Gonadotropin-releasing hormone antagonist

Last updated
Gonadotropin-releasing hormone antagonist
Drug class
Cetrorelix.svg
Cetrorelix, one of the most widely used GnRH antagonists.
Class identifiers
Synonyms GnRH receptor antagonists; 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; Non-peptides
Legal status
In Wikidata

Gonadotropin-releasing hormone antagonists (GnRH antagonists) are a class of medications that antagonize the gonadotropin-releasing hormone receptor (GnRH 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.

Contents

Some GnRH antagonists, such as cetrorelix, are similar in structure to natural GnRH (a hormone made by neurons in the hypothalamus) but that have an antagonistic effect, while other GnRH antagonists, such as elagolix and relugolix, are non-peptide and small-molecule compounds. GnRH antagonists compete with natural GnRH for binding to GnRH receptors, thus decreasing or blocking GnRH action in the body.

Medical uses

Prostate cancer

Testosterone promotes growth of many prostate tumors and therefore reducing circulating testosterone to very low (castration) levels is often the treatment goal in the management of men with advanced prostate cancer. GnRH antagonists are used to provide fast suppression of testosterone without the surge in testosterone levels that is seen when treating patients with GnRH agonists. [1] In patients with advanced disease, this surge in testosterone can lead to a flare-up of the tumour, which can precipitate a range of clinical symptoms such as bone pain, urethral obstruction, and spinal cord compression. Drug agencies have issued warnings regarding this phenomenon in the prescribing information for GnRH agonists. As testosterone surge does not occur with GnRH antagonists, there is no need for patients to receive an antiandrogen as flare protection during prostate cancer treatment. GnRH agonists also induce an increase in testosterone levels after each reinjection of the drug – a phenomenon that does not occur with GnRH antagonists.

The reduction in testosterone levels that occurs during GnRH antagonist therapy subsequently reduces the size of the prostate cancer. This in turn results in a reduction in prostate-specific antigen (PSA) levels in the patient's blood and so measuring PSA levels is a way to monitor how patients with prostate cancer are responding to treatment. GnRH antagonists have an immediate onset of action leading to a fast and profound suppression of testosterone and are therefore especially valuable in the treatment of patients with prostate cancer, where fast control of disease is needed.

The GnRH antagonist abarelix was withdrawn from the United States market in 2005 and is now only marketed in Germany for use in patients with symptomatic prostate cancer. Degarelix is a GnRH antagonist that is approved for use in patients with advanced hormone-sensitive prostate cancer throughout Europe and also in the United States. [2]

Fertility treatment

GnRH antagonists are also used for short periods in the prevention of premature LH surge and endogenous ovulation in patients undergoing ovarian hyperstimulation with FSH in preparation for in-vitro fertilization (IVF). [3] [4] [5] Typically they are administered in the mid-follicular phase in stimulated cycles after administration of gonadotropins and prior to the administration of hCG – which is given to stimulate ovulation. This protocol is likely beneficial in women expected to be hyper-responders, and probably also those expected to be poor responders to ovarian hyperstimulation. [6] There is probably little or no difference between GnRH antagonist and GnRH agonist protocols in terms of live birth or risk of miscarriage but GnRH antagonists probably reduce the risk of ovarian hyperstimulation syndrome. [7] The GnRH antagonists that are currently licensed for use in fertility treatment are cetrorelix and ganirelix.

Uterine disorders

Elagolix is indicated for the treatment of moderate to severe endometriosis pain and relugolix is indicated for the treatment of uterine fibroids.

Other uses

GnRH antagonists are being investigated in the treatment of women with hormone-sensitive breast cancer. [8] [9] In men, they are being investigated in the treatment of benign prostatic hyperplasia [10] and also as potential contraceptive agents. [11] GnRH antagonists could be used as puberty blockers in transgender youth and to suppress sex hormone levels in transgender adolescents and adults, but have not been studied in this context. [12] [13] [14] [15]

Available forms

GnRH antagonists marketed for clinical or veterinary use
NameBrand/code name(s)Approved/intended usesTypeRoute(s)Launch/status*Hits
Abarelix PlenaxisProstate cancerPeptideIM2003116,000
Cetrorelix CetrotideFemale infertility (assisted reproduction)PeptideSC2000134,000
Degarelix FirmagonProstate cancerPeptideSC2008291,000
Elagolix OrilissaEndometriosis; Uterine fibroidsNon-peptideOral2018126,000
Ganirelix OrgalutranFemale infertility (assisted reproduction)PeptideSC2000134,000
Linzagolix KLH-2109; OBE-2109Endometriosis; Uterine fibroidsNon-peptideOralPhase III [16] 9,730
Relugolix ReluminaUterine fibroids, prostate cancerNon-peptideOral201944,900
Notes: Launch/status = Launch year or developmental status (as of February 2018). Hits = Google Search hits (as of February 2018).

