Effect of age at menopause and menopause itself on high sensitivity C-reactive protein, pulse wave velocity, and carotid intima-media thickness in a Chinese population

Abstract

Potential associations between menopause, age at menopause, and clinical indicators related to cardiovascular disease (CVD) have not been elucidated. To identify the risk of CVD early and contribute to its prevention and intervention, the present study used relevant biomarkers to evaluate the risk of CVD among pre- and postmenopausal women. An overall population of 816 women (aged 40–60 y) was evaluated as premenopause, natural early menopause, or natural late menopause (ages ≤ 48 and ≥52 y), with ages 49–51 years as reference (natural menopause). High-sensitivity C-reactive protein, carotid intima-media thickness, and brachial-ankle pulse wave velocity were measured. Triglycerides (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDL-C) of the postmenopausal group were each significantly higher than that of the premenopausal. However, the 3 menopausal groups were similar regarding hypertension, diabetes, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. In the logistic regression model, the CRP, brachial-ankle pulse wave velocity, and carotid intima-media thickness levels were similar among the premenopause and early and late menopause groups. These results were unchanged after further adjustment for multiple confounders including age, smoking, drinking, salt intake habits, presence of hypertension, or diabetes mellitus. Menopause itself is a more important risk factor for CVD compared with menopause that begins at early or late age.

1. Introduction

Estrogen, an important female hormone, has anti-inflammatory and vasodilatation functions which before menopause may be protective against cardiovascular disease (CVD).^[1] Natural menopause occurring early (i.e., before the age of 48 years) may lower the lifetime exposure to endogenous estrogen. The loss of ovarian function in early menopause may increase prolonged renin–angiotensin–aldosterone system activity, resulting in inflammation, immune dysfunction, endothelial dysfunction, and subsequent vascular damage.^[2] Changes in endogenous estrogens influence blood lipids,^[3] and theoretically therefore, women experiencing menopause or early-onset menopause could be at higher risk of CVD.

Biomarkers of CVD include high-sensitivity C-reactive protein (hs-CRP), brachial-ankle pulse wave velocity (baPWV), and carotid intima-media thickness (CIMT). Specifically, hs-CRP is a biomarker of inflammation and associated with many health issues such as CVD, insulin resistance, type 2 diabetes mellitus, and all-cause mortality,^[4] while baPWV is a marker of arterial stiffness, a risk predictor of CVD. The CIMT test is also a powerful predictor of CVD in women.^[5]

Yet, an association between menopause, age at menopause, and CVD is controversial. Associations between age at menopause and the relevant clinical indicators of CVD have not been established. The present study assessed the risk of CVD among pre- and postmenopausal women, as reflected by the biomarkers hs-CRP, baPWV, and CIMT.

2. Materials and methods

The ethics committees of Kailuan General Hospital and Beijing Tiantan Hospital approved this study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from each patient in the study.

2.1. Study design and population

This is a cross-sectional study based on data collected from a subset of the Kailuan study, i.e., the subset termed the APAC or Asymptomatic Polyvascular Abnormalities Community study. The larger Kailuan study comprised 101,510 employees and retirees of the coal mining Kailuan Company, located in Tangshan, Hebei, China, in which participants’ self-reports were followed up every 2 years from 2006 through 2014. The APAC was a prospective long-term follow-up observational study of asymptomatic polyvascular abnormalities in adults aged 40 years or more, with 5440 (40.1% women) subjects randomly selected from the Kailuan study in 2010.

From June 2010 to June 2011, 2183 women in the APAC study completed a baseline survey. The data collected included cardiac risk factors: hypertension, diabetes, smoking, and drinking. Hypertension was defined as taking antihypertensive medication currently, or an average of 3 supine measures >140/90 mm Hg over 10 minutes through brachial blood pressure measurement. Diabetes was considered fasting glucose > 6.5 mmol/L, or a history of diabetes medication. Natural menopause was defined as the absence of menstruation for at least 12 months.^[6] The participants were initially categorized as premenopause, or natural menopause according to age: younger than 40, 41–44, 45–48, 49–51, 52–54, or ≥55 years.

2.2. Measurements of CVD risk factors

An hs-CRP >2 mg/L was considered abnormal (quartile 1), by biochemical test. An automated apparatus (BP-203RPE IU, Omron, China) was used to measure baPWV, and the larger baPWV value on either the subject’s left or right side was taken for analysis. A baPWV ≥ 1400 cm/s indicated peripheral atherosclerosis (quartile 1), in accordance with American Heart Association (1993). CIMIT was measured by high-resolution B-mode ultrasound with a 5-to-12 MHz linear array transducer (Philips iU-22 ultrasound system, Philips Medical Systems, Bothell, WA). On the longitudinal image of each carotid artery, CIMT was defined as the distance from the leading edge of the lumen-intima interface to the leading edge of the media-adventitia interface. A CIMT ≥ 1 mm was considered a sign of arterial intimal thickening (quartile 1). Lipids, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol were measured via laboratory examination.

