Gonadotropin-releasing hormone agonist#Available forms

GnRH agonists are used medically to manage hormone-related conditions such as uterine fibroids and endometriosis, precocious puberty, and hormone-sensitive cancers like prostate and breast cancer, as well as in fertility treatments to control the timing of ovulation. 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:{{cite book |author1=Richard A. Lehne |url=https://books.google.com/books?id=udTsAwAAQBAJ&pg=PA1296 |title=Pharmacology for Nursing Care - E-Book |author2=Laura Rosenthal |date=25 June 2014 |publisher=Elsevier Health Sciences |isbn=978-0-323-29354-9 |pages=1296–}}{{cite book |author=James L. Gulley |url=https://books.google.com/books?id=9EAGOlzrcR0C&pg=PA503 |title=Prostate Cancer |date=20 December 2011 |publisher=Demos Medical Publishing |isbn=978-1-936287-46-8 |pages=503–}}{{cite book |author1=Charles G. D. Brook |url=https://books.google.com/books?id=cLgTCCqVESYC&pg=PA242 |title=Brook's Clinical Pediatric Endocrinology |author2=Peter Clayton |author3=Rosalind Brown |date=22 September 2011 |publisher=John Wiley & Sons |isbn=978-1-4443-1673-5 |pages=242–}}{{cite book |author=Surveen Ghumman |url=https://books.google.com/books?id=UxecCgAAQBAJ&pg=PA96 |title=Principles and Practice of Controlled Ovarian Stimulation in ART |date=22 September 2015 |publisher=Springer |isbn=978-81-322-1686-5 |pages=96–}}

• Short-acting injection (once per day): buserelin, histrelin, leuprorelin, triptorelin
• Long-acting depot injection or injected pellet (once every one to six months): leuprorelin, triptorelin
• Injected implant (once every one to three months): buserelin, goserelin, leuprorelin
• Surgically implanted pellet (once per year): histrelin, leuprorelin
• Nasal spray (two to three times per day): buserelin, nafarelin

Treatment of cancers that are hormonally sensitive and where a hypogonadal state decreases the chances of a recurrence. Thus they are commonly employed in the medical management of prostate cancer and have been used in patients with breast cancer.{{cn|date=January 2025}}

GnRH agonists are used in puberty treatment primarily to manage precocious puberty (early onset of puberty) by suppressing the release of sex hormones, to slow pubertal progression until an appropriate age.{{Citation needed|date=January 2025}} They are also used in gender-affirming care to delay puberty in transgender and non-binary youth, providing time to explore gender identity before irreversible physical changes occur.{{Citation needed|date=January 2025}}

Management of female disorders that are dependent on estrogen production. Women with menorrhagia, endometriosis, adenomyosis, or uterine fibroids may receive GnRH agonists to suppress ovarian activity and induce a hypoestrogenic state.{{cn|date=January 2025}}

• Suppressing sex hormone levels in transgender people, especially transgender women.{{Citation needed|date=January 2025}}
• Severe cases of hyperandrogenism, such as in congenital adrenal hyperplasia.{{Citation needed|date=January 2025}}
• As part of the pharmacologic treatment of paraphilic disorders in sexual offenders or men with a high risk of sexual offending.{{cite journal | vauthors = Turner D, Briken P | title = 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 | journal = The Journal of Sexual Medicine | volume = 15 | issue = 1 | pages = 77–93 | date = January 2018 | pmid = 29289377 | doi = 10.1016/j.jsxm.2017.11.013 | doi-access = free }}

