P-614 Predicting if or when ovarian activation occurs after Drug-Free in vitro Activation (IVA) in primary ovarian insufficiency (POI) patients
Authors: Ferreri Dos Anjos J , Mendez M , Civico S , Calafell J.M , Otero J , Farré R , Manau D , Fàbregues F 
Published: June 2022

Abstract

Study question
Can we predict if or when ovarian activation resumption occurs after Drug-Free in vitro Activation (IVA) in primary ovarian insufficiency (POI) patients?

Summary answer
Duration of amenorrhea alone could predict if ovarian activity resumption occurs. Regarding to when: as early as 21 days until 330 days after surgery.

What is known already
Primary ovarian insufficiency occurs before age 40, leading patients to infertility. Although there are a few remaining follicles, their only chance to achieve pregnancy is through egg donation. Recently, studies have been focusing on the determinants and intracellular signaling pathways involved in the activation of primordial follicles, as the maintenance of a correct ovarian reserve. A new surgical technique known as Drug-Free IVA would activate ovarian function by mechanical fragmentation. For selected patients whose ovaries still contain residual secondary follicles, the fragmentation step alone, which implies a Hippo signaling pathway disruption, would be sufficient to promote follicle growth.

Study design, size, duration
Our study is a prospective observational cohort of patients recruited in a tertiary-care university hospital approved by the Ethics Research Committee from Hospital Clinic of Barcelona (HCB/2017/0856). The diagnostic criteria of POI followed the European Society of Human Reproduction and Embryology (ESHRE) Guideline from 2016. All patients provided written informed consent.Thirty-two women included in our study underwent Drug-Free IVA by laparoscopy between January 2018 and December 2019. After surgery, a year-long follow-up was carried out.

Participants/materials, setting, methods
All patients were younger than 40 years of age; presented oligomenorrhoea or amenorrhea for at least 4 months; and FSH level greater than 25 IU/mL . We also restrict inclusion criteria to low estradiol serum levels (&lt;20 pg/ml) absence of antral follicles in transvaginal ultrasound; and anti-Müllerian hormone (AMH) levels less than 0.10 ng/mL. Regardless of the time from POI diagnosis, all patients had duration of amenorrhea greater than 1 year.

Main results and the role of chance
As for prediction of ovarian activation, duration of amenorrhea was the only factor that could significantly differentiate patients' response to Drug-Free IVA. Since a shorter time of amenorrhea (less than 2 years) was related with ovarian activation during a year follow-up. No differences were found in age at Drug-free IVA, age of menarche, baseline FSH or AMH levels; nor presence of follicles in ovarian tissue biopsy. Regarding to time to response, in 12 patients ovarian activation occurred in the first 6 months after surgery with a total of 5 pregnancies achieved (22.7%)- resulting in 4 heathy live births and, unfortunately, one miscarriage. The other 10 patients showed ovarian activation resumption once the 180 days passed, resulting in 3 pregnancies (pregnancy rate of 30%): 2 healthy live births and one neonatal death due to extreme prematurity. An important concept here is that activation before 6 months after surgery could mean an effect on primary and/or secondary follicles, while beyond 6 months the effect might occurred on primordial follicles. Sugesting that maybe the disruption of the Hippo pathway would not only be able to act in the activation of the secondary follicles but also act in the earlier phases of the folliculogenesis.

Limitations, reasons for caution
The lack of a control group is the main limitation of our study because it would be interesting to seek for the placebo effect or intensive medical attention/care consequences in those patients, whose reported pregnancy rate is as low as 4% in observational studies.

Wider implications of the findings
Our findings define the clinical profile of patients with POI in which Drug-Free IVA would be more effective and report late ovarian follicular resumption. Meaning that disruption of the Hippo signaling pathway by ovarian fragmentation could be capable of acting in the initial phases of folliculogenesis prior to secondary follicles.

Trial registration number
not applicable