Mapping the Endocrine Determinants of Ovarian Stimulation to Optimize Outcomes in Fresh Embryo Transfer Cycles

Study Overview
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Brief Summary
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The goal of this project is to identify autocrine, paracrine and endocrine factors which are associated with intercycle variation in cyclical follicle recruitment. Patients will be monitored in a natural cycle, a stimulated cycle and a follow up. In the stimulated cycle patients will be randomized to co-treatment with aromatase inhibitor or placebo during ovarian stimulation.

Detailed Description
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The primary aim of this project is to explore the putative cyclic recruitment 'gatekeeping' functions of gonadotropins, sex steroids, anti-muellarian hormone and pregnancy associated plasma protein A in normal ovulatory cycles, and the impact of ovarian stimulation on cyclic follicle recruitment in the following cycle. It is further proposed that supra-physiological levels of estradiol and progesterone which arise from ovarian stimulation may modulate the size of the secondarily recruited follicle cohort in the next cycle. In order to explore the relative contribution of sex steroids as determinants of the size of the next cycle 'wave' of recruitment further, a second aim of this study will be investigate whether limiting the rise in sex steroid levels during ovarian stimulation, by co-treatment with aromatase inhibitor impacts on cyclic recruitment.

Official Title
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Reducing the Impact of Ovarian Stimulation - The RIOT Project Study RIOT-B: Mapping the Endocrine Determinants of Ovarian Stimulation to Optimize Outcomes in Fresh Embryo Transfer Cycles

Conditions
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Infertility

Intervention / Treatment
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* Drug: Placebo
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Indication for IVF/ICSI treatment Eligible for IVF/ICSI treatment according to local criteria Regular cycles 21-35 days (both included) Age <40 years AMH 8-32 (both included) Written consent Willing to undergo intensive monitoring in a natural cycle (the cycle prior to the monitored natural cycle must be hormone treatment free), stimulated cycle and follow up in the subsequent cycle Exclusion Criteria: Any contraindication for IVF/ICSI treatment according to local criteria Previous stimulation for IVF/ICSI with < 4 oocytes obtained PCOS Undergoing IVF/ICSI for the purpose of fertility preservation Allergy towards study drug

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Lactose Monohydrate<br>2 tablets of placebo are administered daily from stimulation start to day before hCG as adjunctive therapy to 150 International Units of recFSH | Drug: Placebo<br>* Adjuvant therapy to recFSH during ovarian stimulation<br>* Other names: Lactose Monohydrate;|
| Active Comparator: Letrozole<br>2 tablets of 2,5 mg Letrozole are administered daily from stimulation start to day before hCG as adjunctive therapy to 150 International Units of recFSH | Drug: Letrozole<br>* Adjuvant therapy to recFSH during ovarian stimulation<br>* Other names: Aromatase Inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Size of follicle cohort in relation to serum endocrine and paracrine markers | Markers for analysis include: anti-muellerian hormone, estradiol, follicle stimulating hormone, luteinizing hormone, testosterone, androstenedione, progesterone,17-hydroxyprogesterone, pregnancy associated plasma protein A and A2, Inhibin A and B, Bone morphogenic protein | The change in size of follicle cohort in relation to change in endocrine and paracrine markers assessed throughout the study completion, up to 3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Size of the cyclically recruited follicle cohort after ovarian stimulation with and without co-treatment with Aromatase Inhibitor. |  | The change in size of follicle cohort throughout the study completion, up to 3 years. | 
| Expression of cytokine and growth factors in endometrial secretions following co-treatment with Aromatase Inhibitor compared with placebo control. |  | Assessed in stimulated cycle at time of embryo transfer (throughout study completion, up to 3 years). | 
| Serum E2, P, Tst and Androstenedione levels |  | The change in levels throughout the study completion, up to 3 years. | 
| Area under the curve for P and 17-hydroxyprogesterone. |  | The change in levels throughout the study completion, up to 3 years. | 
| Total International Units of Follicle Stimulating Hormone used per treatment cycle. |  | Assessed throughout study completion, up to 3 years. | 
| Number of follicles > 12 mm |  | Assessed throughout the study completion, up to 3 years. | 
| Number of oocytes obtained |  | Assessed during stimulation treatment (throughout the study completion, up to 3 years). | 
| Proportion of oocytes resulting in top quality day 2, day 3 embryos or day 5/6 embryos according to validated morphological criteria. |  | Assessed during stimulation treatment (throughout the study completion, up to 3 years). | 
| Oocyte fertilization rate |  | Assessed during stimulation treatment (throughout the study completion, up to 3 years). | 
| Number and quality of embryos obtained. |  | Assessed during stimulation treatment (throughout the study completion, up to 3 years). | 
| Endometrial thickness |  | Assessed throughout the study completion, up to 3 years. | 
| Uterine contraction rate (contractions/minute) |  | Assessed throughout the study completion, up to 3 years. | 
| Implantation rate |  | Assessed during stimulation treatment (throughout the study completion, up to 3 years). | 
| Reported side effects |  | From start of stimulation and administration of study medication to pregnancy scan week gestational age 7-8. Assessed throughout the study completion, up to 3 years. | 
| Morphokinetic parameters of embryo quality as measured using a Time Lapse analysis. |  | Assessed from time of oocyte pick-up to embryo transfer following stimulation (throughout study completion, up to 3 years) | 
| Clinical pregnancy rate |  | Pregnancy scan at gestational age week 7-8 (3-4 weeks after the positive hCG in serum) Assessed during stimulation treatment (throughout the study completion, up to 3 years). | 
| Follicular fluid endocrine and paracrine markers following co-treatment with Aromatase Inhibitor compared with placebo control. |  | Assessed during stimulation treatment (throughout the study completion, up to 3 years). | 
| Biochemical pregnancy rate |  | Assessed during stimulation treatment (throughout the study completion, up to 3 years). | 
| Area under the curve for E2, P and LH |  | The change in levels throughout the study completion, up to 3 years. |