- Gonadotropin-releasing hormone (GnRH) is a decapeptide neurohormone produced by specialized neurons in the hypothalamus, and it serves as the central regulator of the hypothalamic-pituitary-gonadal (HPG) axis—the key hormonal system that controls reproduction in both males and females.
- Despite its small size, GnRH plays an outsized role in human development, fertility, and sexual function by stimulating the anterior pituitary gland to secrete two essential gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
- GnRH is synthesized and secreted in a pulsatile fashion, which is critical for its function. The frequency and amplitude of these pulses determine the pattern and quantity of LH and FSH released by the pituitary. This rhythmic secretion begins in fetal life, becomes dormant during childhood, and reactivates at puberty, initiating sexual maturation. In males, LH stimulates the Leydig cells of the testes to produce testosterone, while FSH acts on Sertoli cells to support spermatogenesis. In females, LH and FSH regulate the menstrual cycle, promote the growth of ovarian follicles, trigger ovulation, and support progesterone and estrogen production.
- The activity of GnRH is tightly regulated by a variety of feedback mechanisms. In both sexes, sex steroids (estrogen, progesterone, and testosterone) and inhibins provide negative feedback to the hypothalamus and pituitary to maintain hormonal balance. Interestingly, in females, rising levels of estrogen during the late follicular phase of the menstrual cycle exert a positive feedback effect, resulting in a surge of GnRH that triggers the LH surge and subsequent ovulation.
- GnRH function is also influenced by various internal and external factors, including stress, nutritional status, circadian rhythms, and neurotransmitters such as dopamine, norepinephrine, and kisspeptin. Kisspeptin, in particular, has emerged as a crucial upstream regulator of GnRH secretion and is vital for the onset of puberty and fertility.
- Clinically, disorders in GnRH signaling can lead to significant reproductive dysfunction. Hypogonadotropic hypogonadism, a condition in which low GnRH leads to insufficient production of LH and FSH, results in delayed or absent puberty and infertility. A well-known form of this disorder is Kallmann syndrome, characterized by a lack of GnRH and an impaired sense of smell. On the other end, precocious puberty—early activation of the HPG axis—can result from premature or excessive GnRH activity.
- Synthetic GnRH analogs have been developed for therapeutic use, either as agonists or antagonists. GnRH agonists initially stimulate gonadotropin release but eventually suppress it due to receptor downregulation, and are used in the treatment of hormone-sensitive cancers (e.g., prostate or breast cancer), endometriosis, central precocious puberty, and for controlled ovarian stimulation in assisted reproductive technologies. GnRH antagonists, which act more immediately to block receptor activity, are also used in similar contexts, offering rapid suppression of gonadotropin secretion.
