
C27
C21
C19
C18

The two critical conversion enzymes (LO 1)

Enzyme	Reaction (class → class)	What it removes / changes	Where it's expressed	Clinical target / deficiency
17,20-lyase (activity of CYP17)
Aromatase (CYP19)
5α-reductase
17β-HSD (two isoforms)

Structural signatures — what makes each class unique (LO 1)

Unique feature of all ESTROGENS (not seen in any other steroid)

What does "aromatizing the A-ring" actually mean?

Which pregnane serves as the "gateway" to all three sex-steroid classes?

17,20-lyase deficiency — what's lost, what's preserved?

Aromatase deficiency in 46,XX — clinical phenotype

LO 2

ON EXAM — ANDROGEN ladder (AR affinity): DHT > TESTOSTERONE >> androstenedione > DHEA/DHEA-S. ESTROGEN ladder (ER affinity): 17β-ESTRADIOL (E₂) > estrone (E₁) > estriol (E₃). Estradiol dominates reproductive years; estrone postmenopause; estriol pregnancy. Receptors: AR = 1 gene (X-LINKED), ER = 2 genes (ERα + ERβ), PR = 1 gene — all cytoplasmic Type I nuclear receptors + membrane GPER for rapid non-genomic effects

Androgen potency ladder (LO 2)

Androgen	AR affinity	Role / where it acts	Key clinical relevance
DHT (dihydrotestosterone)
Testosterone
Androstenedione
DHEA / DHEA-S

Estrogen potency ladder + life stage dominance (LO 2)

Estrogen	ER affinity	Dominant life stage	Principal source
17β-Estradiol (E₂)
Estrone (E₁)
Estriol (E₃)

Sex steroid receptors at a glance (LO 2)

Receptor	Gene count / location	Tissue distribution	Key clinical fact
AR (androgen receptor)
ERα (ESR1)
ERβ (ESR2)
PR (progesterone receptor)
Membrane receptors (GPER / GPR30 + others)

AR is on the X CHROMOSOME → Complete Androgen Insensitivity Syndrome (CAIS) shows X-linked recessive inheritance: 46,XY phenotypic female with testes, breasts (aromatization), but NO pubic/axillary hair, blind-ending vagina, primary amenorrhea.

LO 3

ON EXAM — ANDROGEN sources: Leydig cells (testis — testosterone, LH-driven); thecal cells (ovary — androstenedione, LH-driven); zona reticularis (adrenal — DHEA/DHEA-S, ACTH-driven). DHT is NOT directly secreted — made PERIPHERALLY by 5α-reductase. ESTROGEN sources: granulosa cells (ovary, FSH-driven aromatase — TWO-CELL MODEL); placenta (estriol in pregnancy); peripheral aromatase (adipose, bone, skin, brain — dominant postmenopause estrone source). Two-cell/two-gonadotropin: LH → theca → androstenedione → diffuses → FSH → granulosa aromatase → estradiol

Source summary — where each hormone is made (LO 3)

Hormone	Gonadal source	Adrenal source	Peripheral source
Testosterone
DHT
Androstenedione
DHEA / DHEA-S
17β-Estradiol
Estrone
Estriol
Progesterone

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

Which hormone acts on THECAL cells — and what do they produce?

Which hormone acts on GRANULOSA cells — and what do they produce?

Why don't thecal cells make estrogen themselves?

Enzyme on thecal cells that makes androstenedione vs enzyme on granulosa that finishes estradiol

What happens at mid-cycle that triggers ovulation?

Peripheral conversion enzymes (LO 3)

Enzyme	Expressed where	Reaction	Clinical hook
5α-reductase
Aromatase (CYP19)
17β-HSD3 (androgenic)
17β-HSD1 (estrogenic)

Placenta and lifetime hormone shifts (LO 3)

Why placenta needs fetal adrenal DHEA-S to make estriol (what enzyme is placenta missing?)

Why falling estriol in late pregnancy = worrisome sign

Postmenopausal dominant estrogen + how it's made

Why OBESITY raises postmenopausal estrogen (and cancer risk)

PCOS — which two mechanisms drive hyperandrogenism?

