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Approval of Relugolix (Relumina), the Second Orally Active GnRH Antagonist, and Relevance for Transfeminine People

By Aly W. | First published February 23, 2019 | Last modified September 29, 2021

Notice: This page was originally posted as a thread on Reddit and has not yet been properly or fully revised since being moved to Transfeminine Science.

Relugolix (brand name Relumina) is the second non-peptide, small-molecule, orally active gonadotropin-releasing hormone (GnRH) antagonist to be introduced for medical use. It was approved for use in Japan last month, and it’ll likely be approved in the United States sometime in 2020 (with other countries to follow). Elagolix (brand name Orilissa) was the first orally active GnRH antagonist to be introduced. We had an article on it here when it was introduced last year. Once these medications eventually come down in price, they will likely replace all other antiandrogens used in hormone therapy for transfeminine people.

Here is an informational booklet on relugolix. (Albeit in Japanese—so pretty in any case!)

GnRH agonists and antagonists are a class of medications that block the signal from the brain that tells the gonads to make sex hormones. They can completely shut-down gonadal sex-hormone production. In practice, this means that they can suppress testosterone levels by 95% in men and transfeminine people and thereby reduce testosterone levels into the female or male-castrate range.

The currently available GnRH agonists and antagonists are analogues (chemical relatives) of gonadotropin-releasing hormone (GnRH) and hence are peptides—large molecules that are not active orally and that have only a short duration when used parenterally (i.e., by non-oral routes, like injection or nasal spray). Because of this, these medications have only been used by parenteral routes, and have generally required frequent administration either one to three times per day (via injection or nasal spray) or have employed fancy and expensive technologies like microsphere encapsulation (injections) or long-lasting implants to extend the duration to long periods of time (e.g., 1 to 12 months). Due to these factors, GnRH analogues are inconvenient to administer and are very expensive (e.g., US$10,000 per year of treatment).

Scientists were eventually able to develop small-molecule, non-peptide GnRH antagonists that are similar in size to most other drugs. Moreover, these new GnRH antagonists are orally active and have long durations. They do not need to be administered parenterally, and they have no requirement for special and expensive technology to make them last longer in the body—just take a pill by mouth once a day and that’s it. Because of this, these new GnRH antagonists will make administration much easier. And, although they’re very expensive right now due to having just been introduced and still being on-patent (about as expensive as the old peptide GnRH agonists and antagonists at present), these new GnRH antagonists should eventually come way down in cost and end up being very affordable. At which point I’m sure we’ll see widespread adoption in transfeminine people.

GnRH antagonists specifically are also advantageous over GnRH agonists because there is no testosterone flare at the start of treatment—testosterone levels just immediately decline instead, reaching female/castrate levels within about two to three days.

GnRH antagonists are the ideal antiandrogens. They basically just do one thing—dramatically lower testosterone levels—and, when taken in combination with sex-hormone replacement in the form of an estrogen, have essentially no side effects or risks. These new small-molecule, non-peptide, orally active GnRH antagonists will allow for more effective, better-tolerated, and safer transfeminine hormone therapy. And, relative to current peptide GnRH antagonists, they will be more convenient and far less expensive.

Update

In December 2020, relugolix was approved for use as a form of androgen deprivation therapy for the treatment of prostate cancer in the United States.