1. Introduction
Menopause is a natural process related to the loss of generative function of the ovaries, which, in turn, leads to the onset or acceleration of the development of health problems resulting from estrogen deficiency. Estrogens exhibit multidirectional protective action [
1,
2]. The essence of the problem is, however, more complicated than a simple hormone deficiency. A new research trend is to test the hypothesis that alpha estrogen receptor (ERα) polymorphisms may determine various effects of estrogens on the prevalence of health problems [
3,
4]. ERα polymorphisms affect the function of the estrogen receptor and, thus, the response of tissues to estrogen stimulation [
5,
6]. The dominant expression tissues of ERα are: uterus, pituitary gland, liver, hypothalamus, bones, mammary gland, cervix and vagina, adipose tissue, and skeletal muscles [
7].
The genes encoding ERα have many polymorphic variants (there are about 9000 of them), among which the most important—from the clinical point of view—are two polymorphisms of the single nucleotide polymorphism (SNP) type—Xba I and Pvu II [
8]. The Xba I polymorphism (A→G rs9340799) is located in intron 1 of ERα 351 bp at the 5′ end upstream of exon 2, hence its name IVS1-351 [
7]. It is induced by the A→G transition [
9]. Xba I is located approximately 50 bp from the Pvu II polymorphism site (T→C, rs2234693) known as IVS1-397T→C [
10]. It is caused by the T→C transition in intron 1, 397 bp before the 5′ end of exon 2 [
11].
Some studies have shown that ERα Xba I and Pvu II polymorphisms are associated with the risk of such diseases in menopausal women as osteoporosis, cardiovascular disease, endometriosis, neoplasms, systemic lupus erythematosus, Alzheimer’s disease, dyslipidemia, hypertension, and coronary atherosclerosis [
12,
13,
14,
15]. It is, therefore, difficult to state unequivocally which alleles are responsible for specific illnesses. It is known, however, to be a relationship dependent on ethnicity (race) [
11]. AA Xba I and CC Pvu II genotypes are associated with an increased risk of osteoporosis in the Asian population, while an increased risk of osteoporosis in the Caucasian population is associated with the AA Xba I and TT Pvu II genotypes [
13].
ERα polymorphisms are commonly associated with MetS and obesity in women [
16,
17,
18,
19]. Obesity (BMI > 30 kg/m
2) is an increasingly common, multi-factor health problem. Its prevalence is increasing at an alarming rate across the globe, posing a serious public health problem. Weight gain characterized by an unfavorable redistribution of adipose tissue with an increase in visceral fat and a decrease in what is known as lean body mass can be observed in post-menopausal women. European studies of post-menopausal women showed that 28% of them had their BMI within the normal range, while 57% of them were overweight and 15% were obese [
20]. In comparison to this result, 32% of American women aged 45–54-years-old were obese [
21]. In a Polish study, 17% of women aged 44–66 were obese, 39% were overweight, and 44% had normal body mass; moreover, 29% had abdominal obesity, 19% had increased body fat accumulation, and 21% had high adipose tissue accumulation [
22]. The most previous studies showed an association between ERα polymorphisms and obesity and obesity-related symptoms such as waist circumference and BMI in white women [
23,
24], in African-American women [
17], and in Japanese women [
25]. However, no association between ERα polymorphisms and obesity or obesity parameters was demonstrated in Swedish women [
26] and in the Chinese population [
27].
The results of some studies showed that polymorphisms are also associated with MetS and the components of MetS [
17,
24,
28,
29]. Recognizing MetS requires a diagnosis of at least three of the following criteria: abdominal obesity, high triglycerides (TG), low HDL-cholesterol, high blood pressure, and high fasting blood glucose (FBG) [
30]. MetS is spread widely throughout the population and its prevalence is continually rising, causing serious health problems. According to a cross-sectional population study in Brazil, the prevalence of MetS in menopausal women was 56.9% [
31]. In a study on postmenopausal women in Poland, the prevalences of MetS were 70% and 22% in rural and urban areas, respectively [
32]. ERα polymorphisms were also associated with changes in BMI, waist circumference, and components of MetS [
18,
33,
34,
35]. An analysis of the literature showed that ERα polymorphisms are important for the influence of estrogens on the functioning of the body and may implicate the development of many pathological health problems, including obesity and MetS in perimenopausal women. The study aimed to investigate the association between the ERα polymorphism and the prevalence of MetS and obesity, as well as the coexistence of MetS and obesity, in peri- and post-menopausal Polish women.
3. Discussion
We investigated the association between Xba I and Pvu II ERα polymorphisms and the prevalence of MetS, obesity, and the coexistence of MetS and obesity in the peri- and post-menopausal women in Poland. We observed that ERα polymorphisms may be associated with the coexistence of MetS and obesity. To our knowledge, this is the first study on this topic.
