Gonadotropin-releasing hormone agonist

Gonadotropin-releasing hormone agonist
Drug class

Leuprorelin (leuprolide), one of the most widely used GnRH agonists.
Class identifiers
Synonyms GnRH receptor agonists; GnRH blockers; GnRH inhibitors; Antigonadotropins
Use Infertility; Prostate cancer; Precocious puberty; Breast cancer; Endometriosis; Uterine fibroids; Transgender people
Biological target GnRH receptor
Chemical class Peptides
In Wikidata

A gonadotropin-releasing hormone agonist (GnRH agonist, GnRH–A) is a type of drug that acts as an agonist 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][2]

GnRH agonists are pregnancy category X drugs.

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.

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%.[4]

Flare effect and downregulation

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.[5] However, after about 10 to 20 days,[5] 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.

Agonists with double and single substitutions

GnRH agonists are synthetically modeled after the natural GnRH decapeptide with specific modifications, typically in position 6 (amino acid substitution), 9 (alkylation) and 10 (deletion). These substitutions inhibit rapid degradation. Agonists with two substitutions include: leuprolide (Lupron, Eligard), buserelin (Suprefact, Suprecor), histrelin (Supprelin LA, Vantas), goserelin (Zoladex), and deslorelin (Suprelorin, Ovuplant). The agents nafarelin (Synarel) and triptorelin are agonists with single substitutions at position 6.

Administration

These medications can be administered intranasally, by injection, or by implant. Injectables have been formulated for daily, monthly, and quarterly use; and implants can last from 1 to 12 months.

See also

References

  1. ↑ Magon N (October 2011). "Gonadotropin releasing hormone agonists: Expanding vistas". Indian Journal of Endocrinology and Metabolism. 15 (4): 261–7. PMC 3193774 Freely accessible. PMID 22028996. doi:10.4103/2230-8210.85575.
  2. ↑ Roth C, Hegemann F, Hildebrandt J, Balzer I, Witt A, Wuttke W, Jarry H (January 2004). "Pituitary and gonadal effects of GnRH (gonadotropin releasing hormone) analogues in two peripubertal female rat models". Pediatric Research. 55 (1): 126–33. PMID 14605254. doi:10.1203/01.PDR.0000100463.84334.3F.
  3. ↑ 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. PMID 12536358. doi:10.1055/s-2002-36713.
  4. ↑ "Researchers Suggest Hormone Therapy for Prostate Cancer Can Cause Serious Heart Problems and Death". Genetic Engineering & Biotechnology News. 22 September 2009.
  5. 1 2 Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2939–. ISBN 978-1-4160-6911-9.
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