Gonadotropin-releasing hormone antagonists (GnRH antagonists) are a class of medications that antagonize the

gonadotropin-releasing hormone receptor The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin-r ...

(GnRH receptor) and thus the action of gonadotropin-releasing hormone (GnRH). They are used in the treatment of

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, f ...

, uterine fibroids,

female infertility Female infertility refers to infertility in women. It affects an estimated 48 million women, with the highest prevalence of infertility affecting women in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Cen ...

assisted reproduction Assisted reproductive technology (ART) includes medical procedures used primarily to address infertility. This subject involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), cryopreservation of gametes ...

, and for other indications. Some GnRH antagonists, such as cetrorelix, are similar in structure to natural GnRH (a hormone made by

neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

in the hypothalamus) but that have an antagonistic effect, while other GnRH antagonists, such as

elagolix Elagolix, sold under the brand name Orilissa, is a gonadotropin-releasing hormone antagonist (GnRH antagonist) medication which is used in the treatment of pain associated with endometriosis in women. It is also under development for the treatme ...

and

relugolix Relugolix, sold under the brand names Orgovyx and Relumina and as one component of Myfembree, is a gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) medication which is used in the treatment of prostate cancer in men and uteri ...

, are non-peptide and

small-molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...

compounds. GnRH antagonists compete with natural GnRH for binding to GnRH receptors, thus decreasing or blocking GnRH action in the body.

Medical uses

Prostate cancer

Testosterone promotes growth of many prostate tumors and therefore reducing circulating testosterone to very low (

castration Castration is any action, surgical, chemical, or otherwise, by which an individual loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical castration uses pharmaceut ...

) 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. 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 as bone pain, urethral obstruction, and

spinal cord compression Spinal cord compression is a form of myelopathy in which the spinal cord is compressed. Causes can be bone fragments from a vertebral fracture, a tumor, abscess, ruptured intervertebral disc or other lesion. When acute it can cause a medical ...

. 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 an antiandrogen 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 in prostate-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 antagonist

abarelix Abarelix, sold under the brand name Plenaxis, is an injectable gonadotropin-releasing hormone antagonist ( GnRH antagonist) which is marketed in Germany and the Netherlands. It is primarily used in oncology to reduce the amount of testosterone ma ...

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 Degarelix, sold under the brand name Firmagon among others, is a hormonal therapy used in the treatment of prostate cancer. Testosterone is a male hormone that promotes growth of many prostate tumours and therefore reducing circulating testoste ...

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.

Fertility treatment

GnRH antagonists are also used for short periods in the prevention of premature LH surge and endogenous ovulation in patients undergoing ovarian hyperstimulation with FSH in preparation for ''in-vitro'' fertilization (IVF). Typically they are administered in the mid-

follicular phase The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle (or, in primates for example, the menstrual cycle) during which follicles in the ovary mature from primary follicle to a ful ...

in stimulated cycles after administration of

gonadotropins Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chorio ...

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. 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. The GnRH antagonists that are currently licensed for use in

fertility treatment Assisted reproductive technology (ART) includes medical procedures used primarily to address infertility. This subject involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), cryopreservation of gametes ...

are cetrorelix and ganirelix.

Uterine disorders

Elagolix Elagolix, sold under the brand name Orilissa, is a gonadotropin-releasing hormone antagonist (GnRH antagonist) medication which is used in the treatment of pain associated with endometriosis in women. It is also under development for the treatme ...

is indicated for the treatment of moderate to severe

pain and

is indicated for the treatment of uterine fibroids.

Other uses

GnRH antagonists are being investigated in the treatment of women with hormone-sensitive breast cancer. In men, they are being investigated in the treatment of benign prostatic hyperplasia and also as potential

contraceptive Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...

agents. GnRH antagonists are also used as

puberty blocker Puberty blockers, also called puberty inhibitors or hormone blockers, are medicines used to postpone puberty in children. The most commonly used puberty blockers are gonadotropin-releasing hormone (GnRH) agonists, which suppress the production ...

s in

transgender youth Transgender youth are children or adolescents who do not identify with the sex they were assigned at birth. Because transgender youth are usually dependent on their parents for care, shelter, financial support, and other needs, transgender yo ...

and to suppress sex hormone levels in transgender adolescents and adults.

Available forms

Currently approved GnRH antagonists include the peptide molecules

, cetrorelix,

degarelix Degarelix, sold under the brand name Firmagon among others, is a hormonal therapy used in the treatment of prostate cancer. Testosterone is a male hormone that promotes growth of many prostate tumours and therefore reducing circulating testoste ...

, and

ganirelix Ganirelix acetate (or diacetate), sold under the brand names Orgalutran and Antagon among others, is an injectable competitive gonadotropin-releasing hormone antagonist (GnRH antagonist). It is primarily used in assisted reproduction to control o ...

and the

compounds

and

. GnRH antagonists are administered by

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, ...

(cetrorelix, degarelix, ganirelix), by

intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...

(abarelix), or by oral administration (elagolix, relugolix). Another non-peptide and orally-active GnRH antagonist that is in development is linzagolix.

Side effects

As with all hormonal therapies, GnRH antagonists are commonly associated with hormonal side effects such as hot flushes,

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

, nausea and weight gain.Serono. Cetrotide prescribing information 2009. Accessed 18-6-2009.Degarelix US prescribing information 2008. Accessed 28-4-2009.Organon. Ganirelix acetate prescribing information 2009. Accessed 18-6-2009. When used in fertility treatment they can also be associated with abdominal pain and ovarian hyperstimulation. Subcutaneously administered agents are also associated with injection-site reactions and

(neither of these being GnRH agonists, but instead being antagonists) has been linked with immediate-onset systemic allergic reactions.

Pharmacology

GnRH antagonists competitively and reversibly bind to GnRH receptors in the pituitary gland, blocking the release of luteinizing hormone (LH) and

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, an ...

(FSH) from the

anterior pituitary A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...

.Engel JB, Schally AV (February 2007). Drug Insight: clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone. Nat. Clin. Pract. Endocrinol. Metab.: 3: 157-167. In men, the reduction in LH subsequently leads to rapid suppression of testosterone production in the testes; in women it leads to suppression of estradiol and

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

production from the ovaries. GnRH antagonists are able to abolish

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...

al sex hormone production and to suppress sex hormone levels into the

castrate Castration is any action, surgical, chemical, or otherwise, by which an individual loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical castration uses pharmaceut ...

range, or by approximately 95%. Unlike the GnRH agonists, which cause an initial stimulation of the hypothalamic–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 reduce sex hormone levels without an initial surge.Van Poppel H, Nilsson S (June 2008). Testosterone surge: rationale for gonadotropin-releasing hormone blockers? Urology 71: 1001-1006.Gustofson RL, Segars JH, Larsen FW (November 2006). Ganirelix acetate causes a rapid reduction in estradiol levels without adversely affecting oocyte maturation in women pretreated with leuprolide acetate who are at risk of ovarian hyperstimulation syndrome. Hum. Reprod. 21: 2830-2837.

Chemistry

GnRH antagonists include peptides such as cetrorelix and non-peptide and

compounds such as

. Peptide GnRH antagonists are GnRH analogues.

References

External links

Degarelix Product website

Fertility Lifelines website

Fertility Treatments website

Fertility Information website
{{DEFAULTSORT:Gonadotropin-Releasing Hormone Antagonist Antiandrogens Antiestrogens Antigonadotropins Gonadotropin-releasing hormone and gonadotropins Hormonal antineoplastic drugs Human female endocrine system GnRH antagonists