KeywordsVitamin D · Metabolic syndrome · Postmenopausal women · Insulin resistance · Obesity
Vitamin D: Synthesis, Metabolism and Association
Vitamin D, a fat-soluble vitamin, is also known as sunshine vitamin [1]. It is mainly synthesized endogenously in the skin, under ultraviolet (UV) B exposure, and is further activated by the liver and kidney. Foods like eggs, liver, cod liver oil, mushroom, etc., are also rich sources. The serum levels of 25(OH) D in the range of 30–50 ng/ml are considered to be optimum, whereas levels between 21 and 29 ng/ml indicate vitamin D insufficiency [2]. Vitamin D deficiency has been defined as level less than 20 ng/ml [2]. Various studies have established the association of low vitamin D levels with osteomalacia, secondary hyperparathyroidism, osteoporosis [1]. Vitamin D has also been shown to have an inverse association with diabetes, adiposity, dyslipidemia, hypertension and consequently metabolic syndrome (MS) and cardiovascular disease (CVD) events [3]. It is considered as the commonest medical condition and an important public health menace in the world [4].
Recent studies have reported an increase in vitamin
D deficiency globally, as a pandemic [4]. The observed
increase in vitamin D deficiency is due to changes in lifestyle
like use of sunscreens and reduction in outdoor activities,
socioeconomic transition and urbanization [5]. This
fact is supported by the Korean National health and Nutrition
Examination Survey who reported a high prevalence of
hypovitaminosis D among South Korean postmenopausal
women, although South Korea because of its location at
latitudes 33o–
38o receives adequate UVB light for vitamin
D synthesis [5]. Similarly, Chon et al. [6] found that people
with low physical activity, residing in urban areas, had
significantly less proportion of people in high-serum vitamin
D levels compared to those residing in rural areas, with
more physical activity and working outdoors like farming
and fishing.
Vitamin D Deficiency in Postmenopausal Women
Vitamin D deficiency is more prevalent in postmenopausal women owing to loss of estrogen and decreased capacity of absorption of sunlight and synthesis of 25 hydroxy vitamin D (25(OH) D) by the aged skin [7, 8]. Several studies from Indian and Western world have found the incidence ranging from 50 to 90% [6, 9]. Among the cohort of postmenopausal women residing in Jammu and Kashmir in Northern India, Vitamin D deficiency and insufficiency were found to be in 80% and 14.8%, respectively [1]. Similar results have been revealed in the study conducted in South India in postmenopausal women. In this study, 70% women were found to have Vitamin D deficiency, while Vitamin D insufficiency was revealed in 23% postmenopausal women [10]. Study on Han Chinese postmenopausal women found vitamin D deficiency in 31.2% and 50.6% were vitamin D insufficient [11]. This article highlights the recent evidence published concerning the association of vitamin D deficiency with metabolic syndrome in postmenopausal women.
Metabolic Syndrome in Postmenopausal Women
MS is a set of metabolic abnormalities including dyslipidemia;
triglycerides (TG) ≥ 150 mg/dl, high-density lipoprotein–
cholesterol (HDL-C) ≤ 50 mg/dl, waist circumference
≥ 88 cm, systolic blood pressure (SBP) ≥ 130 mmHg or
diastolic blood pressure (DBP) ≥ 85 mmHg or on antihypertensive
medication, fasting blood glucose ≥ 100 mg/dl or on
treatment for type 2 diabetes [12]. Due to the association of
metabolic syndrome and CVD, Indian epidemiologists and
the WHO have been alerting on the rapidly rising burden of
CVD; estimates predict that by the year 2020, CVD would
be the major cause of death and disability in India [13]. Various
definitions have been suggested for metabolic syndrome
by World Health Organization (WHO), the European Group
for the study of Insulin Resistance (EGIR), American Association
of clinical Endocrinologists (AACE), Harmonized
criteria (H-MS), International Diabetes Federation (IDF)
and Modified National Cholesterol Education Program Adult
Treatment Panel III (NCEP ATP III criteria). Out of these,
the most commonly used is the NCEP III criteria. As per the
NCEP ATP III criteria, the diagnosis of MS is made when
three or more of the above-mentioned cofactors exist [12].
