Deficiency: 46,XY ambiguous at birth, virilize at puberty. Finasteride/dutasteride for BPH + baldness
17β-HSD (two isoforms)
17β-HSD3: androstenedione → T. 17β-HSD1: estrone → estradiol
Reduces C-17 ketone to 17β-OH
17β-HSD3 in Leydig; 17β-HSD1 in granulosa + peripheral
17β-HSD3 deficiency: 46,XY ambiguous at birth, partial virilization at puberty
Structural signatures (LO 1)
AROMATIC (benzene) A-ring with 3-OH phenol. No other steroid has this — reflects loss of C-19 methyl + aromatization
Removing C-19 angular methyl + introducing 3 double bonds in A-ring → fully aromatic benzene ring. 3-oxo converted to 3-OH phenol. Catalyzed by aromatase (CYP19)
Pregnenolone (and Δ4 form progesterone) — enters mineralocorticoid, glucocorticoid, and sex steroid pathways
Blocks androgen + estrogen synthesis (estrogens need C19 androgen substrate). Corticoids preserved (progesterone pathway intact). Sexual infantilism without virilization
Fetal androgens not converted to estrogens → virilization in utero (ambiguous genitalia at birth); postnatally: tall stature (no estrogen to close epiphyses), primary amenorrhea, polycystic ovaries, osteopenia
LO 2
ON EXAM — AR ladder: DHT > T >> androstenedione > DHEA. ER ladder: E2 > E1 > E3. E2 = reproductive, E1 = postmenopause, E3 = pregnancy. Receptors: AR 1 gene X-LINKED, ER 2 genes (α+β), PR 1 gene — all Type I nuclear + membrane variants
Androgen potency ladder (LO 2)
Androgen
AR affinity
Role
Clinical relevance
DHT
HIGHEST — 2-5× testosterone
Male external genital differentiation, prostate growth, facial/body hair, scalp balding, voice deepening. Greater AR affinity + slower dissociation
Finasteride/dutasteride (5α-red inhibitors) lower DHT for BPH + male-pattern baldness. 5α-reductase deficiency → 46,XY ambiguous at birth → virilize at puberty
Testosterone
HIGH — primary circulating androgen
Main blood androgen; precursor to DHT (5α-red) and E2 (aromatase). Wolffian development, spermatogenesis, muscle, libido
Used for hypogonadism (IM, transdermal, implant). Anabolic steroid abuse → testicular atrophy
Androstenedione
WEAK
Peripheral precursor; main ovarian thecal androgen; converted to T (17β-HSD3) or estrone (aromatase)
Elevated in CAH (21-OH, 11β-OH), PCOS, adrenal androgen tumors
DHEA / DHEA-S
VERY WEAK
Reservoir; peripherally converted to active androgens/estrogens. DHEA-S sulfated by SULT2A1 — most abundant circulating steroid
DHEA-S preferred lab for adrenal androgen excess (stable, long half-life). Age-related decline = adrenopause
Estrogen potency + life-stage dominance (LO 2)
Estrogen
ER affinity
Dominant life stage
Principal source
17β-Estradiol (E2)
HIGHEST
REPRODUCTIVE years
Ovarian granulosa cells (aromatase on thecal androstenedione); peripheral aromatase contributes
Estrone (E1)
INTERMEDIATE
POSTMENOPAUSE
Peripheral aromatization of adrenal androstenedione in adipose, bone — obesity ↑ postmenopausal estrone + endometrial CA risk
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 — Androgens: Leydig (testis, LH-driven), thecal (ovary, LH-driven), zona reticularis (ACTH-driven). DHT made PERIPHERALLY by 5α-reductase — not secreted. Estrogens: granulosa (two-cell model, FSH-driven aromatase), placenta (E3), peripheral aromatase (E1 postmenopause). Two-cell: LH → theca → androstenedione → granulosa (FSH) → aromatase → estrone → (17β-HSD1) → estradiol
Source summary (LO 3)
Hormone
Gonadal source
Adrenal source
Peripheral source
Testosterone
LEYDIG CELLS (testis) — primary in males; LH-driven (Gs-cAMP)
Minor (via DHEA/androstenedione conversion)
Peripheral conversion of androstenedione by 17β-HSD in liver, skin, fat — significant in females
DHT
NOT made directly
NOT made
PERIPHERAL conversion of T by 5α-reductase in skin, prostate, external genitalia, hair follicles
Androstenedione
THECAL cells (ovary) — primary in females, LH-driven; minor testicular
