GnRH Agonists & Antagonists

Normally, pulsatile release of GnRH from the hypothalamus stimulates the pituitary to make and secrete LH and FSH, and at midcycle a large rise in GnRH produces the LH surge that triggers ovulation. GnRH agonists (leuprolide, goserelin, triptorelin, nafarelin) stimulate the receptor first; given continuously, they cause downregulation of GnRH receptors, lower LH and FSH, and suppress ovarian estradiol and testicular testosterone. The suppression is reversible when the drug is stopped.

GnRH antagonists bind the pituitary receptor competitively and lower LH and FSH right away, with no initial release of gonadotropins: degarelix and relugolix lower testosterone in prostate cancer, elagolix lowers estradiol and progesterone in endometriosis, and cetrorelix and ganirelix prevent a premature LH surge during fertility treatment.

Advanced prostate cancer: leuprolide (Lupron Depot, Eligard, Camcevi), triptorelin (Trelstar), goserelin (Zoladex, also with flutamide for locally confined disease), and the antagonists degarelix (Firmagon, injection) and relugolix (Orgovyx, an oral tablet). Endometriosis: leuprolide (Lupron Depot, alone or with norethindrone acetate add-back), goserelin, nafarelin (Synarel nasal spray) and oral elagolix (Orilissa, for moderate to severe endometriosis pain). Fibroids: leuprolide with iron for preoperative improvement of fibroid-related anemia; goserelin also thins the endometrium before ablation and treats advanced breast cancer in pre- and perimenopausal women.

Central precocious puberty: Lupron Depot-PED, Fensolvi, Triptodur and Synarel. Controlled ovarian stimulation: cetrorelix (Cetrotide) and ganirelix inhibit premature LH surges. Two oral combination products pair a GnRH antagonist with estradiol and norethindrone acetate — Myfembree (relugolix) and Oriahnn (elagolix) — for heavy menstrual bleeding from fibroids (and, for Myfembree, endometriosis pain); in both, the added estradiol may reduce the bone loss that follows estrogen suppression, but these products carry an estrogen-progestin boxed warning for thromboembolic disorders and vascular events.

In the first weeks of agonist therapy, testosterone rises to about 50% above baseline before it falls. Men may have tumor flare — worsening bone pain, urinary obstruction, neurologic symptoms or spinal cord compression — so patients with vertebral metastases or urinary obstruction are watched closely. Antagonists produce no such initial surge.

Androgen deprivation brings its own warnings. The agonist labels for prostate cancer warn of hyperglycemia and diabetes and an increased risk of myocardial infarction, sudden cardiac death and stroke reported with GnRH analogs in men, and agonist and antagonist labels alike warn that androgen deprivation may cause QT prolongation. In children treated for precocious puberty, signs of puberty — including vaginal bleeding — can increase during the first weeks because of the initial stimulatory effect, and psychiatric events, convulsions and pseudotumor cerebri have been reported.

In women, these drugs create a hypoestrogenic state. Bone mineral density falls, and some loss may not reverse, which is why the duration of leuprolide for endometriosis is limited and norethindrone acetate add-back is used to reduce it; elagolix causes dose- and duration-dependent BMD loss and is contraindicated with known osteoporosis. Hot flashes, headache, vaginitis, mood changes and depression are common, and patients are monitored for suicidal ideation on elagolix.

These drugs can cause fetal harm, and several are contraindicated in pregnancy; because they can stop menstruation, they may make a pregnancy harder to recognize. The labels call for non-hormonal contraception. Elagolix can raise liver enzymes, and strong OATP1B1 inhibitors and severe hepatic impairment are contraindications.