2.3. Statistical analysis

All statistical analyses were conducted using SAS (version 9.4). Baseline characteristics are expressed as mean and standard deviation of continuous variables and percentages of categorical variables. Data was not normally distributed, and chi-squared or Kruskal–Wallis tests were applied to analyze group differences. After adjusting for age and other potential confounders, multivariable logistic regression models were constructed to examine hs-CRP levels, CIMT, and baPWV (in quartiles) of the menopause groups. A P-value < .05 indicated statistical significance and all statistical tests were 2-tailed.

3. Results

A total of 1367 potential subjects were excluded, specifically 762, 193, 148, 80, 163, and 21, respectively, for lacking history of age at menopause; bilateral oophorectomy; hysterectomy; use of oral contraceptive; missing data (hs-CRP, baPWV, or CIMT); and use of hormonal therapy. Finally, 816 subjects were eligible and incorporated into the study (Fig. 1).

Figure 1.

Flow diagram of the participant selection. APAC indicates Asymptomatic Polyvascular Abnormalities Community.

There were 350 subjects in the premenopause group. Subjects who entered menopause at ≤40, 41–44, and 45–48 years of age numbered 4, 27, and 123, respectively. Subjects who entered menopause at 49–51, 52–54, and ≥55 years of age numbered 168, 103, and 41. Due to the small number of subjects in the ≤40, 41–44, and ≥55 year-old age groups, the data was consolidated and the final population was recategorized as premenopausal (n = 350), and early (<48 years; n = 154), reference (49–51 years; n = 168), or late menopause (≥52 years; n = 144).

3.1. Clinical characteristics

The overall study population comprised 816 women aged 40 to 60 years (Table 1). The mean age of the subjects at menopause was 49.20 years. The age of the premenopausal group (48.78 y) was younger than that of the postmenopausal group (60.70 y), and the prevalence of hypertension and diabetes was significantly higher in the postmenopausal (P < .01). The age at menarche was strikingly different between the pre- and postmenopausal groups (P < .01).

Table 1.

Baseline characteristics of the subjects.

	Premenopause	Age at natural menopause
		≤48 y	49–51 y	≥52 y	P-value
Number, n	350	154	168	144
Age y	48.78 ± 4.34	60.56 ± 9.29	60.97 ± 8.75	60.10 ± 7.00	<.01
Menopausal age, y		45.7 ± 2.77	50.10 ± 0.74	53.62 ± 1.61	<.01
Smoking	350	154	168	144	.42
Yes	10	9	7	7
No	340	145	161	137
Drinking	350	154	168	144	.08
Yes	330	149	165	141
No	20	5	3	3
Education	350	154	168	144	<.01
Primary school and below	21	19	21	21
Junior middle school	168	92	94	82
High school and above	161	43	53	41
Physical exercise	350	154	168	144	.26
None	131	66	62	44
Occasionally	183	72	87	76
Often	36	16	19	24
Blood lipids, mmol/L
Total cholesterol	5.49 ± 0.98	5.49 ± 0.99	5.58 ± 0.99	5.61 ± 1.06	<.01
TG	1.46 ± 1.14	1.67 ± 1.05	1.53 ± 1.63	1.94 ± 2.84	.01
HDL	1.42 ± 0.42	1.46 ± 0.42	1.46 ± 0.37	1.45 ± 0.41	.29
LDL	2.71 ± 1.97	2.81 ± 0.81	3.06 ± 1.94	2.89 ± 0.90	.01
Body mass index, kg/m2	24.59 ± 3.20	25.18 ± 3.85	24.59 ± 3.87	25.36 ± 3.62	.08
Hypertension, n	350	154	168	144	<.01
Yes	78	77	88	77
No	272	77	80	67
Diabetes	350	154	168	144	<.01
Yes	22	35	33	18
No	328	119	135	126
Ischemic stroke	350	154	168	144	.29
Yes	2	1	3	Nil
No	348	153	165	144
Hemorrhagic stroke	350	154	168	144
Yes	Nil	Nil	2	Nil
No	350	154	166	144	.05
Age at menarche, y	14.90 ± 1.47	15.49 ± 1.73	15.89 ± 1.77	15.50 ± 1.48	<.01

The TG, HDL-C, and LDL-C of the postmenopausal group were each significantly higher than that of the premenopausal. However, the 3 menopausal groups were similar regarding hypertension, diabetes, TG, HDL-C, and LDL-C.

3.2. Hs-CRP, baPWV, and CIMT levels in study subjects

Each of the hs-CRP, baPWV, and CIMT levels in the premenopausal group were significantly lower than that of the 3 postmenopausal groups (P < .0001, .0001, =.0327, respectively), but there were no obvious differences among the postmenopausal groups (Table 2).

Table 2.

The hs-CRP, baPWV, and CIMT levels by age at natural menopause.

	Premenopause	Age at natural menopause
		≤48	49–51	≥52	P
hs-CRP (mg/L)	1.84 ± 2.76	2.61 ± 2.91*	2.75 ± 3.5846*	2.37 ± 2.27**	<.01
RbaPWV (cm/s)	1319.76 ± 246.49	1699.20 ± 677.04*	1740.03 ± 680.73**	1687.63 ± 656.88*	<.01
CIMT (mm)	0.66 ± 0.09	0.70 ± 0.13*	0.70 ± 0.14*	0.70 ± 0.12*	.03

Compared to premenopausal women.

