Menopause, Metabolism, And the Vitamin D Connection: A Comprehensive Review

Vitamin D deficiency and metabolic syndrome are increasingly prevalent globally, with postmenopausal women being a particularly susceptible population. Emerging evidence suggests that hypovitaminosis D is linked to various components of metabolic syndrome, including dyslipidemia, hypertension, diabetes, and obesity. This review aims to synthesize recent findings on the association between vitamin D deficiency and metabolic syndrome in postmenopausal women, highlighting the long-term risks of low vitamin D levels and the importance of supplementation. A comprehensive literature search was conducted using PubMed, Google Scholar, and individual searches.

Vitamin D: Synthesis, Metabolism, and Health Implications

Vitamin D, a fat-soluble vitamin, is uniquely synthesized in the skin through exposure to ultraviolet B (UVB) rays and further activated by the liver and kidney [1]. Dietary sources, such as eggs, liver, cod liver oil, and mushrooms, also contribute to vitamin D levels. Optimal serum levels of 25-hydroxyvitamin D (25(OH)D) range from 30-50 ng/ml, while insufficiency is indicated by levels of 21-29 ng/ml [2]. Deficiency is defined as levels below 20 ng/ml [2].

Research has established a strong link between low vitamin D levels and various health conditions, including osteomalacia, secondary hyperparathyroidism, osteoporosis [1], as well as diabetes, adiposity, dyslipidemia, hypertension, metabolic syndrome, and cardiovascular disease [3]. Vitamin D deficiency is a widespread and significant public health concern globally [4]. Recent studies have reported an alarming increase in vitamin D deficiency worldwide, reaching pandemic proportions [4]. This trend is attributed to modern lifestyle changes, including increased use of sunscreens, reduced outdoor activities, socioeconomic shifts, and urbanization [5].

Surprisingly, even countries with adequate sunlight, such as South Korea (located between latitudes 33°-38°), report high prevalence of vitamin D deficiency. The Korean National Health and Nutrition Examination Survey found that postmenopausal women in South Korea were particularly affected [5]. Further research by Chon et al. [6] revealed that individuals with sedentary lifestyles, residing in urban areas, had significantly lower serum vitamin D levels compared to those living in rural areas, engaging in outdoor activities like farming and fishing, and enjoying higher physical activity levels.

Vitamin D Deficiency in Postmenopausal Women: A Prevalent Issue

Vitamin D deficiency is disproportionately prevalent among postmenopausal women due to decreased estrogen levels and reduced skin capacity to synthesize 25-hydroxyvitamin D (25(OH)D) [7, 8]. Studies from India and Western countries report an alarming incidence rate of 50-90% [6, 9].

In India, a study conducted in Jammu and Kashmir found that 80% of postmenopausal women suffered from vitamin D deficiency, while 14.8% had insufficiency [1]. Similarly, a study in South India reported that 70% of postmenopausal women had vitamin D deficiency, and 23% had insufficiency [10]. A study on Han Chinese postmenopausal women found that 31.2% had vitamin D deficiency, and 50.6% had insufficiency [11].

Metabolic Syndrome (MS): Definition and Criteria

Metabolic syndrome is a cluster of metabolic abnormalities, including:

Dyslipidemia: triglycerides (TG) ≥ 150 mg/dl, high-density lipoprotein-cholesterol (HDL-C) ≤ 50 mg/dl.

Central Obesity: waist circumference ≥ 88 cm.

Hypertension: systolic blood pressure (SBP) ≥ 130 mmHg or diastolic blood pressure (DBP) ≥ 85 mmHg, or on antihypertensive medication.

Hyperglycemia: fasting blood glucose ≥ 100 mg/dl or on treatment for type 2 diabetes.

The association between metabolic syndrome and cardiovascular disease (CVD) has raised concerns among Indian epidemiologists and the World Health Organization (WHO), who predict that CVD will become the leading cause of death and disability in India by 2020 [13].

Several definitions of metabolic syndrome have been proposed, including those by the World Health Organization (WHO), European Group for the Study of Insulin Resistance (EGIR), American Association of Clinical Endocrinologists (AACE), and others. The most commonly used criteria are the Modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, which require the presence of three or more of the above-mentioned cofactors for a diagnosis of metabolic syndrome [12].

