|Gonadotropin-releasing hormone agonist|
Leuprorelin, one of the most widely used GnRH agonists.
|Synonyms||GnRH receptor agonists; GnRH blockers; GnRH inhibitors; Antigonadotropins|
|Use||Fertility medicine; Prostate cancer; Breast cancer; Menorrhagia; Endometriosis; Uterine fibroids; Hyperandrogenism; Hirsutism; Precocious puberty; Transgender people; Chemical castration for paraphilias and sex offenders|
|Biological target||GnRH receptor|
A gonadotropin-releasing hormone agonist (GnRH agonist) is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.
Side effects of GnRH agonists are related to sex hormone deficiency and include symptoms of low testosterone levels and low estrogen levels such as hot flashes, sexual dysfunction, vaginal atrophy, osteoporosis, infertility, and diminished sex-specific physical characteristics. They are agonists of the GnRH receptor and work by increasing or decreasing the release of gonadotropins and the production of sex hormones by the gonads. When used to suppress gonadotropin release, GnRH agonists can lower sex hormone levels by 95% in both sexes.
GnRH was discovered in 1971, and GnRH analogues were introduced for medical use in the 1980s. 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 however, they continue to be very expensive.
GnRH agonists are useful in:
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.
GnRH agonists that have been marketed and are available for medical use include buserelin, gonadorelin, goserelin, histrelin, leuprorelin, nafarelin, and triptorelin. GnRH agonists that are used mostly or exclusively in veterinary medicine include deslorelin and fertirelin. GnRH agonists can be administered by injection, by implant, or intranasally as a nasal spray. Injectables have been formulated for daily, monthly, and quarterly use, and implants are available that can last from one month to a year. With the exception of gonadorelin, which is used as a progonadotropin, all approved GnRH agonists are used as antigonadotropins.
|Name||Brand name(s)||Approved uses||Route(s)||Launch||Hits|
|Azagly‑nafarelin||Gonazon||Veterinary medicine (assisted reproduction; chemical castration)||Implant; Injection||2005a||9,190|
|Buserelin||Suprefact||Breast cancer; Endometrial hyperplasia; Endometriosis; Female infertility (assisted reproduction); Prostate cancer; Uterine fibroids||Nasal spray; Injection; Implant||1984||253,000|
|Deslorelin||Ovuplant; Suprelorin||Veterinary medicine (assisted reproduction; chemical castration)||Implant; Injection||1994||85,100|
|Fertirelin||Ovalyse||Veterinary medicine (assisted reproduction)||Injection||1981||41,000|
|Gonadorelin||Factrel; Others||Cryptorchidism; Delayed puberty; Diagnostic agent (pituitary disorders); Hypogonadotropic hypogonadism; Veterinary medicine (assisted reproduction)||Injection; Infusion pump; Nasal spray||1978||259,000|
|Goserelin||Zoladex||Breast cancer; Endometriosis; Female infertility (assisted reproduction); Prostate cancer; Uterine diseases (endometrial thinning agent); Uterine fibroids; Uterine hemorrhage||Implant||1989||400,000|
|Histrelin||Vantas; Supprelin LA||Precocious puberty; Prostate cancer||Implant||1993||283,000|
|Lecirelin||Dalmarelin||Veterinary medicine (assisted reproduction)||Injection||2000a||19,700|
|Leuprorelin||Lupron; Eligard||Breast cancer; Endometriosis; Menorrhagia; Precocious puberty; Prostate cancer; Uterine fibroids||Injection; Implant||1985||536,000|
|Nafarelin||Synarel||Precocious puberty; Endometriosis||Nasal spray||1990||117,000|
|Peforelin||Maprelin||Veterinary medicine (assisted reproduction)||Injection||2001a||3,240|
|Triptorelin||Decapeptyl||Breast cancer; Endometriosis; Female infertility (assisted reproduction); Paraphilias; Precocious puberty; Prostate cancer; Uterine fibroids||Injection||1986||302,000|
|Notes: Hits = Google Search hits (as of February 2018). Footnotes: a = Launched by this year. Sources: See individual articles.|
GnRH agonists are pregnancy category X drugs.
Side effects of the GnRH agonists are signs and symptoms of hypoestrogenism, including hot flashes, headaches, and osteoporosis. In patients under long-term therapy, small amounts of estrogens could be given back (“add-back regimen”) to combat such side effects and to prevent bone wastage. Generally, long-term patients, both male and female, tend to undergo annual DEXA scans to appraise bone density.
GnRH agonists act as agonists of the GnRH receptor, the biological target of gonadotropin-releasing hormone (GnRH). These drugs can be both peptides and small-molecules. They are modeled after the hypothalamic neurohormone GnRH, which interacts with the GnRH receptor to elicit its biologic response, the release of the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH). However, after the initial "flare" response, continued stimulation with GnRH agonists desensitizes the pituitary gland (by causing GnRH receptor downregulation) to GnRH. Pituitary desensitization reduces the secretion of LH and FSH and thus induces a state of hypogonadotropic hypogonadal anovulation, sometimes referred to as “pseudomenopause” or “medical oophorectomy.” GnRH agonists are able to completely shutdown gonadal testosterone production and thereby suppress circulating testosterone levels by 95% or into the castrate/female range in men.
Agonists do not quickly dissociate from the GnRH receptor. As a result, initially there is an increase in FSH and LH secretion (so-called "flare effect"). Levels of LH may increase by up to 10-fold, while levels of testosterone generally increase to 140 to 200% of baseline values. However, after continuous administration, a profound hypogonadal effect (i.e. decrease in FSH and LH) is achieved through receptor downregulation by internalization of receptors. Generally this induced and reversible hypogonadism is the therapeutic goal. During the flare, peak levels of testosterone occur after 2 to 4 days, baseline testosterone levels are returned to by 7 to 8 days, and castrate levels of testosterone are achieved by 2 to 4 weeks. Following cessation of exogenous GnRH agonist it takes 5 to 8 days before normal gonadotropin secretion is completely restored.
Various medications can be used to prevent the testosterone flare and/or its effects at the initiation of GnRH agonist therapy. 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.
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.
GnRH analogues are also used in veterinary medicine. Uses include:
Initial administration of LHRH agonists reliably causes a transient rise in serum T, with peak T values observed at 2–4 d followed by a reduction to baseline values by 7–8 d, and achievement of castrate levels by 2–4 wk . Most studies demonstrate an increase in peak serum T concentrations by 40–100% above baseline during T flare.