Zona reticularis (along with DHEA/DHEA-S)
Minor (from DHEA conversion)
DHEA / DHEA-S
Minor gonadal
Zona RETICULARIS — PRIMARY. Sulfated by SULT2A1 → DHEA-S for circulation
Sustained high E2 (>200 pg/mL for ~48 h) flips feedback from negative to POSITIVE → LH SURGE → ovulation. Corpus luteum then makes progesterone (luteal phase)
Peripheral conversion enzymes (LO 3)
Enzyme
Where expressed
Reaction
Clinical hook
5α-reductase
Skin (scalp, face), prostate, external genitalia, hair follicles, seminal vesicles. NOT in adrenal cortex
Testosterone → DHT (reduces Δ4). DHT has 2-5× AR affinity
Finasteride/dutasteride for BPH + baldness. 5α-reductase deficiency → 46,XY ambiguous at birth, virilize at puberty
ESTRONE (E1) dominant — peripheral AROMATASE (adipose, bone) on adrenal ANDROSTENEDIONE. Ovary essentially silent after menopause
Adipose has high aromatase → more androstenedione → estrone conversion → unopposed estrogen → endometrial hyperplasia + CA risk; also ↑ postmenopausal breast CA risk
Explains: (1) feminization in aromatase-excess states or estrogen Rx in men; (2) breast development in CAIS (testosterone aromatized to E2 drives ERα despite broken AR); (3) basis of aromatase inhibitor therapy
Ovarian estrogen biosynthesis — two-cell model (LO 4)
5α-REDUCTASE DEFICIENCY: 46,XY infant with ambiguous / female-appearing external genitalia AT BIRTH (no DHT), but VIRILIZES AT PUBERTY as rising testosterone drives late masculinization. Classic "guevedoces" phenotype. Normal T, LOW DHT, elevated T:DHT ratio.
Pharmacologic pathway modulators (LO 4)
5α-reductase inhibitors — finasteride (type 2 selective) for BPH + male-pattern baldness; dutasteride (both types) for more complete DHT suppression. TERATOGENIC in male fetus (pregnancy warning)
Aromatase inhibitors (nonsteroidal, REVERSIBLE). First-line for POSTMENOPAUSAL ER+ breast cancer. Side effects: hot flashes, arthralgia, osteoporosis
Aromatase inhibitor — STEROIDAL, IRREVERSIBLE ("suicide inhibitor"). Different resistance pattern than nonsteroidal AIs. Postmenopausal ER+ breast CA
Premenopausal ovaries respond to low estrogen with ↑ gonadotropin drive → more aromatase → more estrogen — the ovarian feedback loop overwhelms the AI. Can paradoxically INCREASE estrogen. Premenopausal ER+ breast CA uses tamoxifen (or ovarian suppression + AI)
LO 5
ON EXAM — SHBG primary carrier (T > DHT > E2). T distribution: 60% SHBG, 38% albumin, 2% free. E2: 60% SHBG, 20% albumin, 20% free. Half-lives short: T ~1 h, E2 <20 min, PROGESTERONE ~5 MIN (shortest), DHEA-S 7-10 h (longest). SHBG ↑ by estrogen/pregnancy/hyperthyroid/cirrhosis/anorexia. SHBG ↓ by androgens/obesity/insulin/PCOS/hypothyroid. Hepatic glucuronide/sulfate → kidney. Oral T has extensive first-pass metabolism
Circulation (LO 5)
Hormone
Carriers
% free
Half-life
Pearl
Testosterone
SHBG (~60%, high affinity), albumin (~38%), free (~2%)
~2% FREE (active)
Up to ~1 hour
Free T drives biological activity. SHBG key modifier — measure free T when SHBG abnormal (pregnancy, obesity, liver dz)
DHT
SHBG (high affinity), albumin
Low
Short (<20 min)
Made peripherally and acts locally — circulating levels don't reflect tissue-level DHT. T:DHT ratio used for 5α-red diagnosis
Androstenedione
Albumin (primarily, weak)
Moderate
Up to ~1 hour
Elevated in CAH, PCOS, adrenal androgen tumors
DHEA-S
Albumin (HIGH affinity)
Low
7-10 hours (LONGEST steroid)
Most abundant circulating steroid. Sulfate prevents renal filtration → prolonged t½. Preferred lab for adrenal androgen excess
17β-Estradiol
SHBG (~60%), albumin (~20%)
~20% free
<20 min
Dominant reproductive estrogen. Short half-life requires continuous production. Pregnancy → ↑ SHBG → ↑ total E2 but free normal
Free T falls more than total T does — contributes to age-related androgen decline
Androgens (exogenous / excess)
LOWERS SHBG
Raises free T further (positive feedback)
Obesity / hyperinsulinemia (PCOS, T2DM)
