An open labelled, three armed, randomised placebo controlled trial to study the effect of intra-ovarian platelet-rich plasma versus autologous adult bone marrow- derived stem cell instillation in poor ovarian responders

Poor ovarian response (POR) to gonadotropin stimulation in an IVF cycle remains one of the challenges faced by infertility experts, world-wide. In the recent years, the numbers of poor ovarian responders, both expected, as well as unexpected, are on the rise. Despite better understanding of Controlled ovarian stimulation (COS), and recent advances in laboratory techniques, the estimated prevalence of poor responders, according to the POSEIDON criteria, is around 40%. Various strategies have been developed to help these couples produce their own genetic offspring, helping women through better regimens for pituitary suppression, increased gonadotropin dosages and the addition of adjuvant agents during ovarian stimulation however, high-level evidence on the ideal protocol or strategies using uniform standards for POR are lacking. Therefore, in pursuit of other effective strategies, the role of intraovarian platelet rich plasma (PRP) and intraovarian stem cell instillation are being extensively studied over the last few years.

Autologous platelets are believed to promote the development of isolated human primordial and primary follicles to the pre-antral stage, reduce follicular atresia, restore dormant oocytes, thereby restoring fertility. Although there are currently multiple methods for preparing and injecting PRP, there is still no consensus on the optimal method, and there is still controversy over whether ovarian injection of PRP can improve ovarian function. A few case reports, retrospective and prospective cohort, non-randomised studies suggest that PRP treatment may benefit women with poor ovarian response. But, a couple of RCTs have not shown any significant effect of PRP on the oocyte yield. In a recently published RCT conducted by Barrenetxea et al.,(2024), an increase in the number of retrieved oocytes in both the intraovarian PRP group and intraovarian saline group suggests that, beyond the release of growth factor from platelets, a mechanical effect can play a role. They hypothesised that either delivered platelet factors or a potential mechanical effect could be implicated in promoting follicle reactivation.

Stem Cells derived from different sources may have some effect on the rescue of ovary function, such as recovering ovarian sex hormone function, reducing apoptosis of germ cells, and increasing the number of follicles. However, the improved ovarian function after stem-cell transplantation is a complex mix of many unclear factors requiring further investigation including their activation by mechanical stimulation. Recent studies have shown contradictory results in terms of its efficacy. Considering the complexity of an autologous product such as PRP or stem-cell and the need for quality control in clinical applications, the ability to reproduce consistent results must be shown before recommending them in clinical practice. Given this context, to strengthen the evidence in the form of randomised controlled trial, our research question aims to determine whether instilling intraovarian PRP or stem cells or saline leads to improvements in ovarian reserve and IVF outcomes. If found useful, they would signify a paradigm shift in fertility treatment for women with POR.