Association between reproductive span and postmenopausal metabolic syndrome: a cross-sectional study in China

Abstract

Objectives:

The prevalence of metabolic syndrome(MS) among postmenopausal women is increasing, becoming a pressing public health issue. Despite extensive research, the precise etiology of MS in postmenopausal women remains unclear. There is a relative lack of research exploring the association between reproductive span and MS, and the conclusions were inconsistent. The aim of the present study is to investigate the relationship between reproductive span and MS in postmenopausal women.

Methods:

A cross-sectional study was conducted using data from the 2015 follow-up of the China Health and Retirement Longitudinal Study (CHARLS). The data set included household questionnaire information, physical examination data, and blood test results for the respondents. Total sample size: 2,801. A multivariable logistic regression was used to analyze the relationship between reproductive span and MS in postmenopausal women in China.

Results:

As the age at menarche increased, the prevalence of obesity and high triglycerides decreased(P<0.05); as the age at menopause increased, the prevalence of hyperglycemia and hypertension increased(P<0.05); as the reproductive span extended, the prevalence of obesity, hypertension, and hyperglycemia all increased (P<0.05). After adjusting for age, body mass index, education level, smoking, alcohol consumption, number of meals per day, and sleep duration, the reproductive span remained statistically significant between the MS group and the non-MS group. When the reproductive span was treated as a continuous variable, the odds ratio (OR) was 1.019 (95% CI: 1.001-1.038), and the longer the reproductive span, the higher the odds of MS (P=0.042). The OR (95% CI) values for a reproductive span of 32 to 35 years and ≥36 years were 1.305 (95% CI: 1.077-1.581) and 1.381 (95% CI: 1.117-1.708), respectively, both of which were statistically significant (P<0.05).

Conclusions:

The longer the reproductive span of postmenopausal women, the higher the prevalence of MS.

A group of disorders known as metabolic syndrome (MS) include central obesity, abnormal blood glucose levels, blood lipid profiles, and blood pressure. Essentially, MS represents a constellation of cardiovascular disease risk factors that increase the odds of cardiovascular disease and sudden cardiac death, posing a significant threat to the health of postmenopausal women.^25,26 The rising prevalence of MS among postmenopausal women has had a profound impact on their quality of life and has imposed a significant economic burden on families, making it an increasingly important public health issue. Currently, the mechanisms underlying MS in postmenopausal women remain unclear. However, it is suggested that these mechanisms may involve postmenopausal ovarian hormone changes, the influence of inflammatory factors, and gene regulation.¹ With ovarian hypofunction, postmenopausal women experience alterations in sex hormones, leading to endocrine and metabolic disturbances. These changes can also result in structural and functional abnormalities in blood vessels, muscles, and other tissue cells, thereby increasing the odds of MS in women. Current studies have shown that the prevalence of MS in postmenopausal women is significantly higher compared with premenopausal women.^2,13,14 In addition, the prevalence of MS in premenopausal women is lower than that in men of the same age group. However, the prevalence of MS in postmenopausal women rises, reaching or even exceeding that of men in the same age group, indicating that menopause acts as an independent risk factor for MS, irrespective of age.³ Reproductive factors have been reported to be associated with MS and its components. At present, most studies domestically and internationally have focused on the relationship between the age of menarche or menopause and MS. Reproductive span, defined as the difference between the age of menopause and the age of menarche, serves as an indicator of the total exposure time to endogenous estrogen. Our findings suggest that reproductive span is a better indicator of the effect of endogenous estrogen exposure time on metabolic disease than the age of menarche or menopause alone. Previous studies have primarily concentrated on individual components of MS or associated diseases. For example, reproductive span has been shown to be inversely associated with cardiovascular disease^11,12 and sarcopenia.¹⁰ Research on the correlation between reproductive span and MS both domestically and internationally is relatively scarce, and the conclusions are not uniform. A Chinese study involving 1,536 postmenopausal women who had given birth found that a longer reproductive span was significantly associated with an increased incidence of MS.⁸ This finding contrasts with the results of a Korean study, which showed that a longer reproductive span was significantly associated with a reduced prevalence of MS.²⁴ Another study in China explored the relationship between reproductive life span, age of menarche, and MS in postmenopausal women. It showed that as reproductive span increased, so did the prevalence of MS.⁹ The differences between these studies can be attributed to regional biases in the study populations and variations in the confounding factors adjusted for in the analyses. As a result, this study specifically focuses on the correlation between reproductive span and MS. We were careful to make the assumption that there is a correlation between a longer reproductive span and a higher odds of developing MS.

