Role of Vitamin D in the Etiology of Polycystic Ovary Syndrome, A Review

Dr. Nahla Al-Bayyari

Department of Nutrition and Food Technology, Faculty of Al-Huson University College, Al-Balqa Applied University, Al-Salt, Jordan

*Correspondence to: Dr. Nahla Al-Bayyari, Department of Nutrition and Food Technology, Faculty of Al-Huson University College, Al-Balqa Applied University, Al-Salt, Jordan.

Copyright © 2018 Dr. Nahla Al-Bayyari. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. It is characterized by the presence of polycystic ovaries, menstrual dysfunction, infertility and elevated androgens as well as hirsutism and/or acne [1].

Vitamin D plays an important role in the health and fertility for women with polycystic ovary syndrome (PCOS). Despite the importance, research shows that 67-85% of women with PCOS are deficient in vitamin D [2]. A deficiency of Vitamin D not only causes poor bone mineralization but also has been implicated in numerous chronic diseases including diabetes, heart disease, poor immunity, various cancers, multiple sclerosis, rheumatoid arthritis, and high blood pressure.

Vitamin D deficiency may exacerbate symptoms of PCOS, with observational studies showing lower 25OHD levels were associated with insulin resistance, ovulatory and menstrual irregularities, lower pregnancy success, hirsutism, hyperandrogenism, obesity and elevated cardiovascular disease risk factors. There is some, but limited, evidence for beneficial effects of vitamin D supplementation on menstrual dysfunction and insulin resistance in women with PCOS. Vitamin D deficiency may play a role in exacerbating PCOS, and there may be a place for vitamin D supplementation in the management of this syndrome, but current evidence is limited and additional randomized controlled trials are required to confirm the potential benefits of vitamin D supplementation in this population. The objective of this review is to identify the role of vitamin D in the etiology of polycystic ovary syndrome.

Vitamin D Synthesis and Metabolism
Vitamin D is a steroid hormone. The 7-dehydrocholesterol is the vitamin D precursor present in the skin [3,4]. Ultraviolet B (UV-B) radiation induces conversion of 7-dehydrocholesterol to provitamin D3, which spontaneously isomerizes to vitamin D3 (cholecalciferol). (Vitamin D3 is released into the circulation and transported by the vitamin D-binding protein (VDBP) [4]. Vitamin D from the skin and diet is metabolized in the liver to 25-hydroxyvitamin D (25[OH] D), which is metabolized in the kidneys by the enzyme 1α-hydroxylase to its active form, 1,25-dihydroxyvitamin D3 (1,25(OH)₂D3) [3,4]. The active 1,25(OH)₂D can bind to vitamin D receptor- retinoic acid x-receptor complex (VDR-RXR) in the intestine, bone, and parathyroid glands to maintain mineral homeostasis for skeletal functions and other organs such as breast, colon and prostate for non-skeletal functions as illustrated in Figure (1) and (2) [5,6].

Source: Holick and Chen (2008)

Vitamin D Polymorphism in PCOS
Vitamin D receptor (VDR) polymorphisms are related to type 1 diabetes mellitus (T1DM) [7] as well as T2DM [8]. The VDR Apa-I is associated with defective insulin secretion [9] and glucose intolerance as well as metabolic syndrome [8]. While, (Oh and Barrett-Connor in (2002) [8] reported that the VDR Bsm-I polymorphism is associated with insulin resistance, others were not able to detect an association of VDR polymorphism with T2DM [10].

In the literature there is a little data published on the association of vitamin related polymorphism with PCOS. Zadeh-Vakili and his colleagues (2013) [11] conducted a case control study and found that the distributions of genotypes and alleles did not differ between cases and controls, indicating that this single nucleotide polymorphism (SNP) is not associated with increased risk for PCOS but it is associated with the severity of the PCOS phenotype. Therefore, they concluded that the genetic variant of the VDR was found to have an association with severity of clinical features of PCOS, but not with the disease.

