PErsonalized Addition of Recombinant LH in Ovarian Stimulation (PEARL)

March 25, 2026 updated by: Fundación Santiago Dexeus Font

PErsonalized Addition of Recombinant LH in Suboptimal Responders >35 Years Old (POSEIDON Group 2): A Randomized Controlled Trial

Different ovarian stimulation regimens have shown to modify late follicular phase hormonal profiles. Besides, recent studies confirm that progesterone levels and their variation in the last day of oocyte maturation are affected by the dose of gonadotropins administered and by other factors. Progesterone elevation in late follicular phase of in vitro fertilization/intracytoplasmatic sperm injection (IVF/ICSI) cycles under ovarian stimulation compromises implantation rates due to a negative effect on the endometrium. However, there is still conflict in the literature questioning whether progesterone levels alone on the triggering day is a sufficient indicator as progesterone does not give the full picture of the ovarian functions, number of follicles as well as estrogen production that facilitate endometrial growth, thus some studies suggest that especially in aged and poor responders Progesterone/Estrogen (P4/E2) ratio has a better reflection (Progesterone (ng/mL) ×1,000/estradiol(pg/mL)) on the ovarian function.

The scope of the current pilot study is to compare serum progesterone levels as well as P4/E2 ratio on the day of ovulation triggering of women belonging to POSEIDON category group 2 who undergo a new ovarian stimulation with a dose of rhFSH 300 IU or 300 IU rhFSH plus 150 IU recombinant human luteinizing hormone (rhLH) in a gonadotropin-releasing hormone (GnRH) antagonist protocol.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The main objective of assisted reproductive technology is to achieve a healthy child. Many aspects play a role in order to reach this outcome, including female age, the number of oocytes retrieved after ovarian stimulation, and endometrial receptivity. It has been clearly demonstrated that the number of oocytes obtained after ovarian stimulation for IVF/ICSI is a surrogate marker for the success rates following treatment. In general, a high number of oocytes retrieved is translated into a high number of embryos and eventually a high cumulative pregnancy rate (after the transfer of fresh and frozen-thawed embryos). However, although a higher number of oocytes and embryos may ensure an increase in the cumulative pregnancy rate, excessive ovarian response has been postulated to have a detrimental effect on the pregnancy rates following fresh embryo transfer given that raised serum estradiol and progesterone levels associated with a very excessive response may negatively affect embryo implantation.

In assisted reproductive technology (ART) cycles under the GnRH analog regimens, elevated progesterone serum levels at the late follicular phase, in good ovarian reserve women, is thought to be related to multiple follicular development and increased ovarian steroidogenic activity. However, for these patients elevated progesterone was shown to negatively affect the endometrium preparation and thereby implantation rate. Furthermore, in this group of women elevated progesterone is advocated to have no negative effect on the oocyte or embryo quality.

Importantly, more pronounced effect on unbalanced steroidogenesis has been correlated with age and ovarian reserve. For this patient population, serum progesterone/estradiol (P/E2) ratio on the day of human chorionic gonadotropin (hCG) administration was suggested as a more reliable marker predictor to cycle success than solely progesterone rise.

Based on the above-mentioned reports it is relatively clear that the aim of ovarian stimulation should be to result in high oocyte yield and educate endocrine milieu in order to maximize cumulative live birth rates. Nevertheless, despite this goal, a substantial proportion of patients do not manage to reach an optimal oocyte yield, resulting in lower pregnancy rates. These hypo-responders are associated with low follicles growth and reduced estrogen production leading to longer stimulations, and/or greater cumulative FSH doses.

Although, it is widely accepted that poor ovarian responders have significantly low live birth rates as compared with all other groups, an intermediate group of women with a "suboptimal ovarian response", has been recently proposed as a distinct group with significantly worse prognosis from women with normal response. In the same line, the POSEIDON group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) has recently proposed a new stratification for patients with a reduced ovarian reserve or unexpected inappropriate ovarian response to ovarian stimulation, taken into account quantitative and qualitative parameters such as: i. Age and the expected aneuploidy rate; ii. Ovarian biomarkers (mainly antral follicle count (AFC) and anti-Müllerian hormone (AMH)), and iii. Ovarian response to a previous stimulation cycle.