METHODS

Data and study sample

A total of 10,832 postmenopausal women aged 40 to 80 years old were selected from CHARLS’s follow-up data in 2015. Relevant information was collected, and the data were improved in 2015 according to the baseline data in 2011 and the follow-up data in 2013. There were 5,354 cases of women with MS who could not be clearly identified because of missing data, 18 cases of women with a history of malignant tumor, 0 cases of pregnant women, 2,298 cases of women with missing age of menarche and menopause and therefore the reproductive age span could not be calculated, 28 cases of women with menopause age older than their actual age, and 115 cases of women with menopause age of menopause age younger than 40 years. A total of 27 women with abnormal age of menarche (＜8 years old or＞22 years old) were excluded. The data were checked again, and 191 outliers were processed by Z-value. Data items with missing values＞20% were removed. The remaining missing data accounted for the largest proportion of 2.9%. The data were interpolated by multiple interpolation method, and the final data were 2,801 postmenopausal women. The study data were derived from the China Health and Retirement Longitudinal Study (CHARLS).²⁷ CHARLS is an ongoing, nationally representative cohort study designed to longitudinally survey Chinese individuals aged 45 years and older, along with their spouses. The study uses multistage stratified probability-proportional sampling techniques to recruit participants. In total, 17,708 participants from 10,257 households across 150 counties (districts) and 450 villages in 28 provinces of China were included. All participants were assessed using a standardized questionnaire to collect data on sociodemographic and lifestyle factors, as well as health-related information. The initial survey was conducted in 2011 and has been tracked every 2 to 3 years since then. The CHARLS study has been approved by the relevant authorities.

Assessment of reproductive factors and measurement of variables

Age of menarche

The age of menarche was determined by the question, “When did you start menstruating?” in the questionnaire.

Age of menopause

The age of menopause was determined by the question, “When did you start menopause?” in the questionnaire.

Reproductive span

The reproductive span was calculated as the difference between the age of menopause and the age of menarche.

Biochemical index determination

High density lipoprotein-cholesterol (HDL-C), triglycerides (TG), and fasting plasma glucose (FPG): Professional laboratory technicians used enzymatic colorimetric methods to measure the levels of HDL-C, TG, and FPG.

Abnormal blood sugar

Abnormal blood sugar was defined based on the question, “Has a doctor ever told you that you have diabetes or elevated blood sugar?” If the answer was yes or if the fasting plasma glucose (FPG) level was ≥109.8 mg/dL, it was considered abnorma

Abnormal blood pressure

Abnormal blood pressure was defined based on the question, “Has a doctor ever told you that you have high blood pressure?” If the answer was yes or if the systolic blood pressure was ≥130 mmHg (1 mmHg = 0.133kPa) and/or the diastolic blood pressure was ≥85 mmHg, it was considered abnormal.

Other indicators

Waist Circumference. Measured using a soft tape measure around the navel, in centimeters.

Height and Weight. Height: Measured while standing barefoot on the baseplate of a stadiometer, with the back against the vertical backplane of the measuring instrument, arms hanging naturally at the sides, feet together, and toes separate at a 60-degree angle against the vertical backplane. The head was held straight at the level of the eyes and ears. Weight: Measured while standing barefoot.

Body Mass Index (BMI). Calculated using the formula BMI = weight (kg) / height (m²).

Age. Calculated by combining the year of the survey and the date of birth of the respondents.

Education. Categorized into primary school and above, and junior high school and below. The information on smoking, drinking, meal frequency, and sleep duration was collected from the household questionnaire.

Definition of the MetS

MS diagnostic criteria

According to the diagnostic criteria outlined in the Third Report of the Adult Treatment Panel of the National Cholesterol Education Program (2005), individuals meeting three or more of the following criteria are diagnosed with MS.

Central Obesity. Female waist circumference ≥80 cm.

Hyperglycemia. Fasting blood sugar ≥5.6 mmol/L and/or a previous diagnosis of type 2 diabetes with ongoing treatment.

Hypertension. Systolic blood pressure ≥130 mmHg (1 mmHg = 0.133 kPa) and/or diastolic blood pressure ≥85 mmHg and/or a previous diagnosis of hypertension with ongoing treatment.

Elevated Triglycerides. Fasting triglycerides ≥1.70 mmol/L.

Low HDL Cholesterol. Fasting HDL cholesterol <1.29 mmol/L.

Statistical analysis

Data analysis was performed using SPSS version 27.0. Quantitative data were expressed as mean ± SD, and intergroup comparisons were conducted using the t test. Counting data were presented using counts and percentages, and intergroup comparisons were conducted using the χ² test.

