Reproductive endocrine loop. Hypothalamic GnRH (pulsatile) → anterior pituitary LH + FSH → gonadal steroidogenesis. Males: LH → Leydig cells → testosterone; FSH → Sertoli cells → spermatogenesis support + inhibin B. Females: cycle-dependent — FSH drives follicle growth + granulosa-cell estradiol; LH surge triggers ovulation; corpus luteum produces progesterone. Pharmacology: GnRH AGONISTS (leuprolide, goserelin) produce initial flare then downregulation/desensitization → suppression of LH/FSH — used in prostate cancer, endometriosis, central precocious puberty. GnRH ANTAGONISTS (degarelix, cetrorelix) suppress without flare. Aromatase inhibitors (anastrozole, letrozole) block peripheral estradiol synthesis.
Organ Systems
endocrine
reproductive
Pathway Steps
gnrh → lh — via pituitary gonadotrophs (pulsatile GnRH; continuous GnRH causes downregulation). The hypothalamus releases GnRH in pulses that drive the anterior pituitary to secrete luteinizing hormone (LH). The pulse frequency encodes the signal — fast pulses favor LH — and continuous (non-pulsatile) GnRH paradoxically shuts the axis down, the basis of GnRH-agonist therapy in prostate cancer and endometriosis.
gnrh → fsh — via pituitary gonadotrophs (same cell, same GnRH input). GnRH also drives pituitary secretion of follicle-stimulating hormone (FSH); slower GnRH pulses favor FSH over LH. FSH supports gametogenesis — spermatogenesis (Sertoli cells) in males and follicular development in females — complementing LH’s steroidogenic role.
lh → testosterone — via Leydig cell steroidogenesis (males); CYP17 + 3β-HSD + 17β-HSD. In males, LH stimulates testicular Leydig cells to synthesize testosterone, which exerts negative feedback on the hypothalamus and pituitary. This loop is why exogenous androgens suppress the axis (and endogenous production/fertility) — relevant to anabolic-steroid use and testosterone therapy.
lh → estradiol — via theca cell androgens + granulosa cell aromatase (CYP19) (females). In females, LH drives ovarian estradiol synthesis, and the mid-cycle LH surge triggers ovulation. Estradiol feedback is usually negative but switches to positive at mid-cycle to generate that surge — the unique feature of the female HPG axis exploited by hormonal contraception.
Known Modulators
testosterone (substrate) — axis endpoint; suppresses GnRH/LH via negative feedback
testosterone cypionate (substrate) — AR (T cypionate IM depot ester). TRT workhorse; weekly IM; cypionate ester slows release (t½ ~8d as authored 2-comp PK Wave 4b)
testosterone enanthate (substrate) — AR (T enanthate IM depot ester). IM TRT; very similar PK to cypionate; international markets differ in which is standard
testosterone undecanoate (substrate) — AR (T undecanoate IM ultra-depot). IM 10-12 weekly (Aveed); much longer-acting than cypionate/enanthate
nandrolone decanoate (activator) — AR (DHT-resistant — milder androgenic profile). 19-nor T derivative; resists 5α-reductase → preserves muscle anabolism with reduced prostate/scalp DHT load
oxandrolone (activator) — AR (oral C17α-alkylated). mild oral anabolic; HIV wasting + burn recovery + alcoholic hepatitis; hepatic strain
progestin only pill (inhibitor) — cervical mucus + endometrial atrophy + intermittent ovulation suppression. progestin-only contraception; less reliable ovulation suppression vs combined OCs
dhea (substrate) — adrenal androgen precursor (→ androstenedione → T/E2). OTC supplement; conversion downstream to T + E2 is variable + individual; uncontrolled hormone-modulation potential
dhea sulfate (substrate) — circulating depot of DHEA (sulfated for stability). DHEA-S is the predominant circulating form; reservoir for tissue-specific desulfation