gonadotropin-releasing hormone

GnRH is synthesized by neurons in the arcuate nucleus and preoptic area of the hypothalamus and secreted into the hypophyseal portal system, where it acts on GnRH receptors (Gq-coupled) on pituitary gonadotrope cells. Pulsatile secretion (roughly every 60-120 minutes) is critical: pulsatile GnRH stimulates synthesis and release of LH and FSH, while continuous, non-pulsatile exposure downregulates GnRH receptors, causing desensitization and suppression of gonadotropin secretion—this is the pharmacologic basis for GnRH agonists (e.g., leuprolide, goserelin) used to treat prostate cancer, endometriosis, uterine fibroids, precocious puberty, and for fertility treatments (in a flare-then-suppress protocol). GnRH antagonists (e.g., cetrorelix, ganirelix) directly and immediately block the receptor without initial flare, useful in IVF cycles to prevent premature LH surge. Kisspeptin neurons upstream regulate GnRH pulsatility and are essential for puberty onset; mutations in the KISS1/KISS1R system or GnRH receptor gene cause hypogonadotropic hypogonadism (e.g., Kallmann syndrome, associated with anosmia due to failure of GnRH neuron migration from the olfactory placode). Clinically, understanding GnRH pulsatility explains why pulsatile GnRH pump therapy can induce puberty/fertility in hypothalamic hypogonadism, whereas continuous GnRH agonist therapy causes medical castration. LH and FSH released downstream act on Leydig cells (testosterone) and Sertoli cells (spermatogenesis) in males, and on theca and granulosa cells (estrogen, progesterone, follicular development) in females.