Gonadotropin-releasing hormone agonist (GnRH-a) pretreatment duration and letrozole supplementation for optimizing live birth rates in women with adenomyosis undergoing frozen-thawed embryo transfer (GOLD-FET): study protocol for a multicenter, 2 × 2 factorial randomized controlled trial in China

Yujing Xiong, Fang Gu, F Gu, Gu F, Liu Du, Du L, Gu J, Jing Gu, Ke Z, Zhanghong Ke, Yameng Xu, Mol BW, Ben W. Mol, Zheng B, Beihong Zheng, Xiufeng Lin, Lin X, Yanwen Xu, Y Xu, Xu Y
Trials · 2026 · vol. 27(1) · doi:10.1186/s13063-026-09731-2 · PMID:42032741 · PMC13245048 · W7155521035
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This multicenter RCT will compare live birth rates in women with adenomyosis undergoing frozen-thawed embryo transfer using one versus two doses of GnRH-a, with or without letrozole supplementation.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 · read from full text ⓘ

This paper describes a multicenter, open-label 2×2 factorial randomized controlled trial in China enrolling 432 women aged 20–38 years with sonographically diagnosed adenomyosis undergoing single blastocyst frozen-thawed embryo transfer, comparing one versus two doses of GnRH-a (3.75 mg) with or without letrozole (2.5 mg daily for 28 days). The primary outcome is live birth rate, with secondary outcomes covering fertility, pregnancy/obstetric, neonatal outcomes, and safety events including low-estrogen-related adverse events. The study’s key finding will be the live-birth and pregnancy-outcome differences attributable to GnRH-a pretreatment duration and letrozole supplementation, separately and in combination. As a protocol paper, it does not provide results and is explicitly limited to planned assessments, with an internal pilot assessing feasibility based on early recruitment. This paper is centrally about endometriosis and adenomyosis—specifically adenomyosis—evaluating how GnRH-a pretreatment duration and letrozole supplementation affect live birth rates in adenomyosis patients undergoing FET.

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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.
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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. Similar content being viewed by others Abbreviations - AD: - Adenomyosis - AE: - Adverse event - AEI: - Adverse event of interest - ANOVA: - Analysis of variance - aOR: - Adjusted odds ratio - ART: - Assisted reproductive technologies - β-hCG: - Beta-human chorionic gonadotropin - CI: - Confidence interval - CONSORT: - Consolidated Standards of Reporting Trials - CRC: - Clinical Research Coordinator/Collaborative Research Center - DMC: - Data Monitoring Committee - E2 : - Estradiol - EDC: - Electronic data capture - FET: - Frozen-thawed embryo transfer - FIGO: - International Federation of Gynecology and Obstetrics - FISH: - Follicle-stimulating hormone - FAS: - Full analysis set - GCP: - Good Clinical Practice - GDM: - Gestational diabetes mellitus - GLMM: - Generalized linear mixed model - GnRH-a: - Gonadotropin-releasing hormone agonist - HRT: - Hormone replacement therapy - ICSI: - Intracytoplasmic sperm injection - IEC: - Independent Ethics Committee - IQR: - Interquartile range - ITT: - Intention-to-treat - IVF: - In vitro fertilization - IWRS: - Interactive Web Response System - LE: - Letrozole - LH: - Luteinizing hormone - MAR: - Missing at random - MUSA: - Morphological Uterus Sonographic Assessment - NICU: - Neonatal intensive care unit - OR: - Odds ratio - PI: - Principal Investigator - PP: - Per protocol - PRO: - Patient-reported outcome - RCT: - Randomized controlled trial - RR: - Risk ratio - SAE: - Serious adverse event - SAP: - Statistical analysis plan - SD: - Standard deviation - SPIRIT: - Standard Protocol Items: Recommendations for Interventional Trials - SS: - Safety set - SUSAR: - Suspected unexpected serious adverse reaction - VTE: - Venous thromboembolism

Acknowledgements

The authors thank the participants and the study site staff for their continued support for the study and the Data and Safety Monitoring Committee (Professor Yuhua Shi [chair], Professors Qingxue Zzhang and Wei Zhang). Funding This trial is funded by the Fundamental Research Funds for the Central Universities, Clinical Research 5010 Program, Sun Yat-sen University (2025012) and National Natural Science Foundation of China (82201784). Author information Authors and Affiliations Corresponding author Ethics declarations Ethics approval and consent to participate {24} Ethical approval for the trial was granted by the Independent Ethics Committee (IEC) for Clinical Research and Animal Trials of the First Affiliated Hospital of Sun Yat-sen University ([2025]399-1), IEC for Women and Children’s Hospital of Fujian Province (2025KY139) and IEC for BoAi Hospital of Zhongshan (KY-2025-006-02). Written informed consent is sought from each participant prior to enrollment. Consent for publication {32} This manuscript does not contain individual personal data from patients. Competing interests {28} The authors declare that they have no competing interests. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Xiong, Y., Gu, F., Du, L. et al. Gonadotropin-releasing hormone agonist (GnRH-a) pretreatment duration and letrozole supplementation for optimizing live birth rates in women with adenomyosis undergoing frozen-thawed embryo transfer (GOLD-FET): study protocol for a multicenter, 2 × 2 factorial randomized controlled trial in China. Trials (2026). https://doi.org/10.1186/s13063-026-09731-2 Received: Accepted: Published: DOI: https://doi.org/10.1186/s13063-026-09731-2

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Outcome instruments

MUSA

Condition tags

adenomyosis

MeSH descriptors

Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis

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