Effectiveness of Low Dose Gonadotropin Stimulation Protocol Vs High Dose Gonadotropin Protocol in Poor Responders

January 11, 2025 updated by: Nikos Vlahos, University of Athens

The Effect of Clomiphene Citrate Administration in Combination with Low Dose (150 IU) of Gonadotropins Vs High Dose Gonadotropin Protocol in Poor Responders. Impact on Stimulation Characteristics and Pregnancy Outcome.

In the present study we examined the effect of addition of CC to a low dose gonadotropin (150 IU/day) / GnRH antagonist protocol in comparison to a high gonadotropin dose (300 IU/day) regiment (short protocol) in women with poor ovarian responce (POR).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

22 patients diagnosed with poor ovarian response, aged 35-43 years, were enrolled in the study. The definition of poor response was based on the presence of at least one of the following criteria: Age equal or over 40 years old or other cause of subfertility, AFC less than 5-7, AMH 0.5-1,1ng/ml , a previous POR (≤3 oocytes with a conventional stimulation protocol or cancellation due to poor response) . All patients received appropriate counselling . Early follicular phase FSH and estradiol (E2) were measured prior to the initiation of treatment. All women had measurements of serum FSH and estradiol and a pelvic sonogram on the second day of their cycle. Providing that serum FSH level was less than 16 mIU/ml and estradiol level less than 70 pg/ml on cycle day2 , ovarian stimulation was initiated with 300 IU of gonadotropins either in the form of a combination of highly purified urinary FSH and LH or with a combination of recombinant FSH and recombinant LH. All patients were re-evaluated on day 5 of the stimulation, and dosage adjustments were made and the antagonists (Cetrorelix or ganirelix 0.25 mg/day) were initiated when at least one follicle reached a diameter of 14mm . When at least 2 follicles reached an average diameter of 18 mm, final oocyte maturation was triggered with 10,000IU of hCG ( Ovitrelle, Greece Inc.). Oocyte retrieval was performed 34 to 36 hours later. All patients underwent ICSI. Patients with successful fertilization underwent embryo transfer under sonographic guidance on day 5 after retrieval. Serum β-hCG levels were measured 12 days after oocyte retrieval, and clinical pregnancy was confirmed by transvaginal ultrasound 14 days later. Ongoing pregnancy was confirmed at 12 weeks by ultrasound. In case of negative pregnancy test result the same participants received CC (100 mg/day) from day 3 to day 7 of the menstrual cycle, in combination with low-dose gonadotropins (150 IU/day) until the day of hCG administration. The primary outcome measure was ongoing pregnancy rates. Secondary outcomes included the number of follicles, the number of mature oocytes, fertilization rate, total number of embryos and embryo quality in each group. Furthermore, we included biochemical pregnancy rates and miscarriage as secondary outcomes as well.

Study Type

Interventional

Enrollment (Actual)

22

Phase

  • Early Phase 1

Contacts and Locations

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

Study Locations

  • Greece
      • Athens, Greece
        • ARETAIEION University Hospital
    • Attica
      • Athens, Attica, Greece
        • ARETAIEION University Hospital

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

Description

The inclusion criteria, established by the European Society of Human Reproduction and Embryology (ESHRE), define POR as the presence of at least two of the following features, had to be met:

  • Advanced maternal age (≥40 years) or any other risk factor for POR
  • A previous POR (≤3 oocytes with a conventional stimulation protocol)
  • An abnormal ovarian reserve test (Day 3 follicle-stimulating hormone (FSH) > 12 mIU/ml
  • Anti-Müllerian hormone (AMH) < 2ng/ml).

Exclusion Criteria:

The succesful ongoing pregnancy after the first stimulation.

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

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Clomiphene Citrate (CC)/r-FSH

Administration of 100mg/day Clomiphene citrate (CC) from day 3 to day 7 of the cycle (5 days) in combination with low-dose gonadotropins (150IU) according to a short stimulation GnRh antagonists protocol.

