Synchronization of Ovarian Stimulation for in Vitro Fertilization With Follicular Wave Emergence

Study Overview
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Brief Summary
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Ovarian stimulation is an important phase of in vitro fertilization (IVF) treatments. The harvest of a larger number of viable eggs per cycle compensate eventual laboratory difficulties and allow for the selection of embryos with higher implantation potential. In the current protocols, based on the most prevailing theory of ovarian follicular development, stimulation drugs are usually started on the second or third day after the beginning of menses. The follicular phase of the menstrual cycle is believed to be the only favorable moment for follicular development. In the early 2000's a new model of human ovarian follicular development (follicular waves) has been proposed based on frequent transvaginal ultrasound observations between two ovulations. It has been shown that ovarian antral follicles develop in synchronous groups, two to three times in a cycle. In fact the follicular wave phenomenon has been initially described in the 80's on domestic animals, like the mare and the cow. Moreover, studies in these animals have shown that synchronizing the start of the ovarian stimulation drugs with the beginning of a follicular wave yields better results for assisted reproductive treatments. Consequently in ovarian stimulation protocols for animal assisted reproduction it is important to control the initiation of a follicular wave. Current protocols of ovarian stimulation for IVF in women do not consider the start of a follicular wave to begin drug administration. Therefore the purpose of this study is to evaluate two methods to control the emergence of a follicular wave (ovulation induction and dominant follicle aspiration) and to investigate the effects of synchronizing ovarian stimulation for IVF with follicular wave emergence in women compared to one of the current stimulation protocols (flexible GnRH protocol).

Official Title
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The Role of Controlling Follicular Wave Emergence to Synchronize Ovarian Stimulation for in Vitro Fertilization

Conditions
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Infertility

Intervention / Treatment
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* Drug: Ovulation induction with choriogonadotropin alfa
* Procedure: Aspiration of the dominant follicle
* Other: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age < 35 years old body mass index: 19-30 kg/m2 tubal or male factor infertility with indication of in vitro fertilization antral follicle count: 10-20 normal uterus in transvaginal ultrasound scan FSH on the third day of the menstrual cycle below 12mUI/mL and estradiol below 80pg/mL male partner with at least 5 million motile sperm and 1% normal strict morphology on semen analyses Exclusion Criteria: ovarian factor infertility non identification of one or both ovaries in the transvaginal ultrasound scan non treated endocrine disorders smoking habit endometriosis stage III -IV severe male factor infertility (less than one million sperm per mL of semen)

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 |
| --- | --- |
| Active Comparator: Control<br>Patients will be stimulated according to the conventional flexible GnRH antagonist protocol for IVF. Alfa follitropin (150IU a day) will be started on the third day of the menstrual cycle. Treatment monitoring will be done with transvaginal ultrasound scans and serum determinations of estradiol and progesterone 5 days after the start of gonadotropins and every each day thereafter. Once the leading follicle reaches 13 mm in mean diameter 0,25mg of cetrorelix acetate will be administered daily. Once at least two follicles reach 18mm or more in mean diameter 250 micrograms of choriogonadotropin alfa will be administered and 36 hours latter patients will undergo follicle aspiration for IVF. Embryos will be cryopreserved (vitrification) on the third or fifth day of development. Two months after women will undergo uterine preparation for embryo transfer. | Other: Control<br>* Conventional flexible GnRH antagonist protocol of ovarian stimulation for in vitro fertilization, with gonadotropin star at the third day of a natural menstrual cycle.<br>|
| Experimental: Ovulation induction<br>Patients will be monitored with daily transvaginal ultrasound scans from the tenth day of the menstrual cycle on. When the dominant follicle reaches a mean diameter of 16mm or more, patients will receive 250 micrograms of choriogonadotropin alfa subcutaneously. Daily transvaginal ultrasound scans will be done starting two days after the administration of the medication until a cohort of ovarian follicles between 4-6 mm is seen (follicular wave emergence). From this point on patients will undergo the same stimulation protocol as Controls, i.e., flexible GnRH antagonist protocol. | Drug: Ovulation induction with choriogonadotropin alfa<br>* Administration of 250 micrograms of choriogonadotropin alfa subcutaneously when the dominant follicle of a natural menstrual cycle reaches 16mm or more of mean diameter. Verify if this intervention is able to induce follicular wave emergence and synchronize the start of the flexible GnRH antagonist protocol of ovarian stimulation with the start of a follicular wave.<br>|
| Experimental: Dominant follicle aspiration<br>Patients will be monitored with daily transvaginal ultrasound scans from the tenth day of the menstrual cycle on. When the dominant follicle reaches a mean diameter of 16mm or more, patients will then undergo aspiration of the dominant and all follicles greater than 10mm in mean diameter. aspiration will be transvaginal ultrasound guided and under sedation, as for oocyte retrieval. Oocytes eventually obtained at this first aspiration will not be used for IVF. Daily transvaginal ultrasound scans will be done starting the day after the follicular aspiration until a cohort of follicles between 4-6 mm is seen (follicular wave emergence). From this point on patients will undergo the same stimulation protocol as Controls, i.e., flexible GnRH antagonist protocol. | Procedure: Aspiration of the dominant follicle<br>* Aspiration of all follicles greater than 10mm in mean diameter when the dominant follicle of a natural menstrual cycle reaches 16mm or more of mean diameter. Aspiration will be guided by transvaginal ultrasound. Verify if this intervention is able to induce follicular wave emergence and synchronize the start of the flexible GnRH antagonist protocol of ovarian stimulation with the start of a follicular wave.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Emergence of an ovarian follicular wave after dominant follicle aspiration or hCG administration | Evaluate if the aspiration of the dominant follicle is able to induce a follicular wave to emerge. Evaluate if administration of hCG is able to induce ovulation of a dominant follicle larger than 16mm and to induce a follicular wave to emerge. A follicular wave emergence is defined as an increase in the number of ovarian follicles smaller than 10mm seen at the transvaginal ultrasound scan after the interventions | One year | 
| Follicular growth pattern on ultrasound scan | Evaluate with periodic transvaginal ultrasound scan the size (mm), number and growth rate (mm/day) of ovarian follicles in each of the three groups | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estradiol and progesterone levels during ovarian stimulation | Evaluate blood levels of estradiol (pg/mL) and progesterone (ng/mL) during ovarian stimulation in each of the three groups at each visit to evaluate the progress of treatment. | One year | 
| Number of mature oocytes retrieved | Evaluate the number of metaphase II oocytes retrieved in each of the three groups | One year | 
| Total dose of gonadotrophins used | Total dose of gonadotrophins (in international units) necessary to stimulate the ovaries (from the first day of stimulation until the last dose of recombinant FSH administered before the oocyte retrieval) | One year | 
| Fertilization rate | Number of embryos formed in relation with the number of oocytes inseminated | One year | 
| Pregnancy rate | Positive beta hCG determination on blood 10 days after embryo transfer | One year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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in vitro fertilization, ovarian stimulation, follicular waves, luteal phase