The transition from pre to postmenopause is associated
with development of obesity, dyslipidemia and hyperglycemia
attributed directly to ovarian failure or indirectly resulting
from central fat redistribution with estrogen deficiency
[14]. There is high prevalence of metabolic syndrome in
postmenopausal women, and it increases with age, socioeconomic
status, urbanization and lack of physical activity; no
association of MS was found with education, parity, family
history and age at menopause [15, 16]. Korean study found
that the metabolic syndrome prevalence increased from 10.8
to 43.1% from a group of < 50 years to 65–69 years [6]. The
overall prevalence of metabolic syndrome has been reported
to be in the range from 16.8 to 65.7% and is mainly attributed
to overweight and obesity in postmenopausal women [14, 15]. Among postmenopausal women participants from
Gorgan, the reported prevalence of MS was 31% with maximum
prevalence of dyslipidemia and high-waist circumference
[17]. The study on 616 postmenopausal women from
Han Chinese reported prevalence of metabolic syndrome to
be 31.7% [11]. In a cohort of rural block of West Bengal,
46% postmenopausal women had metabolic syndrome [18].
Studies from Brazil and French population have reported
prevalence to be 22.2% and 45.7%, respectively [19]. Studies
have found that, approximately, 50% of female population
in more than 50 years age are suffering from metabolic
syndrome which is a potential risk factor for cardiovascular
disease, the leading cause of mortality in postmenopausal
women [18, 20, 21]. India has around 43 million menopausal
women, and it is projected that by the year 2026, the
menopausal population would increase to nearly 103 million
[22]. These figures represent the national burden of MS and
the possible risk of CVD and type 2 diabetes in this subset
of women.
Metabolic Syndrome and Vitamin D
Vitamin D deficiency and obesity are proinflammatory
states, have increased C reactive protein, fibrinogen, interleukin-
6, tumor necrosis factor-α, etc. They contribute to
insulin resistance and thereby lead to dyslipidemia, diabetes
and metabolic syndrome [3]. Vitamin D deficiency and
vitamin D insufficiency have been reported in 53% and 22%
postmenopausal women with metabolic syndrome, respectively
[18]. In Gorgan study, Vitamin D deficiency was
found in 32.26% postmenopausal women with metabolic
syndrome [17]. The presence of vitamin D receptors (VDR)
in almost all the cells including vascular smooth muscle,
endothelium and cardiomyocytes has proved its association
with MS, obesity, diabetes and CVD [2].
The association of metabolic syndrome with hypovitaminosis
in postmenopausal women remains controversial.
Most of the studies have reported an inverse association of
hypovitaminosis D with metabolic syndrome [8, 23, 24] but
others have not [6, 7, 16–18, 25, 26]. The study by Huang
et al. reported that with decreasing vitamin D levels, there
was a significant increase in adjusted odds ratio (OR) for
metabolic syndrome (P for trend 0.009). There was negative
association of metabolic syndrome and its components with
serum Vitamin D levels [11]. The study in 2012 showed no
significant differences in serum levels of vitamin D among
postmenopausal women with or without metabolic syndrome
[17]. Mitra et al. [7] did study on 64 postmenopausal
women and found that the proportion of subjects with
vitamin D deficiency did not differ between the two groups
of postmenopausal women, with MS or non-MS. The same
was also reported by Alissa et al. [16]. Chon et al. [6] and Mitra et al. [7] found no significant difference in prevalence
of MS between different categories of vitamin D adequacy.
Several studies have reported association with all components
of MS, i.e., increased TGs, cholesterol, body mass
index (BMI), BP, fasting plasma glucose, insulin resistance,
overweight, obesity and lower HDL-C levels in vitamin D
deficient postmenopausal women [27]. However, few studies
have observed association with only some components
like TG [6, 16, 23], fasting plasma glucose [16] and BP
[6, 16, 23]. Contrary to this, the study in 2012 showed no
significant differences in parameters of metabolic syndrome
among postmenopausal women with or without vitamin D
deficiency [16]. Also, Mitra et al. [7] found no correlation
between components of MS and serum vitamin D levels.
Components of MS and Vitamin D
Insulin Resistance, Hyperglycemia and Vitamin D
The vitamin D plays an important role in preserving the
normal insulin metabolic function. The results of animal
studies suggest that vitamin D has a genomic influence
within islets of Langerhans and regulates insulin synthesis
and secretion from pancreatic beta cells. This regulation is
mediated by VDR expression in pancreatic beta cells secreting
insulin and in target tissues like adipocytes and skeletal
muscle. Hypovitaminosis D hinders conversion of proinsulin
to insulin [2]. Experimental and epidemiological studies
suggest an association of decreased levels of 25(OH)D with
decreased levels of insulin release, increased prevalence of
insulin resistance and type 2 diabetes in the elderly [24, 28].
A study in 2017 on West Bengal women found that plasma
levels of 25(OH)D has statistically significant inverse association
with fasting blood glucose (p = 0.01) [18]. There was
significant negative correlation (p = 0.02) between fasting
blood glucose and serum vitamin D levels [18]. A clinical
comparative study calculated homeostasis model assessment
of insulin resistance (HOMA-IR) and compared its levels in
women with hypovitaminosis and normal vitamin D levels.
