Efficacy of Ovarian Stimulation Based on FSHR Genotype Status

Study Overview
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Brief Summary
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Available data from in vitro studies and clinical trials indicate that genetic factors play a significant role in the success of controlled ovarian stimulation (COS) prior to in vitro fertilization - embryo trandfer (IVF-ET). Women with the FSHR Ser680Asn Ser/Ser genotype make up between 13% and 26% of women undergoing IVF-ET and are characterised by higher basal FSH serum concentrations, the need for a higher amount of FSH for COS, and a higher risk of poor response to COS and cycle cancellation. The investigators therefore intend to perform a study to investigate whether a dose-intensified COS protocol based on FSHR genotype status in women with the FSHR Ser680Asn Ser/Ser genotype is more effective than routine management in terms of the mean number of follicles the mean number of embryos the rate of poor responders the rate of women with cycle cancellations, and v) the clinical pregnancy rates. Eligible women will be randomized to a stimulation protocol characterised by a longer duration and increased dosage of FSH stimulation (group A) or a standard stimulation protocol (group B).

Detailed Description
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Women in group A will undergo controlled ovarian stimulation according to the following protocol: Pituitary down-regulation will be achieved using buserelin (Suprefact®, Hoechst, Frankfurt, Germany) at a fixed daily dose of 200 mg s.c., according to a long agonist protocol, starting on day 2 of the normal menstrual cycle. Treatment with r-hFSH (Gonal-F®, Serono Austria GmbH, Vienna, Austria) will be started in women with serum E2 concentrations <200 pmol/l and no follicles >15 mm in diameter or ovarian cysts on ultrasonographic examination. The initial r-hFSH dose will be 250 IU s.c. daily for 5 days, after which the dose will be increased to a maximum of 450 IU per day using a step-up protocol with steps of 50 IU/day. Once the leading follicle has reached a diameter of 14 mm, patients will receive r-hLH (lutropin alfa; Luveris®, Serono Austria GmbH, Vienna, Austria) at a dose of 75 IU s.c. for a maximum of 10 days. A dose of 75 IU LH per day was chosen based on findings from a controlled, prospective, dose-finding study in gonadotrophin-deficient women (WHO I classification) (7). Ovulation will be induced by administration of HCG (Profasi®, Serono Austria GmbH, Vienna, Austria), 10 000 IU i.m. or s.c., when at least two follicles have reached a diameter of >17 mm. Oocyte retrieval will be performed by ultrasound-guided follicular aspiration techniques 34-38 h after administration of HCG. IVF will be performed according to standard practices at our institution. A maximum of three embryos will be transferred 48 h after oocyte retrieval (ESHRE Committee on Good Clinical and Laboratory Practice, 1995 ). Patients will receive micronized progesterone, 600 mg/day, by vaginal administration for at least the first 3 weeks of pregnancy, beginning on the day of embryo transfer. Women in group B will undergo ovarian hyperstimulation according to the following protocol: No pituitary down-regulation will be performed. Treatment with r-hFSH (Gonal-F®, Serono Austria GmbH, Vienna, Austria) will be started in women with serum E2 concentrations <200 pmol/l and no follicles >15 mm in diameter or ovarian cysts on ultrasonographic examination. The r-hFSH dose will be 150 IU s.c. daily for 11 consecutive days. Once the leading follicle has reached a diameter of 14 mm, patients will receive r-hLH (lutropin alfa; Luveris®, Serono Austria GmbH, Vienna, Austria) at a dose of 75 IU s.c. for a maximum of 10 days. A dose of 75 IU LH per day was chosen based on findings from a controlled, prospective, dose-finding study in gonadotrophin-deficient women (WHO I classification) (European Recombinant Human LH Study Group, 1998 ). Ovulation will be induced by administration of HCG (Profasi®, Serono Austria GmbH, Vienna, Austria), 10 000 IU i.m. or s.c., when at least two follicles have reached a diameter of >17 mm. Oocyte retrieval will be performed by ultrasound-guided follicular aspiration techniques 34-38 h after administration of HCG. IVF will be performed according to standard practices at our institution. A maximum of three embryos will be transferred 48 h after oocyte retrieval (ESHRE Committee on Good Clinical and Laboratory Practice, 1995 ). Patients will receive micronized progesterone, 600 mg/day, by vaginal administration for at least the first 3 weeks of pregnancy, beginning on the day of embryo transfer.

Official Title
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Prospective, Randomized Open Trial to Evaluate the Efficacy of an Ovarian Stimulation Protocol Based on FSH Receptor Genotype

Conditions
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Sterility

Intervention / Treatment
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* Drug: follicle stimulating hormone
* Drug: follicle stimulating hormone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 40 Informed consent Indication for IVF-ET Exclusion Criteria: Inability to understand written informed consent form Personal history of ovarian hyperstimulation syndrome

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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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: 1<br>Pituitary down-regulation will be achieved using buserelin (Suprefact®, Hoechst, Frankfurt, Germany) at a fixed daily dose of 200 mg s.c., according to a long agonist protocol, starting on day 2 of the normal menstrual cycle. Treatment with r-hFSH (Gonal-F®, Serono Austria GmbH, Vienna, Austria) will be started in women with serum E2 concentrations <200 pmol/l and no follicles >15 mm in diameter or ovarian cysts on ultrasonographic examination. The initial r-hFSH dose will be 250 IU s.c. daily for 5 days, after which the dose will be increased to a maximum of 450 IU per day using a step-up protocol with steps of 50 IU/day. | Drug: follicle stimulating hormone<br>* Pituitary down-regulation will be achieved using buserelin (Suprefact®, Hoechst, Frankfurt, Germany) at a fixed daily dose of 200 mg s.c., according to a long agonist protocol, starting on day 2 of the normal menstrual cycle. Treatment with r-hFSH (Gonal-F®, Serono Austria GmbH, Vienna, Austria) will be started in women with serum E2 concentrations <200 pmol/l and no follicles >15 mm in diameter or ovarian cysts on ultrasonographic examination. The initial r-hFSH dose will be 250 IU s.c. daily for 5 days, after which the dose will be increased to a maximum of 450 IU per day using a step-up protocol with steps of 50 IU/day.<br>* Other names: buserelin, r-hFSH, r-hLH;|
| Active Comparator: 2<br>No pituitary down-regulation will be performed. Treatment with r-hFSH (Gonal-F®, Serono Austria GmbH, Vienna, Austria) will be started in women with serum E2 concentrations <200 pmol/l and no follicles >15 mm in diameter or ovarian cysts on ultrasonographic examination. The r-hFSH dose will be 150 IU s.c. daily for 11 consecutive days. | Drug: follicle stimulating hormone<br>* No pituitary down-regulation will be performed. Treatment with r-hFSH (Gonal-F®, Serono Austria GmbH, Vienna, Austria) will be started in women with serum E2 concentrations <200 pmol/l and no follicles >15 mm in diameter or ovarian cysts on ultrasonographic examination. The r-hFSH dose will be 150 IU s.c. daily for 11 consecutive days.<br>* Other names: buserelin, r-hFSH, HCG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical pregnancy rate |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| follicle count, cycle cancellation rate, poor responder rate |  | 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ovarian stimulation, FSH, genotyping, polymorphism