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Gonadotropin-releasing hormone antagonist
Drug class
Cetrorelix, one of the most widely usedGnRH antagonists.
Class identifiers
Synonyms	GnRH receptor antagonists; GnRH blockers; GnRH inhibitors; Antigonadotropins
Use	Infertility;Prostate cancer;Precocious puberty;Breast cancer;Endometriosis;Uterine fibroids;Transgender people
Biological target	GnRH receptor
Chemical class	Peptides;Non-peptides
Legal status
In Wikidata

Gonadotropin-releasing hormone antagonists (GnRH antagonists) are a class of medications thatantagonize thegonadotropin-releasing hormone receptor (GnRH receptor) and thus the action ofgonadotropin-releasing hormone (GnRH). They are used in the treatment ofprostate cancer,endometriosis,uterine fibroids,female infertility inassisted reproduction, and for other indications.

Some GnRH antagonists, such ascetrorelix, are similar in structure to natural GnRH (ahormone made byneurons in the hypothalamus) but that have an antagonistic effect, while other GnRH antagonists, such aselagolix andrelugolix, arenon-peptide andsmall-molecule compounds. GnRH antagonistscompete with natural GnRH for binding to GnRH receptors, thus decreasing or blocking GnRH action in the body.

Testosterone promotes growth of many prostatetumors and therefore reducing circulating testosterone to very low (castration) levels is often the treatment goal in the management of men with advanced prostate cancer. GnRH antagonists are used to provide fast suppression of testosterone without the surge in testosterone levels that is seen when treating patients with GnRH agonists.^[1] In patients with advanced disease, this surge in testosterone can lead to a flare-up of the tumour, which can precipitate a range of clinical symptoms such asbone pain,urethral obstruction, andspinal cord compression. Drug agencies have issued warnings regarding this phenomenon in the prescribing information for GnRH agonists. As testosterone surge does not occur with GnRH antagonists, there is no need for patients to receive anantiandrogen as flare protection during prostate cancer treatment. GnRH agonists also induce an increase in testosterone levels after each reinjection of the drug – a phenomenon that does not occur with GnRH antagonists.

The reduction in testosterone levels that occurs during GnRH antagonist therapy subsequently reduces the size of the prostate cancer. This in turn results in a reduction inprostate-specific antigen (PSA) levels in the patient's blood and so measuring PSA levels is a way to monitor how patients with prostate cancer are responding to treatment. GnRH antagonists have an immediate onset of action leading to a fast and profound suppression of testosterone and are therefore especially valuable in the treatment of patients with prostate cancer, where fast control of disease is needed.

The GnRH antagonistabarelix was withdrawn from the United States market in 2005 and is now only marketed in Germany for use in patients with symptomatic prostate cancer.Degarelix is a GnRH antagonist that is approved for use in patients with advanced hormone-sensitive prostate cancer throughout Europe and also in the United States.^[2]

GnRH antagonists are also used for short periods in the prevention of premature LH surge and endogenousovulation in patients undergoingovarian hyperstimulation with FSH in preparation forin-vitro fertilization (IVF).^[3][4][5] Typically they are administered in the mid-follicular phase in stimulated cycles after administration ofgonadotropins and prior to the administration of hCG – which is given to stimulate ovulation. This protocol is likely beneficial in women expected to be hyper-responders, and probably also those expected to be poor responders to ovarian hyperstimulation.^[6] There is probably little or no difference between GnRH antagonist and GnRH agonist protocols in terms of live birth or risk of miscarriage but GnRH antagonists probably reduce the risk of ovarian hyperstimulation syndrome.^[7] The GnRH antagonists that are currently licensed for use infertility treatment are cetrorelix and ganirelix.

Elagolix is indicated for the treatment of moderate to severeendometriosis pain andrelugolix is indicated for the treatment ofuterine fibroids.

GnRH antagonists are being investigated in the treatment of women with hormone-sensitivebreast cancer.^[8][9] In men, they are being investigated in the treatment ofbenign prostatic hyperplasia^[10] and also as potentialcontraceptive agents.^[11] GnRH antagonists could be used aspuberty blockers intransgender youth and to suppresssex hormone levels intransgender adolescents and adults.^{[12][13][14][15]}

Currently approved GnRH antagonists include thepeptide moleculesabarelix,cetrorelix,degarelix, andganirelix and thesmall-molecule compoundselagolix andrelugolix. GnRH antagonists are administered bysubcutaneous injection (cetrorelix, degarelix, ganirelix), byintramuscular injection (abarelix), or byoral administration (elagolix, relugolix).

Another non-peptide and orally-active GnRH antagonist that is in development islinzagolix.^[17]

As with all hormonal therapies, GnRH antagonists are commonly associated with hormonal side effects such ashot flushes,headache,nausea andweight gain.^[18][19][20] When used in fertility treatment they can also be associated with abdominal pain and ovarian hyperstimulation.^[18][20] Subcutaneously administered agents are also associated with injection-site reactions^[19][21] andabarelix (neither of these being GnRH agonists, but instead being antagonists) has been linked with immediate-onset systemic allergic reactions.^[22]

GnRH antagonists competitively and reversibly bind to GnRH receptors in thepituitary gland, blocking the release ofluteinizing hormone (LH) andfollicle-stimulating hormone (FSH) from theanterior pituitary.^[23][24] In men, the reduction in LH subsequently leads to rapid suppression oftestosteroneproduction in thetestes; in women it leads to suppression ofestradiol andprogesterone production from theovaries. GnRH antagonists are able to abolishgonadal sex hormone production and to suppress sex hormone levels into thecastrate range, or by approximately 95%.

Unlike the GnRH agonists, which cause an initial stimulation of thehypothalamic–pituitary–gonadal axis (HPG axis) that leads to a surge in testosterone or estrogen levels, GnRH antagonists have an immediate onset of action and rapidly reducesex hormone levels without an initial surge.^[1][25]

GnRH antagonists includepeptides such ascetrorelix andnon-peptide andsmall-molecule compounds such aselagolix. Peptide GnRH antagonists areGnRH analogues.

• Gonadotropin-releasing hormone modulator
• Gonadotropin-releasing hormone agonist

• Antiandrogens
• Antigonadotropins
• Gonadotropin-releasing hormone and gonadotropins
• Hormonal antineoplastic drugs
• Human female endocrine system
• GnRH antagonists

• Articles with short description
• Short description matches Wikidata
• Articles lacking reliable references from November 2014
• All articles lacking reliable references