Endocrine Module 05Sex Steroid Synthesis & Action

1 · Gonadal sources — Leydig vs thecal cells

• Leydig cells (interstitial):
  • Located between seminiferous tubules.
  • Primary source of testosterone.end05 lecture; B&B 4.02 Male Reproductive Hormones
  • Stimulated by LH (which is Gs-coupled → cAMP).
• Sertoli cells (seminiferous tubule):
  • Nurse spermatogonia; produce androgen-binding protein (ABP) to concentrate testosterone locally.
  • Produce inhibin B (selective FSH inhibitor) and anti-Müllerian hormone (AMH) in fetal life.

• Thecal cells:
  • Surround each developing follicle.
  • Produce androstenedione primarily (LH-stimulated).end05 lecture; B&B 4.03 Female Reproductive Hormones
  • Most of the androgen diffuses into granulosa cells for estrogen synthesis.
• Granulosa cells:
  • Inner follicle cells.
  • FSH-stimulated; aromatase converts thecal androstenedione → estrone → estradiol.

2 · Two-cell / two-gonadotropin model

• Rule:
  • LH stimulates thecal cells to make androstenedione.B&B 4.03 Female Reproductive Hormones; FA 3.11
  • FSH stimulates granulosa cells to aromatize androstenedione → estrogens.
• Clinical relevance:
  • LH spike at mid-cycle (from the estradiol positive-feedback surge) triggers ovulation.
  • This coordinated 2-cell / 2-hormone dance is the basis of the menstrual cycle.

3 · Adrenal sources

• Zona reticularis:
  • Primary adrenal source of DHEA, DHEA-S, and some androstenedione.FA 3.11 Adrenal steroids and CAH; end04 lecture
  • Small contribution to circulating testosterone via peripheral conversion.
  • Adrenarche begins at age 6–8, peaks in mid-20s.
• Clinical:
  • Adrenal androgen excess (CAH, tumors) → virilization.

4 · Peripheral conversion

• 5α-reductase (skin, prostate, external genitalia, hair follicles):
  • Converts testosterone → DHT (more potent).end05 lecture; Bootcamp 6.14 5-α-reductase Deficiency
  • DHT drives male external genital formation in utero + secondary sexual characteristics at puberty.
• Aromatase (adipose, bone, brain, gonads):
  • Converts androgens → estrogens.
  • Major contributor to postmenopausal estrogen production.end05 lecture
• 17β-HSD (tissue-specific isoforms):
  • 17β-HSD3 (androgenic): androstenedione → testosterone in Leydig cells.
  • 17β-HSD1 (estrogenic): estrone → estradiol in granulosa cells.end05 lecture

5 · Placenta and pregnancy

• Fetal-placental unit:
  • Placenta lacks 17α-hydroxylase; cannot make DHEA on its own.
  • Uses fetal adrenal DHEA-S → placenta desulfates → aromatizes → estriol.AI Generated · obstetrics
• Clinical:
  • Estriol is a marker of fetal-placental health.
  • Progesterone maintained by placenta through most of pregnancy.

6 · Lifetime changes

• Premenopausal:
  • 17β-estradiol dominant (from granulosa cells).
• Postmenopausal:
  • Ovarian output drops drastically.
  • Estrone becomes dominant — produced peripherally from adrenal androstenedione.end05 lecture
  • Obesity increases postmenopausal estrogen (more aromatase in adipose) → risk factor for endometrial hyperplasia and breast cancer.AI Generated · oncology

1 · Testosterone synthesis — the Leydig cell pathway

• Starting material:
  • Cholesterol → pregnenolone via desmolase (as in adrenal steroidogenesis).end05 lecture
• Key Δ5 pathway steps:
  • Pregnenolone → 17-OH-pregnenolone (17α-hydroxylase).
  • 17-OH-pregnenolone → DHEA (17,20-lyase).
• Convert to Δ4:
  • DHEA → androstenedione (3β-HSD).
• Final reduction to testosterone:
  • Androstenedione → testosterone (17β-HSD3, the "androgenic" 17β-HSD).
  • Reduction reaction (ketone → alcohol at C17).end05 lecture

2 · Ovarian estrogen synthesis — the two-cell model

• LH at theca:
  • LH binds Gs-coupled receptor → ↑ cAMP → ↑ steroidogenesis.B&B 4.03 Female Reproductive Hormones
  • Thecal cells make androstenedione (primary product).
  • Thecal cells LACK aromatase.

