GnRH for Luteal Support - Mechanism of Action

May 26, 2026 updated by: Heli Alexandroni

Gonadotropin-Releasing Hormone Agonist as a Single Luteal Support - What is Its Mechanism of Action?

This prospective observational study will include women undergoing IVF treatment with a GnRH antagonist protocol and fresh embryo transfer at the IVF unit of Shaare Zedek Medical Center. Patients will undergo controlled ovarian stimulation followed by ovulation triggering with hCG, GnRH agonist, or dual trigger according to OHSS risk. After oocyte retrieval and fertilization by IVF/ICSI, embryos will be cultured and transferred. Luteal phase support will consist of either intranasal GnRH agonist (Synarel) or vaginal progesterone. Blood and follicular fluid samples will be collected at predefined time points to assess hormonal, inflammatory, and angiogenic markers, including LH, FSH, estradiol, progesterone, IL-6, IL-8, VEGF, PEDF, and relaxin.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Luteal phase support is essential in IVF treatment to overcome luteal phase deficiency and improve pregnancy outcomes, yet the optimal protocol remains unclear. In recent years, GnRH agonists have emerged as a promising option for luteal support, administered either by subcutaneous injection or intranasal spray, with the latter offering a convenient and non-invasive route. Previous studies demonstrated that GnRH agonist supplementation during the luteal phase improves pregnancy and live birth rates, including a prospective randomized study from our group showing significantly higher positive βhCG rates compared with standard progesterone support. Although the exact mechanism remains uncertain, proposed explanations include stimulation of LH secretion, direct effects on the endometrium and embryo, and modulation of placental βhCG production. Evidence also suggests a luteotrophic effect through maintenance of corpus luteum function, reflected by higher progesterone levels and continued pregnancy progression after treatment discontinuation. However, important limitations remain, including variable patient response, possible underlying endocrine or receptor-related factors, and a potential association with ovarian hyperstimulation syndrome (OHSS). Therefore, this study aims to investigate the mechanism of action of GnRH agonists as sole luteal support and identify predictors of treatment success or failure.

The study is a prospective observational study, which will be conducted among women undergoing IVF treatments based on GnRH antagonist protocol with a fresh embryo transfer (ET) at the IVF unit in Shaare Zedek medical center.

About 800 egg retrieval procedures take place at our unit every year, not including pre-implantation genetic testing (PGT) and oocyte cryopreservation cycles. Approximately 80% of the cycles use the antagonist protocol. It is estimated that in 400 of them, patients are administrated with GnRH agonist for luteal support.

During the visit to the clinic, the women's demographic and clinical data will be collected.

All patients will undergo ovarian stimulation based on GnRH antagonist protocol: Ovarian stimulation with gonadotropins (recombinant FSH and\or hMG depending on patients' age, BMI, and basal serum FSH levels) will begin within the first 2-3 days of the menstrual period. When the leading follicle reaches a diameter of >12mm, treatment with daily injections of GnRH antagonist (0.25 mg Orgalutran or 0.25 mg Cetrotide) will be added and continued until the day of ovulation induction. Once sonography will demonstrate three or more follicles at size ≥17mm, ovulation triggering will be administrated. The stimulation for egg maturation will be performed by either recombinant hCG (250 mcg Ovitrelle), GnRH agonist (0.2 mg Decapeptyl), or a combination of the two -dual triggering (250 mcg Oviterelle plus 0.2 mg Decapeptyl). The stimulation type will be chosen according to the decision of the attending physician, usually based on the estimated risk of OHSS (based on laboratory and sonographic markers).

The eggs will be retrieved 36 hours after the ovulation triggering and fertilized by IVF or by intracytoplasmic sperm injection (ICSI). Fertilized embryos will be incubated until the day of ET. During incubation time and before ET, the quality of embryos will be evaluated and graded according to the accepted criteria in the laboratory.

Following egg retrieval, patients will receive luteal phase support with either intranasal GnRH agonist - spray of 200 mcg Nafarelin (Synarel) twice a day for two weeks or vaginal progesterone. After two weeks, at βhCG examination day, Synarel treatment will be stopped, regardless of the test results and progesterone treatment will continue until 8-10 weeks pregnancy.

Blood samples will be collected for each patient at the six following stages:

  1. Ovum pick-up day
  2. Day of ET
  3. 7 days after ovum pick-up (mid-luteal phase)
  4. 12 days after ET
  5. 14 days after ET In addition, follicular fluid from the OPU of each woman will be centrifuged and tested as well.

Laboratory markers will include LH, FSH, βhCG, Estradiol and Progesterone. IL-6. Relaxin, IL-8, VEGF and PEDF will be analyzed by enzyme-linked immunosorbent assay (ELISA) using commercial kits. All samples will undergo appropriate freezing for future testing.

Study variables will include demographic characteristics (age, BMI, obstetric and infertility history), IVF cycle parameters (stimulation protocol, hormonal response, oocyte and embryo characteristics), blood and follicular fluid biomarkers (including LH, FSH, βhCG, steroid hormones, relaxin, IL-6, IL-8, VEGF, and PEDF), and pregnancy outcomes such as positive βhCG, clinical pregnancy, miscarriage, live birth, OHSS, and vaginal bleeding.

Study Type

Observational

Enrollment (Estimated)

150

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Israel
      • Jerusalem, Israel, 9103102
        • Recruiting
        • Shaare Zedek Medical Center
        • Contact:
        • Principal Investigator:
          • Heli Alexandroni, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Probability Sample

Study Population

women undergoing IVF treatment with OPU and ET

Description

Inclusion Criteria:

  • Women included in the study will be 18-45 years old
  • undergoing IVF treatments due to ovulation disorder, mechanical factor, primary ovarian insufficiency, or male infertility.
  • All women will be at their first to the third cycle of treatment
  • women will undergo a fresh ET.

Exclusion Criteria:

  • repeated implantation failure (more than 3 cycles of good quality ET without implantation)
  • moderate-severe endometriosis
  • hydrosalpinx
  • fibroid uterus
  • BMI more than 35 or less than 19
  • women with hypogonadotropic hypogonadism
  • PGT of embryos
  • use of surgical techniques for sperm retrieval
  • preference of the long GnRH-agonist protocol
  • women with rhinitis or nasal congestion.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Luteal support with GnRH agonist
spray of 200 mcg Nafarelin (Synarel) twice a day for two weeks
Drug: GnRH agonist
spray of 200 mcg Nafarelin (Synarel) twice a day for two weeks
Other Names:
  • Synarel nasal spray
Luteal support with vaginal progesterone
progesterone administered until hCG day and continued for 8-10 weeks if positive
Drug: Progesterone
PV progesterone administered until hCG day and continued for 8-10
Other Names:
  • uterogestane
  • endometrin
  • crinon

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Positive pregnancy rate
Time Frame: 2 weeks
serum βhCG ≥ 25 IU/L, measured 14 days after ET.
2 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Level of blood markers along the luteal phase
Time Frame: 2 weeks
LH, FSH (secreted from pituitary gland), steroid hormones, cytokines, and other proteins secreted from CL (Estradiol, Progesterone, Relaxin, IL-6, IL-8)
2 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Heli Alexandroni

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 18, 2026

Primary Completion (Estimated)

December 31, 2026

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

May 18, 2026

First Submitted That Met QC Criteria

May 26, 2026

First Posted (Actual)

June 2, 2026

Study Record Updates

Last Update Posted (Actual)

June 2, 2026

Last Update Submitted That Met QC Criteria

May 26, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SZMC-0357-22

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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