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GnRH agonist
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    GnRH agonist

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    Gonadotropin-releasing hormone agonist
    Drug class
    Leuprorelin.svg
    Leuprorelin, one of the most widely used GnRH agonists.
    Class identifiers
    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
    Chemical class Peptides
    In Wikidata

    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, penile 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, they continue to be very expensive.

    Medical uses

    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.

    Available forms

    GnRH agonists marketed for clinical or veterinary use
    Name Brand names Approved uses Routes 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; Procren 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.

    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.

    The clinically used desensitizing GnRH agonists are available in the following pharmaceutical formulations:

    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. 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%.

    Pharmacology

    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 the cessation of exogenous GnRH agonists, 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.

    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

    External links


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