The oral GnRH antagonists, a new class of drugs in gynecology: from pharmacokinetics to possible clinical applications

Marta Barretta, Barretta M, Michele Vignali, Vignali M, M. Vignali, La Marca A, Antonio La Marca, Grandi G, Giovanni Grandi
Expert opinion on drug metabolism & toxicology · 2024 · vol. 21(3) , pp. 265–277 · doi:10.1080/17425255.2024.2441981 · PMID:39666595 · W4405315417
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Oral GnRH antagonists demonstrate efficacy in treating uterine fibroids and endometriosis by suppressing estrogen, offering advantages in administration, reversibility, and tolerability, though long-term comparative studies are needed.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-16 · read from full text ⓘ

This paper is a review of the pharmacology and clinical evidence for the latest non-peptide oral GnRH antagonists, focusing on their pharmacokinetics, dosing, safety, and potential gynecologic applications across the spectrum of steroid-dependent conditions. Across analyzed randomized clinical trials, oral GnRH antagonists reportedly showed significant efficacy in reducing heavy menstrual bleeding in women with uterine fibroids and pelvic pain in women with endometriosis, with over 70% meeting primary endpoints. The review highlights rapid, immediate, dose-dependent estrogen suppression without a flare phenomenon and notes that add-back hormonal therapy minimized bone mineral density loss, with generally well-tolerated, dose-dependent adverse events. As a caveat, it emphasizes that longer-term trials are needed and that future studies must compare these agents with existing treatments; this paper is centrally about endometriosis — it reviews oral GnRH antagonists and their reported efficacy in reducing endometriosis-related pelvic pain, as well as related pharmacologic mechanisms and safety considerations.

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Abstract

INTRODUCTION: In ovarian steroid-dependent diseases such as uterine fibroids, endometriosis and adenomyosis, oral GnRH antagonists have emerged as new therapeutic alternatives. These oral GnRH antagonists offer key advantages, including oral administration, dose-dependent estrogen suppression and rapid reversibility. AREAS COVERED: This review examines the pharmacological, clinical and therapeutic profiles of the latest non-peptide oral GnRH antagonists, through an analysis of clinical evidence and randomized clinical trials, to provide a comprehensive and up-to-date overview of their clinical applications and potential benefits. EXPERT OPINION: The clinical trials examined demonstrated significant efficacy in reducing heavy menstrual bleeding in women with fibroids and pelvic pain in women with endometriosis, with more than 70% of patients achieving primary endpoints. The use of add-back therapy minimized bone mass density loss, ensuring long-term safety. Adverse events were dose-dependent but generally well tolerated. In our opinion, the strength of oral GnRH antagonists lies in their pharmacological properties. Oral administration increases convenience, allows adjustable dosing and ensures a dose-dependent effect. These drugs provide an immediate antagonistic effect without the flare-up phenomenon. Furthermore, they are expected to act on ectopic endometrial and smooth muscle cell receptors, potentially providing additional anti-proliferative effects. However, further research is needed: long term clinical trials must compare them with existing treatments.
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ABSTRACT Introduction In ovarian steroid-dependent diseases such as uterine fibroids, endometriosis and adenomyosis, oral GnRH antagonists have emerged as new therapeutic alternatives. These oral GnRH antagonists offer key advantages, including oral administration, dose-dependent estrogen suppression and rapid reversibility. Areas covered This review examines the pharmacological, clinical and therapeutic profiles of the latest non-peptide oral GnRH antagonists, through an analysis of clinical evidence and randomized clinical trials, to provide a comprehensive and up-to-date overview of their clinical applications and potential benefits. Expert opinion The clinical trials examined demonstrated significant efficacy in reducing heavy menstrual bleeding in women with fibroids and pelvic pain in women with endometriosis, with more than 70% of patients achieving primary endpoints. The use of add-back therapy minimized bone mass density loss, ensuring long-term safety. Adverse events were dose-dependent but generally well tolerated. In our opinion, the strength of oral GnRH antagonists lies in their pharmacological properties. Oral administration increases convenience, allows adjustable dosing and ensures a dose-dependent effect. These drugs provide an immediate antagonistic effect without the flare-up phenomenon. Furthermore, they are expected to act on ectopic endometrial and smooth muscle cell receptors, potentially providing additional anti-proliferative effects. However, further research is needed: long term clinical trials must compare them with existing treatments. Article highlights Three types of oral GnRH antagonist are available: elagolix, relugolix, linzagolix. They have four peculiarities: oral administration, rapid reversibility of hormonal suppression, immediate suppression, dose-dependent effect. Approved for the treatment of heavy menstrual bleeding associated with uterine fibroids and endometriosis related pelvic pain in women of reproductive age. Favorable safety profile when used at low dosage or for short duration (up to 6 months). The addition of an add back hormonal therapy ensures long-term administration while maintaining efficacy and safety. Further comparative studies with other available drugs are mandatory to confirm their effectiveness. Declaration of interest G. Grandi received honoraria for sponsored lectures and participation in advisory boards from Bayer AG, Teva/Theramex, Exeltis, Organon, Italfarmaco, Opocrin and Gedeon Richter. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Reviewer disclosures One reviewer was involved in the clinical development of elagolix but is no longer employed by AbbVie (drug manufacturer) anymore. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

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