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

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.