LOWERS SHBG
Raises free T — major mechanism in PCOS and T2DM hyperandrogenism
Hypothyroidism
LOWERS SHBG
Less clinically significant than hyperthyroid effect
Inactivation and clearance (LO 5)
Glucuronide and sulfate conjugation at hydroxyl groups → water-soluble → kidney excretion. Also oxidation/reduction reactions. Liver is major clearance organ
17β-HSD2 (OXIDATIVE, opposite of HSD1) converts estradiol → estrone. 16α-hydroxylation (liver) converts estrone → estriol. Both weaker than E2 but can still bind ER
Extensive FIRST-PASS hepatic metabolism → very little reaches circulation. Low bioavailability + hepatotoxicity risk with oral 17α-alkylated variants
IM (cypionate, enanthate — long-acting depot), transdermal (patch, gel), implantable pellets, intranasal. Avoid oral 17α-alkylated forms (hepatotoxic)
Dominant in BREAST, UTERUS, LIVER, BONE, hypothalamus. Drives classic estrogenic effects — breast proliferation, endometrial growth, bone preservation, hepatic clotting factor + binding protein synthesis. Main SERM target
Dominant in PROSTATE, OVARY, CNS, cardiovascular, lung, colon. Often opposes / modulates ERα. Newer selective ERβ agonists under investigation
Different tissues have distinct ERα/ERβ ratios + distinct coactivator/corepressor availability + distinct chromatin contexts. SERM-bound receptor adopts a conformation favoring coactivators in some tissues (agonist) and corepressors in others (antagonist)
SERMs (LO 6)
SERM
Breast
Endometrium
Bone
Use
Tamoxifen
ANTAGONIST
AGONIST (↑ endometrial CA risk)
AGONIST (preserves bone)
Adjuvant ER+ breast CA (PRE- and postmenopausal); prevention in high-risk. SE: endometrial CA, VTE, hot flashes
Raloxifene
ANTAGONIST
ANTAGONIST (no endometrial risk)
AGONIST
Postmenopausal osteoporosis prevention/treatment + breast CA prevention in high-risk women
Anastrozole, letrozole (nonsteroidal, reversible); exemestane (steroidal, irreversible). Block peripheral androgen → estrogen conversion. FIRST-LINE POSTMENOPAUSAL ER+ breast CA. SE: hot flashes, arthralgia, osteoporosis
Flutamide (hepatotoxic), bicalutamide, enzalutamide (best CNS penetration, for castration-resistant prostate CA). AR antagonists — block AR at target. Often combined with leuprolide (combined androgen blockade)
5α-reductase inhibitors — finasteride (type 2) for BPH + baldness; dutasteride (both types) for more complete DHT drop. TERATOGENIC in male fetus — pregnant women shouldn't handle broken tablets
Nonselective MR antagonist with OFF-TARGET AR ANTAGONISM + PR AGONISM. For AR block: PCOS hirsutism, transgender hormone therapy (off-label), women's acne. SE: gynecomastia, menstrual irregularities, hyperkalemia
PR antagonist (RU-486) + GR antagonist. Medical abortion (PR); Cushing syndrome with hyperglycemia (GR, off-label)
GnRH agonist in continuous administration → gonadotrope desensitization + downregulation → ↓ LH/FSH → ↓ sex steroids ("medical castration"). Uses: prostate CA, endometriosis, central precocious puberty, IVF. Initial "flare" requires antiandrogen cover 2-4 weeks in prostate CA
Clinical syndromes (LO 6)
Complete Androgen Insensitivity Syndrome — AR loss-of-function mutation (X chromosome). X-LINKED RECESSIVE. 46,XY with functional Sertoli + Leydig cells but nonfunctional AR
Leydig cells make testosterone normally. Peripheral AROMATASE converts T → 17β-estradiol → ERα drives breast development. Uterus + upper vagina absent (MIS from Sertoli cells caused Müllerian regression)
Pubic + axillary hair are AR-dependent (driven by DHT). Nonfunctional AR → fail to develop despite high T/DHT. Scalp hair preserved (estrogen-dependent). Classic CAIS finding
(1) Increased ENDOMETRIAL CANCER risk (agonist in endometrium) — always investigate postmenopausal bleeding. (2) VTE (DVT, PE). Also hot flashes, cataracts, hepatic steatosis
LO 1–6 · USMLE Step 1 Style
10 questions — answers pre-revealed.
