Once-daily oral Gonadotropin-Releasing Hormone (GnRH) antagonists in the treatment of uterine fibroids: from evidence to clinical practice.

Authors

Mikel Goitia Ibarra, Santiago Díez Lázaro, Ainhoa Azkuenaga Fernández, Elena Urquijo Beamonte, Maider Andrés Arribalzaga, Naroa Martínez Zilloniz, Almudena Cearsolo Michelena

Published in

European journal of obstetrics, gynecology, and reproductive biology. Volume 326. Pages 115365. Aug 10, 2026. Epub Aug 10, 2026.

Abstract

Oral non-peptide gonadotropin-releasing hormone antagonists (GnRHa) represent a paradigm shift in the treatment of uterine myomas, enabling reversible, dose-dependent estrogen suppression. Among these agents, two once-daily oral GnRHa are approved for uterine fibroids: relugolix combination therapy (CT) (Ryeqo in the EU, Myfembree in the US), taken as a single tablet daily with add-back incorporated (relugolix 40 mg + estradiol 1 mg + norethindrone acetate 0.5 mg); and linzagolix, administered as 100 mg daily (partial suppression) or 200 mg daily (full suppression) (Yselty in the EU/UK), without or with add-back (an additional tablet with 1 mg estradiol + 0.5 mg norethindrone acetate). This narrative expert review evaluates data from pivotal phase III GnRHa trials (LIBERTY 1 and 2 for relugolix-CT; PRIMROSE 1 and 2 for linzagolix), regulatory documents, and available real-world evidence. The analysis focuses on the efficacy of both agents in controlling heavy menstrual bleeding (HMB) and anemia, favouring amenorrhea, reducing fibroid and uterine volume, improving quality-of-life (QoL) outcomes, and preserving bone mineral density (BMD), as well as on their respective safety profiles. Owing to the absence of head-to-head clinical trials, all comparisons between relugolix combination therapy and linzagolix presented throughout this review are indirect and do not represent direct comparative evidence. Relugolix-CT demonstrated sustained efficacy in controlling HMB, with responder rates of 87.7%, amenorrhea in 70% of patients, and significant improvements in hemoglobin and QoL after 52 weeks of treatment. Long-term data further demonstrated sustained efficacy and minimal BMD loss, attributable to integrated add-back therapy. Linzagolix 200 mg also demonstrated sustained efficacy through 52 weeks, with HMB responder rates of 89.9% and amenorrhea rates of 67-87% when combined with add-back therapy. Linzagolix efficacy was dose-dependent (100 mg HMB responder rate of 55%; amenorrhea rate of 41.4%) and add-back therapy improves effectiveness in HMB reduction, tolerability and bone health. Without add-back, linzagolix 200 mg offers short-term volume reduction but increases hypoestrogenic risks; therefore, its use is limited to a maximum of 6 months. In conclusion, both relugolix-CT and linzagolix offer effective, reversible, and patient-centered management options for fibroid-associated symptoms. Relugolix-CT represents a valuable option for symptomatic fibroid control providing sustained efficacy, simplified administration, and bone safety, favouring long-term use. Linzagolix 200 mg is a suitable option for short-term preoperative fibroid reduction. Their distinct pharmacological profiles and dosing strategies may support different therapeutic objectives, including long-term symptom control and short-term preoperative management.

PMID:
42632338
Bibliographic data and abstract were imported from PubMed on 23 Aug 2026.

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