Abstract
Objective This study aims to investigate the effect of combining calcium and vitamin D supplements with metformin on menstrual cycle abnormalities, gonadotropins, and IGF-1 system in vitamin D-deficient/insufficient PCOS women. Study Design This is a randomized, placebo-controlled clinical trial. Setting This study was performed in Damascus University of Obstetrics and Gynecology Hospital and Orient Hospital, in Damascus, Syria. Materials and Methods Forty PCOS women with 25-OH-vitamin D < 30 ng/ml were randomly assigned to take either metformin (1500 mg/daily) plus placebo or metformin (1500 mg/daily) plus calcium (1000 mg/daily) and vitamin D3 (6000 IU/daily) orally for 8 weeks. Serum levels of gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-1 (IGFBP-1) were detected at the baseline during the early follicular phase of a spontaneous or induced menstrual cycle and after 8 weeks of intervention (except for the final gonadotropins levels which were assayed from samples obtained during the early follicular phase of a spontaneous menstrual cycle). Results Thirty-four patients (85%) completed the study. After 8 weeks of intervention, calcium and vitamin D co-supplementation led to a significant increase in 25-OH-vitamin D levels and calcium levels in the supplementation group compared to the other group (change in 25-OH-vitamin D levels: +19.38 ± 7.78 vs +0.11 ± 4.79 ng/ml, respectively; p value=0.0001) (change in calcium levels: +0.83 ± 0.82 vs +0.01 ± 0.86 mg/dl, respectively; p value=0.014). An improvement in menstrual cycle irregularity was detected in 38.5% and 58.8% of patients in metformin-placebo group and metformin-calcium-vitamin D group, respectively; but the change was statistically significant only in the supplementation group (p value=0.002). Nevertheless, the means of changes from baseline in gonadotropins levels (serum levels of LH, FSH, and LH to FSH ratio) and the studied parameters of IGF-1 system (serum levels of IGF-1, IGFBP-1, and IGF-1 to IGFBP-I ratio) did not differ significantly between the two groups. Conclusions Calcium and vitamin D supplements can support metformin effect on regulation of menstrual cycle irregularity in vitamin D-deficient/insufficient PCOS patients, but this effect is not associated with any significant changes in gonadotropins or IGF-1 system. These results suggest a possible role of calcium and vitamin D supplements in managing PCOS. However, further studies are needed to identify the underlying mechanisms. The Clinical Trial Registration Number is NCT03792984.
Highlights
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among females of reproductive age, with a worldwide prevalence of 5–20% depending on the criteria used [1, 2]. e main manifestations of this syndrome are ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology [2]
Previous data demonstrated that, compared to normoovulatory women, PCOS patients might exhibit a dysregulation in the IGF system represented as an elevation in the serum levels of free insulin-like growth factor-1 (IGF-1) and a reduction in the serum levels of insulin-like growth factor binding protein-1 (IGFBP-1) [4]. e IGF system plays an important role in the regulation of oocyte maturation, folliculogenesis, ovarian steroidogenesis, and metabolism [5, 6]. us, abnormality in the IGF system may play a role in the pathogenesis of PCOS
On the top of that, vitamin D regulates over 300 genes, including genes that are important for glucose and lipid metabolism. us, vitamin D deficiency may be the missing link between insulin resistance and PCOS [3]
Summary
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among females of reproductive age, with a worldwide prevalence of 5–20% depending on the criteria used [1, 2]. e main manifestations of this syndrome are ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology [2]. Vitamin D deficiency is a common condition among women with PCOS [16, 17], and several studies indicated an association between low levels of serum 25-hydroxyvitamin D (25-OH-vitamin D) and manifestations of PCOS including insulin resistance [16,17,18,19,20], hyperandrogenism [18], and infertility [21, 22]. Considering the aforementioned data, we conducted this placebo-controlled clinical trial to assess the effect of calcium and vitamin D supplements as an adjuvant therapy to metformin on menstrual cycle abnormalities, gonadotropins, and IGF-1 system in vitamin D-deficient/insufficient PCOS women
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