Vitamin D and PCOS
The relationship between vitamin D levels and different PCOS symptoms, including insulin resistance (IR), infertility and hirsutism has been demonstrated in several studies [12-14]. Science based evidence suggests that the levels of vitamin D are similar in women with and without PCOS [15]; however, lower levels [16,17] and higher levels [18] have been reported in women with PCOS. Many studies have reported low levels of 25(OH)D with a range between 11 and 31ng/ml, [12,15,18,19] with the majority having values <20ng/ml (67-85%) [2,12,13,15] in women with PCOS. Vitamin D deficiency is also common in the general population in different countries of the world, with 10-60% of adults having values <20ng/ml [20].

Vitamin D and Insulin Resistance
Research evidence has proposed that low levels of vitamin D is a risk factor that plays an important role in the development of insulin resistance and the pathogenesis of T2DM through affecting either insulin sensitivity or β-cell function, or both [21,22]. The 1,25-dihydroxyvitamin D (1,25(OH)₂D) improves insulin sensitivity, β-cell function and protects β- cells from immune attacks directly and indirectly [23]. The potential role of vitamin D deficiency in insulin resistance is shown in Table (1) [6].

VDBP: vitamin D binding protein; VDR: vitamin D receptor; CYP1alpha: vitamin D 1alpha-hydroxylase; IL-12: interleukin-12; INF-γ: interferon-γ; TNF α: tumor necrosis factor α; NF-κB: nuclear factor κB; IκB-α: the inhibitor of NF-κB; TLR: Toll-like receptors; PTH: parathyroid hormone.

Source: (Sung et al., 2012)

Vitamin D Levels and Body Mass Index (BMI) in PCOS
Several research studies have reported an inverse association between body weight (BMI, body fat and waist measurements) and serum 25(OH)D levels in women with PCOS [12,19,24], and levels of 25(OH)D were reported to be 27-56% lower in obese women with PCOS compared with non-obese women with PCOS [12,19]. Muscogiuri and his colleagues (2012) [19] found that low levels of 25(OH)D were specified by the degree of adiposity (BMI and total fat mass) and were not directly affected by the development of IR in women with PCOS. Of the possible explanations of the high prevalence of vitamin D deficiency in women with PCOS is related to obesity [15], because vitamin D is trapped in adipose tissue [25], and obese women may spend less time outdoors exposed to sunlight. It is also possible that dietary preferences and vitamin D metabolism may differ between obese and non-obese individuals [2]. Meanwhile, there are inadequate data available regarding the difference in vitamin D status between lean and obese women with PCOS.

Vitamin D Levels, Pathogenesis of PCOS and Insulin Resistance
Vitamin D deficiency may contribute to the pathogenesis of IR and MS in PCOS as shown in Figure (3) [26,27]. The pathogenesis of PCOS has been linked to the effects of VDRs polymorphisms on luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels [28], testosterone levels, IR and serum insulin levels [16,29]. Vitamin D deficiency increases parathyroid hormone (PTH) production which is independently associated with PCOS, anovulatory infertility and increased testosterone [30]. It has been suggested that vitamin D deficiency and inadequate dietary calcium may be responsible for the menstrual abnormalities in case of PCOS [31]. Vitamin D regulates estrogen biosynthesis and aromatase gene expression by maintaining extracellular calcium homoeostasis [32]. In human ovarian tissue, estrogen and progesterone production is stimulated by 1,25(OH)₂D3, and testosterone production decreases may be by boosting of aromatase activity through vitamin D [33]. In the follicles of PCOS women compared to controls, aromatase gene expression decreased and LH levels had increased but follicular production of progesterone and estradiol decreased [34]. As a result of these effects, vitamin D deficiency may arise PCOS symptoms. Meanwhile, the exact mechanism underlying vitamin D and insulin resistance is not known but some cellular and molecular mechanisms have been attempted to explain this association [2]. For example, 1,25(OH)D may enhance insulin action by enhancing insulin synthesis and release, increasing insulin receptor expression or suppression of proinflammatory cytokines [35]. Furthermore, vitamin D may improve insulin sensitivity by improving calcium status, increasing local production of 25(OH)D, which leads to transcriptional regulation of specific genes or suppressing serum levels of PTH [35].

