Gonadotropin-releasing hormone agonist

A gonadotropin-releasing hormone agonist (GnRH agonist) is a type of medication which affects gonadotropins and sex hormones.[1] 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.

Gonadotropin-releasing hormone agonist
Drug class
Leuprorelin, one of the most widely used GnRH agonists.
Class identifiers
SynonymsGnRH receptor agonists; GnRH blockers; GnRH inhibitors; Antigonadotropins
UseFertility medicine; Prostate cancer; Breast cancer; Menorrhagia; Endometriosis; Uterine fibroids; Hyperandrogenism; Hirsutism; Precocious puberty; Transgender people; Chemical castration for paraphilias and sex offenders
Biological targetGnRH receptor
Chemical classPeptides
In Wikidata

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.[2][3][4][5]

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:

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
NameBrand namesApproved usesRoutesLaunchHits
Azagly‑nafarelinGonazonVeterinary medicine (assisted reproduction; chemical castration)Implant; Injection2005a9,190
BuserelinSuprefactBreast cancer; Endometrial hyperplasia; Endometriosis; Female infertility (assisted reproduction); Prostate cancer; Uterine fibroidsNasal spray; Injection; Implant1984253,000
DeslorelinOvuplant; SuprelorinVeterinary medicine (assisted reproduction; chemical castration)Implant; Injection199485,100
FertirelinOvalyseVeterinary medicine (assisted reproduction)Injection198141,000
GonadorelinFactrel; OthersCryptorchidism; Delayed puberty; Diagnostic agent (pituitary disorders); Hypogonadotropic hypogonadism; Veterinary medicine (assisted reproduction)Injection; Infusion pump; Nasal spray1978259,000
GoserelinZoladexBreast cancer; Endometriosis; Female infertility (assisted reproduction); Prostate cancer; Uterine diseases (endometrial thinning agent); Uterine fibroids; Uterine hemorrhageImplant1989400,000
HistrelinVantas; Supprelin LAPrecocious puberty; Prostate cancerImplant1993283,000
LecirelinDalmarelinVeterinary medicine (assisted reproduction)Injection2000a19,700
LeuprorelinLupron; Eligard; ProcrenBreast cancer; Endometriosis; Menorrhagia; Precocious puberty; Prostate cancer; Uterine fibroidsInjection; Implant1985536,000
NafarelinSynarelPrecocious puberty; EndometriosisNasal spray1990117,000
PeforelinMaprelinVeterinary medicine (assisted reproduction)Injection2001a3,240
TriptorelinDecapeptylBreast cancer; Endometriosis; Female infertility (assisted reproduction); Paraphilias; Precocious puberty; Prostate cancer; Uterine fibroidsInjection1986302,000
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:[10][11][12][13]

Contraindications

GnRH agonists are pregnancy category X drugs.

Side effects

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.

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%.[14]

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.”[1] 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.[5]

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,[15][16] while levels of testosterone generally increase to 140 to 200% of baseline values.[17] However, after continuous administration, a profound hypogonadal effect (i.e. decrease in FSH and LH) is achieved through receptor downregulation by internalization of receptors.[15] 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.[17][15] Following cessation of exogenous GnRH agonist it takes 5 to 8 days before normal gonadotropin secretion is completely restored.[18]

Various medications can be used to prevent the testosterone flare and/or its effects at the initiation of GnRH agonist therapy.[16][19][20] 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.[16][19][20][21][22][23][24]

Hormone levels with GnRH agonists and antagonists
  • Testosterone levels during the first month of androgen deprivation therapy in men with prostate cancer treated with subcutaneous injections of a GnRH antagonist (degarelix) or agonist (leuprorelin). Doses were 240 then 80 mg/month and 7.5 mg/month, respectively.[25]
  • Testosterone levels in the long-term androgen deprivation therapy of men with prostate cancer by different GnRH agonists administered at 3 month intervals (goserelin, triptorelin and leuprorelin). Dotted line is the threshold for the castrate range.[26]

Chemistry
See also: Gonadotropin-releasing hormone receptor § Agonists

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.

Chemical structures of GnRH agonists

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

References
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  18. Cedrin-Durnerin I, Bidart JM, Robert P, Wolf JP, Uzan M, Hugues JN (May 2000). "Consequences on gonadotrophin secretion of an early discontinuation of gonadotrophin-releasing hormone agonist administration in short-term protocol for in-vitro fertilization". Human Reproduction. 15 (5): 1009–14. doi:10.1093/humrep/15.5.1009. PMID 10783343.
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