Clinical trial NCT01310647: Antral Follicle Priming Prior to ICSI (Intracytoplasmic Sperm Injection) in Previously Diagnosed Low Responders
Official title: Prospective Randomized Controlled Trial of Antral Follicle Priming Prior to IVF-ICSI in Previously Diagnosed Low Responders.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ovarian Diseases
Keywords: estradiol
testosterone
combined oral contraceptive
low responders
ICSI
Lead sponsor: Instituto de Investigacion Sanitaria La Fe
Sponsor class: OTHER
First posted: 2011-03-08
Enrollment: 66
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 41
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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)
2. 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

Primary outcomes:
measure: Number of MII oocytes retrieved
timeFrame: 36h after GnRH analogue administration
Secondary outcomes:
measure: Total number of follicles punctured
timeFrame: 36h after GnRH analogue administration
measure: Total number of oocytes retrieved
timeFrame: 36h after GnRH analogue administration
measure: Total number of viable embryos
timeFrame: 48h after follicular puncture
measure: Serum and Follicular hormonal levels (testosterone, androstenedione, estradiol)
timeFrame: 36h after GnRH analogue administration
measure: Granulosa cells genetic expression profile
timeFrame: 36h after GnRH analogue administration
measure: Implantation rate
timeFrame: 15 days after embryo transfer
measure: Pregnancy rate
timeFrame: 15 days after embryo transfer
measure: Clinical pregnancy rate
timeFrame: 5 weeks after embryo transfer
Other outcomes:
Locations:
city: Valencia
country: Spain
facility: La Fe University Hospital. Department of Obstetrics and Gynecology
Study officials:
affiliation: La Fe University Hospital. Department of Obstetrics and Gynecology
name: César Díaz, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: La Fe University Hospital. Department of Obstetrics and Gynecology
name: Antonio Pellicer, Professor
role: STUDY_DIRECTOR
affiliation: La Fe University Hospital. Department of Obstetrics and Gynecology
name: Alicia Marzal, M.D.
role: STUDY_CHAIR
References:
citation: Fanchin R, Salomon L, Castelo-Branco A, Olivennes F, Frydman N, Frydman R. Luteal estradiol pre-treatment coordinates follicular growth during controlled ovarian hyperstimulation with GnRH antagonists. Hum Reprod. 2003 Dec;18(12):2698-703. doi: 10.1093/humrep/deg516.
citation: Fabregues F, Penarrubia J, Creus M, Manau D, Casals G, Carmona F, Balasch J. Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial. Hum Reprod. 2009 Feb;24(2):349-59. doi: 10.1093/humrep/den428. Epub 2008 Dec 3.
citation: Escriva AM, Diaz-Garcia C, Monterde M, Rubio JM, Pellicer A. Antral Follicle Priming Before Intracytoplasmic Sperm Injection in Previously Diagnosed Low Responders: A Randomized Controlled Trial (FOLLPRIM). J Clin Endocrinol Metab. 2015 Jul;100(7):2597-605. doi: 10.1210/jc.2015-1194. Epub 2015 May 8.