Clinical trial NCT04524026: RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF-Study 2
Official title: RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF - Study 2
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: IVF
Keywords: Letrozole, aromatase inhibitor, luteal phase, IVF
Lead sponsor: Zealand University Hospital
Sponsor class: OTHER
Collaborators: name: Gedeon Richter Ltd.
name: Igenomix
First posted: 2020-08-24
Enrollment: 25
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Length of luteal phase (days from aspiration untill bleeding)
timeFrame: Up to three weeks
Secondary outcomes:
measure: Phase of endometrial receptivity according to Endometrial Receptivity Array (ERA) test
timeFrame: ERA-test is taken 5 days after aspiration of oocytes.
measure: Estradiol (E2),progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels.
timeFrame: Blood samples are taken on 1 day of oocyte aspiration, 2 days after, 5 days after and 14 days after.
measure: Endometrium thickness.
timeFrame: Endometrium thickness is measured on 1 day of oocyte aspiration, 2 days after and 5 days after.
Other outcomes:
Locations:
city: Herlev
country: Denmark
facility: Herlev Hospitals Fertilitetsklinik
city: Køge
country: Denmark
facility: Sjællands Fertilitetsklinik
Study officials:
affiliation: Professor
name: Nicholas Stephen Macklon, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: PhD student
name: Marianne Dreyer Holt, MD
role: STUDY_DIRECTOR
References:
citation: Dreyer Holt M, Skouby SO, Bulow NS, Englund ALM, Birch Petersen K, Macklon NS. The Impact of Suppressing Estradiol During Ovarian Stimulation on the Unsupported Luteal Phase: A Randomized Controlled Trial. J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3633-e3643. doi: 10.1210/clinem/dgac409.