Gonadotropin-releasing hormone agonist

Last updated

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
Legal status
In Wikidata

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. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

Contents

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-nafarelin GonazonVeterinary medicine (assisted reproduction; chemical castration)Implant; Injection2005a9,190
Buserelin SuprefactBreast cancer; Endometrial hyperplasia; Endometriosis; Female infertility (assisted reproduction); Prostate cancer; Uterine fibroidsNasal spray; Injection; Implant1984253,000
Deslorelin Ovuplant; SuprelorinVeterinary medicine (assisted reproduction; chemical castration)Implant; Injection199485,100
Fertirelin OvalyseVeterinary medicine (assisted reproduction)Injection198141,000
Gonadorelin Factrel; OthersCryptorchidism; Delayed puberty; Diagnostic agent (pituitary disorders); Hypogonadotropic hypogonadism; Veterinary medicine (assisted reproduction)Injection; Infusion pump; Nasal spray1978259,000
Goserelin ZoladexBreast cancer; Endometriosis; Female infertility (assisted reproduction); Prostate cancer; Uterine diseases (endometrial thinning agent); Uterine fibroids; Uterine hemorrhageImplant1989400,000
Histrelin Vantas; Supprelin LAPrecocious puberty; Prostate cancerImplant1993283,000
Lecirelin DalmarelinVeterinary medicine (assisted reproduction)Injection2000a19,700
Leuprorelin Lupron; Eligard; Procren; Prostap; StaladexBreast cancer; Endometriosis; Menorrhagia; Precocious puberty; Prostate cancer; Uterine fibroidsInjection; Implant1985536,000
Nafarelin SynarelPrecocious puberty; EndometriosisNasal spray1990117,000
Peforelin MaprelinVeterinary medicine (assisted reproduction)Injection2001a3,240
Triptorelin DecapeptylBreast 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

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 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, [16] [17] while levels of testosterone generally increase to 140 to 200% of baseline values. [18] However, after continuous administration, a profound hypogonadal effect (i.e. decrease in FSH and LH) is achieved through receptor downregulation by internalization of receptors. [16] 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 two to four weeks. [18] [16] A 7 day study of infertile women found that restoration of normal gonadotropin secretion takes 5 to 8 days after cessation of exogenous GnRH agonists. [19]

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]

Hormone levels with GnRH agonists and antagonists

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.

Chemical structures of GnRH agonists

Veterinary uses

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

See also

Related Research Articles

<span class="mw-page-title-main">Diethylstilbestrol</span> Chemical compound

Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency, treatment of prostate cancer and breast cancer, and other uses. By 2007, it was only used in the treatment of prostate cancer and breast cancer. In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer. While most commonly taken by mouth, DES was available for use by other routes as well, for instance, vaginal, topical, and by injection.

<span class="mw-page-title-main">Gonadotropin-releasing hormone</span> Mammalian protein found in Homo sapiens

Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

<span class="mw-page-title-main">Goserelin</span> Chemical compound

Goserelin, sold under the brand name Zoladex among others, is a medication which is used to suppress production of the sex hormones, particularly in the treatment of breast cancer and prostate cancer. It is an injectable gonadotropin releasing hormone agonist.

<span class="mw-page-title-main">Leuprorelin</span> Manufactured (artificial) injectable hormone

Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, for early puberty, or as part of transgender hormone therapy. It is given by injection into a muscle or under the skin.

<span class="mw-page-title-main">Nafarelin</span> Pharmaceutical drug

Nafarelin, sold under the brand name Synarel among others, is a gonadotropin-releasing hormone agonist medication which is used in the treatment of endometriosis and early puberty. It is also used to treat uterine fibroids, to control ovarian stimulation in in vitro fertilization (IVF), and as part of transgender hormone therapy. The medication is used as a nasal spray two to three times per day.

<span class="mw-page-title-main">Buserelin</span> Chemical compound

Buserelin, sold under the brand name Suprefact among others, is a medication which is used primarily in the treatment of prostate cancer and endometriosis. It is also used for other indications such as the treatment of premenopausal breast cancer, uterine fibroids, and early puberty, in assisted reproduction for female infertility, and as a part of transgender hormone therapy. In addition, buserelin is used in veterinary medicine. The medication is typically used as a nasal spray three times per day, but is also available for use as a solution or implant for injection into fat.

<span class="mw-page-title-main">Flutamide</span> Chemical compound

Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.

<span class="mw-page-title-main">Triptorelin</span> GnRH-agonist

Triptorelin, sold under the brand name Decapeptyl among others, is a medication that acts as an agonist analog of gonadotropin-releasing hormone, repressing expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

<span class="mw-page-title-main">Gonadotropin-releasing hormone antagonist</span> Class of medications

Gonadotropin-releasing hormone antagonists are a class of medications that antagonize the gonadotropin-releasing hormone receptor and thus the action of gonadotropin-releasing hormone (GnRH). They are used in the treatment of prostate cancer, endometriosis, uterine fibroids, female infertility in assisted reproduction, and for other indications.

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-releasing hormone (GnRH). Agonist binding to the GnRH receptor activates the Gq/11 family of heterotrimeric G proteins. The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate.

<span class="mw-page-title-main">Histrelin</span> Chemical compound

Histrelin acetate, sold under the brand name Supprelin among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency. When present in the bloodstream, it acts on particular cells of the pituitary gland called gonadotropes. Histrelin stimulates these cells to release luteinizing hormone and follicle-stimulating hormone. Thus it is considered a gonadotropin-releasing hormone agonist or GnRH agonist.

Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval for use in in vitro fertilisation (IVF), or be given time to ovulate, resulting in superovulation which is the ovulation of a larger-than-normal number of eggs, generally in the sense of at least two. When ovulated follicles are fertilised in vivo, whether by natural or artificial insemination, there is a very high risk of a multiple pregnancy.

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<span class="mw-page-title-main">Degarelix</span> Chemical compound

Degarelix, sold under the brand name Firmagon among others, is a hormonal therapy used in the treatment of prostate cancer.

<span class="mw-page-title-main">Androgen deprivation therapy</span> Hormonal treatment for prostate cancer

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Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

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References

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