• FSH at granulosa:
  • FSH binds Gs-coupled receptor → ↑ cAMP → ↑ aromatase.
  • Granulosa cells express aromatase.
• Aromatase actions:
  • Androstenedione → estrone (E1).
  • Testosterone → 17β-estradiol (E2) directly (via aromatization).
• 17β-HSD1 (estrogenic):
  • Estrone → 17β-estradiol.
  • Higher affinity for estrogen substrates than 17β-HSD3.end05 lecture

3 · Peripheral conversion

• Where expressed:
  • Skin (esp. scrotum, face, scalp), prostate, external genitalia, hair follicles.end05 lecture; Bootcamp 6.14 5-α-reductase Deficiency
• Function:
  • Testosterone → DHT.
  • DHT binds AR with 2–5× affinity vs. testosterone.
• Physiologic role:
  • Male external genital differentiation in utero.
  • Secondary sexual characteristics at puberty (facial hair, deepening voice, prostate growth).
• Pharmacologic inhibition:
  • Finasteride, dutasteride — used for BPH, male-pattern baldness.AI Generated · urology pharm

• Where expressed:
  • Ovarian granulosa, adipose, skin, bone, brain, placenta.end05 lecture
• Function:
  • Converts androgens → estrogens.
• Pharmacologic inhibition:
  • Anastrozole, letrozole (nonsteroidal); exemestane (steroidal).
  • Postmenopausal ER+ breast cancer first-line.AI Generated · oncology pharm

4 · Enzyme deficiencies

• Genetics:
  • Autosomal recessive.Bootcamp 6.14
• Mechanism:
  • Cannot make DHT → male external genital differentiation fails in utero.
  • Internal male structures (derived from Wolffian ducts, which need testosterone only) form normally.
• Presentation:
  • 46,XY infants with ambiguous or female-appearing external genitalia.
  • At puberty, rising testosterone triggers virilization ("guevedoces").
• Treatment:
  • Depends on clinical / social context; DHT can be supplemented.

• Mechanism:
  • Cannot convert androstenedione → testosterone in Leydig cells.AI Generated · endocrine / repro
• Presentation:
  • Similar to 5α-reductase deficiency: 46,XY ambiguous genitalia at birth.
  • Some virilization at puberty from peripheral conversion.

1 · SHBG — the main sex steroid carrier

• Preferences:
  • Testosterone and DHT (high affinity).end05 lecture; FA 3.11
  • Estradiol (lower affinity than testosterone).
• Clinical impact:
  • SHBG level strongly determines free testosterone — the biologically active pool.

• ↑ SHBG (reduces free T):
  • Estrogen (pregnancy, OCPs, hyperthyroidism, cirrhosis, anorexia).AI Generated · end01 carrier concepts + clinical elsewhere
  • Aging (gradual rise in men).
• ↓ SHBG (raises free T):
  • Androgens, obesity, hyperinsulinemia (PCOS, T2DM), hypothyroidism.
• Clinical consequence:
  • PCOS: ↓ SHBG → ↑ free testosterone → hirsutism, acne, irregular menses.AI Generated · repro
  • Hyperthyroidism: ↑ SHBG → can reveal low free testosterone in men (gynecomastia).

2 · Short half-lives — why sex steroids don't last

• Why short:
  • Relatively small free fraction + efficient hepatic uptake and conjugation.end05 lecture
  • Unlike cortisol (~70 min) or DHEA-S (7–10 h), sex steroids cycle fast.
• Progesterone is the shortest:
  • ~5 min half-life.
  • Weak CBG/albumin binding.
• Clinical implication:
  • Oral testosterone undergoes extensive first-pass metabolism — IM/transdermal/implantable preferred.AI Generated · urology pharm

3 · Hepatic inactivation

• Glucuronide / sulfate conjugation:
  • Liver conjugates at various hydroxyl groups → water-soluble → kidney excretion.end05 lecture
• Estradiol → weaker estrogens:
  • 17β-estradiol → estrone (17β-HSD2, oxidative) → estriol (hydroxylation).
  • Estrone and estriol are weaker than estradiol but can still bind ER.

