PCOS is a multiple metabolic disorders syndrome characterized by obesity, IR, dyslipidemia and other metabolic abnormalities. Studies have confirmed that PCOS women are prone to obesity, IGT, IR, and about 10% of them will progresses to T2DM. In addition, women with PCOS also have an increased risk of cardiovascular disease, hypertension (3 to 5 times higher than normal women, with increased SBP), NAFLD, abnormal lipid metabolism (increased TG and LDL-C levels) and MS [21]. IR occurs in women with PCOS, is significantly associated with different metabolic disorders including increased aromatase activity, elevated androgen secretion, and damaged progesterone synthesis in granulosa cells [16]. Accumulating evidence suggests that vitamin D deficiency and insufficiency are important factors in the pathogenesis of IR, metabolic disorders and CVD in PCOS [9]. Indeed, a high prevalence of vitamin D deficiency is observed among PCOS women, especially in those women with obesity or IR [11].
It has been proven that insulin secretion is a calcium-dependent process, so vitamin D may affect pancreatic β-cells through the regulation of calcium concentrations [22]. Also, a beneficial effect of combined vitamin D and calcium on glucose metabolism and lipid profiles in patients with T2DM has previously been reported [23]. However, the effects of vitamin D supplementation on metabolic parameters of women with PCOS are controversial. The data in our study demonstrated that significant increases in vitamin D concentrations were shown at different time points after vitamin D supplementation. Furthermore, with the extension of treatment time, the serum 25(OH)D concentration gradually increased. The BMI, WHR, serum insulin concentrations and HOMA-IR in women of vitamin D group were significantly lower than that in control group. Although IR is not within any of the diagnostic criteria of PCOS in different countries, it occurs in most lean and overweight women with PCOS, who have a form of IR intrinsic and the compensatory hyperinsulinaemia drives many of the phenotypic features of PCOS. Additionally, compared with lean PCOS women, women with obesity are more likely to accompany IR. In fact, obesity and IR interact with each other and form a vicious cycle, which are also difficult to treat clinically. Vitamin D dramatically improves glucose metabolism by increasing insulin production, insulin receptor expression and reducing pro-inflammatory cytokines [24]. Findings from the current study revealed that the serum insulin concentrations and HOMA-IR at different time points of OGTT in women of vitamin D group (obesity) were significantly lower than that in control group (obesity). Moreover, the BMI, WHR, TG concentration, TC concentration and LDL-C concentration in women of vitamin D group (IR) were significantly lower than that in control group (IR). Nevertheless, no significant difference was seen in metabolic parameters between vitamin D group (non-obesity) and control group (non-obesity), as well as between vitamin D group (non-IR) and control group (non-IR). A systematic review and meta-analysis of RCT reported that PCOS women with continuous low dose of vitamin D supplementation improve fasting glucose concentration and HOMA-IR, but the meta-analysis included studies of vitamin D in combination with other micronutrients [25]. Similarly, Menichini et al. confirmed that vitamin D supplementation (4000 IU/day) for a period of at least 12 weeks lead to improvement in terms of glucose level, insulin sensitivity, hyperlipidemia, and hormonal functionality in PCOS women [26].
The mechanism for vitamin D improving IR includes the following aspects: (a) Vitamin D receptor (VDR) is a key modulator of inflammation and β cell survival, whihc restored β cell function and ameliorate hyperglycemia in murine T2D models [27]. (b) Vitamin D increases insulin responsiveness for glucose transport through the binding of 1,25(OH)2D-VDR complex to the vitamin D response element of the insulin receptor [28]. (c) Vitamin D regulates the extracellular and intracellular calcium concentration, which is important for the mediation of glucose transport in the target tissues [29]. Nevertheless, Trummer et al. reported that Vitamin D supplementation had no significant effect on metabolic and endocrine parameters in PCOS [17]. Similarly, Ardabili et al. displayed that the fasting serum insulin and glucose levels, the insulin sensitivity and HOMA-IR did not change significantly by the end of the study [30]. The different results may be explained by different types of studies, dose and time of vitamin D supplementation, treatment with vitamin D alone or with other micronutrients, participants with pre-processed or not, lifestyles of the participants, place of residence and so on.
Our findings demonstrated that compared to control group, vitamin D supplementation significantly improved dyslipidemia in PCOS women with vitamin D deficiency and insufficiency, including reduced the serum TG, TC and LDL-C concentrations. Additionally, the serum TG, TC and LDL-C concentrations in women of vitamin D group (obesity) were significantly lower than that in control group (obesity). Similarly, some studies shown that vitamin D supplementation plus Calcium for eight weeks among vitamin D deficient women with PCOS had beneficial effects on serum TG and VLDL-cholesterol levels, but it did not affect other lipid profiles [31]. Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control lipid homeostasis. Asano et al. screened a chemical library of endogenous molecules and identified 25-hydroxyvitamin D (25OHD) as an inhibitor of SREBPs activation. They found that vitamin D may regulate lipoprotein lipase gene expression and therefore, might decrease serum TC concentration [32]. However, the beneficial effect of vitamin D supplementation on lipid profiles was not found in other studies [33]. Different study designs and dosages of vitamin D supplementation, baseline data of participants might provide explanation for different results. Several mechanisms can explain the effects of vitamin D supplementation on serum TG and VLDL-cholesterol levels. On the one hand, 1,25-dihydroxy-cholecalciferol represses the expression of the apolipoprotein A-I (apo A-I) gene in hepatocytes, and vitamin D receptor modulators in hepatocytes and intestinal cells differentially regulate expression of the apo A-I gene [34]. On the other hand, the increased intracellular Calcium due to vitamin D supplementation in liver leads to stimulating microsomal triglycerides transfer protein (MTP), which is implicated in the formation and secretion of VLDL, and then results in decreased serum TG and VLDL-cholesterol levels [35]. However, the effect of vitamin D supplementation on lipid profiles in PCOS patients and its specific mechanism still needs further exploration.
Some limitations must be considered in this study. First, this was a single-centre RCT study in the city of Xi’an in Shaanxi, China. Second, the metabolic parameters observed in this study were relatively limited, and androgen metabolic parameters and inflammatory indicators were not observed. Therefore, future studies are required to confirm the effectiveness of vitamin D on metabolic parameters of PCOS women, and the specific regulation mechanism are also need to be further explored.