Gonadotropin-releasing hormone agonist

A gonadotropin-releasing hormone agonist (GnRH agonist) is a type of medication which affects

GnRH was discovered in 1971, and GnRH analogues were introduced for medical use in the 1980s.[6]^[7] Their nonproprietary names usually end in -relin. The most well-known and widely used GnRH analogues are leuprorelin (brand name Lupron) and triptorelin (brand name Decapeptyl). GnRH analogues are available as generic medications. Despite this, they continue to be very expensive.

Medical uses

GnRH agonists are useful in:

• trigger oocyte release. GnRH agonists routinely used for this purpose are: buserelin, leuprorelin, nafarelin, and triptorelin.^[8]
• GnRH antagonist instead of a GnRH agonist for suppression of spontaneous ovulation
  , because using GnRH agonist for that purpose as well inactivates the axis for which it is intended to work for final maturation induction.
• Treatment of cancers that are hormonally sensitive and where a hypogonadal state decreases the chances of a recurrence. Thus they are commonly employed in the medical management of prostate cancer and have been used in patients with breast cancer.
• Delaying puberty in individuals with precocious puberty.
• Delaying puberty pending treatment decisions in children with gender dysphoria
  .
• Management of female disorders that are dependent on
  menorrhagia, endometriosis, adenomyosis, or uterine fibroids
  may receive GnRH agonists to suppress ovarian activity and induce a hypoestrogenic state.
• Suppressing sex hormone levels in
  transgender women
  .
• Severe cases of hyperandrogenism, such as in congenital adrenal hyperplasia.
• As part of the pharmacologic treatment of paraphilic disorders in sexual offenders or men with a high risk of sexual offending.^[9]

Women of reproductive age who undergo cytotoxic chemotherapy have been pretreated with GnRH agonists to reduce the risk of oocyte loss during such therapy and preserve ovarian function. Further studies are necessary to prove that this approach is useful.

Available forms

GnRH agonists that have been marketed and are available for medical use include

The clinically used desensitizing GnRH agonists are available in the following pharmaceutical formulations:^{[10][11][12][13]}

• Short-acting injection (once per day): buserelin, histrelin, leuprorelin, triptorelin
• Long-acting depot injection or injected pellet (once every one to six months): leuprorelin, triptorelin
• Injected implant (once every one to three months): buserelin, goserelin, leuprorelin
• Surgically implanted pellet (once per year): histrelin, leuprorelin
• Nasal spray (two to three times per day): buserelin, nafarelin

Contraindications

GnRH agonists are pregnancy category X drugs.

Side effects

Common side effects of the GnRH agonists and antagonists include symptoms of hypogonadism such as hot flashes, gynecomastia, fatigue, weight gain, fluid retention, erectile dysfunction and decreased libido. Long term therapy can result in metabolic abnormalities, weight gain, worsening of diabetes and osteoporosis. Rare, but potentially serious adverse events include transient worsening of prostate cancer due to surge in testosterone with initial injection of GnRH agonists and pituitary apoplexy in patients with pituitary adenoma. Single instances of clinically apparent liver injury have been reported with some GnRH agonists (histrelin, goserelin), but the reports were not very convincing. There is no evidence to indicate that there is cross sensitivity to liver injury among the various GnRH analogues despite their similarity in structure.^[14] There is also a report that GnRH agonists used in the treatment of advanced prostate cancer may increase the risk of heart problems by 30%.^[15]

Pharmacology

GnRH agonists act as

Various medications can be used to prevent the testosterone flare and/or its effects at the initiation of GnRH agonist therapy.[17]^[20][21] These include antigonadotropins such as progestogens like cyproterone acetate and chlormadinone acetate and estrogens like diethylstilbestrol, fosfestrol (diethylstilbestrol diphosphate), and estramustine phosphate; antiandrogens such as nonsteroidal antiandrogens like flutamide, nilutamide, and bicalutamide; and androgen synthesis inhibitors such as ketoconazole and abiraterone acetate.^{[17][20][21][22][23][24][25]}

Chemistry

GnRH agonists are synthetically modeled after the natural GnRH decapeptide with specific modifications, usually double and single substitutions and typically in position 6 (amino acid substitution), 9 (alkylation) and 10 (deletion). These substitutions inhibit rapid degradation. Agonists with two substitutions include: leuprorelin, buserelin, histrelin, goserelin, and deslorelin. The agents nafarelin and triptorelin are agonists with single substitutions at position 6.

Veterinary uses

GnRH analogues are also used in veterinary medicine. Uses include:

• Temporary suppression of fertility in female dogs
• Induction of ovulation in mares

See also

• Gonadotropin-releasing hormone
• Gonadotropin-releasing hormone antagonist
• Progonadotropin

References