The Association between Vitamin D and Anti-Müllerian Hormone: A Systematic Review and Meta-Analysis.

Accumulating evidence from animal and human studies indicates a role for vitamin D in female reproductive physiology, and numerous clinical studies have suggested its potential benefit for various aspects of human reproduction. Anti-Müllerian hormone (AMH) is an ovarian biomarker that plays an important role in folliculogenesis. It is the most sensitive ovarian reserve marker and is widely used clinically in reproductive medicine. While initial studies have suggested that vitamin D may be associated with ovarian reserve markers, including AMH, evidence has been conflicting. Currently, there is considerable debate in the field whether vitamin D has the capacity to influence ovarian reserve, as indicated by the AMH level. The current systematic review aims to evaluate and summarize the available evidence regarding the relationship between vitamin D and AMH. In total, 18 observational studies and 6 interventional studies were included in this systematic review. Cross-sectional studies have reported largely discrepant findings regarding an association between serum vitamin D and AMH levels, which are likely due to the heterogeneity in study populations, as well as the apparently complex relationship that may exist between vitamin D and AMH. However, meta-analysis of interventional studies performed herein that examined the effects of vitamin D supplementation on serum AMH levels indicates a cause-effect relationship between vitamin D and AMH, the direction of which appears to depend on a woman's ovulatory status. Serum AMH was significantly decreased following vitamin D supplementation in polycystic ovarian syndrome (PCOS) women (standardized mean difference (SMD) -0.53, 95% CI -0.91 to -0.15, p < 0.007), while it was significantly increased following vitamin D supplementation in ovulatory women without PCOS (SMD 0.49, 95% CI 0.17 to 0.80, p = 0.003). In conclusion, the results of this systematic review demonstrate that the relationship between vitamin D and AMH is a complex one, and large, randomized trials of vitamin D supplementation focusing on different vitamin D status ranges are necessary to gain more insight into the nature of this relationship and the potential benefit of vitamin D to female reproduction in general.

Vitamin D Supplementation Ameliorates Metabolic Dysfunction in Patients with PCOS: A SystematicReview of RCTs and Insight into the Underlying Mechanism.

OBJECTIVE: Evidence suggests that vitamin D deficiency correlated with metabolic disorders in women with polycystic ovary syndrome (PCOS). We conducted this systematic review and meta-analysis to evaluate the impact of vitamin D supplementation alone on glucose, lipid, and androgen parameters and inflammation biomarkers in women with PCOS. METHODS: Literature research was conducted in Pubmed, Embase, Web of Science, Clinical Trials, and Cochrane Library to identify relevant randomized controlled trials (RCTs) up to March 2020. The effect of vitamin D supplementation alone on women with PCOS was compared with administration of placebo. The systematic review and meta-analysis protocol was registered in the International Prospective Register of Systematic Reviews (Prospero) as number CRD42020157444. RESULTS: Thirteen randomized controlled trials with 824 patients in total were included. Serum FPG, fasting insulin, HOMA-IR, and VLDL-C were significantly decreased in the vitamin D group versus placebo. Vitamin D supplementation group also showed a significantly elevated level of QUICKI. No significant impact was seen on serum triglyceride, total-C, LDL-C, HDL-C, total testosterone, DHEAS, SHBG, or hs-CRP. Subgroup analysis demonstrated that oral vitamin D intake had significantly decreased serum triglyceride and total-C level in women with PCOS who have vitamin D deficiency (serum vitamin D < 20 ng/ml). CONCLUSION: The findings of the present meta-analysis indicate that vitamin D supplementation exerted favorable effects among women with PCOS on glucose metabolism and lipid metabolism, especially in vitamin D deficient women, but had no significant effect on the androgenic profile or inflammation status.

Vitamin D Decreases Serum VEGF Correlating with Clinical Improvement in Vitamin D-Deficient Women with PCOS: A Randomized Placebo-Controlled Trial.

