Ultra-Long GnRH-a Pretreatment for FET Outcomes in Patients With Deep Infiltrating Endometriosis (DIE-GnRHa-FET)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Infertility; Deep Infiltrating Endometriosis (DIE)
• Intervention / Treatment: Drug: Triptorelin (GnRH agonists); Other: Hormone Replacement Therapy (HRT)

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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jie Mei, PhD; Phone Number: +86 15051839536 Email; Email: meijie560@163.com
• Study Contact Backup: Name: Yuan Yan; Phone Number: +86 15950526117

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 216000
      • Recruiting
      • The Affiliated Drum Tower Hospital of Nanjing University Medical School
      • Contact: Jie Mei, PhD; Phone Number: +86 15051839536 Email; Email: meijie560@163.com
      • Contact: Yuan Yan; Phone Number: +86 15950526117

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Female patients aged 18 to 39 years.
2. Diagnosed with deep infiltrating endometriosis by ultrasound at the study center.
3. Undergoing the first frozen-thawed embryo transfer cycle with hormone replacement therapy for endometrial preparation.
4. Having at least one good-quality frozen embryo.
5. 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:

1. Abnormal chromosomal karyotype.
2. 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.
3. Recurrent implantation failure.
4. Contraindications to hormone replacement therapy or long-acting GnRH-a treatment.
5. Osteoporosis or depressed mood.
6. Currently participating in another clinical study.
7. Unable to adhere to study visits and follow-up, or planning to receive other treatment during the follow-up period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ultra-Long GnRH-a Pretreatment Group; Participants in this 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.	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 Names: GnRHa
Active Comparator: Routine HRT Group; Participants in this group will undergo routine hormone replacement therapy for endometrial preparation before frozen-thawed embryo transfer without GnRH-a pretreatment.	Other: Hormone Replacement Therapy (HRT); Routine hormone replacement therapy will be used for endometrial preparation before frozen-thawed embryo transfer.; Other Names: HRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Pregnancy Rate	Clinical pregnancy is defined as the presence of a gestational sac detected by transvaginal ultrasound 30 ± 3 days after embryo transfer. Clinical pregnancy rate will be calculated as the number of clinical pregnancy cycles divided by the total number of embryo transfer cycles.	30 ± 3 days after embryo transfer

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Implantation Rate	Implantation rate will be calculated based on the number of gestational sacs observed by ultrasound relative to the number of embryos transferred.	30 ± 3 days after embryo transfer
Ectopic Pregnancy Rate	Ectopic pregnancy rate will be calculated as the number of ectopic pregnancy cases divided by the total number of embryo transfer cycles.	Up to 49 ± 7 days after embryo transfer
Early Spontaneous Abortion Rate	Early spontaneous abortion rate will be calculated as the number of early spontaneous abortions divided by the number of clinical pregnancy cycles.	Up to 12 weeks of gestation
Ongoing Pregnancy Rate at 12 Weeks of Gestation	Ongoing pregnancy rate will be calculated as the number of participants with ongoing pregnancy at 12 weeks of gestation divided by the total number of embryo transfer cycles.	12 weeks of gestation
Delivery Rate	Delivery rate will be calculated as the number of participants who deliver divided by the total number of embryo transfer cycles.	At delivery, up to study completion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events After GnRH-a Injection	Adverse events after long-acting GnRH-a injection will be recorded, including hot flashes, headache, sleep disturbance, vaginal bleeding or spotting, night sweats, and mood changes.	From first GnRH-a injection to embryo transfer

Collaborators and Investigators

• Sponsor: Li-jun Ding
• Investigators: Principal Investigator: Jie Mei, Department of Reproductive Medicine, Nanjing Drum Tower Hospital

Publications and helpful links

General 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.
• 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.
• Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022 Nov 14;379:e070750. doi: 10.1136/bmj-2022-070750.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: July 6, 2026
• First Submitted That Met QC Criteria: July 6, 2026
• First Posted (Actual): July 10, 2026

Study Record Updates

• Last Update Posted (Actual): July 10, 2026
• Last Update Submitted That Met QC Criteria: July 6, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Infertility; Frozen-thawed embryo transfer; Hormone replacement therapy; Deep infiltrating endometriosis; Clinical pregnancy rate; GnRH-a; Triptorelin
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Infertility; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Therapeutics; Drug Therapy; Gonadotropin-Releasing Hormone; Triptorelin Pamoate; Hormone Replacement Therapy
• Other Study ID Numbers: DIE-GnRHa-FET-RCT-2025-01; 2025-0564 (Other Identifier: The Affiliated Drum Tower Hospital of Nanjing University Medical School Ethics Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No