Synthesis and Mechanism of Action
GnRH is secreted by the arcuate, supraoptic, and paraventricular nuclei of the hypothalamus.
It travels to the adenohypophysis via humoral transport through the specialized hypophyseal portal system. This vascular network ensures bidirectional communication between the hypothalamus and the pituitary gland.
In the pituitary, the hormone acts on gonadotrophs, stimulating the release of two gonadotropic hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Because of this dual action, the umbrella term gonadotropin-releasing hormone (GnRH) is used synonymously with luliberin; a separate follicle-stimulating releasing hormone has never been isolated.
Subsequently, LH and FSH regulate the gonads:
- In males: LH stimulates Leydig cells to produce testosterone; FSH stimulates Sertoli cells to produce androgen-binding protein.
- In females: FSH stimulates follicular growth and estrogen secretion, whereas the mid-cycle LH surge serves as the direct trigger for ovulation.
Secretion Pattern
The secretion of GnRH is genetically programmed and exhibits a pulsatile (circahoral) pattern.
Peaks of increased secretion last for several minutes and alternate with intervals of low activity. The arcuate nuclei generate a pulse approximately every 1 to 3 hours.
The frequency and amplitude of GnRH pulses determine whether LH or FSH is preferentially secreted by the adenohypophysis, driving morphological and secretory changes in the gonads.
Regulation of GnRH Secretion
- Negative feedback: Estrogens suppress GnRH and FSH release; testosterone produced by Leydig cells inhibits secretion at both the hypothalamic and pituitary levels.
- Neurotransmitters:
- Stimulate GnRH release: Norepinephrine, acetylcholine, $\gamma$-aminobutyric acid (GABA).
- Inhibit GnRH release: Dopamine, serotonin.
- Neuropeptides: Endogenous opioid peptides, corticotropin-releasing factor, and galanin modulate hypothalamic function.
- Higher CNS centers: Psychoemotional factors can influence reproductive function; the cerebral cortex and subcortical structures synthesize neurotransmitters and neuropeptides that project to the hypothalamus.
Clinical Significance and Analogue Applications
- GnRH analogues (agonists) (triptorelin, goserelin, leuprolide, buserelin) constitute a distinct pharmacological group due to their chemical structure resembling native GnRH. They are used for the medical management of central precocious puberty (CPP), uterine fibroids (leiomyomas), and as preoperative therapy for certain forms of endometriosis.
- Uterine fibroids: GnRH agonists reduce the volume of myomatous nodes by up to 55%. Following cessation of therapy, menstrual function returns, though some patients may experience expansive fibroid regrowth with signs of ischemic degeneration.
- Preoperative management of fibroids: GnRH agonists reduce intra- and perinodular blood flow; maximal effect is achieved after 2–3 injections.
- Pathologies: Impaired dopaminergic regulation of GnRH secretion contributes to the pathogenesis of central polycystic ovary syndrome (PCOS). Impaired migration of GnRH-secreting neurons to the hypothalamus during congenital forebrain malformations is a known cause of hypogonadism.