Gonadotropin-releasing hormone agonist

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Gonadotropin-releasing hormone agonist
Drug class
Leuprorelin.svg
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

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.

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

GnRH was discovered in 1971 and GnRH analogues were introduced for medical use in the 1980s.[6][7] The most well-known and widely used GnRH analogue is leuprorelin (brand name Lupron). GnRH analogues are available as generic medications. Despite this however, they continue to be very expensive.

Medical uses[edit]

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[edit]

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]

GnRH agonists marketed for clinical or veterinary use

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.

Contraindications[edit]

GnRH agonists are pregnancy category X drugs.

Side effects[edit]

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[edit]

GnRH agonists acts 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]

Chemistry[edit]

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[edit]

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

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

See also[edit]

References[edit]

  1. ^ a b Magon N (October 2011). "Gonadotropin releasing hormone agonists: Expanding vistas". Indian Journal of Endocrinology and Metabolism. 15 (4): 261–7. doi:10.4103/2230-8210.85575. PMC 3193774. PMID 22028996.
  2. ^ Hemat RA (2 March 2003). Andropathy. Urotext. pp. 120–. ISBN 978-1-903737-08-8.
  3. ^ Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 973–. ISBN 978-0-7817-1750-2.
  4. ^ Corson SL, Derman RJ (15 December 1995). Fertility Control. CRC Press. pp. 249–250. ISBN 978-0-9697978-0-7.
  5. ^ a b Novara G, Galfano A, Secco S, Ficarra V, Artibani W (2009). "Impact of surgical and medical castration on serum testosterone level in prostate cancer patients". Urologia Internationalis. 82 (3): 249–55. doi:10.1159/000209352. PMID 19440008.
  6. ^ Gardner DK, Simón C (26 June 2017). Handbook of In Vitro Fertilization (Fourth ed.). CRC Press. pp. 131–. ISBN 978-1-4987-2947-5.
  7. ^ Jameson JL, De Groot LJ (25 February 2015). Endocrinology: Adult and Pediatric E-Book. Elsevier Health Sciences. pp. 2135–. ISBN 978-0-323-32195-2.
  8. ^ van Loenen AC, Huirne JA, Schats R, Hompes PG, Lambalk CB (November 2002). "GnRH agonists, antagonists, and assisted conception". Seminars in Reproductive Medicine. 20 (4): 349–64. doi:10.1055/s-2002-36713. PMID 12536358.
  9. ^ Turner D, Briken P (January 2018). "Treatment of Paraphilic Disorders in Sexual Offenders or Men With a Risk of Sexual Offending With Luteinizing Hormone-Releasing Hormone Agonists: An Updated Systematic Review". The Journal of Sexual Medicine. 15 (1): 77–93. doi:10.1016/j.jsxm.2017.11.013. PMID 29289377.
  10. ^ Richard A. Lehne; Laura Rosenthal (25 June 2014). Pharmacology for Nursing Care - E-Book. Elsevier Health Sciences. pp. 1296–. ISBN 978-0-323-29354-9.
  11. ^ James L. Gulley (20 December 2011). Prostate Cancer. Demos Medical Publishing. pp. 503–. ISBN 978-1-936287-46-8.
  12. ^ Charles G. D. Brook; Peter Clayton; Rosalind Brown (22 September 2011). Brook's Clinical Pediatric Endocrinology. John Wiley & Sons. pp. 242–. ISBN 978-1-4443-1673-5.
  13. ^ Surveen Ghumman (22 September 2015). Principles and Practice of Controlled Ovarian Stimulation in ART. Springer. pp. 96–. ISBN 978-81-322-1686-5.
  14. ^ "Researchers Suggest Hormone Therapy for Prostate Cancer Can Cause Serious Heart Problems and Death". Genetic Engineering & Biotechnology News. 22 September 2009.
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  16. ^ a b c Thompson IM (2001). "Flare Associated with LHRH-Agonist Therapy". Rev Urol. 3 Suppl 3: S10–4. PMC 1476081. PMID 16986003.
  17. ^ a b Krakowsky Y, Morgentaler A (July 2017). "Risk of Testosterone Flare in the Era of the Saturation Model: One More Historical Myth". Eur Urol Focus. doi:10.1016/j.euf.2017.06.008. PMID 28753828. 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 [10]. Most studies demonstrate an increase in peak serum T concentrations by 40–100% above baseline during T flare.
  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.
  19. ^ a b Scaletscky R, Smith JA (April 1993). "Disease flare with gonadotrophin-releasing hormone (GnRH) analogues. How serious is it?". Drug Saf. 8 (4): 265–70. doi:10.2165/00002018-199308040-00001. PMID 8481213.
  20. ^ a b Vis AN, van der Sluis TM, Al-Itejawi HH, van Moorselaar RJ, Meuleman EJ (January 2015). "Risk of disease flare with LHRH agonist therapy in men with prostate cancer: myth or fact?". Urol. Oncol. 33 (1): 7–15. doi:10.1016/j.urolonc.2014.04.016. PMID 25159013.
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  22. ^ Shimizu TS, Shibata Y, Jinbo H, Satoh J, Yamanaka H (1995). "Estramustine phosphate for preventing flare-up in luteinizing hormone-releasing hormone analogue depot therapy". Eur. Urol. 27 (3): 192–5. doi:10.1159/000475159. PMID 7541359.
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External links[edit]