Ultra-Long GnRH-a Pretreatment for FET Outcomes in Patients With Deep Infiltrating Endometriosis

Official title

A Randomized Controlled Study of Ultra-Long GnRH-a Pretreatment to Improve Frozen-Thawed Embryo Transfer Outcomes in Patients With Deep Infiltrating Endometriosis

Overview

Deep infiltrating endometriosis is a severe form of endometriosis that may reduce fertility and negatively affect pregnancy outcomes after assisted reproductive treatment. Gonadotropin-releasing hormone agonist pretreatment may suppress endometriotic lesions, reduce inflammation, and improve endometrial receptivity, but its benefit before frozen-thawed embryo transfer remains uncertain. This randomized controlled study will evaluate whether ultra-long GnRH-a pretreatment before hormone replacement therapy improves clinical pregnancy outcomes in patients with deep infiltrating endometriosis undergoing their first frozen-thawed embryo transfer cycle. Eligible participants will be randomly assigned to either the GnRH-a pretreatment group or the control group. Participants in the GnRH-a group will receive two injections of long-acting GnRH-a before hormone replacement therapy for endometrial preparation, while participants in the control group will receive routine hormone replacement therapy alone. The primary outcome is clinical pregnancy rate, defined as the presence of a gestational sac on transvaginal ultrasound 30 ± 3 days after embryo transfer. Secondary outcomes include implantation rate, ectopic pregnancy rate, early spontaneous abortion rate, ongoing pregnancy rate at 12 weeks of gestation, and delivery rate. Safety will be evaluated by recording adverse events after GnRH-a injection. The planned enrollment is 120 participants.

Detailed description

Deep infiltrating endometriosis is a severe subtype of endometriosis that may involve pelvic organs and is associated with infertility, impaired endometrial receptivity, chronic pelvic inflammation, reduced implantation, increased miscarriage risk, and poorer outcomes after assisted reproductive treatment. For patients with deep infiltrating endometriosis who require frozen-thawed embryo transfer, the optimal endometrial preparation strategy remains uncertain.

Gonadotropin-releasing hormone agonists may suppress ovarian estrogen production, inhibit the activity of endometriotic lesions, reduce inflammatory mediators, and potentially improve the endometrial environment before embryo transfer. However, current evidence regarding GnRH-a pretreatment before frozen-thawed embryo transfer in patients with endometriosis is inconsistent, and high-quality prospective randomized controlled studies are limited. This study is designed to evaluate whether ultra-long GnRH-a pretreatment improves pregnancy outcomes in patients with deep infiltrating endometriosis undergoing frozen-thawed embryo transfer.

This is a prospective, randomized, controlled, single-center clinical study. A total of 120 eligible participants will be enrolled. Participants must be younger than 40 years, diagnosed with deep infiltrating endometriosis by ultrasound at the study center, undergoing their first frozen-thawed embryo transfer cycle with hormone replacement therapy for endometrial preparation, and have at least one good-quality frozen embryo. Eligible participants will be randomly assigned in a 1:1 ratio to the experimental group or the control group.

Participants in the experimental group will receive ultra-long GnRH-a pretreatment before frozen-thawed embryo transfer. Long-acting GnRH-a will be administered on menstrual cycle days 2 to 4, followed by a second injection 28 to 30 days later. Hormone replacement therapy for endometrial preparation will begin 28 to 30 days after the second GnRH-a injection, followed by frozen-thawed embryo transfer according to routine clinical practice.

Participants in the control group will undergo routine hormone replacement therapy for endometrial preparation before frozen-thawed embryo transfer without GnRH-a pretreatment.

The primary outcome is clinical pregnancy rate, defined as the presence of a gestational sac detected by transvaginal ultrasound 30 ± 3 days after embryo transfer. Secondary outcomes include implantation rate, ectopic pregnancy rate, early spontaneous abortion rate, ongoing pregnancy rate at 12 weeks of gestation, and delivery rate. Additional pregnancy, obstetric, and neonatal outcomes may be followed according to the study protocol, including biochemical pregnancy, late spontaneous abortion, preterm birth, stillbirth, live birth, pregnancy complications, delivery outcomes, and birth weight.

