Cardiovascular health in the menopause transition: a longitudinal study of up to 3892 women with up to four repeated measures of risk factors

Abstract

Background: Women experience adverse changes in cardiovascular health in mid-life; whether the menopausal transition influences these remains strongly debated. The aim of this study was to examine associations of reproductive age (time since final menstrual period (FMP)) with change in carotid intima media thickness (CIMT) and cardiovascular risk factors and determine the role of chronological and reproductive age.

Methods: We used data from 1702 women from a pregnancy-based UK cohort who had up to four repeat cardiovascular health measures between mean age 51 (SD = 4.0) and 56 (SD = 3.6) years and experienced a natural menopause. Multilevel models were used to assess the relationship between cardiovascular measures and time since FMP (reproductive age), whilst adjusting for the underlying effects of chronological age and confounders (socioeconomic factors, body mass index, smoking, alcohol, parity, age at menarche). In addition, we looked at the relationship between cardiovascular measures by chronological age according to menopausal stages (pre-menopause, peri-menopause and post-menopause) using information from women who had and had not experienced menopause (N = 3892).

Results: There was no strong evidence that reproductive age was associated with CIMT (difference in mean 0.8 μm/year, 95% CI - 0.4, 2.1), whereas there was a strong positive association of chronological age (7.6 μm/year, 95% CI 6.3, 8.9). Consistent with this, we found weaker linear associations of reproductive compared with chronological age for atherosclerotic risk factors, such as with systolic blood pressure (- 0.1 mmHg/year, 95% CI - 0.3, 0.1, and 0.4 mmHg/year, 95% CI 0.2, 0.5, respectively) and non-HDL-cholesterol (0.02 mmol/l/year, 95% CI 0.005, 0.03, and 0.06, 95% CI 0.04, 0.07, respectively). In contrast, associations with fat mass (0.06 kg/m²/year, 95% CI 0.03, 0.10, and 0 kg/m²/year, 95% CI - 0.04, 0.04, respectively) and C-reactive protein (0.01, 95% CI 0.001, 0.02, and 0.01, 95% CI - 0.001, 0.02 natural logged mg/l/year, respectively) were stronger for reproductive compared with chronological age. Both reproductive and chronological age were (weakly) positively associated with glucose (0.002, 95% CI 0.0001, 0.003, and 0.002, 95% CI 0.0001, 0.003 natural logged mmol/l/year, respectively).

Conclusions: Our results suggest that going through the menopausal transition does not further increase women's risk of atherosclerosis (measured by CIMT) beyond effects of ageing. Menopausal transition may, in additional to ageing, modestly increase adiposity and glucose levels and therefore a possible associated diabetes risk.

Keywords: ALSPAC; CIMT; Cardiovascular; Menopausal transition; Menopause; Reproductive age; Time to final menstrual period.

Fig. 1

Participant flow into eligible and analysis groups in ALSPAC women, 2011-2015. LMP, last menstrual period; HRT, hormone replacement therapy. Surgical menopause refers to any woman who had any of the following: hysterectomy, oophorectomy, endometrial ablation, or radio- or chemotherapy related to reproductive organs

Fig. 2

Associations of reproductive and chronological aging with carotid intima media thickness. The left-hand panel shows the main analysis results: mean difference in carotid intima media thickness (CIMT) per year for reproductive and chronological age with mutual adjustment for each age variable and pre-pregnancy body mass index (BMI), age at menarche, parity, maternal education, smoking status and alcohol intake, undertaken in 1627 women with 2561 observations. The right-hand panel shows the additional analyses undertaken to explore possible selection bias in the main analysis. The figure shows the mean difference in CIMT per year in chronological age by menopausal stage (pre, peri or post), undertaken in all eligible women (total N = 3765 women with 5628 observations, with 2238 (2652), 1209 (1254) and 1344 (1722) women (observations) contributing data to pre, peri and post-menopause, respectively). Each trajectory was restricted to the middle 95% of the data, except for the youngest ages in the premenopausal group and the oldest ages in the postmenopausal group. The 5th and 95th percentile of chronological age in pre, peri and post-menopausal stage are 40–52, 47–55, and 49–61, respectively. The p-value for interaction, a test for any difference in the linear association between any of the three menopause stages, is reported in Table S6 (and by age in Table S7)

Fig. 3

Associations of reproductive and chronological ageing with cardiovascular measures including anthropometry, blood pressure, lipids and C-reactive protein and glucose. Figure 3(a) shows the main analysis results: mean difference in cardiovascular measures per year for reproductive and chronological age with mutual adjustment for each age variable and pre-pregnancy body mass index (BMI), age at menarche, parity, maternal education, smoking status, and alcohol intake, undertaken in 1702 women with 4734 observations. The best fitting model between reproductive age and fat mass and non-HDL-c was reproductive age to the power of a half and the addition of a cubic term respectively; however, the linear term is shown here for completeness. The non-linear models are graphically shown in Supplementary Figure S1. The p-value for interaction, a test for any difference in the linear association between any of the three menopause stages, is reported in Table S6 (and by age in Table S7). Figure 3(b) shows the additional analyses undertaken to explore possible selection bias in the main analysis. This shows the mean difference in cardiovascular measures per year in chronological age by menopausal stage (pre, peri or post), undertaken in all eligible women (total N = 3892 women with 9841 observations, with 2313 (4118), 1666 (2388) and 1550 (3335) women (observations) contributing data to pre, peri, and post-menopause, respectively).