Effect of LH Supplementation on the Endometrial Gene Expression Profile in Poor Ovarian Responders

Study Overview
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Brief Summary
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This is a prospective randomized open-label cross-over study. Poor responder patients will undergo two ovarian stimulation cycles. One with recombinant follicle stimulation hormone (FSH), and an other stimulation with recombinant FSH and recombinant luteinizing hormone (LH). In both groups, a freeze-all strategy will be applied and an endometrial biopsy will be taken 7 days after final oocyte maturation trigger. Endometrial gene expression analysis will be performed on both biopsies. After completion of both treatment cycles, a frozen embryo transfer of a single embryo will be performed.

Detailed Description
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This is a prospective randomized open-label cross-over study, in which patients will be randomized to either start in the control group or in the study group. Participants will undergo both treatments with an interval of minimum 1 and maximum 6 months. In both treatment arms, ovarian stimulation will be started at day 2/3 of the menstrual cycle. In the control group, 225 IU of recombinant FSH will be administered in a fixed antagonist protocol. In the study group, 225 IU of recombinant FSH plus 112,5 IU of recombinant LH will be administered. Cycle monitoring will be performed through serum estradiol (E2), progesterone (P), and luteinizing hormone (LH) assessments, combined with serial ultrasound examinations. Both groups will undergo dual triggering with gonadotropin releasing hormone agonist (GnRHa) 0,2ml and human chorionic gonadotrophin (hCG) 6500IU if one or more follicles of ≥ 17 mm are observed. The oocyte retrieval (OR) will be performed between 34 and 36 hours after final oocyte maturation trigger. At each OR, follicles will be individually meas-ured, aspirated and searched for the presence of cumulus oocyte complexes (COC). Metaphase II (MII) oocytes will then be injected to standard intra-cytoplasmatic sperm injection (ICSI) procedures. In both groups, a freeze-all strategy will be applied. An endometrial biopsy (Pipelle de Cornier ®) will be taken 7 days after final oocyte maturation trigger. After completion of both treatment cycles, a frozen embryo transfer of a single embryo will be performed.

Official Title
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Endometrial Gene Expression Profiles During Ovarian Stimulation With Recombinant FSH With or Without the Addition of Recombinant LH in Genuine Poor Responders

Conditions
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Poor Response to Ovulation Induction

Intervention / Treatment
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* Drug: Lutropin alfa
* Drug: Follitropin alfa
* Diagnostic Test: Endometrial biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 35-40 years Undergoing IVF/ICSI BMI ≥ 19 and ≤ 30 AMH <1.2 ng/mL Previous conventional ovarian stimulation (OS) with < 4 metaphase II (MII) oocytes Regular menstrual cycle (26-35 days) Non-smokers Acceptance to do 2 consecutive ovarian stimulation cycles (between 1-6 months) Signed informed consent Exclusion Criteria: Endometriosis > rAFS grade II Testicular sperm extraction Recurrent miscarriage (>2 previous miscarriages) Ovarian stimulation for pre-implantation genetic testing (PGT-A/M) Medical/social oocyte vitrification In vitro maturation (IVM) Untreated auto-immune, endocrine or metabolic disorders Asherman's syndrome

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: prospective randomized open-label cross-over study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control arm<br>In the control group, 225 IU of recombinant FSH will be administered in a fixed antagonist protocol. | Drug: Follitropin alfa<br>* recombinant follicle stimulating hormone (FSH)<br>Diagnostic Test: Endometrial biopsy<br>* pipelle de cornier biopsy<br>|
| Experimental: Study arm<br>In the study group, 225 IU of recombinant FSH plus 112,5 IU of recombinant LH will be administered. | Drug: Lutropin alfa<br>* addition of recombinant luteinizing hormone<br>Drug: Follitropin alfa<br>* recombinant follicle stimulating hormone (FSH)<br>Diagnostic Test: Endometrial biopsy<br>* pipelle de cornier biopsy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| endometrial gene expression | gene expression profile of the endometrium | 7 days after finale oocyte maturation trigger | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulus cell gene expression |  | 3-6 months | 
| endometrial histologic analysis based on Noyes' classification system |  | 3-6 months | 
| progesterone level at oocyte triggering |  | 3-6 months | 
| follicular fluid (FF) hormonal analysis |  | 3-6 months | 
| number of preovulatory follicles |  | 3-6 months | 
| number of MII oocytes |  | 3-6 months | 
| number of oocytes fertilized |  | 3-6 months | 
| number of good quality embryos |  | 3-6 months | 
| total dose of gonadotropins administered |  | 3-6 months | 
| duration of stimulation |  | 3-6 months | 
| endometrial thickness at the day of endometrial biopsy |  | 3-6 months | 
| implantation rate |  | 6-12 months | 
| clinical pregnancy rate |  | 6-12 months | 
| live birth rate |  | 20 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IVF, LH supplementation, endometrial gene expression