PCOS is one of the most common gynecologic endocrine diseases, and although its incidence has risen in recent years, there is currently no radical cure available. PCOS not only causes infertility related to ovulatory disorders but is also associated with insulin resistance, type 2 diabetes, obesity, cardiovascular disease, depression, and endometrial cancer [3]. Letrozole and clomiphene have typically been adopted for ovulation induction to treat PCOS-related ovulatory disorders and infertility. However, as the pregnancy rate with ovulation-induction regimens remains relatively low and treatment usually requires a lengthy period, any new adjuvant therapies for PCOS necessitate further investigation.
Vitamin D is a lipid-soluble vitamin that belongs to the steroid hormone family. Vitamin D, administered via the skin or food, is metabolized into its active form 25-(OH) D3 in the liver; and this, then, is the vitamin D derivative with the highest concentration in the circulation. Since 25-(OH) D3 exhibits a longer half-life and remains unaffected by calcium uptake, it is considered to be the optimal indicator for measuring vitamin D nutritional status[12]. The biologic functions of vitamin D are mediated by vitamin D receptors that are present in various tissues—including the reproductive system that comprises the ovaries, uterus, placenta, pituitary gland, and hypothalamus. A growing body of evidence has revealed that vitamin D plays an important role in the female reproductive system[9]. For example, according to Parikh [13], vitamin D enhances the activity of aromatase and regulates sex hormone production from the ovaries and placenta through vitamin D receptors, thus participating in ovarian follicle formation. In PCOS patients, vitamin D deficiency exerts an adverse impact on sex hormone levels and thus interferes with the formation of the dominant follicle. It has been shown that vitamin D regulates the expression of the HOXA 10 gene in endometrial stromal cells and that this gene is crucial for endometrial development and embryonic implantation. Therefore, vitamin D levels appear to influence both endometrial receptivity as well as embryonic implantation [14, 15]. Vitamin D itself is involved in the regulation of calcium ion concentrations in the placenta and is critical in promoting endometrial decidualization [16]. A variety of studies thus appear to indicate that vitamin D is closely related to reproductive system activities and PCOS.
It was recently demonstrated that a low vitamin D level was present in many PCOS patients [7]. A retrospective study [17] revealed explicitly that the serum vitamin D level in PCOS women was significantly lower than that in normal women and that a strong correlation existed between the two. A total of 639 women with PCOS were described by these studies, constituting the largest epidemiologic study conducted on PCOS to date.
Our data indicated that the mean serum vitamin D level in our PCOS patients was 14.57 ng/mL compared with 22.24 ng/mL in the control group of healthy women of child-bearing age, consistent with previous studies in China and elsewhere. In our study, 82.5% of PCOS patients manifested vitamin D deficiency, with only two PCOS patients of the 200 patients showing normal vitamin D levels. Intriguingly, the incidence of vitamin D deficiency was also relatively high in normal healthy females at 37.5%. It is noteworthy that the mean vitamin D level was below the normal limit in both the PCOS patients and healthy women of child-bearing age, indicating that vitamin D deficiency is prevalent in women of child-bearing age in Beijing, particularly those with PCOS. In addition, our subjects were recruited over a time span of 1–1.5 years, which included all four seasons of the year; and we did not consider the potential influence of seasonal factors.
Recent studies have revealed [18, 19] that vitamin D levels are closely related to pregnancy outcomes in PCOS patients and that supplementation with vitamin D can improve one's fertility. Usadi et al [20]. demonstrated that raising the vitamin D level promoted successful ovulation induction, and these authors proposed vitamin D levels to be a potential predictor of reproductive success after induction. Rudick et al. [21] showed that subjects with serum 25(OH) D3 sufficiency exhibited a higher pregnancy rate than those with 25(OH) D3 insufficiency. The likely reason for this is that vitamin D influences pregnancy outcomes by affecting endometrial receptivity. A study [22] on in vitro fertilization among patients with PCOS-related infertility depicted an association between improved vitamin D levels and augmented pregnancy rates, with considerable significance attributed to normal vitamin D levels in pregnancy outcomes after in vitro fertilization. However, the underlying mechanism of vitamin D action in PCOS remains unknown.
The pregnancy rate for PCOS patients was 48.32% after ovulation induction with letrozole, and the mean serum vitamin D level in the pregnant patients was 16.06 ng/mL, much higher than that in non-pregnant patients (13.54 ng/mL). When the subjects were stratified by vitamin D levels, we found that the pregnancy rate of vitamin D non-deficient subjects was significantly higher relative to that of vitamin D-deficient subjects. The aforementioned data indicated that vitamin D levels were related to pregnancy rate after ovulation-induction therapy in PCOS, congruent with extant studies [20, 21]. According to our results, the mean vitamin D levels in both the pregnant and non-pregnant groups were significantly lower than the classical limit, and we therefore hypothesized that a higher pregnancy rate would be expected after elevating vitamin D to normal levels in PCOS patients.
We know of no therapeutic regimen centered around vitamin D supplementation for PCOS patients with vitamin D deficiency. However, according to the guidelines released by the American Association of Clinical Endocrinologists in 2011 on the Evaluation, Prevention, and Treatment of Vitamin D deficiency[23], two therapeutic regimens are currently recommended for all adults with vitamin D deficiency: one is supplementation with 50,000 units of vitamin D every week, once weekly for 8 weeks consecutively; the other is supplementation with 6000 units of vitamin D daily until the serum vitamin D level exceeds 30 ng/mL, followed by a daily maintenance dose of 1500–2000 units. It is also indicated in the guidelines that the tolerable upper limit for vitamin D in adults is 10,000 units daily and that excessive supplementation should be avoided.