Previous scientific studies showed different distributions of Xba I and Pvu II ERα polymorphisms in different populations. The results of our study are consistent with Mysliwska’s study in which 20% of the white female population are homozygous CC, slightly over 20% are homozygous TT, and most are heterozygous TC [
36]. Similarly, Koch and Shearman found that the TC genotype was the most common, and the CC Pvu II genotype was the least common [
37,
38]. In the study of post-menopausal white women, Lamon-Fava observed that among the women, the TC genotype of the Pvu II polymorphism was the most common, whereas CC was the least common. The same study showed that with regard to the Xba I ERα polymorphism, most women had the AG genotype, and the least women had GG [
39]. Lian reported that the AG Xba I and TC Pvu II genotypes were the most common among Europeans, while Dai found that the AA Xba I and TC Pvu II genotypes were the most common in Asians. Interestingly, both researchers reported that among both the white and Asian populations, the least common genotypes were GG Xba I and CC Pvu II [
40,
41,
42,
43].
Results similar to ours, regarding overweight and obesity in the population of menopausal women, were obtained in other studies [
44,
45]. In the female population in Turkey, it was observed that a significantly reduced risk of obesity in menopausal women was found in carriers of the AG genotype and in carriers of the G allele [
18]. Another study indicated that the G allele was associated with a lower BMI and a lower waist circumference in African-American families [
17], and that the prevalence of obesity was higher in the women with TC and TT than in the women with CC [
46]. Carrying the G allele in the homozygous or heterogenous form (genotypes GG or AG) is associated with a higher BMI and a higher waist circumference [
47]. In the Gomes-Rochette study, the TC genotype was associated with a lower level of body fat and a higher level of lean mass and water in the body, whereas the AG genotype was associated with a higher BMI [
33].
Earlier studies showed that the less common G allele of the Xba I polymorphism was more commonly observed in the patients with MetS than in the control group (AG and GG were found in 55% and 30% of the patients, respectively, and in 55.3% and 30% of the control group, respectively) [
47].
A study by Yang et al. showed that neither the Pvu II nor Xba I polymorphisms are associated with a risk of MetS [
29]. In other studies, the T Pvu II allele was associated with the risk of hyperlipidemia in post-menopausal Chinese women [
48], with increased amounts of small LDL particles [
49], with decreased HDL-cholesterol and increased TG serum concentrations, as well as with increased susceptibility to lipid metabolism disorders [
39]. A recent study conducted on Brazilian post-menopausal women showed no effect of the Pvu II polymorphism on total cholesterol, LDL-cholesterol, HDL-cholesterol, and TG in the patients with dyslipidemia, while the Xba I polymorphism was associated with changes in TG and total lipids, mainly in obese and overweight women [
33]. On the contrary, an Egyptian study found that both Pvu II and Xba I are associated with increased levels of TG, total cholesterol, and LDL-cholesterol [
50]. Carriers of the homozygous or heterozygous G allele (GG or AG genotypes) had higher systolic and diastolic blood pressure, FBG, fasting serum insulin, as well as total cholesterol and LDL-cholesterol [
33,
47].
A study by Toaima et al. showed that the patients with the CC genotype had better glycemic control than the patients with other genotypes [
46]. A meta-analysis conducted in 2018 and consisting of eight studies showed that it was polymorphism Pvu II, but not polymorphism Xba I, that was associated with type 2 diabetes mellitus (T2DM) [
43]. The C allele of the Pvu II polymorphism showed a protective role in T2DM in the Chinese population [
7], while the G allele of the Xba I polymorphism was associated with a reduced risk of T2DM in the Caucasian population [
29].
A recent study found that the presence of a less common G allele favored lower waist circumference and BMI compared to a more common A allele, regardless of age, smoking habits, alcohol consumption, physical activity, diabetes, or menopausal status [
18]. Women with AG Xba I had significantly higher TG and total cholesterol serum concentrations than women with other genotypes of this polymorphism, referring to both obese and older women [
33].
Although the pathogenesis of obesity and MetS are thought to be correlated with many factors, genetics is considered as one of the significant determinants. Studies using the estrogen receptor ERα knockout mice have demonstrated that ERα plays an essential role in estrogen-mediated metabolic regulation [
51]. Therefore, changing estrogen levels during the menopausal transition in women may influence peri and postmenopausal metabolic changes. It has been confirmed that the Pvu II polymorphism may affect the expression levels of mRNA, thus altering the protein expression [
52]. In addition, a possible functional mechanism that is attributed to PvuII and Xba I is that these polymorphisms could change the expression of the ERα gene by alternating the binding of transcription factors and influence the alternative splicing of the ERα gene [
53]. Furthermore, the ERα gene polymorphism may affect the levels of plasma adiponectin in postmenopausal women [
54], which plays a wide-ranging role in metabolic processes, such as food intake and metabolism of carbohydrates and lipids [
55].
The limitation of our study is the number of respondents and the number of polymorphisms because of the high costs of genetic studies. Because this study was based on cross-sectional data, the cause-and-effect relationship should not be assumed. It would be worth conducting further research such as cause–effect and longitudinal studies on the association between the ERα polymorphism and MetS and BMI changes in the same women in different periods of their lives: pre-, peri-, and post-menopause. In the future, a larger sample size, more accurate sample information, and a more rigorous and sensible study design are needed to comprehensively validate an association between the ERα polymorphism and MetS and BMI. It is necessary to define the molecular mechanisms thanks to the ERα gene polymorphism affecting MetS and obesity in the peri- and post-menopausal women group. This requires further research on a larger sample.