Hypothalamic GnRH neurons fire pulsatile bursts (90-min interpulse interval in adult ♀ follicular phase, faster luteal) under upstream control of kisspeptin/KNDy neurons (arcuate nucleus). GnRH → anterior pituitary gonadotropes → LH + FSH → gonadal sex-steroid synthesis. Pulsatile GnRH stimulates; continuous GnRH desensitizes (paradoxical castration). Therapeutic exploitation: pulsatile GnRH (gonadorelin) for hypothalamic infertility; continuous GnRH agonists (leuprolide, triptorelin, goserelin) → initial flare → desensitization → chemical castration for prostate cancer + central precocious puberty + endometriosis; GnRH antagonists (cetrorelix, ganirelix, degarelix) suppress without flare. Kisspeptin (KISS1 + kisspeptin-10 = KP-10 minimum agonist fragment) directly activates KISS1R on GnRH neurons — research-stage as a GnRH-pulse stimulator.
Organ Systems
endocrine
reproductive
Pathway Steps
kisspeptin → gnrh-release — via KISS1R on GnRH neurons → Gq → IP3 → GnRH exocytosis. Kisspeptin neurons (hypothalamic arcuate nucleus) are the master pulse generator driving episodic GnRH release — the true upstream switch of reproduction. Kisspeptin signaling triggers puberty, and its loss causes hypogonadotropic hypogonadism.
gnrh-release → lh-fsh-release — via GnRH-R on gonadotropes → Gq → LH/FSH secretion. Pulsatile GnRH drives pituitary LH and FSH secretion, with pulse frequency setting the LH:FSH ratio. The pulsatility is essential — continuous GnRH desensitizes the pituitary and shuts the axis down, how GnRH-agonist depots achieve medical castration in prostate cancer and endometriosis.
Known Modulators
gonadorelin (activator) — GnRH-R (pulsatile dosing). pulsatile pump → physiologic gonadotropin release for hypothalamic infertility; opposite effect of continuous depot