Reproductive characteristics and MS

To investigate the relationship between reproductive characteristics (reproductive span, age of menarche, age of menopause) and MS and its components, the participants were classified into three groups according to the tertiles of related variables, respectively.

Reproductive Span. ≤31 years, 32 to 35 years, ≥36 years.

Age of Menarche. ≤14 years, 15 to 16 years, ≥17 years.

Age of Menopause. ≤48 years, 49 to 50 years, ≥51 years.

Multivariate logistic regression analysis was used to assess the impact of reproductive span on MS, adjusting for potential confounding factors. The confounding factors reported to be associated with MS previously included age, BMI, education level, smoking status and alcohol drinking status, p-value <0.05 was considered statistically significant.

RESULTS

Characteristics of study sample of MS

The total sample population consisted of 2,801 postmenopausal middle-aged and elderly women aged between 45 and 80 years. Among them, 1,265 cases (45.2%) had MS, and 1,536 cases (54.8%) did not have MS. A higher proportion of those had an education level of primary school or below, never smoked, and never drank alcohol. Compared with the non-MS group, the age and BMI of women in the MS group were significantly greater, and the difference was statistically significant (P < 0.05). See Table 1. The age of menarche in the MS group was earlier, the age of menopause was later, and the reproductive span (age of menopause – age of menarche) was longer, with statistical significance (P < 0.05). There were no differences in sleep time and daily meal frequency between the two groups.

TABLE 1.

Characteristics of study sample of metabolic syndrome

	MS
Characteristics	No (n=1,536)	Yes (n=1,265)	P
The number of times for eating	3.12±0.37	3.12±0.36	0.836
Sleeping time, h	6.04±2.12	6.10±2.16	0.453
Age, y	63.44±6.93	64.71 ±6.87	<0.001
BMI, kg/m2	22.85±3.53	25.77±3.43	<0.001
Age at menarche, y	16.54±2.23	16.35±2.26	0.021
Age at menopause, y	49.02±3.84	49.47±4.01	0.002
Duration of reproductive years, y	32.48±4.44	33.13±4.63	<0.001
Smoke
Yes	174 (11.33)	129 (10.20)	0.338
No	1,362 (88.67)	1,136 (89.80)
Ever drink alcoholic beverages
I never had a drink	1,320 (85.94)	1,096 (86.64)	0.857
I used to drink less than once a month	134 (8.72)	106 (8.38)
I used to drink more than once a month	82 (5.34)	63 (4.98)
Highest level of education
Elementary school or below	1,242 (80.86)	1,014 (80.16)	0.874
Middle school	200 (13.02)	173 (13.68)
High school or above	94 (6.12)	78 (6.17)

BMI, body mass index; MS, metabolic syndrome.

Data are presented as mean ± SE or n (%) for categorical variables.

P-values <0.05 are shown in bold. P-value refers to the comparison of parameters between the MS group and the non-MS group.

Comparison of prevalence of each component of MS after grouping by reproductive factors (%)

For each independent component of MS, the prevalence of obesity and high TG showed a decreasing trend with an increase in menarche age (P < 0.05). With an increase in menopause age, the prevalence of hyperglycemia and hypertension increased (P < 0.05). As the reproductive span increased, the prevalence of obesity, hypertension, and hyperglycemia also increased (P < 0.05). However, there was no such trend observed for high TG and reproductive span. (See Table 2)

TABLE 2.

Comparison of prevalence of each component of MS after grouping by reproductive factors （%）

	Each component of MS
Characteristics	Elevated waist circumference	Elevated blood glucose	Elevated blood pressure	Elevated triglyceride	Reduced HDL-C
Age at menarche, y
≤14	79.18%	38.85%	49.07%	37.36%	45.54%
15-16	74.78%	37.66%	47.93%	36.68%	44.65%
≥17	73.35%	36.45%	46.92%	31.85%	42.69%
P	0.030	0.601	0.687	0.018	0.449
Age at menopause, y
≤48	73.41%	33.77%	44.59%	33.21%	43.75%
49-50	74.75%	38.27%	47.81%	35.47%	41.41%
≥51	77.09%	40.81%	51.43%	35.08%	46.66%
P	0.182	0.005	0.012	0.526	0.089
Duration of reproductive years, y
≤31	72.05%	32.90%	44.00%	31.42%	43.31%
32-35	75.14%	38.56%	48.30%	36.58%	42.53%
≥36	78.61%	41.55%	51.77%	35.69%	46.59%
P	0.008	<0.001	0.005	0.035	0.211

HDL-C, high-density lipoprotein-cholesterol; MS, metabolic syndrome.