The Menopause-Metabolic Syndrome Connection

Vitamin D deficiency and obesity are characterized by chronic inflammation, marked by elevated levels of C-reactive protein, fibrinogen, interleukin-6, and tumor necrosis factor-alpha [3]. This proinflammatory state contributes to insulin resistance, leading to dyslipidemia, diabetes, and metabolic syndrome.

Notably, vitamin D deficiency and insufficiency are prevalent among postmenopausal women with metabolic syndrome, affecting 53% and 22% of this population, respectively [18]. Similarly, a study in Gorgan found that 32.26% of postmenopausal women with metabolic syndrome had vitamin D deficiency [17].

The widespread presence of vitamin D receptors (VDR) in cells, including vascular smooth muscle, endothelium, and cardiomyocytes, underscores the association between vitamin D and metabolic syndrome, obesity, diabetes, and cardiovascular disease [2].

Research on the association between vitamin D deficiency and metabolic syndrome in postmenopausal women has yielded conflicting results. While most studies suggest an inverse relationship between vitamin D levels and metabolic syndrome [8, 23, 24], others have found no significant correlation [6,7,16-18,25,26].

Some studies have reported a significant association:

• Huang et al. found a negative correlation between vitamin D levels and metabolic syndrome, with a significant increase in adjusted odds ratio for metabolic syndrome with decreasing vitamin D levels [11].

In contrast, other studies have found no significant differences:

• A 2012 study found no significant differences in serum vitamin D levels among postmenopausal women with or without metabolic syndrome [17].
• Mitra et al. and Alissa et al. reported no significant differences in vitamin D deficiency between postmenopausal women with and without metabolic syndrome [7,16].
• Chon et al. and Mitra et al. found no significant difference in metabolic syndrome prevalence across different categories of vitamin D adequacy [6,7].

Research has yielded mixed results on the association between vitamin D deficiency and metabolic syndrome components in postmenopausal women.

Some studies have found significant associations between vitamin D deficiency and:

All metabolic syndrome components, including increased triglycerides (TGs), cholesterol, body mass index (BMI), blood pressure (BP), fasting plasma glucose, insulin resistance, and lower HDL-C levels [27].

Specific components, such as:

• Elevated TGs [6, 16, 23]
• High fasting plasma glucose [16]
• Increased BP [6, 16, 23]

However, other studies have found no significant associations:

• A 2012 study reported no differences in metabolic syndrome parameters among postmenopausal women with or without vitamin D deficiency [16].
• Mitra et al. found no correlation between metabolic syndrome components and serum vitamin D levels [7].

Components of MS and Vitamin D

Insulin Resistance, Hyperglycemia and Vitamin D

Vitamin D plays a crucial role in maintaining normal insulin function and glucose metabolism. Animal studies suggest that vitamin D has a genomic influence on pancreatic beta cells, regulating insulin synthesis and secretion through vitamin D receptors (VDR) expressed in these cells, adipocytes, and skeletal muscle [2]. Vitamin D deficiency (hypovitaminosis D) impairs the conversion of proinsulin to insulin.

Epidemiological and experimental studies have consistently shown that low levels of 25-hydroxyvitamin D (25(OH)D) are associated with:

• Decreased insulin release
• Increased insulin resistance
• Higher prevalence of type 2 diabetes in older adults [24, 28]

Recent studies have confirmed these findings:

• A 2017 study in West Bengal women found a significant inverse association between plasma 25(OH)D levels and fasting blood glucose (p=0.01) [18].
• The same study reported a negative correlation between fasting blood glucose and serum vitamin D levels (p=0.02) [18].
• A clinical comparative study found that women with adequate vitamin D levels had lower homeostasis model assessment of insulin resistance (HOMA-IR) levels compared to those with hypovitaminosis D [8].
• A study in Han Chinese women reported a negative correlation between serum vitamin D levels and fasting glucose, fasting insulin, and HOMA-IR [11].
• Fondjo et al. found significantly higher fasting glucose, HbA1C, and HOMA-IR levels in postmenopausal women with vitamin D deficiency compared to those without deficiency [29].