LO 4

ON EXAM — Testosterone (Leydig cell): cholesterol → pregnenolone (desmolase) → 17-OH-pregnenolone (17α-hyd) → DHEA (17,20-lyase) → androstenedione (3β-HSD) → testosterone (17β-HSD3). Peripheral: T → DHT (5α-reductase in skin/prostate/external genitalia/hair follicles); T → estradiol (aromatase). Ovarian two-cell: theca → androstenedione → granulosa aromatase → estrone → (17β-HSD1) → estradiol. Deficiencies: 5α-reductase (46,XY ambiguous at birth → virilize at puberty); 17β-HSD3 (similar picture); aromatase (tall stature + virilization)

Testosterone biosynthesis — Leydig cell pathway (LO 4)

Step	Substrate	Product
1	Cholesterol	Pregnenolone
2	Pregnenolone	17-OH-Pregnenolone
3	17-OH-Pregnenolone	DHEA
4	DHEA	Androstenedione
5	Androstenedione	Testosterone

Peripheral conversions of testosterone (LO 4)

Substrate	Enzyme	Product	Importance
Testosterone		DHT
Testosterone		17β-Estradiol

Ovarian estrogen biosynthesis — two-cell model (LO 4)

Cell	Stimulated by	Enzyme activity	Product
Thecal cell
Granulosa cell (step 1: aromatize)
Granulosa cell (step 2: reduce to E₂)

Critical sex-steroid enzymes — deficiency table (LO 4)

Enzyme	Reaction	Location	Deficiency phenotype
17,20-lyase
17β-HSD3
5α-reductase
Aromatase (CYP19)

5α-REDUCTASE DEFICIENCY: 46,XY infant with ambiguous / female-appearing external genitalia AT BIRTH (no DHT for external virilization), but VIRILIZES AT PUBERTY as rising testosterone drives late masculinization. Classic "guevedoces" phenotype. Normal testosterone, LOW DHT, elevated T:DHT ratio.

Pharmacologic pathway modulators (LO 4)

Finasteride / dutasteride — enzyme blocked, clinical use

Anastrozole, letrozole — enzyme blocked, clinical use, population used in

Exemestane — what's different about it (mechanism)

Why are aromatase inhibitors NOT effective in premenopausal women?

LO 5

ON EXAM — SHBG is the PRIMARY sex steroid carrier (testosterone > DHT > estradiol affinity). Testosterone distribution: ~60% SHBG, ~38% albumin, ~2% FREE. Estradiol: ~60% SHBG, ~20% albumin, ~20% FREE. Half-lives all SHORT: testosterone ~1 h, estradiol <20 min, progesterone ~5 MIN (shortest). DHEA-S = longest at 7–10 h (adrenal androgen reservoir). SHBG regulation: ↑ by estrogen/pregnancy/OCPs/hyperthyroid/cirrhosis/anorexia; ↓ by androgens/obesity/insulin/PCOS/hypothyroid. Only FREE hormone is active. Inactivation: liver glucuronide/sulfate → kidney. Oral testosterone has extensive first-pass metabolism

Circulation — carriers, free fraction, half-life (LO 5)

Hormone	Primary carrier(s)	% free	Half-life	Pearl
Testosterone
DHT
Androstenedione
DHEA-S
17β-Estradiol
Estrone / estriol
Progesterone

SHBG regulation — who raises it, who lowers it (LO 5)

Effect	Direction	Clinical consequence
Estrogen (pregnancy, OCPs)
Hyperthyroidism
Cirrhosis
Anorexia / malnutrition
Aging (in men)
Androgens (exogenous, endogenous excess)
Obesity / hyperinsulinemia (PCOS, T2DM)
Hypothyroidism

Inactivation and clearance (LO 5)

Principal inactivation step in the liver

Estradiol → weaker estrogens: name the enzymes & direction

Why can't testosterone be given orally with good efficacy?

Preferred routes for testosterone replacement

How does cirrhosis alter sex steroid balance (gynecomastia, spider angiomas)?