Vascular endothelial growth factor (VEGF) has been suggested to play a role in the pathophysiology of polycystic ovary syndrome (PCOS) and may contribute to increased risk of ovarian hyperstimulation syndrome (OHSS) in affected individuals. Vitamin D (VitD) supplementation improves multiple clinical parameters in VitD-deficient women with PCOS and decreases VEGF levels in several other pathologic conditions. Unveiling the basic mechanisms underlying the beneficial effects of vitamin D on PCOS may enhance our understanding of the pathophysiology of this syndrome. It may also suggest a new treatment for PCOS that can improve it through the same mechanism as vitamin D and can be given regardless of vitamin D levels. Therefore, we aimed to explore the effect of VitD supplementation on serum VEGF levels and assess whether changes in VEGF correlate with an improvement in characteristic clinical abnormalities of PCOS. This is a randomized placebo-controlled trial conducted between October 2013 and March 2015. Sixty-eight VitD-deficient women with PCOS were recruited. Women received either 50,000 IU of oral VitD3 or placebo once weekly for 8 weeks. There was a significant decrease in serum VEGF levels (1106.4 ± 36.5 to 965.3 ± 42.7 pg·mL-1; p < 0.001) in the VitD group. Previously reported findings of this trial demonstrated a significant decrease in the intermenstrual intervals, Ferriman-Gallwey hirsutism score, and triglycerides following VitD supplementation. Interestingly, ∆VEGF was positively correlated with ∆triglycerides (R² = 0.22; p = 0.02) following VitD supplementation. In conclusion, VitD replacement significantly decreases serum VEGF levels correlating with a decrease in triglycerides in women with PCOS. This is a novel molecular explanation for the beneficial effects of VitD treatment. It also suggests the need to investigate a potential role of VitD treatment in reducing the incidence or severity of OHSS in VitD-deficient women with PCOS.

Vitamin D Supplementation Decreases TGF-ß1 Bioavailability in PCOS: A Randomized Placebo-Controlled Trial.

CONTEXT: There is an abnormal increase in TGF-ß1 bioavailability in women with polycystic ovary syndrome (PCOS), which might play a role in the pathophysiology of this syndrome. Vitamin D (VD) supplementation improves various clinical manifestations of PCOS and decreases TGF-ß1 levels in several diseases including myelofibrosis. OBJECTIVE: The objective of the study was to determine the effect of VD supplementation on TGF-ß1 bioavailability in VD-deficient women with PCOS and assess whether changes in TGF-ß1/soluble endoglin (sENG) levels correlate with an improvement in PCOS clinical manifestations. DESIGN: This was a prospective, randomized, placebo-controlled trial. SETTING: The study was conducted at an academic-affiliated medical center. PARTICIPANTS: Sixty-eight VD-deficient women with PCOS who were not pregnant or taking any exogenous hormones were recruited between October 2013 and January 2015. INTERVENTIONS: Forty-five women received 50 000 IU of oral vitamin D3 and 23 women received oral placebo once weekly for 8 weeks. MAIN OUTCOMES MEASURES: Serum TGF-ß1, sENG, lipid profile, testosterone, dehydroepiandrosterone sulfate, and insulin resistance were measured. The clinical parameters were evaluated before and 2 months after treatment. RESULTS: The VD level significantly increased and normalized after VD supplementation (16.3 ± 0.9 [SEM] to 43.2 ± 2.4 ng/mL; P < .01), whereas it did not significantly change after placebo. After the VD supplementation, there was a significant decrease in the following: the interval between menstrual periods (80 ± 9 to 60 ± 6 d; P = .04), Ferriman-Gallwey score (9.8 ± 1.5 to 8.1 ± 1.5; P < .01), triglycerides (138 ± 22 to 117 ± 20 mg/dL; P = .03), and TGF-ß1 to sENG ratio (6.7 ± 0.4 to 5.9 ± 0.4; P = .04). In addition, the ΔTGF-ß1 to sENG ratio was positively correlated with Δtriglycerides (r = 0.59; P = .03). CONCLUSIONS: VD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF-ß1, which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel mechanism that could explain the beneficial effects of VD supplementation in women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-ß drugs.