Q1. Rank androgens by AR affinity.
A. Androstenedione > DHT > T > DHEA
B. DHT > testosterone >> androstenedione > DHEA
C. T > DHT > DHEA > androstenedione
D. DHEA > DHEA-S > T > DHT
E. All equal
B — DHT > T >> androstenedione > DHEA. DHT has 2–5× AR affinity vs testosterone. Androstenedione + DHEA are WEAK androgens that serve mainly as peripheral precursors. Why 5α-reductase inhibition produces clinical effects in DHT-dependent tissues (scalp, prostate).
Q2. 16-year-old phenotypically female with primary amenorrhea, normal breasts, sparse axillary/pubic hair, blind-ending vagina. 46,XY. Bilateral inguinal masses. Diagnosis?
A. Kallmann
B. 5α-reductase deficiency
C. Complete AIS — X-linked AR mutation
D. Turner syndrome
E. MRKH
C — CAIS. 46,XY, functional Sertoli → MIS → Müllerian regression (no uterus, blind vagina). Leydig make testosterone, but AR nonfunctional → no AR signaling → Wolffian regresses, external defaults female. Breasts from peripheral AROMATASE (T → E2 → ERα). Sparse pubic/axillary hair because those are AR-dependent. AR on X chromosome → X-linked recessive.
Q3. 3-week-old 46,XY with ambiguous genitalia. Normal testosterone, LOW DHT, elevated T:DHT ratio. Virilizes at puberty with deepening voice, phallic growth, muscle mass. Enzyme deficient?
A. 17,20-lyase
B. 17β-HSD3
C. Aromatase
D. 5α-reductase
E. 21-hydroxylase
D — 5α-reductase deficiency. Converts T → DHT in peripheral tissues. Without DHT, external masculinization fails IN UTERO → ambiguous genitalia at birth. Wolffian preserved (T-dependent, not DHT). At PUBERTY, rising T overcomes DHT deficit → late virilization (“guevedoces”). Lab: normal T, LOW DHT, HIGH T:DHT.
Q4. Two-cell / two-gonadotropin model — correct pairing?
A. Theca — FSH — aromatase → E2
B. Granulosa — LH — androstenedione
C. Theca — LH — androstenedione; granulosa — FSH — aromatase → estrone → (17β-HSD1) → E2
D. Theca — FSH — progesterone; granulosa — LH — testosterone
E. Both FSH-driven
C — LH theca/androstenedione; FSH granulosa/aromatase. Thecal cells lack aromatase — can't make estrogens themselves — but LH (Gs-cAMP) stimulates their androgen output. Androstenedione diffuses into granulosa, where FSH-driven aromatase → estrone, and 17β-HSD1 → 17β-estradiol. Foundation of menstrual cycle physiology.
Q5. 58-year-old postmenopausal woman with ER+ breast CA. Dominant estrogen source?
A. Ovarian granulosa (remaining follicles)
B. Adrenal cortex directly
C. Peripheral aromatization of adrenal ANDROSTENEDIONE to ESTRONE in adipose
D. Placental estriol
E. Liver synthesis
C — Peripheral aromatization of androstenedione to estrone in adipose. After menopause, ovaries depleted and granulosa E2 stops. Dominant postmenopausal estrogen = estrone, produced when adrenal androstenedione is aromatized by peripheral aromatase in adipose (+ bone, skin, brain). Obesity RAISES postmenopausal estrone → endometrial hyperplasia/CA risk. Why aromatase inhibitors are first-line for postmenopausal ER+ breast CA.
