Vitamin D metabolism in polycystic ovary syndrome (PCOS)

Vitamin D metabolism

Vitamin D is a steroid hormone, synthesized mainly by the skin on exposure to natural sunlight, with < 10%–20% deriving from the diet . Vitamin D is hydroxylated to 25-hydroxyvitamin D (25(OH)D) or calcifediol by the liver; then, calcifediol is converted by renal 1α-hydroxylase to the active form 1,25-dihydroxyvitamin D3 [1,25-(OH) ₂ D ₃ ] or calcitriol. The enzyme 1α-hydroxylase is expressed in other tissues, such as ovaries, brain, breast, prostate, and colon, thus permitting the local synthesis of the active form of vitamin D and paracrine effects . Calcitriol circulates in the blood bound to vitamin D-binding protein until its target tissues where it acts via binding to the nuclear vitamin D receptor (VDR) . In a study on VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq), Ramagopalan et al. identified 2776 genomic positions occupied by VDR and 229 genes significantly responsive to vitamin D stimulation in more than 30 different tissues, such as skeleton, brain, breast, pancreas, parathyroid glands, immune cells, cardiomyocytes and reproductive organs, including ovaries, placenta, uterus, and testes .

The main physiologic role of vitamin D is to promote intestinal calcium absorption and to regulate osteoclast function, maintaining calcium/phosphorus homeostasis and controlling bone mineralization; however, vitamin D has pleiotropic effects . In addition to its role in calcium-regulating tissues, vitamin D has been implicated in a wide range of extra-skeletal effects such as glucose homeostasis, cardiovascular disease, cancer, reproductive dysfunctions, autoimmune diseases, and endocrine conditions, including polycystic ovary syndrome (PCOS) .

The guidelines of the Endocrine Society defined vitamin D deficiency as 25(OH)D levels < 20 ng/mL and insufficiency as a level between 21 and 29 ng/mL . Vitamin D deficiency is very common worldwide not only in the older population but also in the younger population . A relatively high prevalence of vitamin D deficiency is observed in women with PCOS (about 67%–85%) .

Vitamin D and female reproductive physiology

The role of vitamin D pathway in the pathogenesis of PCOS can be understood by underlying the importance of this vitamin in the female reproductive physiology, even if the exact underlying mechanism remains unclear . VDR is expressed in reproductive tissues of cycling mice, including endometrium, ovaries, and fallopian tubes; in pregnant mice, VDR is expressed also in the placenta and decidua . Furthermore, VDR knockout mice have impaired folliculogenesis, hypergonadotropic hypogonadism with decreased aromatase activity and CYP19 gene expression . In humans, in vitro exposure of ovarian cells to vitamin D increased the production of progesterone, estrogen, and estrone .

Vitamin D appears to regulate follicular maturation through a direct effect on anti-Mullerian hormone (AMH) gene, whose product is considered a marker of the ovarian reserve, via a vitamin D-response element (VDRE) located in the human AMH promoter region . Furthermore, vitamin D promotes the differentiation and the development of human granulosa cells (GC) . AMH is secreted by the GC of preantral/antral ovarian follicles; however, women with PCOS have abnormally increased levels of serum and intrafollicular AMH, due to a rise in the number of arrested small antral follicles, besides AMH hypersecretion by the GC themselves . In a study on GC of the hen, calcitriol significantly decreased the expression of AMH mRNA levels . However, in a study on 54 women who underwent in vitro fertilization, Merhi et al. found a twofold increase in AMHR-II expression in GC of women with insufficient follicular fluid 25(OH)D (< 30 ng/mL) compared with women with follicular fluid vitamin D levels > 30 ng/mL . Furthermore, exposure of human GC to vitamin D3 increased progesterone production in the presence of pregnenolone, suggesting that vitamin D alters AMH signaling and steroidogenesis in human cumulus GC, possibly reflecting a state of GC luteinization potentiation. . Another in vitro study on human ovarian cells showed that, upon binding to VDR, vitamin D3 increases estrogen, progesterone, estrone, and insulin-like growth factor-binding protein 1 secretion . Moreover, vitamin D3 acted synergistically with insulin to stimulate estradiol production, and vitamin D enhanced the inhibitory effect of insulin on IGFBP-1 production .

In vitro, vitamin D is capable of increasing 3β-HSD mRNA levels and progesterone production in the ovarian GC; thus, it may enhance key steroidogenic enzymes involved in the synthesis of androgens and estrogens . In addition, vitamin D modulates follicular sensitivity to FSH . Although the relationship between vitamin D and FSH receptor (FSHR) is unclear, there is evidence for a correlation between AMHR-II and FSHR gene expression, with a probable involvement of vitamin D in the regulation of both AMHR-II and FSHR . Although conflicting, these findings suggest that vitamin D influences AMH gene expression and probably, it could neutralize the inhibitory effect of AMH on GC differentiation and follicular growth by inhibiting AMHR-II expression and downstream signaling .

In the last few years, it has been debated whether vitamin D is capable of influencing ovarian folliculogenesis, as indicated by the AMH levels and what kind of relationship exists . Most cross-sectional studies demonstrated a negative correlation between serum levels of AMH and serum levels of vitamin D, but other studies reported a positive relationship . Such differences could be explained by the heterogeneity in the enrolled populations, the individual vitamin D levels and the seasonal variations . Interventional studies revealed that vitamin D supplementation influences AMH serum levels but the effect depends on the ovulatory status of the women: AMH levels increase in ovulatory non-PCOS women but they decrease in women with PCOS .

Vitamin D and PCOS

Several studies showed that the vitamin D pathway might have a role in the development of various symptoms of PCOS including ovulatory dysfunction with infertility, insulin resistance (IR), hirsutism, and cardiovascular risk . Upon comparing PCOS with non-PCOS women, serum levels of vitamin D were reported either lower in the first group or statistically similar . Interventional studies revealed that vitamin D supplementation might improve menstrual irregularity and follicular development in women with PCOS .