A common use of GnRHa is in fertility treatment and assisted reproduction technology. These medications are often used to moderate or reduce increases in luteinizing hormone when a person is preparing for an oocyte retrieval for in vitro fertilization.{{Cite journal |last1=Siristatidis |first1=Charalampos S |last2=Yong |first2=Li Ning |last3=Maheshwari |first3=Abha |last4=Ray Chaudhuri Bhatta |first4=Smriti |date=2025-01-09 |editor-last=Cochrane Gynaecology and Fertility Group |title=Gonadotropin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction |url=http://doi.wiley.com/10.1002/14651858.CD006919.pub5 |journal=Cochrane Database of Systematic Reviews |language=en |volume=2025 |issue=1 |pages=CD006919 |doi=10.1002/14651858.CD006919.pub5|pmid=39783453 |pmc=12043201 |pmc-embargo-date=January 9, 2026 }} GNRHa's act as a suppressor of spontaneous ovulation as part of controlled ovarian hyperstimulation, which is an essential component in in vitro fertilisation (IVF). Typically, after GnRH agonists have induced a state of hypoestrogenism, exogenous FSH is given to stimulate ovarian follicle, followed by human chorionic gonadotropins (hCG) to trigger oocyte release. GnRH agonists routinely used for this purpose are: buserelin, leuprorelin, nafarelin, and triptorelin.{{cite journal |vauthors=van Loenen AC, Huirne JA, Schats R, Hompes PG, Lambalk CB |date=November 2002 |title=GnRH agonists, antagonists, and assisted conception |url=http://www.medscape.com/viewarticle/447779_4 |journal=Seminars in Reproductive Medicine |volume=20 |issue=4 |pages=349–64 |doi=10.1055/s-2002-36713 |pmid=12536358 |s2cid=45436435|url-access=subscription }} In addition, GnRHa medications may be used to assist with final maturation induction after having performed controlled ovarian hyperstimulation. Usage of GnRH agonist for this purpose necessitates using a GnRH antagonist instead of a GnRH agonist for suppression of spontaneous ovulation, because using GnRH agonist for that purpose as well inactivates the axis for which it is intended to work for final maturation induction.{{Citation needed|date=January 2025}}

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.{{cite journal | author=Zeev Blumenfeld| title=How to Preserve Fertility in Young Women Exposed to Chemotherapy? The Role of GnRH Agonist Cotreatment in Addition to Cryopreservation of Embrya, Oocytes, or Ovaries| url=https://academic.oup.com/oncolo/article/12/9/1044/6398789| journal=The Oncologist| volume=12| issue=9| pages=1044–1054| date=September 2007 | doi=10.1634/theoncologist.12-9-1044| pmid=17914074}}

GnRH agonists are pregnancy category X drugs.

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.LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Gonadotropin Releasing Hormone (GnRH) Analogues. [Updated 2018 Mar 20]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547863/

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%.{{cite web | url = http://www.genengnews.com/news/bnitem.aspx?name=63455946&source=genwire | title = Researchers Suggest Hormone Therapy for Prostate Cancer Can Cause Serious Heart Problems and Death | website = Genetic Engineering & Biotechnology News | date = 22 September 2009 }}

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,{{cite book|vauthors = Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA|title=Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set|url=https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2939|date=25 August 2011|publisher=Elsevier Health Sciences|isbn=978-1-4160-6911-9|pages=2939–}}{{cite journal | vauthors = Thompson IM | title = Flare Associated with LHRH-Agonist Therapy | journal = Rev Urol | volume = 3 | pages = S10–4 | date = 2001 | issue = Suppl 3 | pmid = 16986003 | pmc = 1476081 }} while levels of testosterone generally increase to 140 to 200% of baseline values.{{cite journal | vauthors = Krakowsky Y, Morgentaler A | title = Risk of Testosterone Flare in the Era of the Saturation Model: One More Historical Myth | journal = Eur Urol Focus | volume = 5| issue = 1| pages = 81–89| date = July 2017 | pmid = 28753828 | doi = 10.1016/j.euf.2017.06.008 | s2cid = 10011200 | quote = 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.}} 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 two to four weeks. 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.{{cite journal | vauthors = Cedrin-Durnerin I, Bidart JM, Robert P, Wolf JP, Uzan M, Hugues JN | title = Consequences on gonadotrophin secretion of an early discontinuation of gonadotrophin-releasing hormone agonist administration in short-term protocol for in-vitro fertilization | journal = Human Reproduction | volume = 15 | issue = 5 | pages = 1009–14 | date = May 2000 | pmid = 10783343 | doi = 10.1093/humrep/15.5.1009 | doi-access = }}