One of the most interesting group of patients fulfilling the POSEIDON criteria is undeniably, POSEIDON GROUP 2: Women ≥35 years with adequate ovarian reserve parameters (AFC≥5; AMH≥1.2 ng/ml) and with unexpected poor or suboptimal ovarian response:

  • Subgroup 2a: <4 oocytes after standard ovarian stimulation.
  • Subgroup 2b: 4-9 oocytes after standard ovarian stimulation.

Patients belonging to the POSEIDON group 2 are women with an objectively good ovarian reserve who do not manage to respond as expected following ovarian stimulation. Consequently, taking into account that these patients are women who do not respond in accordance to their ovarian reserve following ovarian stimulation, identifying the optimal treatment protocol for these women remains of paramount importance, namely these patients show slow response to FSH stimulation in terms of estradiol levels and follicle growth, require longer stimulations, and/or greater cumulative FSH doses despite their correct ovarian parameters.

In this regard, different gonadotropins used for ovarian stimulation have shown to affect differently late follicular phase hormonal levels. In fact, although the role of LH in the follicular phase of ovarian stimulation is still a matter of debate, it seems that IVF/ICSI cycles under LH activity reach lower progesterone levels on the day of ovulation triggering. However, no study has evaluated late follicular phase progesterone levels in Poseidon 2 group patients receiving recombinant FSH (rhFSH) versus rhFSH and rhLH for ovarian stimulation.

Taking into account the above-mentioned evidence, the investigators set out to perform a pilot study in women with suboptimal response (fulfilling Poseidon 2 criteria), in order to examine whether the addition of rhLH to rhFSH significantly changes late follicular phase progesterone levels as compared to rhFSH alone.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Phase 4

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

  • Name: Nikolaos P Polyzos, MD PhD
  • Phone Number: 0034932274700
  • Email: nikpol@dexeus.com

Study Contact Backup

Study Locations

  • Spain
      • Barcelona, Spain, 08028
        • Recruiting
        • Hospital Universitario Quiron Dexeus
        • Contact:

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

35 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Able and willing to sign the Patient Consent Form and adhere to study visitation schedule.
  • ≥ 35 years ≤40 years old.
  • AFC ≥5 and or AMH ≥1.2 ng/mL.
  • <4 or 4-9 oocytes retrieved in a previous IVF/ICSI cycle with a starting dose of ≤225 IU with any gonadotropin under a GnRH antagonist protocol.
  • Up to 3 previous ovarian stimulation cycles with a starting dose of ≤225 IU in which dose adjustments during stimulation did not exceed 300 IU.
  • Ovarian stimulation for IVF/ICSI

Exclusion Criteria:

  • Poor ovarian responders according to the Bologna criteria.
  • Polycystic ovary syndrome (PCOS) patients according to the Rotterdam criteria.
  • AFC>20.
  • Age >40 or <35 years old.
  • Women with >10 oocytes retrieved in a previous IVF/ICSI cycle with 150-225 IU starting dose.
  • Women who required dose adjustments during stimulation >300 IU with any gonadotropin in their previous cycle
  • Uterine abnormalities.
  • Recent history of any current untreated endocrine abnormality.
  • Unilateral or bilateral hydrosalpinx (visible on ultrasound scan (USS), unless clipped).
  • Contraindications for the use of medicine used for ovarian stimulation (gonadotropins, GnRH antagonist, progesterone vaginal gel)
  • Recent history of severe disease requiring regular treatment (Clinically significant concurrent medical condition that could compromise subject safety or interfered with the trial assessment and patients with any contraindication to pregnancy).
  • Preimplantation Genetic Testing for Aneuploidies (PGT-a).
  • Testicular Sperm Aspiration or Testicular Sperm Extraction (TESA or TESE)