^*<.01.

^**>.05.

In the logistic regression, the subjects were classified according to hs-CRP, baPWV, and CIMT levels, with the following cutoff points: CRP ≥ 2 mg/L; baPWV ≥ 1400 cm/s; and CIMT ≥ 1.0 mm. After adjusting for age, and taking the menopausal women aged 49–51 years as reference, the hs-CRP, baPWV, and CIMT levels of the premenopause and early and late menopause groups were similar. These results were unchanged after further adjustment for multiple confounders, including smoking, drinking, salt intake habits, presence of hypertension, and diabetes mellitus (Fig. 2).

Figure 2.

Logistic regression of hs-CRP, baPWV, and CIMT levels between different at natural menopause age groups. (1) Adjustment for age, (2) adjustment for multiple confounders including age, smoking, drinking, salt intake habits, presence of hypertension, and diabetes mellitus.

4. Discussion

This study found that biomarkers of CVD risk (hs-CRP, baPWV, and CIMT) were significantly higher in the postmenopausal women compared with the premenopausal, and TC, TG, and LDL-C levels were also significantly higher. This suggests that in postmenopausal women, menopause itself is a biologic marker of CVD.

This is consistent with results from other studies. In a demographic study conducted in the Netherlands, Witteman et al^[7] found that women who experienced natural menopause were at 3-times greater risk of atherosclerosis compared with premenopausal women. Menopause is a risk factor for age-related increase in arterial stiffness.^[8] Another peer study also showed a higher rate of CVD events in postmenopausal women.^[9] Age at menopause is not only a sign of reproductive aging, but also a high-risk indicator of CVD.^[10]

In the present study, there were no significant differences among the postmenopausal groups regarding hs-CRP, baPWV, or CIMT levels. After adjusting for age and other confounding factors (smoking, drinking, salt intake habits, hypertension, and diabetes mellitus), the hs-CRP, baPWV, and CIMT levels of women in the early and late menopause groups (≤48 and ≥52 y) did not differ significantly from that of the reference group (49–51 y). This suggests that there was no association between age at menopause and risk of CVD. This result is similar to that of other studies. The Japan Collaborative Cohort Study reported that early menopause had no significant association with stroke mortality.^[11] Another study of 3304 Chinese women showed that women who experienced menopause at 46 years or younger were no more likely to have CVD than women aged 50 years at menopause.^[12]

By contrast, some studies have obtained opposite results. A previous peer study showed that early menopause (≤45 y) was associated with a higher rate of stroke (OR, 1.69; 95% CI, 1.25–2.30) compared with menopause at ages 45 to 52 years.^[13] Women with premature or early-onset menopause (<40 and 40–44 y) had a significantly higher risk of a nonfatal cardiovascular event before the age of 60 years, compared with women with menopause at 50 to 51 years.^[14] Muka et al^[15] found that among women who experienced early-onset menopause (<45 y), the risk of CVD, cardiovascular mortality, and overall mortality were higher compared with women 45 years or older at menopause. Ley et al^[16] reported that, after multivariable adjustment, women with a reproductive life span of <30 years experienced a 1.32-fold higher rate of CVD compared with women whose reproductive life was at least 42 years. The different outcomes among studies may be due to variations in population ethnicity, study design, or end point indicators.

In addition, an increase of CVD may occur only in the first few years after menopause. The early stage of menopause (i.e., <3 y after onset) is associated with a dynamic hormonal imbalance that may constitute a specific cardiovascular hazard.^[17] A study by Kryczka et al^[18] showed that the transition period, rather than menopause itself, was associated with an increased cardiovascular risk. In the present study, the average age of the postmenopausal population was over 60 years, and most were in the late menopausal period. Thus, the risk factors had presumably stabilized.

Interestingly, a higher risk of CVD may influence the age at menopause rather than the reverse. In premenopausal women, a preemptive CVD event before the age of 35 years doubled the risk of early menopause, while those women with a first CVD event after the age of 35 years experienced a normal menopause around the age of 51 years.^[19]

4.1 . Limitations

This study comprised middle- and low-income women in the northern area of China. Therefore, the observed associations may not generalize to entire populations. Menopausal status was by self-report, which may increase the probability of bias. This was cross-sectional research, and as such it is difficult to draw a definitive conclusion about the true association between CVD and menopause or other risk factors. Furthermore, women who had undergone hysterectomy were not recruited in this research, being too few.

5. Conclusion

Menopause itself is a more important risk factor for CVD compared with menopause that begins at early or late age.

Author contributions

Conceptualization: Ying Chen, Xingquan Zhao.

Data curation: Anxin Wang, Xiaoli Zhang.

Formal analysis: Anxin Wang, Xiaoli Zhang.

Project administration: Xingquan Zhao.

Writing – original draft: Ying Chen, Fengqin Xia.

Writing – review & editing: Xingquan Zhao.