The prevalence is expressed as a percentage, P-values <0.05 are shown in bold.

Association between duration of menstruation and prevalence of MS

According to the three-digit grouping of relevant variables, they were divided into reproductive span (≤31 y, 32-35 y, and ≥36 y), age of menarche (≤14 y, 15-16 y, and ≥17 y), and age of menopause:(≤48 y, 49-50 y, and ≥51 y). After adjusting for the effects of age, BMI, education level, smoking status, alcohol consumption, number of meals per day, and sleep time, the ratios of reproductive span, age of menarche, and age of menopause between MS and non-MS women were compared. The three were analyzed as continuous variables and categorical variables, respectively.

Reproductive span as a continuous variable

People with MS have a longer reproductive span than those without MS. The odds ratio (OR) for reproductive span as a continuous variable is 1.019 (95% CI: 1.001-1.038), indicating that a longer reproductive span is associated with a higher odds of MS (P = 0.042).

Reproductive span as a categorical variable

When analyzing reproductive span as a categorical variable, using a reproductive span of ≤31 years as the reference, the OR (95% CI) for a reproductive span of 32 to 35 years is 1.305 (95% CI: 1.077-1.581). The OR (95% CI) for a reproductive span of ≥36 years is 1.381 (95% CI: 1.117-1.708). Both intervals show statistical significance (P < 0.05), suggesting that a longer reproductive span is associated with a higher odds of developing MS. After adjusting for the effects of age, BMI, education level, smoking status, alcohol consumption, daily meal times, and sleep time. The age of menarche and age of menopause were not statistically significant between the MS group and the non-MS group. (See Table 3)

TABLE 3.

Association between duration of menstruation and prevalence of metabolic syndrome

	Model 1		Model 2
Characteristics	OR (95% CI)	P	OR (95% CI)	P
Age at menarche, y	0.962 (0.930-0.994)	0.022	0.975 (0.940-1.012)	0.187
Age at menopause, y	1.030 (1.011-1.050)	0.002	1.017 (0.996-1.039)	0.111
Duration of reproductive years, y	1.032 (1.015-1.050)	＜0.001	1.019 (1.001-1.038)	0.042
Age at menarche, y
≤14	1		1
15-16	0.913 (0.738-1.130)	0.403	1.031 (0.815-1.304)	0.802
≥17	0.779（0.637-0.952)	0.015	0.852 (0.682-1.065)	0.159
Age at menopause, y
≤48	1		1
49-50	1.112 (0.930-1.331)	0.244	1.059 (0.870-1.289)	0.569
≥51	1.339 (1.117-1.606)	0.002	1.195 (0.979-1.460)	0.080
Duration of reproductive years, y
≤31	1		1
32-35	1.308 (1.098-1.557)	0.003	1.305 (1.077-1.581)	0.006
≥36	1.552 (1.281-1.880)	＜0.001	1.381 (1.117-1.708)	0.003

OR, odds ratio.

Data are shown as ORs (95% CIs). P-values <0.05 are shown in bold.

Model 1：unadjusted

Model 2：adjusted for age, BMI, highest level of education, smoke, ever drink alcoholic beverages, the number of times for eating, sleeping time.

DISCUSSION

Previous studies have primarily focused on the correlation between age at menarche or age at menopause and the components of MS, with fewer studies examining reproductive span, and the conclusions have been inconsistent. Compared with age at menarche or age at menopause, reproductive span better reflects the duration of estrogen exposure in women. The results of this study showed that compared with the non-MS population, people with MS had a longer reproductive span. After adjusting for the effects of age, BMI, education level, smoking status, alcohol consumption, daily meal times, and sleep time: The age of menarche and age of menopause were not statistically significant between the MS group and the non-MS group. This finding is inconsistent with previous research.

