Gonadorelin

Gonadorelin is the synthetic form of gonadotropin-releasing hormone (GnRH), a naturally occurring decapeptide secreted in pulses by hypothalamic neurons to regulate the hypothalamic-pituitary-gonadal (HPG) axis. It is FDA-approved as Factrel for GnRH stimulation testing and as Lutrepulse for pulsatile delivery in female infertility due to hypogonadotropic hypogonadism.

Gonadorelin is the identical sequence to native human GnRH: pyroglutamyl-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2. The N-terminal pyroglutamate (pGlu) and C-terminal amide protect against degradation. Its very short half-life (~2–4 minutes in plasma) is biologically intentional — it necessitates pulsatile delivery for therapeutic HPG stimulation, since continuous exposure leads to receptor downregulation and paradoxical gonadotropin suppression.

Gonadorelin binds GnRHR (a Gq/Gs-coupled GPCR) on anterior pituitary gonadotrophs. Pulsatile binding every 60–90 minutes produces sequential LH and FSH secretion: - **LH** acts on Leydig cells (males) or granulosa/luteal cells (females) → testosterone/estradiol/progesterone synthesis - **FSH** stimulates Sertoli cells (spermatogenesis, males) and follicular development (females)

The pulsatile requirement reflects receptor biology: GnRHR undergoes rapid downregulation with continuous agonist exposure. This pharmacological feature is exploited clinically — continuous-delivery GnRH agonist depots (leuprolide, buserelin) are used to pharmacologically castrate patients with hormone-sensitive prostate cancer, which is the opposite of gonadorelin's intended therapeutic effect.

The complete HPG feedback axis remains intact with pulsatile gonadorelin: testosterone and estradiol exert their normal negative (and in females, positive) feedback on hypothalamic GnRH neurons, providing physiological regulation that synthetic gonadotropin (hCG/FSH) protocols cannot replicate.