LO 6

ON EXAM — AR, ER, PR are Type I nuclear receptors: cytoplasmic + HSP90 chaperoned at rest → ligand binds → HSP dissociates → dimerization → nuclear translocation → HRE binding (ARE/ERE/PRE). ERα (ESR1) dominant in breast/uterus/bone/liver. ERβ (ESR2) dominant in prostate/ovary/CNS/vasculature. Membrane receptors (GPER for estrogen; mPR for progesterone) mediate rapid non-genomic effects (seconds–minutes). SERMs (tamoxifen, raloxifene, clomiphene) have tissue-selective agonist/antagonist activity. Aromatase inhibitors, anti-androgens, 5α-reductase inhibitors, mifepristone round out the pharmacology

Canonical Type I nuclear receptor mechanism (LO 6)

Step	What happens
1. Resting state
2. Ligand entry
3. Chaperone release
4. Dimerization + translocation
5. DNA binding
6. Timescale of genomic effect
7. Non-genomic mechanism (membrane)

ERα vs ERβ tissue distribution (LO 6)

ERα (ESR1) — where dominant + principal effects

ERβ (ESR2) — where dominant + principal effects

Why do SERMs have tissue-specific agonist / antagonist profiles?

SERMs (selective estrogen receptor modulators) (LO 6)

SERM	Breast	Endometrium	Bone	Use case
Tamoxifen
Raloxifene
Clomiphene

Other sex steroid pharmacology (LO 6)

Anastrozole / letrozole / exemestane — class + target population

Flutamide / bicalutamide / enzalutamide — class + target

Finasteride / dutasteride — class + uses + key teratogenicity warning

Spironolactone — off-target effect + clinical applications

Mifepristone — receptors targeted + uses

Leuprolide (continuous) — MOA + uses

Clinical syndromes (LO 6)

Complete Androgen Insensitivity Syndrome (CAIS) — genetics + key features

Why do CAIS patients have breasts and female external genitalia despite testes?

Why do CAIS patients lack pubic/axillary hair?

5α-reductase deficiency — birth presentation vs puberty presentation

Tamoxifen side effects to remember (2 key ones)

LO 1–6 · USMLE Step 1 Style

10 questions — weighted across all LOs.

Q1. A researcher is asked to rank androgens by AR affinity. Which ordering is CORRECT?

A. Androstenedione > DHT > testosterone > DHEA
B. DHT > testosterone >> androstenedione > DHEA
C. Testosterone > DHT > DHEA > androstenedione
D. DHEA > DHEA-S > testosterone > DHT
E. All have equal AR affinity

B — DHT > testosterone >> androstenedione > DHEA.
DHT has 2–5× the AR affinity of testosterone. Androstenedione and DHEA are WEAK androgens that primarily serve as peripheral precursors (converted to more potent androgens in target tissues). This is why 5α-reductase inhibition (finasteride) produces clinically meaningful anti-androgenic effects in DHT-dependent tissues like scalp (baldness) and prostate (BPH).

Q2. A 16-year-old phenotypically female patient presents with primary amenorrhea. Exam: normal breast development, sparse axillary/pubic hair, blind-ending vagina. Karyotype is 46,XY; bilateral inguinal masses are palpable. Which BEST explains her presentation?

A. Kallmann syndrome
B. 5α-reductase deficiency
C. Complete androgen insensitivity syndrome (CAIS) — X-linked loss-of-function AR mutation
D. Turner syndrome
E. Müllerian agenesis (MRKH)

C — CAIS (complete AIS).
46,XY with functional Sertoli cells makes MIS → Müllerian regression (no uterus, blind vagina). Leydig cells make testosterone, but AR is non-functional → no AR signaling → Wolffian structures regress, external genitalia default to FEMALE. Breasts develop because peripheral AROMATASE converts circulating testosterone to estradiol → ERα drives breast growth. Pubic/axillary hair is SPARSE because those are AR-dependent tissues. AR is on the X chromosome → X-LINKED recessive inheritance.

