Effect of Calcium and Vitamin D Supplements as an Adjuvant Therapy to Metformin on Menstrual Cycle Abnormalities, Hormonal Profile, and IGF-1 System in Polycystic Ovary Syndrome Patients: A Randomized, Placebo-Controlled Clinical Trial

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.

Impact of Short-Term Isoflavone Intervention in Polycystic Ovary Syndrome (PCOS) Patients on Microbiota Composition and Metagenomics

“…This could be one reason why an equol/incretin/microbiome interaction may play a crucial role in insulin secretion and glucose metabolism in PCOS [ 82 ]. The positive effect of Ca 2+ in the context of PCOS has been shown in other studies that hypothesize a potential estrogen agonistic effect [ 83 , 84 , 85 ].…”

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…Of great importance for normalization of the steroidogenic function in the ovaries can be MF-induced decrease in the blood LH level and the LH/FSH ratio, which are significantly increased in PCOS [ 216 , 217 , 218 , 219 ] ( Figure 2 ). An increase in the LH/FSH ratio due to abnormal gonadotropin pulsatility and hypersecretion of LH by the pituitary is a significant factor responsible for the deterioration of folliculogenesis and oogenesis in PCOS [ 219 , 220 , 221 , 222 , 223 , 224 ].…”

“…The restoration of this ratio leads to normalization of the ovulatory cycle and triggers the development of the dominant follicle, improving the rate and outcomes of pregnancy [ 222 , 225 ]. Eight-week treatment of PCOS women with MF (1500 mg/daily) results in a 32% decrease in the blood LH levels and a 42% decrease in the LH/FSH ratio [ 218 ]. There is reason to believe that, as in the case of SHBG, the sensitivity of PCOS women to MF therapy depends on the LH level and the LH/FSH ratio.…”

“…In the PCOS ovaries, the important mechanism of suppression of PTEN expression and hyperactivation of the insulin and IGF-1 signaling pathways is an increase in the expression of two microRNAs of miR-200 family, miR-200b and miR-200c, which negatively affect the expression of the PTEN gene [ 252 ]. In addition, a decrease in the expression of miR-99a, a negative regulator of IGF-1 receptor expression, leads to an increase in the sensitivity of granulosa cells to IGF-1 [ 218 ]. An increase in the expression and activity of the receptor and postreceptor components of the FSH-, insulin- and IGF-1-regulated signaling systems in PCOS results in the accelerated growth and proliferation of the ovarian cells, primarily granulosa cells, in the response to the stimulating effect of these hormones.…”

Lifestyle management of polycystic ovary syndrome: a single-center study in Bosnia and Herzegovina

“…In a randomized control trial involving 90 insulin-resistant PCOS patients, high-dose vitamin D (4000 IU) had beneficial effects on total testosterone, sex hormone-binding globulin, free androgen index, serum hs-CRP, and plasma total antioxidant capacity levels compared with low-dose vitamin D (1000 IU) and placebo groups [41] , [42] . Co-supplementation with calcium and vitamin D (Ca 1000 mg/day, vitamin D 6000 IU/day during 8 weeks) was shown to significantly improve menstrual cycle regularity when added to metformin (1500 mg/day) in the randomized placebo-controlled clinical trial in 40 vitamin D-deficient PCOS patients [43] . Similar results were reported in a few more randomized clinical trials, although with higher vitamin D dose [44] , [45] .…”