Vitamin D deficiency may be disease modifying but not causal for polycystic ovary syndrome

Sir,

With interest we read the article by Tandon et al¹, about a retrospective, single-center study on the influence of vitamin D deficiency on lipid levels, insulin resistance as assessed by homeostatic model assessment (HOMA), and fasting blood sugar in 175 female participants with polycystic ovary syndrome (PCOS)¹. It was found that metabolic syndrome was highly prevalent among participants with PCOS but vitamin D deficiency only correlated with high-density lipoprotein (HDL) but not with any other of the evaluated parameters¹. While the study is relevant it has some limitations that are discussed here.

The main limitation of this study is that neither a healthy nor a diseased control group matched for age and sex was examined to compare the findings with those of the PCOS cohort. Without such a control group the significance of the findings remains limited. Particularly, one does not know if the correlation between vitamin D deficiency and HDL is specific to individuals with PCOS or whether it was observed in controls as well. Whether the connection between metabolic syndrome, HDL levels, and vitamin D is relevant, therefore remains unproven.

An argument against vitamin D deficiency to play a causative role in the development of PCOS is that vitamin D deficiency is a common finding ubiquitously and usually not symptomatic or associated with disease². Vitamin D deficiency is commonly found in apparently healthy subjects and there are numerous individuals with vitamin D deficiency who do not become symptomatic or develop PCOS or other diseases³.

A further argument against a causal relationship between vitamin D deficiency and PCOS is that a number of previous studies⁴ did not find a connection between vitamin D deficiency and PCOS. In a bidirectional two-sample Mendelian randomization (MR) study⁵ on 4890 individuals with PCOS and 20405 controls to evaluate a possible causal association between PCOS and 25-hydroxy vitamin D, the multivariate MR did not find a causal relation when adjusting the influence of obesity and insulin resistance⁵. Neither univariate nor multivariate MR supported at causal effect of vitamin D deficiency on PCOS⁵. In a study on 60 women with PCOS, the body mass index (BMI), antral follicle count (AFC), and the anti-Muellerian hormone (AMH) were increased compared to controls⁶. With increasing BMI values, the vitamin D levels and AMH levels decreased in the PCOS cohort⁶. However, vitamin D deficiency did not affect the main markers of ovarian reserve⁶.

Another limitation in the study by Tandon et al¹ was that the calcium levels were not measured. Since vitamin D is implicated in the regulation of calcium homeostasis, it is essential to know whether the observed vitamin D deficiency had implications on the calcium metabolism. Since vitamin D deficiency manifests with tiredness, exhaustion, mood swings, increased susceptibility to infections, and hair loss, it would have added value to know how many of the participants with PCOS who also had vitamin D deficiency exhibited any of these symptoms.

Overall, addressing the issues raised would strengthen the conclusions the study discussed. Since only HDL was correlated with vitamin D deficiency, a causal relationship seems unlikely. PCOS does not appear to be causally related to vitamin D deficiency, but low vitamin D may affect the clinical manifestations and thereby the progression, prognosis, and outcome of PCOS.