Beyond Body Mass Index: Re‐Examining Vitamin D Deficiency in Infertile Women With PCOS

To the Editor,

Yari et al. [1] report a significantly higher odds of vitamin D deficiency among infertile women with polycystic ovary syndrome (PCOS) compared with fertile healthy controls, with an adjusted odds ratio of 1.89 even after controlling for age, body mass index (BMI), socioeconomic status, and seasonality. Their work adds valuable provincial data from western Iran, where both PCOS and hypovitaminosis D are highly prevalent, and aligns with current international guidance that emphasizes metabolic risk assessment, including nutritional factors, in women with PCOS [2].

This case–control study has several strengths. PCOS was defined using the Rotterdam criteria, infertility was clearly characterized, and key confounders of vitamin D status, particularly BMI and season, were entered into multivariable logistic models [1, 2]. The demonstration that PCOS remains associated with vitamin D deficiency beyond the effect of adiposity supports the hypothesis that endocrine and reproductive pathways specific to PCOS may influence vitamin D metabolism or vice versa [3].

However, the interpretation of these findings would benefit from further discussion in the context of the heterogeneous observational literature. Clinic‐based studies have often reported markedly lower 25‐hydroxyvitamin D [25(OH)D] levels and adverse metabolic profiles in women with PCOS compared with controls [3, 4]. In contrast, large population‐based data from the Northern Finland Birth Cohort 1966 showed similar or even slightly higher adjusted vitamin D levels in women with self‐reported PCOS, suggesting that obesity and lifestyle can largely explain crude differences [5]. Asian clinic cohorts have similarly reported no consistent difference in vitamin D levels between women with and without PCOS after adjusting for BMI [6]. By showing a persistent association despite adjustment for BMI, the present Iranian data occupy an interesting middle ground and may reflect region‐specific factors such as clothing, latitude, dietary patterns, and cultural sun‐avoidance [3, 5].

Several methodological aspects limit causal inference and point towards priorities for future research. First, the retrospective case–control design and single measurement of 25(OH)D preclude assessment of temporal direction. Vitamin D deficiency may be a consequence rather than a cause of PCOS‐related lifestyle factors such as reduced outdoor activity. Prospective cohort designs starting before the onset of PCOS features, or before infertility work‐up, would help clarify temporality [3, 5].

Second, important determinants of vitamin D status, dietary intake, supplement use, skin phototype, clothing practices, and objective measures of sun exposure were not reported. These unmeasured confounders are particularly relevant in Middle Eastern settings, where traditional dress and limited outdoor exposure can drive profound hypovitaminosis D even in otherwise healthy women [3, 5]. Incorporating these variables, as well as free 25(OH)D and vitamin D–binding protein, would strengthen future analyses.

Third, the study focuses on the binary presence of vitamin D deficiency rather than more nuanced analyses of dose–response. Modeling 25(OH)D as a continuous exposure, examining severity strata, and testing for thresholds could better align with recent dose–response meta‐analyses suggesting nonlinear relationships between vitamin D levels and reproductive outcomes, with a possible plateau around 24 ng/mL [7].

Fourth, PCOS is a heterogeneous condition. The authors did not report analyses stratified by PCOS phenotype (hyperandrogenic vs. normoandrogenic, ovulatory vs. anovulatory) or by markers of insulin resistance. Prior cross‐sectional and interventional studies suggest that the association between vitamin D status and metabolic derangements may be strongest in obese or insulin‐resistant PCOS phenotypes [3, 4, 8, 9]. Stratified analyses could reveal whether vitamin D deficiency clusters in the higher‐risk metabolic subgroups within their cohort.

The clinical implications of vitamin D deficiency in PCOS also merit cautious framing. Observational data and early reviews have linked low vitamin D to insulin resistance, adverse lipid profiles, and hyperandrogenism [3, 4]. More recent systematic reviews and meta‐analyses of randomized trials indicate that vitamin D supplementation can modestly improve insulin resistance, lipid parameters, and some androgen indices, particularly in women with obesity or established insulin resistance [8, 9, 10]. A 2024 meta‐analysis reported beneficial effects on luteinising hormone, testosterone, and menstrual regularity [10], while another systematic review found consistent though modest improvements in insulin metabolism and inflammatory markers [8, 9]. Nevertheless, the magnitude of these effects is small, and vitamin D is best viewed as an adjunct to, rather than a replacement for, lifestyle modification and evidence‐based pharmacological therapy for PCOS [2, 8, 9].

Finally, given that the participants were infertile women with PCOS, it would be highly informative to link vitamin D status to reproductive endpoints such as ovulation, clinical pregnancy, and live birth, either spontaneously or with assisted reproductive techniques. Recent dose–response meta‐analysis of assisted reproductive treatment suggests that women with sufficient vitamin D levels have higher clinical pregnancy and live‐birth rates than those who are deficient, with a non‐linear association at lower concentrations [7]. Future studies in similar infertility clinic populations could incorporate vitamin D into multifactorial prognostic models for treatment outcomes.

Overall, Yari et al. [1] provide important regional evidence that PCOS is independently associated with vitamin D deficiency in infertile women after adjustment for BMI and other confounders. We suggest that future work build on this foundation by incorporating detailed lifestyle and sun‐exposure data, PCOS phenotypes, continuous analyses of 25(OH)D, and reproductive as well as metabolic outcomes. Such studies will help determine whether correcting vitamin D deficiency in women with PCOS primarily improves long‐term metabolic health, short‐term fertility outcomes, or both.

Author Contributions

Sushma Narsing Katkuri: conceptualization, writing – review and editing. Nivedita Nikhil Desai: conceptualization, writing – original draft. Nirupma Gupta: conceptualization, validation. Pankaj Nainwal: conceptualization, supervision. Saumya Das: writing – review and editing. Jeffrin Reneus Paul: conceptualization, writing and original draft.

Funding

The authors received no specific funding for this work.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

No new datasets were created or analyzed in this study.