GnRH Agonists & Antagonists

GnRH is secreted in a pulsatile fashion into the hypophyseal portal circulation and binds the GnRH receptor on anterior pituitary gonadotropes, a seven-transmembrane G protein–coupled receptor. Most GnRH receptors are Gq-coupled: phospholipase C splits PIP2 into IP3, which releases intracellular calcium, and DAG, which activates protein kinase C — signals that drive gonadotropin synthesis and release.

The pituitary decodes pulse frequency. Rapid pulses favor LH and slow pulses favor FSH, and in women the frequency changes through the cycle, becoming continuous before ovulation to produce the LH surge. Upstream, KNDy neurons (kisspeptin, neurokinin B, dynorphin) feed the GnRH neurons (the hypothalamic–pituitary–ovarian axis itself is taught on the Hormonal Contraceptives page). Pulsatility is the point: following an initial stimulation, chronic exposure to a GnRH agonist downregulates GnRH receptors, reduces LH and FSH release, and suppresses ovarian estradiol and testicular testosterone — an effect that reverses when the drug is stopped.

Because an agonist stimulates before it suppresses, testosterone rises to about 50% above baseline in the first weeks of leuprolide. In prostate cancer that surge can cause tumor flare — bone pain, neuropathy, hematuria, bladder outlet obstruction and spinal cord compression — so men with vertebral metastases or urinary obstruction are watched closely, and flare protection with an antiandrogen is taught on the Antiandrogens page. Children treated for central precocious puberty can show a temporary increase in pubertal signs, including vaginal bleeding, because of the initial stimulatory effect.

Antagonists compete with GnRH at the receptor and lower LH and FSH without any initial release. Degarelix binds the pituitary receptor reversibly and suppresses testosterone below castration levels; with oral relugolix, more than half of men reached castrate testosterone by day 4. In fertility treatment, cetrorelix and ganirelix suppress LH within hours and delay the LH surge — and ovulation — while the ovaries are stimulated, an effect that fully reverses within about 48 hours of stopping ganirelix.

Switching off testosterone treats advanced prostate cancer: leuprolide, triptorelin and goserelin as depots or implants, degarelix by injection, and relugolix as an oral tablet. Switching off estrogen makes estrogen-dependent tissue quiescent: leuprolide, goserelin and nafarelin for endometriosis; leuprolide with iron to correct anemia before fibroid surgery; goserelin to thin the endometrium before ablation and for advanced breast cancer in pre- and perimenopausal women; and oral elagolix, which suppresses LH and FSH in a dose-dependent way, for endometriosis pain. Suppressing LH and FSH in a child halts central precocious puberty, and blocking the LH surge prevents premature ovulation during controlled ovarian stimulation.

In women the drugs induce a hypoestrogenic state. Bone mineral density falls and some of the loss may not reverse, so treatment duration is limited; elagolix’s loss is dose- and duration-dependent, and it is contraindicated with known osteoporosis. Add-back restores just enough hormone: norethindrone acetate with leuprolide for endometriosis reduces the BMD loss, and leuprolide is not retreated without it. The oral combinations Myfembree (relugolix) and Oriahnn (elagolix) build the add-back in with estradiol and norethindrone acetate — the estradiol may reduce the bone resorption caused by low estrogen — at the price of an estrogen-progestin boxed warning for thromboembolic disorders and vascular events (Menopausal Hormone Therapy page).

In men, androgen deprivation brings hot flashes, sexual dysfunction and testicular atrophy, and the agonist labels add hyperglycemia and diabetes, metabolic changes and an increased risk of myocardial infarction, sudden cardiac death and stroke. Agonist and antagonist labels alike warn that androgen deprivation may prolong the QT interval, to be weighed in congenital long QT, heart failure, electrolyte abnormalities or QT-prolonging drugs. Mood effects matter in both sexes: depression with GnRH agonists in women, suicidal ideation with elagolix, and emotional lability in children.