Mechanism of action of Vitamin D (1,25-(OH)2-D3) on ovarian follicle growth: implications for women with Vitamin D deficiency and PCOS
Numerous observational and interventional studies have investigated the link between Vitamin D (VD) deficiency and reproductive outcomes, with contradictory results. VD is known to regulate steroidogenic enzymes crucial for human granulosa and cumulus cell function and genes that play a critical role in folliculogenesis have a vitamin D response element (VDRE) on their promoters. This study investigated whether deficient levels of 1,25-(OH)2-D3 altered ovarian cell function; and if the ovary could obtain bioactive 1,25-(OH)2-D3 via local enzymatic expression of CYP27B1, to counteract systemic deficiency. A variety of cells and tissues were used for the in vitro experiments as practicable. We have shown for the first time an increase in VDR expression in theca of larger compared to smaller follicles, which along with the ability of 1,25-(OH)2-D3 to decrease Anti-Mullerian hormone (AMH) expression, supports a role for 1,25-(OH)2-D3 in theca and granulosa cell function. Conversely, we have shown that very levels of 1,25-(OH)2-D3 equivalent to hypovitaminosis, inhibited thecal production of androstenedione and cAMP-driven E2 production. Human thecal and unluteinised GC are incredibly hard to obtain for research purposes, highlighting the uniqueness of our data set. For the first time we have demonstrated that deficient levels of 1,25-(OH)2-D3 also down-regulated insulin receptor expression, potentially reducing insulin sensitivity. We have shown that the ovary expresses CYP27B1 allowing it to make local bioactive 1,25-(OH)2-D3 which along with the upregulation in VDR expression in all ovarian cellular compartments, could be protective locally in counteracting systemic VD deficiency. To conclude a severely deficient VD environment (<2nM or <1ng/ml) could contribute to impaired ovarian cell function and hence potentially affect folliculogenesis/ovulation, but levels associated with mild deficiency may have less impact, apart from in the presence of hyperinsulinemia and insulin resistance.