Vitamin D deficiency is common and there exists a huge gap between recommended dietary vitamin D intakes and the poor vitamin D supply in the general population. While vitamin D is important for musculoskeletal health, there are accumulating data suggesting that vitamin D may also be important for fertility, pregnancy outcomes and lactation. Significant changes in vitamin D metabolism during pregnancy such as increased production of the “active vitamin D hormone” calcitriol support the important role of vitamin D in this setting. Observational studies show that vitamin D deficiency is a risk marker for reduced fertility and various adverse pregnancy outcomes and is associated with a low vitamin D content of breast milk. Meta-analyses of randomized controlled trials (RCTs) document that physiological vitamin D supplementation during pregnancy is safe and improves vitamin D and calcium status, thereby protecting skeletal health. Although certain RCTs and/or meta-analyses reported some other beneficial effects, it is still not clear whether vitamin D supplementation improves fertility or decreases the risk of adverse pregnancy outcomes such as low birth weight, pre-eclampsia and neonatal mortality, or reduces wheeze/asthma in the infants. Nevertheless, vitamin D supplementation in pregnant women is frequently required to achieve a sufficient vitamin D status as recommended by nutritional vitamin D guidelines. In this review, we provide an overview of systematic reviews, meta-analyses and large trials reporting clinical data on the role of vitamin D for fertility, pregnancy and lactation.

During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied.

As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches.

Vitamin D status may be associated with insulin resistance and other key features of polycystic ovary syndrome (PCOS), but data from preliminary randomized controlled trials (RCTs) are conflicting. Therefore, we aimed to investigate the effects of vitamin D supplementation on plasma glucose area under the curve (AUCgluc, primary outcome measure) and on other metabolic and endocrine parameters (secondary outcome measures).

Background: Polycystic ovary syndrome (PCOS) affects 5–20% of women of reproductive age worldwide and is associated with disorders of glucose metabolism. Hormone and metabolic signaling may be influenced by phytoestrogens, such as isoflavones. Their endocrine effects may modify symptom penetrance in PCOS. Equol is one of the most active isoflavone metabolites, produced by intestinal bacteria, and acts as a selective estrogen receptor modulator. Method: In this interventional study of clinical and biochemical characterization, urine isoflavone levels were measured in PCOS and control women before and three days after a defined isoflavone intervention via soy milk. In this interventional study, bacterial equol production was evaluated using the log(equol: daidzein ratio) and microbiome, metabolic, and predicted metagenome analyses were performed. Results: After isoflavone intervention, predicted stool metagenomic pathways, microbial alpha diversity, and glucose homeostasis in PCOS improved resembling the profile of the control group at baseline. In the whole cohort, larger equol production was associated with lower androgen as well as fertility markers. Conclusion: The dynamics in our metabolic, microbiome, and predicted metagenomic profiles underline the importance of external phytohormones on PCOS characteristics and a potential therapeutic approach or prebiotic in the future.

Bone turnover markers (BTMs) are used to evaluate bone health together with bone mineral density and fracture assessment. Vitamin D supplementation is widely used to prevent and treat musculoskeletal diseases but existing data on vitamin D effects on markers of bone resorption and formation are inconsistent. We therefore examined the effects of vitamin D supplementation on bone-specific alkaline phosphatase (bALP), osteocalcin (OC), C-terminal telopeptide (CTX), and procollagen type 1 N-terminal propeptide (P1NP). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial, a single-center, double-blind, randomized, placebo-controlled trial (RCT) performed at the Medical University of Graz, Austria (2011–2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D (25[OH]D) levels <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for eight weeks. One hundred ninety-seven participants (60.2 ± 11.1 years; 47% women) were included in this analysis. Vitamin D had no significant effect on bALP (mean treatment effect (MTE) 0.013, 95% CI −0.029 to 0.056 µg/L; p = 0.533), CTX (MTE 0.024, 95% CI −0.163 to 0.210 ng/mL, p = 0.802), OC (MTE 0.020, 95% CI −0.062 to 0.103 ng/mL, p = 0.626), or P1NP (MTE −0.021, 95% CI −0.099 to 0.057 ng/mL, p = 0.597). Analyzing patients with 25(OH)D levels <50 nmol/L separately (n = 74) left results largely unchanged. In hypertensive patients with low 25(OH)D levels, we observed no significant effect of vitamin D supplementation for eight weeks on BTMs.