Treatment schedule:

Serum AMH levels were measured before the stimulation began. Estradiol and FSH levels were measured on the third day of the participants' menstrual cycle. Ovarian stimulation started on the same day with 150 IU of recombinant human Follicle-Stimulating Hormone (r-FSH) after a transvaginal ultrasound was performed, provided that serum FSH levels were below 16 mIU/ml and estradiol levels were under 70 pg/ml (r-FSH group). All patients underwent routine monitoring with transvaginal ultrasound. The GnRH antagonist cetrorelix acetate, at a dose of 0.25 mg/day was given when a dominant follicle reached 14 mm in diameter. Oocyte retrieval (OPU) was performed 34-36 hours after hCG administration followed by IVF/ICSI and embryo transfer on day 3 after OPU
Drug: Clomiphane citrate
Clomiphene citrate 100mg/day from day 3 to day 7 of the cycle (5 days) will be added to the low-dose (150 IU) short GnRh antagonist protocol (recombinant human Follicle-Stimulating Hormone (r-FSH-alfa) (Gonal-f; Merck Serono Hellas AE))
Other Names:
  • Clomiphene citrate 50mg/tab
  • Serpafar 50mg/tab
Drug: recombinant human Follicle-Stimulating Hormone (r-FSH-alfa)

All patients will undergo ovarian stimulation with the standard-dose GNRH-antagonist protocol.

Ovarian stimulation will be initiated with 150 IU of of recombinant human Follicle-Stimulating Hormone (r-FSH-alfa) (Gonal-f; Merck Serono Hellas AE)

Other Names:
  • Gonal-f 150 Iu/day
  • Gonal-f 300 IU/day
Active Comparator: High-dose Gonadotropins (r-FSH)

Patients in this group will be stimulated according to the high-dose short r-FSH antagonist protocol.

Treatment schedule:

Ovarian stimulation started on day 3 with 300 IU of recombinant human Follicle-Stimulating Hormone (r-FSH) after a transvaginal ultrasound was performed, provided that serum FSH levels were below 16 mIU/ml and estradiol levels were under 70 pg/ml (r-FSH group). All patients underwent routine monitoring with transvaginal ultrasound and serum estradiol measurements. The GnRH antagonist cetrorelix acetate, at a dose of 0.25 mg/day, was given when a dominant follicle reached 14 mm in diameter. Oocyte retrieval (OPU) was performed 34-36 hours after hCG administration, followed by IVF/ICSI and embryo transfer on day 3 after OPU.
Drug: recombinant human Follicle-Stimulating Hormone (r-FSH-alfa)

All patients will undergo ovarian stimulation with the standard-dose GNRH-antagonist protocol.

Ovarian stimulation will be initiated with 150 IU of of recombinant human Follicle-Stimulating Hormone (r-FSH-alfa) (Gonal-f; Merck Serono Hellas AE)

Other Names:
  • Gonal-f 150 Iu/day
  • Gonal-f 300 IU/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ongoing pregnancy rates
Time Frame: 28 months from start of study
succesfull clinical pregnancy after performing ultrasound on 12 weeks of pregnancy
28 months from start of study

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of follicles
Time Frame: 24 months from start of study
Calculated on the day of triggering
24 months from start of study
Number of mature oocytes
Time Frame: 24 months from start of study
MII
24 months from start of study
Fertilization rate
Time Frame: 24 months from start of study
Percentage
24 months from start of study
Total number of embryos in each group
Time Frame: 24 months from start of study
Total number of embryos
24 months from start of study
Biochemical pregnancy rates
Time Frame: 24 months from start of study
Absence of clinical pregnancy
24 months from start of study
Miscarriage rates
Time Frame: 28 months from start of study
Percentage of pregnancies that did not reach viability
28 months from start of study

Collaborators and Investigators

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

Sponsor

University of Athens

Investigators

  • Principal Investigator: Olga Triantafyllidou, MD,, University of Athens School of Medicine

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

Helpful Links

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)

January 1, 2022

Primary Completion (Actual)

January 1, 2024

Study Completion (Actual)

April 30, 2024

Study Registration Dates

First Submitted

October 5, 2024

First Submitted That Met QC Criteria

January 11, 2025

First Posted (Actual)

March 25, 2025

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

January 11, 2025

Last Verified

January 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ARETAIEION IVF UNIT

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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