Various medications can be used to prevent the testosterone flare and/or its effects at the initiation of GnRH agonist therapy.{{cite journal | vauthors = Scaletscky R, Smith JA | title = Disease flare with gonadotrophin-releasing hormone (GnRH) analogues. How serious is it? | journal = Drug Saf | volume = 8 | issue = 4 | pages = 265–70 | date = April 1993 | pmid = 8481213 | doi = 10.2165/00002018-199308040-00001 | s2cid = 36964191 }}{{cite journal | vauthors = Vis AN, van der Sluis TM, Al-Itejawi HH, van Moorselaar RJ, Meuleman EJ | title = Risk of disease flare with LHRH agonist therapy in men with prostate cancer: myth or fact? | journal = Urol. Oncol. | volume = 33 | issue = 1 | pages = 7–15 | date = January 2015 | pmid = 25159013 | doi = 10.1016/j.urolonc.2014.04.016 }} 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.{{cite journal | vauthors = Kotake T, Usami M, Akaza H, Koiso K, Homma Y, Kawabe K, Aso Y, Orikasa S, Shimazaki J, Isaka S, Yoshida O, Hirao Y, Okajima E, Naito S, Kumazawa J, Kanetake H, Saito Y, Ohi Y, Ohashi Y | title = Goserelin acetate with or without antiandrogen or estrogen in the treatment of patients with advanced prostate cancer: a multicenter, randomized, controlled trial in Japan. Zoladex Study Group | journal = Jpn. J. Clin. Oncol. | volume = 29 | issue = 11 | pages = 562–70 | date = November 1999 | pmid = 10678560 | doi = 10.1093/jjco/29.11.562 | doi-access = free }}{{cite journal | vauthors = Shimizu TS, Shibata Y, Jinbo H, Satoh J, Yamanaka H | title = Estramustine phosphate for preventing flare-up in luteinizing hormone-releasing hormone analogue depot therapy | journal = Eur. Urol. | volume = 27 | issue = 3 | pages = 192–5 | date = 1995 | pmid = 7541359 | doi = 10.1159/000475159 }}{{cite journal | vauthors = Sugiono M, Winkler MH, Okeke AA, Benney M, Gillatt DA | title = Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer--a pilot study | journal = Prostate Cancer Prostatic Dis. | volume = 8 | issue = 1 | pages = 91–4 | date = 2005 | pmid = 15711607 | doi = 10.1038/sj.pcan.4500784 | doi-access = | s2cid = 9151853 }}{{cite journal | vauthors = Pokuri VK, Nourkeyhani H, Betsy B, Herbst L, Sikorski M, Spangenthal E, Fabiano A, George S | title = Strategies to Circumvent Testosterone Surge and Disease Flare in Advanced Prostate Cancer: Emerging Treatment Paradigms | journal = J Natl Compr Canc Netw | volume = 13 | issue = 7 | pages = e49–55 | date = July 2015 | pmid = 26150586 | doi = 10.6004/jnccn.2015.0109 | doi-access = free }}

{{Hormone levels with gonadotropin-releasing hormone agonists and antagonists}}

{{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.{{cn|date=January 2025}}

GnRH analogues are also used in veterinary medicine. Uses include:{{cn|date=January 2025}}

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

• Gonadotropin-releasing hormone
• Gonadotropin-releasing hormone antagonist
• Progonadotropin

{{Reflist}}

• [https://patient.info/medicine/buserelin-for-women-suprecur Buserelin website]
• [https://web.archive.org/web/20051210124110/http://www.endometriosis.org/gnrh.html Use of agonists in endometriosis]
• [https://www.lupron.com/ Lupron, by manufacturer]
• [http://www.supprelinla.com/ SupprelinLA, by Endo Pharmaceuticals, Inc.]
• [https://web.archive.org/web/20051208062611/http://www.zoladex.com/professional/zoladex/ Information of use of Zoladex in prostate cancer]

{{GnRH and gonadotropins}}

{{Assisted reproductive technology}}

{{GnRH and gonadotropin receptor modulators}}

{{DEFAULTSORT:Gonadotropin-Releasing Hormone Agonist}}

Category:Antiandrogens

Category:Antigonadotropins

Category:Fertility medicine

Category:Hormonal antineoplastic drugs

Category:Gonadotropin-releasing hormone and gonadotropins

Category:Progonadotropins