4 · Pregnancy and lifetime changes

• Pregnancy:
  • Estrogen ↑↑ → ↑ SHBG, CBG, TBG (all carrier proteins).
  • Total testosterone rises but free testosterone stays normal (feedback maintains it).AI Generated · obstetrics
  • Estriol dominates from the fetal-placental unit.
• Postmenopause:
  • Estrogen production falls; estrone becomes dominant via peripheral aromatase.
  • FSH and LH rise (loss of negative feedback).
• Aging in men:
  • Gradual decline in testosterone with rising SHBG → free testosterone falls.
  • "Andropause" controversial — not a sharp physiologic event.

1 · Canonical nuclear receptor mechanism

• Resting state:
  • AR, ER, PR sit in the cytoplasm bound to HSP90 (like MR and GR).end05 lecture; FA 3.15 Signaling pathways of steroid hormones
• Activation:
  • Lipophilic hormone crosses plasma membrane → binds receptor → HSPs dissociate.
  • Receptor dimerizes, translocates to nucleus.
  • Dimer binds palindromic hormone response element on DNA (ARE / ERE / PRE).
  • Modulates transcription (up or down depending on coactivators/corepressors).
• Timescale:
  • Hours for full transcriptional / translational effects.

2 · ERα vs ERβ

• ERα (ESR1):
  • Dominant in breast, uterus, liver, hypothalamus, bone.end05 lecture; B&B 4.03
  • Drives classic estrogenic effects: breast proliferation, endometrial growth, bone preservation, lipid regulation.
• ERβ (ESR2):
  • Dominant in prostate, ovary, CNS, cardiovascular tissues.
  • Often opposes or modulates ERα activity.
  • Target of some SERMs.
• Clinical implication:
  • SERM tissue selectivity reflects differential ERα / ERβ engagement + tissue coregulator context.

3 · AR is X-linked — inheritance of AIS

• Mechanism:
  • AR gene is on the X chromosome.end05 lecture
  • Loss-of-function mutation in a 46,XY individual → Complete Androgen Insensitivity Syndrome (CAIS).
• Phenotype:
  • Phenotypic female at birth; no axillary/pubic hair at puberty; primary amenorrhea; blind-ending vagina; testes in abdomen or inguinal canal.AI Generated · genetics / repro
• Inheritance:
  • X-linked recessive — carrier mothers have unaffected daughters and 50% affected sons.

4 · Non-genomic (rapid) effects

• Membrane receptors:
  • GPER / GPR30 is a membrane estrogen receptor that triggers rapid MAPK / PI3K signaling.end05 lecture
  • Membrane PR also exists.
• Effects:
  • Seconds to minutes (too fast for transcription).
  • Examples: estrogen-induced vasodilation, rapid CNS effects.
• Clinical significance:
  • Less well-characterized than genomic effects but increasingly appreciated in cardiovascular and CNS pharmacology.

5 · Pharmacologic modulators

• Tamoxifen:
  • Antagonist in breast; agonist in bone and endometrium.
  • Adjuvant in ER+ breast cancer (pre- and postmenopausal).
  • Increases risk of endometrial cancer and VTE.AI Generated · oncology pharm
• Raloxifene:
  • Antagonist in breast and endometrium; agonist in bone.
  • Osteoporosis treatment + breast cancer prevention.
  • No endometrial cancer risk.
• Clomiphene:
  • Antagonist at hypothalamic ER → ↑ GnRH pulsatility → ↑ LH, FSH → ovulation induction.AI Generated · repro pharm

• Nonsteroidal (reversible):
  • Anastrozole, letrozole.
  • Used in postmenopausal ER+ breast cancer.AI Generated · oncology pharm
• Steroidal (irreversible):
  • Exemestane.

• AR antagonists:
  • Flutamide, bicalutamide, enzalutamide (prostate cancer).AI Generated · oncology pharm
  • Spironolactone (off-target AR antagonism) — PCOS, hirsutism, transgender care.
• 5α-reductase inhibitors:
  • Finasteride, dutasteride (BPH, male-pattern baldness).
• GnRH modulation:
  • Leuprolide (continuous) → suppresses LH/FSH → chemical castration (prostate CA, endometriosis).AI Generated · see end02

• Mifepristone (RU-486):
  • PR antagonist (also GR antagonist).
  • Medical abortion; Cushing syndrome (off-label).AI Generated · repro / endocrine pharm