Excessive Vitamin E Supplementation: Implications for Ovarian Physiology and Reproductive Health

Infertility, a major global health problem affecting ~17.5% of couples, is influenced by various intrinsic (e.g., individual genetics) and extrinsic (e.g., related to environmental stimuli) factors. Oxidative stress and reactive oxygen species (ROS) are at the crossroads of these different stimulus-response pathways for both male and female gametes. While ROS are essential for ovarian processes such as folliculogenesis and oocyte maturation, changes in the ovarian ROS generation/recycling equilibrium can lead to impaired reproductive outcomes. Against this backdrop, noninvasive therapeutic approaches aimed at supplementing antioxidant (AO) molecules have emerged to correct prooxidant imbalances encountered in various stress situations. Numerous molecules have been tested, alone or in combination, for their beneficial effects on reproductive success in both men and women. The aim of this study was to investigate the effects of vitamin E supplementation at different levels on female reproductive performance and the molecular pathways involved. Groups of mice were treated with three different doses of vitamin E (optimal, overdose and severe overdose) and compared with control groups (no supplementation, sham groups [water and olive oil]). The results showed that both overdose and severe overdose of vitamin E showed significant reductions in pregnancy rates, litter size, and oocyte development capacity compared to the other groups. Blastocyst formation rates and quality were also significantly lower in these vitamin E overdosed groups, reflecting compromised embryonic quality. Severe vitamin E overdosage resulted in impaired folliculogenesis, with fewer antral follicles and corpora lutea and an increased number of atretic follicles. Notably, uterine thickness was significantly reduced in the severe vitamin E overdose group. Molecular analyses revealed increased GSH/GSSG ratios and higher ROS levels in granulosa cells. Intriguingly, in a context of increased ROS, we did not record any stimulation of the Nrf2 pathway and associated genes. A decrease in apoptosis in the ovarian environment marked by a lower Bax/Bcl2 ratio accompanied situations of vitamin E overdose. These findings shed new light on the consequences of excessive vitamin E intake and its implications for reproductive health. While optimal supplementation promotes fertility, excessive intake disrupts the redox balance, adversely affecting ovarian function and reproductive outcomes. This study highlights the importance of precise AO management to mitigate stress-induced infertility and provides a framework for further research into the molecular mechanisms underlying vitamin E's effects on ovarian physiology.