HPG axis

**Components and flow** - Hypothalamus (arcuate nucleus; kisspeptin neurons drive GnRH pulses) secretes GnRH in a PULSATILE fashion (~every 60-90 min). - Anterior pituitary gonadotrophs release LH and FSH. - Gonads: testes or ovaries produce sex steroids, inhibin, and gametes.

**Male** - LH acts on Leydig cells (cAMP; ↑ cholesterol desmolase, the rate-limiting step) to make testosterone. Testosterone is converted to DHT by 5α-reductase (external genitalia, prostate) and to estradiol by aromatase. - FSH acts on Sertoli cells to support spermatogenesis, and to make androgen-binding protein and inhibin B. - Feedback: testosterone inhibits GnRH and LH. Inhibin B inhibits FSH selectively.

**Female** - LH acts on theca cells to make androgens (androstenedione) from cholesterol. - FSH acts on granulosa cells to induce aromatase, which converts androgens to estradiol. This is the "two-cell, two-gonadotropin" model. - Feedback: Low-to-moderate estrogen and progesterone give negative feedback. Sustained high estradiol at mid-cycle gives positive feedback, causing the LH surge and ovulation (~24-36 h later). Inhibin B inhibits FSH. - After ovulation, LH maintains the corpus luteum, which secretes progesterone.

**Key clinical correlations (patterns of labs)** - Primary hypogonadism (testicular/ovarian failure): ↓ sex steroids, ↑ LH/FSH. Examples: Klinefelter (47,XXY), Turner (45,X), premature ovarian insufficiency, mumps orchitis, chemotherapy. - Secondary (central) hypogonadism: ↓ sex steroids, ↓ LH/FSH. Examples: pituitary tumor or hyperprolactinemia (prolactin inhibits GnRH), Sheehan syndrome, functional hypothalamic amenorrhea (athletes, anorexia, ↓ leptin), and Kallmann syndrome (failed GnRH neuron migration, anosmia, ↓ GnRH). - PCOS: ↑ LH:FSH ratio, hyperandrogenism, anovulation, insulin resistance. - Precocious puberty: central (early HPG activation, ↑ LH; treated with continuous GnRH agonist, e.g., leuprolide) vs peripheral (↑ sex steroids with ↓ LH/FSH; e.g., McCune-Albright, tumors). - Exogenous anabolic steroids: negative feedback leads to ↓ LH/FSH, testicular atrophy, and oligospermia. - Hyperprolactinemia: inhibits GnRH, causing amenorrhea/galactorrhea in women and ↓ libido/ED in men.

**Pharmacology** - Pulsatile GnRH (e.g., gonadorelin) is used to induce ovulation in hypothalamic amenorrhea. - Continuous GnRH agonists (leuprolide) desensitize the pituitary after an initial flare, so they are used for prostate cancer (with an antiandrogen like flutamide to block the flare), endometriosis, fibroids, and central precocious puberty. - GnRH antagonists (degarelix, elagolix) suppress the axis without a flare. - Clomiphene (SERM) blocks hypothalamic estrogen receptors, which ↑ GnRH/LH/FSH to induce ovulation. Letrozole (aromatase inhibitor) is first-line for ovulation induction in PCOS. - Combined OCPs use estrogen plus progestin negative feedback to suppress LH/FSH and prevent ovulation. - hCG mimics LH (used for ovulation trigger or cryptorchidism/hypogonadotropic hypogonadism).

**High-yield pearls** - Pulsatile GnRH stimulates; continuous GnRH inhibits. - Inhibin acts on FSH; sex steroids act on both LH and FSH. - Think "LH → androgens (Leydig/theca); FSH → gametogenesis/aromatase (Sertoli/granulosa)." - Initial workup of amenorrhea: rule out pregnancy, then check TSH, prolactin, and FSH/LH to localize the lesion.