Vitamin D's Association with Dyslipidemia

Research suggests a significant inverse relationship between vitamin D levels and dyslipidemia, as well as obesity [1, 16, 27, 30]. Several studies have investigated this association:

• Chon et al. [6] analyzed data from 4364 Korean postmenopausal women and found a statistically significant decrease in metabolic syndrome components with increasing serum vitamin D levels.
• Specifically, they reported a significant association between higher serum vitamin D levels and decreased prevalence of elevated triglycerides (TGs) and low HDL-C (p=0.014 and 0.002, respectively) [6].
• The study also found a decrease in odds ratio trend for the prevalence of increased TGs and reduced HDL-C with increasing tertiles of serum vitamin D levels (p for trends = 0.043 and 0.010, respectively) [6].
• Schmitt et al. [8] reported increased cholesterol and triglycerides in women with vitamin D deficiency (p lessthan 0.05).
• Huang et al. [11] found a negative association between vitamin D levels and TGs, as well as a positive association with HDL-C.
• Branco et al. [31] reported a negative correlation between TGs and vitamin D levels in postmenopausal women with type 2 diabetes.
• Srimani et al. [18] found that median vitamin D levels decreased with increasing triglyceride levels and decreasing HDL cholesterol levels, although the differences were not statistically significant.

Vitamin D and Hypertension: An Exploratory Association

Research has investigated the potential link between vitamin D deficiency (hypovitaminosis D) and hypertension in postmenopausal women:

• A study in West Bengal found an inverse, albeit insignificant, association between serum 25-hydroxyvitamin D (25(OH)D) levels and systolic and diastolic blood pressure [18].
• In contrast, a Korean study reported a statistically significant association between elevated blood pressure and vitamin D levels (p = 0.020) [6].
• The same study found that increasing serum 25(OH)D levels were associated with a decreasing trend in the odds ratio for elevated blood pressure (p for trend = 0.066) [6].
• The mechanism underlying this association may involve the regulation of the renin-angiotensin system, which is suppressed by vitamin D receptor activation. Without sufficient vitamin D, this system may become overactive, leading to hypertension [32].
• Huang et al. [11] reported a negative association between serum 25(OH)D levels and both systolic and diastolic blood pressure.

Vitamin D and Obesity: An Inverse Relationship

Research has consistently shown an inverse association between obesity, waist circumference, and serum vitamin D levels [1, 16, 18, 30]. Specifically:

• Decreasing 25-hydroxyvitamin D (25(OH)D) levels have been linked to increasing waist circumference and prevalence of abdominal obesity in Korean postmenopausal women [6].
• Joshi et al. found a significant association between low serum vitamin D levels and high body mass index (BMI) (p ≤ 0.02), suggesting that vitamin D deficiency is associated with obesity [1].
• The mechanism underlying this association may involve the sequestration of vitamin D by subcutaneous fat, leading to lower circulating levels of vitamin D.
• A study in a rural block of West Bengal found a significant increase in median 25(OH)D levels among subjects with waist circumference lessthan 80 cm compared to those with waist circumference greaterthan 80 cm [18].

Vitamin D Supplementation in Postmenopausal Women

Research on vitamin D supplementation in postmenopausal women is limited. However, available studies suggest that vitamin D supplementation can have beneficial effects on metabolic variables.

A 2019 review article concluded that vitamin D supplementation with cholecalciferol and calcifediol can maintain sufficient vitamin D levels in postmenopausal women, potentially improving metabolic outcomes [33].

A recent study investigated the effects of 1000 IU vitamin D3 supplements on postmenopausal women with vitamin D deficiency. After 9 months, the study found:

• Reduced insulin levels (-13.7%)
• Decreased triglyceride levels (-12.2%)
• Improved insulin resistance (-17.9%)

However, no changes were observed in blood pressure or anthropometric measures. The authors suggested that longer-term supplementation may be necessary to observe effects on these outcomes [2].

In contrast, another study of 305 postmenopausal women found no significant changes in cholesterol, triglycerides, HDL, or insulin levels after daily supplementation with 1000 IU vitamin D [34].

A review article by Bentes et al. [35] analyzed five clinical trials and concluded that vitamin D supplementation alone, at doses below 1000 IU/day, can increase serum vitamin D levels but has no significant impact on physical fitness levels in postmenopausal women with metabolic disorders.

Compliance with Ethical Standards

Conflict of interest the authors declare that they have no conflict of interest.