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: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: rhFSH+rhLH
Ovarian Stimulation with rhFSH+rhLH
Drug: rhFSH+rhLH
300 IU of rhFSH and 150 IU of rhLH (Pergoveris®) GnRH antagonist: cetrorelix 0.25 mg (Cetrotide® - Merck) GnRH antagonist: cetrorelix 0.25 mg (Cetrotide® - Merck) Recombinant human chorionic gonadotropin (rhCG) 6500 IU (Ovitrelle® - Merck) micronized progesterone 90 mg (Crinone 8% ® - Merck)
Active Comparator: rhFSH
Ovarian Stimulation with rhFSH
Drug: rhFSH
300 IU rhFSH (Gonal-F®- Merck) GnRH antagonist: cetrorelix 0.25 mg (Cetrotide® - Merck) GnRH antagonist: cetrorelix 0.25 mg (Cetrotide® - Merck) rhCG 6500 IU (Ovitrelle® - Merck) micronized progesterone 90 mg (Crinone 8% ® - Merck)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum progesterone levels on the day of ovulation triggering.
Time Frame: 5 -20 days from initiation of ovarian stimulation
The outcome will be evaluated on the day of ovulation triggering
5 -20 days from initiation of ovarian stimulation
P/E2 ratio
Time Frame: 5 -20 days from initiation of ovarian stimulation
Progesterone / estradiol ratio
5 -20 days from initiation of ovarian stimulation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progesterone Profile
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
Estradiol Profile
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
FSH Profile
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
Testosterone Profile
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
LH Profile
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
P/E2 ratio Profile
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
Values of Progesterone-to-follicle Index (PFI)
Time Frame: on the day of ovulation triggering.
on the day of ovulation triggering.
Oocytes retrieved
Time Frame: 7 -20 days from initiation of ovarian stimulation
7 -20 days from initiation of ovarian stimulation
Metaphase II (MII) oocytes retrieved
Time Frame: 7 -20 days from initiation of ovarian stimulation
7 -20 days from initiation of ovarian stimulation
Follicle to Oocyte Indexs (FOI)
Time Frame: 7 -20 days from initiation of ovarian stimulation
ratio between the total number of oocytes collected at the end of ovarian stimulation and the number of antral follicles available at the start of stimulation
7 -20 days from initiation of ovarian stimulation
Follicular Output Rates (FORT)
Time Frame: Day 1 at the start of stimulation
ratio of the number of preovulatory follicles and the number of antral follicles available at the start of stimulation
Day 1 at the start of stimulation
Percentage of patients with optimal number of oocytes retrieved (≥10 oocytes).
Time Frame: 7 -20 days from initiation of ovarian stimulation
7 -20 days from initiation of ovarian stimulation
Percentage (%) of top-quality embryos
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Blastocyst formation rates (%).
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Clinical pregnancy
Time Frame: at 6-7 weeks of gestation
defined as the presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity
at 6-7 weeks of gestation
Ongoing pregnancy
Time Frame: at 8-9 weeks of gestation
defined as the presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity
at 8-9 weeks of gestation
Biochemical pregnancy
Time Frame: 2 weeks after embryo transfer
defined as positive pregnancy test
2 weeks after embryo transfer

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ovarian hyperstimulation syndrome (OHSS) (percent).
Time Frame: Until 15 days after the end of ovarian stimulation
Number of subjects with OHSS during the ovarian stimulation period and their severity
Until 15 days after the end of ovarian stimulation
Miscarriages
Time Frame: before completion of 12 weeks of gestation
any spontaneous abortion that occurred after confirmation of clinical pregnancy
before completion of 12 weeks of gestation
Cycle cancelation
Time Frame: Until 15 days after the beginning of ovarian stimulation
when no follicle has adequate maturation or the follicle is lost due to spontaneous LH surge
Until 15 days after the beginning of ovarian stimulation
Incidence of adverse events and serious adverse events
Time Frame: Until 15 days after the end of ovarian stimulation
Until 15 days after the end of ovarian stimulation

Collaborators and Investigators

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

Sponsor

Fundación Santiago Dexeus Font

Collaborators

Merck, S.L., Spain

Investigators

  • Study Chair: Nikolaos P Polyzos, MD PhD, Hospital Universitari Dexeus

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)

February 4, 2021

Primary Completion (Estimated)

August 1, 2027

Study Completion (Estimated)

November 1, 2027

Study Registration Dates

First Submitted

January 14, 2021

First Submitted That Met QC Criteria

January 19, 2021

First Posted (Actual)

January 22, 2021

Study Record Updates

Last Update Posted (Actual)

March 30, 2026

Last Update Submitted That Met QC Criteria

March 25, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FSD-RHLH-2019-08

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

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.

Clinical Trials on Infertility

Clinical Trials on rhFSH+rhLH

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Uganda

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe