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Approval of Elagolix (Orilissa), the first Orally Active Gonadotropin-Releasing Hormone Antagonist, and Relevance for Transfeminine People

By Aly W. | First published August 2, 2018 | Last modified September 29, 2021

Gonadotropin-releasing hormone (GnRH) is a hormone that acts as the master regulator of the gonads. Upon puberty, it starts to be secreted and tells the gonads to make sex hormones and to initiate and maintain fertility. By pharmacologically modulating the GnRH receptor, the biological target of GnRH, it is possible to increase or decrease the effects of GnRH in the body. GnRH modulators, which include GnRH agonists and GnRH antagonists, are a class of medications that can effectively turn off the gonads, and are able to fully suppress gonadal testosterone production in people with testes. Clinically used GnRH modulators have historically been GnRH analogues, or bulky peptides derived from GnRH, and have usually required administration by injection or implant. Moreover, although GnRH agonists cause an initial flare in gonadal hormone production while GnRH antagonists do not, GnRH antagonists have been more expensive and more limitedly available than GnRH agonists.

Elagolix (brand name Οrilissa) is a new GnRH antagonist which has just been introduced for medical use in the United States. It is the first orally active GnRH modulator to be marketed. Unlike all other clinically used GnRH modulators to date, elagolix is not a GnRH analogue, nor a peptide. Instead, it is a small molecule, and this is the reason that it is able to be effective when taken orally. Elagolix was approved by the Food and Drug Administration (FDA) on July 24th, 2018 specifically for the treatment of endometriosis (painful uterine overgrowth) in cisgender women. This condition is stimulated by estrogens, and by suppressing the production of estradiol by the ovaries, elagolix can treat it. Clinical studies showed that elagolix dose-dependently suppresses gonadal hormone production in cisgender women, with estradiol levels reduced to the castrate range at the highest approved dosage.

Elagolix is very expensive at present (US$875/month without insurance) due to being a brand new medication and having patent protection. In time however, its cost should come down. This may also be aided by the fact that several other similar oral GnRH antagonists, such as relugolix and linzagolix, are under development, and if or when they’re introduced, may make the market more competitive and reduce the costs of all of these drugs. Eventually, many years in the future (10 to 15 years usually), the patent protection of these new oral GnRH antagonists will expire, and it’s reasonable to expect that they’ll become much more affordable at that time. In contrast to GnRH analogues, which have been marketed since the 1980s and have long been off-patent but remain very costly, oral small-molecule GnRH antagonists don’t require special drug formulations (e.g., long-lasting injectable or implant technology), and this may result in them being comparatively much less expensive once generics become available.

Oral GnRH antagonists, once they are more widely used and affordable, will allow gonadally intact transfeminine people to easily and conveniently abolish gonadal testosterone production. This will be possible without concerns about efficacy, tolerability, or safety, in contrast to the case of many of the antiandrogenic approaches used in transfeminine hormone therapy currently. Moreover, the degree of testosterone suppression with oral GnRH antagonists is uniquely adjustable among GnRH modulators as they can be used at lower doses to achieve partial suppression of the gonads. This may be useful for transfeminine people who wish to go slower with hormone therapy or who desire some testosterone, as well as for non-binary transfeminine people with non-conventional hormonal goals. It is probable that once the current obstacles to their use are removed, oral GnRH antagonists will become the gold standard for antiandrogenic therapy in gonadally intact transfeminine people. Excessively high and supraphysiological doses of estradiol, which have greater risk of health complications like blood clots, and current mainstream antiandrogens like cyproterone acetate and spironolactone, which have undesirable side effects, safety issues, and/or efficacy concerns, will no longer be necessary.