Current studies both domestically and internationally indicate that the trend of decreasing age at menarche and the trend of delayed age at menopause coincide with the increasing prevalence of chronic noncommunicable diseases globally.^20,28 Numerous studies have shown that age at menarche is associated with certain chronic diseases and can serve as an important predictive factor for future chronic disease risk.⁵ The age of menarche is a critical marker of female sexual maturity. It has been hypothesized that the association between the age of menarche and the pathogenesis of MS may be fundamentally driven by childhood obesity, as the onset of puberty is triggered by a specific amount and distribution of body fat.¹⁷ Studies have shown that early menarche is associated with high estrogen levels and low sex hormone-binding globulin (SHBG) levels, which persist into adulthood. Low SHBG is a risk factor for the onset of MS and is independent of obesity. The relationship between SHBG level and MS is bidirectional and complex, and the two may cause and effect each other.¹⁸ Similarly, studies have shown that 17-beta estradiol can act on estrogen receptors in pancreatic β-cells to enhance insulin secretion. This insulinotropic effect can be achieved through the mediation of enhanced glucose-stimulated insulin secretion. This may explain why an early age at menarche can independently affect the risk of diabetes in women, even apart from obesity factors.²⁹ Therefore, the age of menarche may influence the development of MS through hormonal changes. In addition, Earlier age of menarche is also linked to genetic factors. Genome-wide association studies have confirmed that the FTO gene is associated with earlier menarche.¹⁵ The FTO gene is a candidate gene for obesity, diabetes, and MS.¹⁶ The results of this study suggested differences in the age of menarche between the MS and non-MS groups. The prevalence of obesity and high TG in the MS group showed a decreasing trend as the age of menarche increased. However, after adjusting for confounding factors in multivariate logistic regression, there was no statistical significance in the age of menarche between the MS and non-MS groups. This finding contrasts with the results of previous studies. Recent studies have shown that an earlier age of menarche increases the odds of cardiovascular disease,⁷ diabetes,⁶ MS^4,5 and other diseases.

Domestic and international studies have reported varying results regarding the correlation between menopause age and MS and its components. The results of this study indicate differences in menopause age between the MS and non-MS groups. As menopause age increases, the prevalence of hyperglycemia and hypertension in the MS components shows an upward trend. However, after adjusting for confounding factors in multivariate logistic regression, there was no statistical significance in the age of menopause between the MS and non-MS groups. This finding contrasts with previous studies. Some previous studies found no correlation between menopause age and MS.^4,19 Other studies have identified a U-shaped relationship between menopause age and MS, with the lowest risk at around 50 years of age. Both early and late menopause ages are associated with a higher odds of developing MS.²⁰ The discrepancies in conclusions among the studies may be related to differences in age structure, inclusion and exclusion criteria, and statistical analysis methods. Regarding the mechanisms linking age at menopause with MS, current research suggests that the levels of estrogen or the duration of estrogen exposure may play a significant role in metabolic disturbances. An earlier age at menopause indicates lower estrogen levels or shorter exposure to estrogen, which can increase abdominal obesity and thus contribute to MS.²⁰ A later age at menopause suggests higher estrogen levels or longer exposure to estrogen. Higher levels of estrogen may inhibit metabolic processes in muscle tissue and insulin-stimulated glucose oxidation.³⁰ In postmenopausal women, studies have also found a positive correlation between estrogen levels and the incidence of insulin resistance and diabetes; this implies that excessively high estrogen levels can increase the odds of obesity, abnormal blood sugar levels, and elevated blood pressure, further promoting the development of MS.³¹ The increased odds of MS caused by early menopause may be due to low estrogen levels and shorter exposure time. The mechanisms by which late menopause increases the odds of MS are still being explored. Studies have found that estrogen levels are positively correlated with insulin resistance,²¹ the incidence of diabetes,²² and hypertension.²³ High estrogen levels are associated with an increased odds of obesity, abnormal blood sugar, and elevated blood pressure, which can further promote the development of MS. In addition, through studies on the association between earlier age of menarche and a higher odds of MS, it has been cautiously inferred that prolonged exposure to estrogen may also be detrimental. In conclusion, we can cautiously infer that reproductive span reflects endogenous estrogen exposure more accurately than the age at menarche or the age at menopause. The longer the reproductive span, the longer the duration of endogenous estrogen exposure, and the higher the prevalence of MS. This inference is consistent with the results of this study.

Strengths and limitations

Compared with previous studies, this study has a larger sample size and includes participants from multiple regions in China, which helps to reduce selection bias accordingly. At the same time, the reproductive span, age of menarche and age of menopause of the participant were included in the multifactor analysis to avoid the collinearity problem caused by the correlation between the three subjects.

This study was a cross-sectional study, and although an association was observed between reproductive span and MS in postmenopausal women, the causal relationship is uncertain, and future longitudinal studies are needed to further verify it. In this study, questionnaire data from the CHARLS database were used, and the data on the age of menarche and menopause were self-reported, which had certain recall bias. Among the confounders adjusted in this study, important factors such as eating habits, physical activity, residence and genetic susceptibility were not considered, which can be used as research points in the future.

CONCLUSIONS

On the basis of the findings, we can conclude that a longer reproductive span is associated with a higher prevalence of MS in postmenopausal women. In the future, further research should include long-term prospective studies with large sample sizes to better understand the relationship between reproductive span and MS and to explore the underlying mechanisms.