Source: (Thomson et al., 2012)

Vitamin D, PCOS and Metabolic Disturbances
Vitamin D deficiency was independently associated with lower insulin sensitivity, lower high-density lipoprotein cholesterol (HDL-C) levels [14,36] and obesity [37]. The association of low vitamin D levels with IR might be mediated by obesity [37]. Furthermore, 25(OH)D levels have been reported to be lower in obese PCOS women compared with normal weight PCOS women [18,37].

It has also been demonstrated by previous studies that vitamin D deficiency is associated with other features of metabolic syndrome (MS) including glucose intolerance, hypertension, dyslipidemia, and chronic inflammation [36,38]. These metabolic risk factors are commonly found in women with PCOS, but roles for vitamin D deficiency in PCOS and MS is not entirely clear yet [36,39].

The impact of vitamin D supplementation on metabolic disturbances was studied and results showed improvements in serum triglycerides (TG) and HDL, with no changes in BMI [40] and significant decreases in fasting and stimulated glucose, TG and hip circumference (HC), but total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol were increased, and BMI, HDL, blood pressure and waist circumference (WC) were unchanged [41]. Likewise, the improvement in 25(OH)D levels was significantly correlated with the reduction in high sensitivity c-reactive protein (CRP), but not with total cholesterol (TC), TG, HOMA-IR or free androgen index (FAI) [42].

Vitamin D and Reproductive Function in Women with PCOS
There is accumulating evidence that vitamin D plays an important role in reproductive function because VDRs have been found in the ovary, endometrium and placenta [33,43]. Vitamin D deficiency is associated with calcium dysregulation, which participates in the development of follicular arrest in women with PCOS and results in menstrual and fertility dysfunction [31]. Ozkan, et al. (2010) [44] conducted a study on women with PCOS and undergoing in vitro fertilization (IVF), they found that the women who achieved pregnancy exhibited significantly higher follicular fluid levels of 25(OH)D and each ng/ml increase in follicular fluid 25(OH)D increased the likelihood for achieving pregnancy by 7% [44]. Moreover, 25(OH) D deficiency was associated with lower rates of follicle development and pregnancy after stimulation with clomiphene-citrate in women with PCOS, suggesting a possible role of vitamin D supplementation in infertile PCOS women who undergo ovarian stimulation [45].

Rashidi and his colleagues (2009) [46] studied the effects of calcium-vitamin D and metformin in regulating the menstrual cycle in women with PCOS and concluded that metformin and calcium-vitamin D could be effective for the treatment of anovulation and oligomenorrhoea in women with PCOS. Furthermore, in a recent uncontrolled pilot study on 46 women with PCOS, the authors also observed improvements in reproductive function and in menstrual frequency of oligo- or amenorrhoeic women after 24 weeks of weekly cholecalciferol (20,000 IU), which significantly increased 25(OH)D levels [41].

Vitamin D and Hyperandrogenism in Women with PCOS
The associations between markers of hyperandrogenism and vitamin D status have been found in observational studies [2]. Hirsute women with PCOS had lower 25(OH)D levels compared with women with PCOS but without hirsutism [13]. In women with PCOS, the 25(OH)D levels have been positively associated with SHBG [13,15] and negatively associated with the degree of hirsutism [13,37], free androgen index (FAI) [15], total testosterone and dehydroepiandrosterone sulphate [12]. Likewise, SHBG levels were lower in PCOS women with severe vitamin D deficiency, but after adjusting for BMI this was no longer significant [13,15,37], indicating that obesity is a common determinant for both SHBG and 25(OH)D [2]. Limited studies have examined the effect of vitamin D supplementation on hyperandrogenism measures, and have shown no changes in levels of testosterone, SHBG and FAI [41,47].

Conclusion
Many observational studies suggest a possible role of vitamin D in an inverse association between vitamin D status and metabolic disturbances in PCOS, but it is still inconclusive to draw a definite conclusion in the causal relationship due to inconsistent findings from various studies and from meta-analysis report of a systematic review.

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