Q3. A 3-week-old 46,XY infant born with ambiguous genitalia (clitoromegaly, labioscrotal fusion) has normal testosterone, LOW DHT, and an elevated testosterone-to-DHT ratio. The mass is subsequently raised female but virilizes at puberty with deepening voice, phallic growth, and muscle mass. Which enzyme is deficient?

A. 17,20-lyase
B. 17β-HSD3
C. Aromatase (CYP19)
D. 5α-reductase
E. 21-hydroxylase

D — 5α-reductase deficiency.
5α-reductase converts testosterone to DHT in peripheral tissues (skin, prostate, external genitalia). Without DHT, external genital masculinization fails IN UTERO → ambiguous / female-appearing genitalia at birth. But Wolffian ducts (which need only testosterone, not DHT) form normally. AT PUBERTY, rising testosterone overcomes the DHT deficit and drives late virilization — the “guevedoces” phenotype. Lab: normal T, LOW DHT, HIGH T:DHT ratio.

Q4. In the ovary, the “two-cell / two-gonadotropin” model describes coordinated steroidogenesis between thecal and granulosa cells. Which of the following correctly pairs the cell, its gonadotropin, and its product?

A. Thecal cell — FSH — aromatase → estradiol
B. Granulosa cell — LH — androstenedione
C. Thecal cell — LH — androstenedione; granulosa cell — FSH — aromatase → estrone → (17β-HSD1) → estradiol
D. Thecal cell — FSH — progesterone; granulosa cell — LH — testosterone
E. Both cells are FSH-driven

C — LH drives theca (androstenedione); FSH drives granulosa (aromatase → estrone → estradiol).
Thecal cells lack aromatase, so they can't make estrogens themselves — but LH (Gs-cAMP) stimulates their androgen output. Androstenedione diffuses into granulosa cells, where FSH-driven aromatase converts it to estrone, and 17β-HSD1 reduces estrone to 17β-estradiol. This coordinated 2-cell / 2-gonadotropin dance is the foundation of menstrual cycle physiology.

Q5. A 58-year-old postmenopausal woman is diagnosed with ER+ invasive ductal breast carcinoma. Despite menopause, her tumor growth is fueled by low-level estrogen. Which of the following is the PRIMARY source of her circulating estrogen?

A. Ovarian granulosa cells (remaining follicles)
B. Adrenal cortex directly secreting estradiol
C. Peripheral aromatization of adrenal ANDROSTENEDIONE to ESTRONE in adipose tissue
D. Placental estriol
E. Liver synthesis from cholesterol

C — Peripheral aromatization of androstenedione to estrone in adipose.
After menopause, ovarian follicles are depleted and granulosa-cell estradiol production stops. The dominant postmenopausal estrogen is estrone, produced when adrenal androstenedione is aromatized by peripheral aromatase in adipose tissue (and bone, skin, brain). Obesity RAISES postmenopausal estrone → endometrial hyperplasia / cancer risk. This is why aromatase inhibitors (anastrozole, letrozole, exemestane) are first-line for postmenopausal ER+ breast cancer — they target the peripheral production step.

Q6. A 28-year-old woman with PCOS has hirsutism, oligomenorrhea, acne, and a BMI of 33. Her free testosterone is elevated, but total testosterone is only at the upper limit of normal. Which mechanism BEST explains the elevated free testosterone?

A. Adrenal androgen tumor
B. HYPERINSULINEMIA and obesity suppress hepatic SHBG synthesis, raising the free fraction
C. Hepatic failure with markedly elevated SHBG
D. CAH with 17α-hydroxylase deficiency
E. Exogenous testosterone use

B — Hyperinsulinemia and obesity LOWER SHBG.
In PCOS, two pathways drive hyperandrogenism: (1) ovarian thecal overproduction of androgens (LH-driven), and (2) hyperinsulinemia + obesity both SUPPRESS hepatic SHBG synthesis → more FREE testosterone for the same total. Metformin and weight loss raise SHBG and mitigate clinical hyperandrogenism. Conversely, pregnancy/OCPs/hyperthyroidism RAISE SHBG.