Q6. 28-year-old PCOS patient: hirsutism, oligomenorrhea, acne, BMI 33. Free T elevated; total T at upper limit of normal. Mechanism for elevated free T?
A. Adrenal tumor
B. HYPERINSULINEMIA and obesity suppress hepatic SHBG → raise free T
C. Hepatic failure with markedly ↑ SHBG
D. 17α-OH CAH
E. Exogenous T
B — Hyperinsulinemia + obesity LOWER SHBG. PCOS hyperandrogenism has TWO mechanisms: (1) ovarian thecal overproduction (LH-driven), (2) hyperinsulinemia + obesity suppress hepatic SHBG → more free T for the same total. Metformin and weight loss raise SHBG. Converse: pregnancy/OCPs/hyperthyroid RAISE SHBG.
Q7. Postmenopausal woman on tamoxifen for adjuvant ER+ breast CA — expected effect?
A. Agonist in breast (blocks tumor)
B. Antagonist in breast (blocks tumor) + AGONIST in endometrium (↑ endometrial CA risk) + agonist in bone (maintains density)
C. Antagonist in all tissues
D. Aromatase inhibitor
E. PR antagonist
B — Tamoxifen: antagonist breast; agonist endometrium + bone. SERM tissue selectivity from differential coactivator/corepressor recruitment + ERα/ERβ ratios. Tamoxifen BLOCKS breast ER (tumor suppression) but STIMULATES endometrium (↑ endometrial hyperplasia/CA risk) + bone (maintains density). Also ↑ VTE. Raloxifene: antagonist in breast AND endometrium but agonist in bone — osteoporosis + breast CA prevention without endometrial risk.
Q8. 35-year-old with anovulatory PCOS wants to conceive. Clomiphene mechanism?
A. Direct ovarian follicle stimulation
B. ER agonist at hypothalamus
C. ER ANTAGONIST at hypothalamus → removes negative feedback → ↑ GnRH pulsatility → ↑ LH/FSH → ovulation
D. PR agonist
E. Aromatase inhibitor
C — Clomiphene blocks hypothalamic ER. Clomiphene blocks estrogen feedback at hypothalamic ER → hypothalamus “thinks” estrogen is low → ↑ GnRH pulse frequency/amplitude → ↑ LH/FSH from pituitary → follicle recruitment + ovulation. First-line for ovulatory induction in PCOS. Letrozole (AI) now also used off-label.
Q9. Pregnant woman with markedly elevated TOTAL testosterone but normal FREE T and no hyperandrogenism signs. Explanation?
A. Luteoma of pregnancy
B. Estrogen-driven ↑ hepatic SHBG synthesis raises total but not free testosterone
C. Placental aromatase failure
D. PCOS relapse
E. Adrenal androgen tumor
B — Pregnancy estrogen ↑ SHBG. Pregnancy dramatically raises estrogen → hepatic SHBG synthesis up. Total T rises (more bound) but biologically active FREE T stays normal (HPG axis defends it). Same principle: CBG (total cortisol up, free normal) and TBG (total T4 up, free normal) — all driven by estrogen-hepatic binding-globulin effect. Don't misinterpret elevated total as hyperandrogen state.
Q10. 32-year-old man on flutamide for prostate CA. Mechanism?
A. 5α-reductase inhibitor
B. Aromatase inhibitor
C. AR antagonist — blocks androgen at the receptor
D. GnRH agonist
E. PR antagonist
C — Flutamide is an AR antagonist. Flutamide, bicalutamide, enzalutamide are nonsteroidal AR antagonists for prostate CA — often combined with GnRH agonist leuprolide for COMBINED ANDROGEN BLOCKADE. Bind AR and prevent T/DHT from activating it. SE: gynecomastia (unopposed estradiol signaling), hepatotoxicity (especially flutamide). Compare: 5α-reductase inhibitors (finasteride) block DHT synthesis; AIs block estrogen synthesis; leuprolide continuous desensitizes GnRH receptors.