Women with adequate Vitamin D levels had lower levels of
HOMA-IR compared to those with hypovitaminosis D [8].
A study on Han Chinese women found negative correlation
between serum vitamin D levels and fasting glucose,
fasting insulin and HOMA-IR [11]. Fondjo et al. reported
statistically significant increase in fasting glucose, HbA1C
and HOMA-IR in postmenopausal vitamin D deficient group
compared to vitamin D non-deficient group [29].
Dyslipidemia and Vitamin D
Several studies suggest an inverse association of vitamin D levels with dyslipidemia and obesity [1, 16, 27, 30]. Chon et al. [6] in his study on 4364 Korean postmenopausal women observed statistically significant decrease in the individual components of metabolic syndrome with increasing serum vitamin D levels. They reported a statistically significant association of decrease in prevalence of elevated TGs and low HDL-C with higher serum levels of 25(OH) D (p = 0.014 and 0.002 respectively) [6]. With an increase in tertiles of serum levels of 25(OH)D, there was decrease in odds ratio trend for the prevalence of increase TGs and reduced HDL-C (p for trends = 0.043 and 0.010, respectively) [6]. Schmitt et al. reported increased cholesterol and triglycerides in women with hypovitaminosis D (p < 0.05) [8]. Huang et al. [11] found negative association of vitamin D levels with TGs and positive association with HDL-C. Branco et al. in 2019 reported negative correlation of TG with vitamin D levels in postmenopausal women with type 2 diabetes [31]. Srimani et al. [18]found that median 25 (OH) D level decreased with increase in triglyceride levels and also median vitamin D level decreased with decrease in HDL cholesterol level, but there was no significant difference.
Hypertension and Vitamin D
The association between hypovitaminosis D and hypertension was studied among postmenopausal women in West Bengal. They found an insignificant inverse association of serum 25(OH)D with systolic and diastolic blood pressure [18]. However, a statistically significant association between elevated blood pressure and vitamin D was observed in Korean study (p = 0.020) [6]. With increasing serum levels of serum 25(OH)D, the OR for prevalence of elevated blood pressure showed a decreasing trend (p for trend = 0.066) [6]. The absence of vitamin D receptors activation leads to decreased suppression of rennin angiotensin system and ultimately leads to hypertension [32]. Huang et al. [11] reported negative association of serum 25(OH)D level with systolic and diastolic blood pressure.
Obesity and Vitamin D
Studies have reported an inverse association between obesity, waist circumference and serum levels of vitamin D [1, 16, 18, 30]. With decrease in 25(OH)D levels, there was increase in waist circumference and prevalence of abdominal obesity among Korean postmenopausal women [6]. Joshi et al. found a statistically significant association of low serum levels of vitamin D with high BMI (p ≤ 0.02). They concluded that vitamin D deficiency is associated with obesity as vitamin D synthesized in the skin is sequestered by the subcutaneous fat leading to low circulating levels of vitamin D [1]. Srimani et al. [18] did study in a rural block of West Bengal and found significant increase in median 25(OH)D level among subjects with waist circumference < 80 cm to > 80 cm.
Vitamin D Supplementation
There are very scarce studies on vitamin D supplementation in postmenopausal women. The review article in 2019 concluded that vitamin D supplementation with cholecalciferol and calcifediol can maintain sufficient vitamin D levels in postmenopausal women. They concluded that maintaining adequate vitamin D levels could improve metabolic variables in postmenopausal women [33]. A recent study gave vitamin D supplements of 1000 IU vitamin D3 to postmenopausal women for 9 months and reported reduction in MS risk profile in women with vitamin D deficiency [2]. After 9 months of treatment, they found reduction in blood insulin levels (− 13.7%), decrease in blood triglyceride levels (− 12.2%) and HOMA-IR (− 17.9%). However, the authors did not observe any change in blood pressure and anthropometric measures. They proposed that to see the effect of vitamin D supplementation on anthropometric measures, there needs to be a long-term vitamin D supplementation. Contrary to this study, another study done on 305 postmenopausal women reported no change in cholesterol, TG, HDL and insulin levels after daily supplementation with 1000 IU vitamin D [34]. Bentes et al. [35] review article included five clinical trials and concluded that vitamin D supplementation alone, with doses of less than 1000 IU/day, can only increase serum vitamin D levels with no significant increase in physical fitness levels of postmenopausal women with metabolic disorders.
Conflict of interest The authors declare that they have no conflict of interest.
