Trials. 2026 Apr 24. doi: 10.1186/s13063-026-09731-2. Online ahead of print.
ABSTRACT
BACKGROUND: Adenomyosis, an estrogen-dependent condition characterized by endometrial invasion into the myometrium, is associated with reduced live birth rates and increased miscarriage risk in women undergoing assisted reproductive technologies (ART). Gonadotropin-releasing hormone agonists (GnRH-a) are commonly used for pretreatment before frozen-thawed embryo transfer (FET) in adenomyosis patients, but optimal duration remains unclear. Letrozole, an aromatase inhibitor, may enhance GnRH-a efficacy by mitigating its flare-up effect and reducing peripheral estrogen production, yet high-level evidence on their combined effect is lacking. This study aims to compare the live birth rate and other pregnancy outcomes between one and two doses of GnRH-a pretreatment with or without letrozole supplementation in women with adenomyosis undergoing FET.
METHODS: This is a 2 × 2 factorial, multi-center, open-label, randomized controlled trial (RCT) conducted at three reproductive medical centers in China, with a planned enrollment of 432 women aged 20-38 years with sonographically diagnosed adenomyosis scheduled for single blastocyst FET. This study is designed as a superiority trial. Recruitment will be conducted by trained clinical research coordinators. Participants are randomized in a 1:1:1:1 ratio to four arms: one dose of GnRH-a (3.75 mg), two doses of GnRH-a, one dose of GnRH-a with letrozole (2.5 mg daily for 28 days), or two doses of GnRH-a with letrozole (2.5 mg daily for 28 days). The primary outcome is live birth rate. Secondary outcomes include fertility outcomes, pregnancy and obstetric outcomes, and neonatal outcomes. Safety outcomes, including the incidence and severity of low-estrogen-related adverse events (e.g., hot flashes, bone loss, vaginal dryness) and other serious adverse events, will be collected and compared. An internal pilot phase will assess procedural feasibility when approximately 25 participants are randomized per arm. Data are collected via medical records and follow-up assessments up to 6 months postpartum.
DISCUSSION: This factorial RCT is the first to assess the synergistic effects of GnRH-a dosage and letrozole supplementation, overcoming limitations of single-factor studies. By comprehensively evaluating pregnancy outcomes, the study aims to optimize pretreatment strategies, inform clinical guidelines, and improve pregnancy outcomes for adenomyosis patients undergoing FET.
TRIAL REGISTRATION: ClinicalTrials.gov NCT07065539. Registered on 14 July 2025. https://clinicaltrials.gov/study/NCT07065539. The first participant was enrolled in August 2025.
PMID:42032741 | DOI:10.1186/s13063-026-09731-2