Safety will be assessed by monitoring and recording adverse events after GnRH-a injection, including hot flashes, headache, sleep disturbance, vaginal bleeding or spotting, night sweats, and mood changes. Participants will be followed after embryo transfer and, if pregnancy occurs, through pregnancy and delivery according to the protocol-defined follow-up schedule.

Interventions

• Drug Triptorelin (GnRH agonists)
  Long-acting GnRH-a pretreatment will be administered before hormone replacement therapy for endometrial preparation. Participants will receive two injections of triptorelin 3.75 mg: the first on menstrual cycle days 2 to 4 and the second 28 to 30 days later.
• Other Hormone Replacement Therapy (HRT)
  Routine hormone replacement therapy will be used for endometrial preparation before frozen-thawed embryo transfer.

Primary outcome measures

• Clinical Pregnancy Rate [Time frame: 30 ± 3 days after embryo transfer]

Secondary outcome measures (5)

• Implantation Rate [Time frame: 30 ± 3 days after embryo transfer]
• Ectopic Pregnancy Rate [Time frame: Up to 49 ± 7 days after embryo transfer]
• Early Spontaneous Abortion Rate [Time frame: Up to 12 weeks of gestation]
• Ongoing Pregnancy Rate at 12 Weeks of Gestation [Time frame: 12 weeks of gestation]
• Delivery Rate [Time frame: At delivery, up to study completion]

Eligibility criteria

Inclusion criteria

• Female patients aged 18 to 39 years.
• Diagnosed with deep infiltrating endometriosis by ultrasound at the study center.
• Undergoing the first frozen-thawed embryo transfer cycle with hormone replacement therapy for endometrial preparation.
• Having at least one good-quality frozen embryo.
• Willing to participate in this randomized controlled study of GnRH-a pretreatment for deep infiltrating endometriosis and able to personally sign the written informed consent form.

Exclusion criteria

• Abnormal chromosomal karyotype.
• Other uterine diseases or conditions that may affect uterine cavity morphology or pregnancy outcomes, including intrauterine adhesions affecting the uterine cavity, intramural uterine fibroids, moderate to severe adenomyosis, congenital uterine malformation, endometrial tuberculosis, or endometrial thickness less than 8 mm on the transformation day.
• Recurrent implantation failure.
• Contraindications to hormone replacement therapy or long-acting GnRH-a treatment.
• Osteoporosis or depressed mood.
• Currently participating in another clinical study.
• Unable to adhere to study visits and follow-up, or planning to receive other treatment during the follow-up period.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The Affiliated Drum Tower Hospital of Nanjing University Medical School — Nanjing

Publications

• Surrey ES, Katz-Jaffe M, Kondapalli LV, Gustofson RL, Schoolcraft WB. GnRH agonist administration prior to embryo transfer in freeze-all cycles of patients with endometriosis or aberrant endometrial integrin expression. Reprod Biomed Online. 2017 Aug;35(2):145-151. doi: 10.1016/j.rbmo.2017.05.004. Epub 2017 May 17. PMID 28601378
• Tamura H, Takasaki A, Nakamura Y, Numa F, Sugino N. A pilot study to search possible mechanisms of ultralong gonadotropin-releasing hormone agonist therapy in IVF-ET patients with endometriosis. J Ovarian Res. 2014 Oct 21;7:100. doi: 10.1186/s13048-014-0100-8. PMID 25331066
• Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022 Nov 14;379:e070750. doi: 10.1136/bmj-2022-070750. PMID 36375827

Identifiers

NCT: NCT07696351 · DIE-GnRHa-FET-RCT-2025-01 · 2025-0564

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