FOLLICULAR ACTIVATION IN POOR OVARIAN RESPONDERS (FAPPOR): A RANDOMIZED CONTROLLED TRIAL

Abstract

Mechanical fragmentation of the ovarian cortex to activate dormant follicles by suppressing the Hippo pathway (called in vitro activation [IVA] or ovarian fragmentation for follicular activation [OFFA]) has been proposed as a therapeutic option for women with poor ovarian response (POR) and premature ovarian insufficiency (POI). A number of case series and cohort studies suggested improved reproductive outcomes with ovarian fragmentation, either alone (drug-free) or in combination with biomolecules that act upon the Akt/PTEN pathway to further promote follicular activation. In this study we aimed to investigate if ovarian fragmentation improves ovarian reserve markers and IVF outcomes in women with POR. Randomized controlled trial (NCT02354963). Thirty-four women with POR according to ESHRE Bologna criteria who were < 40 years of age were randomized to undergo ovarian fragmentation by laparoscopy in one ovary (n=16), or to no intervention (control group, n=18). Ovarian reserve markers were followed bi-weekly for 6 months and IVF cycles initiated when patients doubled antral follicle count (AFC) or at the end of follow-up. Baseline characteristics for enrolled patients showed no difference between the groups. Ovarian fragmentation was performed in 15 women and effectiveness of the procedure was confirmed by detecting an 18.8% reduction in the phospho-YAP/YAP protein ratio and increased BIRC and CCN gene expression after fragmentation (p<0.05 for each). Ovarian fragmentation resulted in an increase in the AFC in the intervention ovary compared to the control ovary in the same patient (p=0.048). When control and surgery groups were compared, total AFC was increased in the intervention group (p=0.021) due to the improvement in the number of follicles in the ovary in which ovarian fragmentation was carried out (p=0.008). However, serum AMH or FSH levels were not different before or after the surgery or between the groups. Following the intervention, 15 patients from each arm underwent at least 1 IVF cycle. In the control group, 33 MII oocytes were retrieved, 28 cleavage stage embryos developed and 18 embryo transfers (ETs) were performed with 20% pregnancy rate (PR) and 18.7% live birth rate (LBR) per cycle. In the surgery group, 23 MII oocytes were retrieved, 12 embryos developed, and 11 ETs were performed with 13.3% PR and 6.7% LBR per cycle. Statistically significant differences were not detected in any of the IVF-related outcomes between study groups. A total of 3 pregnancies and 4 live births (1 twin pregnancy) were recorded in the control group, while 2 pregnancies and 1 healthy live birth were recorded in the surgery group. Ovarian fragmentation promoted follicle development and increased antral follicular counts, but it did not improve IVF outcomes in POR women when compared to controls during a 6-month intensive follow-up.