Currently approved GnRH antagonists include the peptide molecules abarelix, cetrorelix, degarelix, and ganirelix and the small-molecule compounds elagolix and relugolix. GnRH antagonists are administered by subcutaneous injection (cetrorelix, degarelix, ganirelix), by intramuscular injection (abarelix), or by oral administration (elagolix, relugolix).

Another non-peptide and orally-active GnRH antagonist that is in development is linzagolix. [17]

Side effects

As with all hormonal therapies, GnRH antagonists are commonly associated with hormonal side effects such as hot flushes, headache, nausea and weight gain. [18] [19] [20] When used in fertility treatment they can also be associated with abdominal pain and ovarian hyperstimulation. [18] [20] Subcutaneously administered agents are also associated with injection-site reactions [19] [21] and abarelix (neither of these being GnRH agonists, but instead being antagonists) has been linked with immediate-onset systemic allergic reactions. [22]

Pharmacology

GnRH antagonists competitively and reversibly bind to GnRH receptors in the pituitary gland, blocking the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. [23] [24] In men, the reduction in LH subsequently leads to rapid suppression of testosterone production in the testes; in women it leads to suppression of estradiol and progesterone production from the ovaries. GnRH antagonists are able to abolish gonadal sex hormone production and to suppress sex hormone levels into the castrate range, or by approximately 95%.

Unlike the GnRH agonists, which cause an initial stimulation of the hypothalamic–pituitary–gonadal axis (HPG axis) that leads to a surge in testosterone or estrogen levels, GnRH antagonists have an immediate onset of action and rapidly reduce sex hormone levels without an initial surge. [1] [25]

Hormone levels with GnRH agonists and antagonists

Chemistry

GnRH antagonists include peptides such as cetrorelix and non-peptide and small-molecule compounds such as elagolix. Peptide GnRH antagonists are GnRH analogues.

Chemical structures of peptide GnRH antagonists
CompoundAmino acid sequenceMarketed
Cetrorelix Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2Yes
Abarelix Ac-D-Nal-D-Cpa-D-Pal-Ser-N-MeTyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH2Yes
Ganirelix Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-hArg(Et)2-Leu-hArg(Et)2-Pro-D-Ala-NH2Yes
Degarelix Ac-D-Nal-D-Cpa-D-Pal-Ser-Aph(Hor)-D-Aph(Cba)-Leu-Lys(iPr)-Pro-D-Ala-NH2Yes
Teverelix Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-hCit-Leu-Lys(iPr)-Pro-D-Ala-NH2No
Ozarelix Ac-D-Nal-D-Cpa-D-Pal-Ser-N-MeTyr-D-hCit-Nle-Arg-Pro-D-Ala-NH2No
Ornirelix Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Pic)-D-Orn(6Anic)-Leu-Lys(iPr)-Pro-D-Ala-NH2No
Iturelix Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Nic)-D-Lys(Nic)-Leu-Lys(iPr)-Pro-D-Ala-NH2No
Acyline Ac-D-Nal-D-Cpa-D-Pal-Ser-Aph(Ac)-D-Aph(Ac)-Leu-Lys(iPr)-Pro-D-Ala-NH2No
Azaline B Ac-D-Nal-D-Cpa-D-Pal-Ser-Aph(Atz)-D-Aph(Atz)-Leu-Lys(iPr)-Pro-D-Ala-NH2No
Sources: [28]

See also

Related Research Articles

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Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

<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.

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

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

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

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<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