Q7. A postmenopausal woman is started on tamoxifen for adjuvant therapy of ER+ breast cancer. Which of the following is an expected EFFECT of this SERM?

A. Estrogen agonist in breast (blocks tumor)
B. Estrogen antagonist in breast (blocks tumor) + AGONIST in endometrium (↑ endometrial cancer risk) + agonist in bone (maintains bone density)
C. Antagonist in all tissues — universal estrogen block
D. Aromatase inhibitor
E. PR antagonist

B — Tamoxifen: antagonist in breast; agonist in endometrium + bone.
SERMs are tissue-selective because of the differential recruitment of coactivators and corepressors in different tissues (plus ERα/ERβ ratios). Tamoxifen BLOCKS ER signaling in breast (tumor suppression) but STIMULATES ER in endometrium (↑ endometrial hyperplasia/cancer risk) and bone (maintains bone density). Also ↑ venous thromboembolism risk. Raloxifene, in contrast, is antagonist in breast AND endometrium but agonist in bone — used for osteoporosis + breast cancer prevention without endometrial risk.

Q8. A 35-year-old woman with anovulatory PCOS wants to conceive. Her gynecologist prescribes clomiphene for ovulation induction. Which of the following BEST describes clomiphene's mechanism?

A. Direct stimulation of ovarian follicles
B. Estrogen agonist at the hypothalamus
C. ER ANTAGONIST at the hypothalamus → removes estrogen's negative feedback → ↑ GnRH pulsatility → ↑ LH/FSH → ovulation
D. Progesterone receptor agonist
E. Aromatase inhibitor

C — Clomiphene is an ER antagonist at the hypothalamus.
Clomiphene blocks estrogen feedback at the hypothalamic ER → the hypothalamus “thinks” estrogen is low → increases GnRH pulse frequency/amplitude → ↑ LH/FSH from pituitary → follicle recruitment and ovulation. First-line for ovulatory induction in PCOS. Letrozole (aromatase inhibitor) is now also commonly used off-label because it produces similar hypothalamic effects without anti-estrogen endometrial effects.

Q9. A pregnant woman has markedly elevated TOTAL testosterone on routine labs, but normal FREE testosterone and no clinical signs of hyperandrogenism. Which of the following BEST explains her lab finding?

A. Luteoma of pregnancy secreting testosterone
B. Estrogen-driven INCREASE in hepatic SHBG synthesis raises total but not free testosterone
C. Placental aromatase failure
D. PCOS relapse
E. Androgen-producing adrenal tumor

B — Pregnancy estrogen ↑ SHBG.
Pregnancy dramatically raises estrogen → hepatic SHBG synthesis is up-regulated. Total testosterone rises because more is bound to SHBG, but the biologically active FREE testosterone remains in normal range (HPG axis defends it). Same principle applies to CBG (total cortisol up, free normal) and TBG (total T₄ up, free normal) during pregnancy — all driven by the same estrogen-hepatic binding-globulin effect. Don't misinterpret an elevated total as a hyperandrogen state.

Q10. A 32-year-old man with prostate cancer is started on flutamide. Which of the following BEST describes its mechanism of action?

A. 5α-reductase inhibitor → ↓ DHT
B. Aromatase inhibitor → ↓ estrogens
C. AR antagonist → blocks androgen action at the receptor
D. GnRH agonist → chemical castration
E. PR antagonist

C — Flutamide is an AR antagonist.
Flutamide, bicalutamide, and enzalutamide are nonsteroidal AR antagonists used for prostate cancer (often combined with GnRH agonist leuprolide to produce combined androgen blockade). They bind the androgen receptor and prevent testosterone/DHT from activating it. Side effects include gynecomastia (from unopposed estradiol signaling) and hepatotoxicity (especially flutamide). Contrast: 5α-reductase inhibitors (finasteride/dutasteride) block DHT synthesis; aromatase inhibitors block estrogen synthesis; leuprolide continuous administration desensitizes GnRH receptors → ↓ LH/FSH → ↓ testosterone.

Sex Steroid Synthesis & Action — Active Recall