What are the effects of Gonadotropin-Releasing Hormone (GnRH)?

Effects of Gonadotropin-Releasing Hormone (GnRH)

GnRH is a key regulator of the reproductive system that primarily controls the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn regulate gonadal function and reproductive processes.

Physiological Effects of GnRH

• GnRH is a decapeptide that acts as the primary hypothalamic regulator of the reproductive system by binding to GnRH receptors in the anterior pituitary 1, 2
• When secreted in a pulsatile pattern, GnRH stimulates the production and release of LH and FSH from gonadotropic cells of the anterior pituitary 3, 1
• These gonadotropins (LH and FSH) then stimulate sex steroid hormone synthesis and gametogenesis in the gonads 4
• In females, the positive estradiol feedback at midcycle enhances GnRH liberation, resulting in an LH surge that induces ovulation of the dominant follicle 3

GnRH in Extrapituitary Tissues

• GnRH and its receptor are expressed in various extrapituitary tissues, including the ovary, breast, endometrium, placenta, and prostate 5, 4
• In the ovary, both forms of GnRH (GnRH-I and GnRH-II) and their common receptor are expressed in various compartments 5
• The ovarian GnRH/GnRHR system is regulated by gonadal steroids, gonadotropins, and GnRH itself 5
• GnRH acting in a paracrine/autocrine manner can influence ovarian steroidogenesis and affect proliferation and apoptosis of ovarian cells 5

Pharmacological Applications of GnRH Analogues

GnRH Agonists

• Continuous administration of GnRH agonists initially stimulates gonadotropin release but subsequently leads to desensitization of the pituitary and suppression of LH and FSH production 1, 6
• This suppression results in a hypogonadotropic hypogonadal state that forms the basis for various clinical applications 1
• GnRH agonists are used in the treatment of:
  • Central precocious puberty - they work by desensitizing gonadotrophs through continuous stimulation, reducing LH release and halting ovarian stimulation 7
  • Hormone-sensitive cancers, particularly breast cancer - recommended for ovarian suppression in premenopausal women with hormone receptor-positive breast cancer 8
  • Endometriosis and uterine fibroids 1, 6

GnRH Antagonists

• GnRH antagonists competitively block GnRH receptors, resulting in rapid but reversible suppression of gonadotropin secretion 3, 1
• Unlike agonists, antagonists do not cause an initial stimulation of gonadotropin release 1
• Cetrorelix acetate, a GnRH antagonist, blocks the effects of natural GnRH on LH and FSH secretion 3
• GnRH antagonists are used to prevent premature ovulation during controlled ovarian stimulation for assisted reproduction 3

Controversial Applications

• The use of GnRH analogues for fertility preservation during chemotherapy is controversial 9
• Multiple guidelines, including those from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), state that GnRH analogues are not an effective method for fertility preservation 10, 9
• Some studies show benefit in maintaining menstrual function, while others show no advantage 9
• GnRH analogues should not be considered a reliable means of fertility preservation, and established methods like embryo or egg cryopreservation should be preferred 10, 9

Side Effects and Considerations

• Common side effects of GnRH agonists include menopausal symptoms and accelerated bone loss with prolonged use 8
• For GnRH antagonists like cetrorelix, side effects may include local irritation at injection sites 3
• Complete ovarian suppression with GnRH analogues is not achieved for several weeks after administration 10

GnRH and its analogues have revolutionized reproductive medicine, with applications ranging from fertility treatments to management of hormone-dependent conditions, demonstrating the central role of this hormone in reproductive physiology and pathology 6, 2.