RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF-Study 2

Study Overview
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Brief Summary
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The goal of the randomised controlled study (RCT) is to identify novel strategies that can improve the luteal phase endocrinology after ovarian stimulation, with the aim of using less or no luteal support in IVF while making the endometrium thinner and more receptive to embryo implantation.

Detailed Description
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The high estradiol levels generated in IVF by multiple dominant follicles at the follicular-luteal phase transition generate powerful negative feedback at the pituitary gland, effectively switching off gonadotropin production. Without stimulation by endogenous luteinizing hormone (LH), the corpora lutea undergo involution and menstruation follows, preventing the establishment of pregnancy. To address these detrimental effects of ovarian stimulation, the investigators will do a RCT with the use of aromatase inhibitors, which suppress the conversion of androgens to estrogens to ameliorate the unwanted effects of high estrogens. This study is designed to test the hypothesis that preventing supra-physiological estrogen levels during ovarian stimulation restricts pituitary suppression sufficiently to allow LH levels to rise and support the corpora lutea, leading to a normal post-ovulatory luteal phase, evidenced by a normal duration and luteal phase endocrine profile. To test this, consenting oocyte donors will be randomized to receive co-treatment with aromatase inhibitors or no co-treatment during ovarian stimulation. Following oocyte retrieval, no luteal support will be provided to donors in both Groups.

Official Title
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RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF - Study 2

Conditions
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IVF

Intervention / Treatment
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* Drug: Letrozole 5 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet the clinical criteria for acceptance as oocyte donors (healthy women who volunteers to donate oocytes to other women). Regular ovulatory cycle of 26-32 days. Age: 18-35 years old. Written consent. Exclusion Criteria: Contraindications for ovarian stimulation or aspiration of oocytes according to local guidelines Polycystic Ovary Syndrome (PCOS) Allergy towards study drug Women who have had a hormone or copper intra-uterine device (IUD) within 3 months Exclusion of patients after earlier inclusion in the study in case of Patient withdrawal of consent Lack of compliance with medication Medical complication arising from IVF treatment that requires the cycle to be terminated Serious adverse events (SAE) or serious adverse reactions (SAR) including severe allergy to study drug. Specific ARs to study drug: severe degree of hot flushed, severe degree of nausea/vomiting, severe diarrhea, severe degree of muscle and joint pain. In case of exclusion of a patient after earlier inclusion in the study, a new patient will be included.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>recFSH and co-treatment with letrozole 5 mg/day from stimulation day 1 on cycle day 2 or 3 until the day before gonadotrophin releasing hormone(GnRH) agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support. | Drug: Letrozole 5 mg<br>* recFSH and co-treatment with letrozole 5 mg/day from stimulation day 1 on cycle day 2 or 3 until the day before GnRH agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support.<br>* Other names: Aromatase inhibitor;|
| No Intervention: Control group<br>recFSH from stimulation day 1 on cycle day 2 or 3 until the day before GnRH agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of luteal phase (days from aspiration untill bleeding) | Difference in lengths of days until bleeding (from aspiration until first day of bleeding) of the luteal phase between intervention group and control group. | Up to three weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase of endometrial receptivity according to Endometrial Receptivity Array (ERA) test | Difference in established endometrial tissue and secretion markers of endometrial receptivity between intervention group and controls (genomic profile assessed by ERA test). | ERA-test is taken 5 days after aspiration of oocytes. | 
| Estradiol (E2),progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels. | Differences in the area under the curve for plasma E2, P, LH and FSH levels from day of OPU until day 14 post OPU between intervention group and control group. | Blood samples are taken on 1 day of oocyte aspiration, 2 days after, 5 days after and 14 days after. | 
| Endometrium thickness. | Difference in endometrium thickness 5 days post oocyte pick-up (OPU) between intervention group and controls. | Endometrium thickness is measured on 1 day of oocyte aspiration, 2 days after and 5 days after. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Letrozole, aromatase inhibitor, luteal phase, IVF