Follicular Activation in Poor Responders (FAPPOR)

Follicle Activation in Patients With Poor Ovarian Response Through Fragmentation of the Ovarian Tissue.

This study aims to assess whether activation of primordial follicles through ovarian cortex fragmentation may increase the number of antral follicles present in the ovary of patients with diminished ovarian reserve. Secondary outcomes include number of oocytes retrieved and pregnancy rates after IVF.

Hypothesis; Evaluate whether the proposed intervention increases the pool of antral follicles (potentially stimulable ones).

Study Overview

• Status: Completed
• Conditions: Infertility
• Intervention / Treatment: Procedure: In vitro fragmentation of the ovarian tissue

Detailed Description

Controlled, randomized, assessor-blind clinical trial.

Thirty-six patients of La Fe University Hospital (Valencia), previously confirmed as poor responders according to the European Society of Human Reproduction and Embryology (ESHRE) criteria, will be randomized to two treatment arms:

• Arm 1 (control): no intervention.
• Arm 2 (intervention): ovarian cortex extraction by unilateral laparoscopic biopsy and ovarian tissue fragmentation in aliquots of 1 mm2. These fragments will be grafted under the ovarian cortex and meso-ovarium ipsilateraly.

Subsequently the number of antral follicles in both intervention groups will be compared and also will be the number of antral follicles in the native ovary and the grafted one in each of the patients.

Patients will receive a standard IVF treatment for poor responders according to the protocols of the assisted reproduction unit of La Fe University Hospital.

The final aim is to assess the pregnancy rate in both groups, as well as parameters related to the reproduction technique when required.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Valencia, Spain
    • La Fe University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria (must meet one):

• At least two episodes of poor ovarian response (≤ 3 oocytes retrieved with a standard protocol).
• A previous IVF cycle with ≤ 3 oocytes (following a standard stimulation protocol) and presence of an abnormal ovarian reserve test (antral follicle count of ≤ 5 or antimüllerian hormone ≤ 5pm).

Exclusion Criteria (must not meet any):

• Patients under 18 or over 40 years.
• Clinical signs of endometriosis.
• Previous ovarian surgery.
• Genital tract malformations.
• Anovulatory patient (defined by the presence of irregular cycles and serum progesterone ≤ 10 ng / mL on cycle day 21).
• Partner with severe male factor: severe oligoasthenozoospermia, oligoasthenoteratozoospermia and azoospermia.
• All those patients who do not voluntarily give their express written consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control arm; No intervention is performed. Assessment of antral follicle count. IVF treatment.
Experimental: Experimental arm; Perform intervention described: Laparoscopy. In vitro fragmentation of the ovarian tissue. Assessment of antral follicle count. IVF treatment.	Procedure: In vitro fragmentation of the ovarian tissue; Unilateral ovarian cortex extraction, in vitro fragmentation and reimplantation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Metaphase II (MII)	Number of mature MII oocytes retrieved in the IVF cycles after triggering.	36 hours after triggering

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Antral Follicle Count (AFC) - Initial Measure	AFC assessment was done on day 2-5 of the menstrual cycle. Ultrasound scan was performed using a GE iVoluson (General Electric, Spain) equipped with a 3D vaginal probe (6.5-9MHz). A bilateral two-dimensional scan was performed and the mean of the two largest diameters of each intra-ovarian avascular anechoic image was recorded. Antral follicles with a mean diameter from 2 to 10 mm were counted to establish AFC. Initial data refers to the measure taken before treatment.	Baseline, day 2-5 of the menstrual cycle prior to treatment
Total Antral Follicle Count (AFC) - Final	AFC assessment was done on day 2-5 of the menstrual cycle and was followed for 6-month. To determine AFC, ultrasound scan was performed using a GE iVoluson (General Electric, Spain) equipped with a 3D vaginal probe (6.5-9MHz). A bilateral two-dimensional scan was performed and the mean of the two largest diameters of each intra-ovarian avascular anechoic image was recorded. Antral follicles with a mean diameter from 2 to 10 mm were counted to establish AFC. Final measure refers to the AFC count after ovarian fragmentation treatment.	Day 2-5 of the menstrual cycle 6 months after treatment
Initial Antimüllerian Hormone (AMH) Levels	AMH levels were determined on day 2-5 of the menstrual cycle to establish the initial baseline levels for each patient. A microparticle immunoassay kit integrated in the ABBOTT AxSYM® Plus system and software 5.20 (Abbott Laboratories, Abbot Park, IL, USA) was used to determine AMH levels prior treatment.	Baseline, day 2-5 of the menstrual cycle prior to treatment
Final AMH Levels	AMH levels were determined using a microparticle immunoassay kit integrated in the ABBOTT AxSYM® Plus system and software 5.20 (Abbott Laboratories, Abbot Park, IL, USA) 6 months after recruitment or basaline assessment.	Day 2-5 of the menstrual cycle 6 months after the treatment
Number of Cancelled IVF Cycles	Number of cancelled IVF cycles for low or no response to controlled ovarian stimulation. Cycles were cancelled because of a lack of an adequate follicular formation (one follicle of at least 17 mm) the day of triggering.	End of stimulation cycle (less than or equal to 30 days)
Fertilization Rate	All the mature oocytes retrieved were inseminated by intracytoplasmic sperm injection (ICSI). Percentage of successfully fertilized oocytes were registered 18 hours after oocyte insemination.	18 hours after insemination
Number of Cycles With Embryo Transfer (ET)	One or 2 embryos were transferred on day 3 after egg collection. This outcome represents the number of cycles that culminate with embryo transfer.	On day 3 after egg collection
Number and Percentage of Cycles With Clinical Pregnancy	Clinical pregnancy was defined as the presence of a gestational sac and heart beat under ultrasonography	6 weeks after embryo transfer
Live Birth Rate	Live birth rate was calculated by dividing the number of patients who achieved live birth in each cycle by the number of patients who initiated that cycle	9 months or birth of one or more live babies

Collaborators and Investigators

• Sponsor: César Díaz García
• Investigators: Principal Investigator: Cesar Diaz-Garcia, MD, La Fe University Hospital. University of Valencia

Publications and helpful links

General Publications

• Diaz-Garcia C, Herraiz S, Pamplona L, Subira J, Soriano MJ, Simon C, Seli E, Pellicer A. Follicular activation in women previously diagnosed with poor ovarian response: a randomized, controlled trial. Fertil Steril. 2022 Apr;117(4):747-755. doi: 10.1016/j.fertnstert.2021.12.034.

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Actual): February 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: January 22, 2015
• First Submitted That Met QC Criteria: February 2, 2015
• First Posted (Estimated): February 3, 2015

Study Record Updates

• Last Update Posted (Estimated): January 8, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Poor ovarian reserve; Poor ovarian response; Salvador/Warts/Hippo pathway; Follicular activation
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Infertility
• Other Study ID Numbers: FAPPOR (2014/0004)