Antral Follicle Priming Prior to ICSI (Intracytoplasmic Sperm Injection) in Previously Diagnosed Low Responders

Study Overview
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Brief Summary
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The aim of this study is to compare the effectiveness of testosterone,estradiol and a combined treatment with estrogens/progestagens prior to IVF-ICSI in previously diagnosed low responder patients.

Detailed Description
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During controlled ovarian hyperstimulation (COH), most of the early antral follicles are required to grow coordinately. Marked follicular size discrepancies during COH imply that an important number of follicles undergo unsatisfactory maturation. It has been proved that follicular priming with estradiol during the luteal phase of the cycle prior to COH or testosterone treatment during the early follicular phase of the COH cycle may increase the amount of oocytes and embryos retrieved. Nevertheless there are no prospective studies comparing such approaches. The present study consist of two phases: The present study consists of two different phases: Phase I: (Non randomized) Identification of confirmed low responder patients. Potential low responder patients will be subjected to an standardized ovarian hyperstimulation protocol Phase II: (Randomized) those patients, once confirmed as low responders, will be offered the opportunity to enter the interventional part of the study, being randomized to three different treatment groups: estradiol, testosterone or combined progestagens and estrogens prior to the IVF-ICSI cycle. The previous cycle (phase I) will be used as a self-control for each patient.

Official Title
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Prospective Randomized Controlled Trial of Antral Follicle Priming Prior to IVF-ICSI in Previously Diagnosed Low Responders.

Conditions
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Ovarian Diseases

Intervention / Treatment
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* Drug: Testosterone
* Drug: Estradiol
* Drug: CombEq


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1 (Non randomized. The patient must fit the first plus at least other 2 criteria) Infertility requiring an IVF/ICSI treatment Age ≥ 38 years Basal FSH ≥ 10 mUI/ml (day 3 of the cycle) Serum AMH ≤ 5 pmol/l Antral follicular count ≤ 6 (day 3 of the cycle) Phase 2 (Randomized. The patient must fit at least one criterion regarding the day of GNRH analogue administration during the cycle performed in Phase 1) Less than 4 follicles which mean diameter measuring more than 16mm Serum estradiol levels ≤ 500 pg/ml 4 MII or less than 4 MII oocytes retrieved Exclusion Criteria: Patients suffering of endometriosis Patients having progesterone levels ≤ 4 ng/ml (day 21 of the cycle) Patients having a partner affected by severe oligo/astheno/teratozoospermia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 41 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: Testosterone<br>Transdermal testosterone (20µg/day) from day 24 of the previous cycle until day 2 of the ICSI cycle | Drug: Testosterone<br>* Transdermal testosterone (20µg/kg/day)from day 24 of the previous cycle to day 2 of the ICSI cycle<br>* Other names: Testopatch, Pierre Fabre Ibérica S.A.;|
| Experimental: Estradiol<br>Transdermal estradiol (200µg/day)from day 20 of the previous cycle to day 3 of the ICSI cycle | Drug: Estradiol<br>* Transdermal estradiol (200µg/day)from day 20 of the previous cycle to day 3 of the ICSI cycle<br>* Other names: Alcis 100, Chiesi España;|
| Experimental: CombEq<br>(150µg Desogestrel + 30µg Ethinylestradiol)/day during the luteal phase of the two cycles prior to the ICSI Estradiol valerate 4 mg/day during 10 days, starting the second day of the cycle prior to the ICSI cycle. | Drug: CombEq<br>* (150µg Desogestrel + 30µg Ethinylestradiol)/day during the luteal phase of the two cycles prior to the ICSI. Valerate estradiol 4mg/day during 10 days, starting the second day of the cycle prios to the ICSI cycle.<br>* Other names: Meriestra 2mg, Novartis Farmacéutica, S.A.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of MII oocytes retrieved |  | 36h after GnRH analogue administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total number of follicles punctured |  | 36h after GnRH analogue administration | 
| Total number of oocytes retrieved |  | 36h after GnRH analogue administration | 
| Total number of viable embryos |  | 48h after follicular puncture | 
| Serum and Follicular hormonal levels (testosterone, androstenedione, estradiol) |  | 36h after GnRH analogue administration | 
| Granulosa cells genetic expression profile |  | 36h after GnRH analogue administration | 
| Implantation rate |  | 15 days after embryo transfer | 
| Pregnancy rate |  | 15 days after embryo transfer | 
| Clinical pregnancy rate |  | 5 weeks after embryo transfer | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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estradiol, testosterone, combined oral contraceptive, low responders, ICSI