Randomized, Placebo-controlled, Double-blind, Single-center Trial to Evaluate the Possible Action of Resveratrol in Improving the Outcomes of Controlled Ovarian Stimulation During the IVF/ICSI Cycles in Couples With Unexplained Infertility

On the basis of the last estimates, the global lifetime prevalence of infertility is 17.5%, which means that approximately one in six people have experienced infertility at some stage in their lives.

Despite an improvement in conventional diagnostic investigations, still today, around 25% of the causes of couple infertility remain unexplained.

In fact, several crucial moments of the human reproductive process cannot be studied and, therefore, specific reproductive alterations remain undiagnosed. Just thinking of the process of ovarian folliculogenesis, oocyte development, embryonic implantation, all ones real "biological mysteries".

Among these different biological aspects, it is known that the oocyte quality is the main predictor of clinical pregnancy after IVF/ICSI. Indeed, oocyte maturation process influences the embryo development and, consequently, the embryo viability. Although the mechanisms that determine a good quality oocyte are not known, nevertheless energy-dependent processes are supposed to play a major role in oocyte development. These processes are mediated by mitochondria, whose concentration in oocytes is the highest among the other cells of human body. The oocyte nuclear and cytoplasmic maturation is strictly connected with the growth of granulosa cells (GCs). These cells surround the oocyte and establish a functional bidirectional cross-talk with the oocyte itself through gap junctions and paracrine factors. During folliculogenesis, GCs increase the consumption of glucose and metabolize glucose into pyruvate which passes to the oocyte. All this determines an increase in the energy supply to the oocyte itself, demonstrated by the increase in ATP production, which allows the latter cell to prepare for fertilization and the first stages of embryonic development which, as known, is totally oocyte dependent .

Resveratrol seems to be able to fit into this area of cellular functioning. It is a natural polyphenol, widespread in foods, plants, drinks and it seems to induce GCs proliferation through an anti-apoptotic effect in a SIRT1-dependent manner. Furthermore, in GCs, resveratrol reduces the oxidative stress, increases the mitochondria biogenesis and the intracellular ATP levels, determining a high energy availability which favours the oocyte growth. Resveratrol seems to reduce in rat granulosa cells the expression of Vascular Endothelial Growth Factor (VEGF), implicated in angiogenesis and vascular permeability, potentially showing a protective effect on the risk of Ovarian Hyperstimulation Syndrome (OHSS), a life-threatening condition associated with ovarian stimulation, whose VEGF is the main mediator.