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

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References

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  2. ↑ Anderson J (May 2009). Degarelix: a novel gonadotropin-releasing hormone blocker for the treatment of prostate cancer. Future Oncol. 5: 433-443.
  3. ↑ Bodri D, Vernaeve V, Guillen JJ, et al (September 2006). Comparison between a GnRH antagonist and a GnRH agonist flare-up protocol in oocyte donors: a randomized clinical trial. Hum. Reprod. 21: 2246-2251.
  4. ↑ Lambalk CB, Leader A, Olivennes F, et al (March 2006). Treatment with the GnRH antagonist ganirelix prevents premature LH rises and luteinization in stimulated intrauterine insemination: results of a double-blind, placebo-controlled, multicentre trial. Hum. Reprod. 21: 632-639.
  5. ↑ Lee TH, Lin YH, Seow KM, et al (July 2008). Effectiveness of cetrorelix for the prevention of premature luteinizing hormone surge during controlled ovarian stimulation using letrozole and gonadotropins: a randomized trial. Fertil. Steril. 90: 113-120.
  6. ↑ La Marca, A.; Sunkara, S. K. (2013). "Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: From theory to practice". Human Reproduction Update. 20 (1): 124–40. doi: 10.1093/humupd/dmt037 . PMID   24077980.
  7. ↑ Al-Inany, HG; Youssef, MA; Ayeleke, RO; Brown, J; Lam, WS; Broekmans, FJ (29 April 2016). "Gonadotrophin-releasing hormone antagonists for assisted reproductive technology" (PDF). The Cochrane Database of Systematic Reviews. 4 (8): CD001750. doi:10.1002/14651858.CD001750.pub4. PMC   8626739 . PMID   27126581.
  8. ↑ Engel JB, Audebert A, Frydman R, et al (October 2007). Presurgical short term treatment of uterine fibroids with different doses of cetrorelix acetate: a double-blind, placebo-controlled multicenter study. Eur. J. Obstet. Gynecol. Reprod. Biol. 134: 225-232.
  9. ↑ Weiss JM, Diedrich K, Ludwig M (2002). Gonadotropin-releasing hormone antagonists: pharmacology and clinical use in women. Treat. Endocrinol. 1: 281-291.
  10. ↑ Debruyne F, Gres AA, Arustamov DL (July 2008). Placebo-controlled dose-ranging phase 2 study of subcutaneously administered LHRH antagonist cetrorelix in patients with symptomatic benign prostatic hyperplasia. Eur. Urol. 54: 170-177.
  11. ↑ Amory JK (March 2007). Contraceptive developments for men. Drugs Today (Barc.) 43: 179-192.
  12. ↑ Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, Rosenthal SM, Safer JD, Tangpricha V, T'Sjoen GG (November 2017). "Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline". J. Clin. Endocrinol. Metab. 102 (11): 3869–3903. doi: 10.1210/jc.2017-01658 . PMID   28945902.
  13. ↑ Randolph JF (December 2018). "Gender-Affirming Hormone Therapy for Transgender Females". Clin Obstet Gynecol. 61 (4): 705–721. doi:10.1097/GRF.0000000000000396. PMID   30256230. S2CID   52821192.
  14. ↑ Wiik, Anna; Andersson, Daniel P.; Brismar, Torkel B.; Chanpen, Setareh; Dhejne, Cecilia; Ekström, Tomas J.; Flanagan, John N.; Holmberg, Mats; Kere, Juha; Lilja, Mats; Lindholm, Malene E.; Lundberg, Tommy R.; Maret, Eva; Melin, Michael; Olsson, Sofie M.; Rullman, Eric; Wåhlén, Kerstin; Arver, Stefan; Gustafsson, Thomas (2018). "Metabolic and functional changes in transgender individuals following cross-sex hormone treatment: Design and methods of the GEnder Dysphoria Treatment in Sweden (GETS) study". Contemporary Clinical Trials Communications. 10: 148–153. doi:10.1016/j.conctc.2018.04.005. ISSN   2451-8654. PMC   6046513 . PMID   30023449.
  15. ↑ Aarthi Arasu (2016). "Clinical Vignette: Transgender Care". Proceedings of UCLA Healthcare. 20. Archived from the original on 2019-04-22. Retrieved 2018-11-12.
  16. ↑ "Linzagolix - Kissei Pharmaceutical/ObsEva - AdisInsight".
  17. ↑ Ezzati, Mohammad; Carr, Bruce R (2015). "Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain". Women's Health. 11 (1): 19–28. doi: 10.2217/whe.14.68 . ISSN   1745-5057. PMID   25581052.
  18. 1 2 Serono. Cetrotide prescribing information 2009. Accessed 18-6-2009.
  19. 1 2 Degarelix US prescribing information 2008. Accessed 28-4-2009.
  20. 1 2 Organon. Ganirelix acetate prescribing information 2009. Accessed 18-6-2009.
  21. ↑ Klotz L, Boccon-Gibod L, Shore ND, et al (December 2008). The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU. Int. 102: 1531-1538.
  22. ↑ Debruyne F, Bhat G, Garnick MB (December 2006). Abarelix for injectable suspension: first-in-class gonadotropin-releasing hormone antagonist for prostate cancer. Future Oncol. 2: 677-696.
  23. ↑ Broqua P, Riviere PJ, Conn PM, et al (April 2002). Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: degarelix. J. Pharmacol. Exp. Ther. 301: 95-102.
  24. ↑ Engel JB, Schally AV (February 2007). Drug Insight: clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone. Nat. Clin. Pract. Endocrinol. Metab.: 3: 157-167.
  25. ↑ Gustofson RL, Segars JH, Larsen FW (November 2006). Ganirelix acetate causes a rapid reduction in estradiol levels without adversely affecting oocyte maturation in women pretreated with leuprolide acetate who are at risk of ovarian hyperstimulation syndrome. Hum. Reprod. 21: 2830-2837.
  26. ↑ Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH (December 2008). "The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer". BJU Int. 102 (11): 1531–8. doi:10.1111/j.1464-410X.2008.08183.x. PMID   19035858.
  27. ↑ Shim M, Bang WJ, Oh CY, Lee YS, Cho JS (July 2019). "Effectiveness of three different luteinizing hormone-releasing hormone agonists in the chemical castration of patients with prostate cancer: Goserelin versus triptorelin versus leuprolide". Investig Clin Urol. 60 (4): 244–250. doi:10.4111/icu.2019.60.4.244. PMC   6607074 . PMID   31294133.
  28. ↑ Mezo G, Manea M (December 2009). "Luteinizing hormone-releasing hormone antagonists". Expert Opin Ther Pat. 19 (12): 1771–85. doi:10.1517/13543770903410237. PMID   19939192. S2CID   11906496.
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