Type of menopause, age of menopause and variations in the risk of incident cardiovascular disease: pooled analysis of individual data from 10 international studies

Abstract

STUDY QUESTION How does the risk of cardiovascular disease (CVD) vary with type and age of menopause? SUMMARY ANSWER Earlier surgical menopause (e.g. <45 years) poses additional increased risk of incident CVD events, compared to women with natural menopause at the same age, and HRT use reduced the risk of CVD in women with early surgical menopause. WHAT IS KNOWN ALREADY Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality, but the extent that this risk of CVD varies by type of menopause and the role of postmenopausal HRT use in reducing this risk is unclear. STUDY DESIGN, SIZE, DURATION Pooled individual-level data of 203 767 postmenopausal women from 10 observational studies that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Postmenopausal women who had reported menopause (type and age of menopause) and information on non-fatal CVD events were included. Type of menopause (natural menopause and surgical menopause) and age at menopause (categorised as <35, 35–39, 40–44, 45–49, 50–54 and ≥55 years) were exposures of interest. Natural menopause was defined as absence of menstruation over a period of 12 months (no hysterectomy and/or oophorectomy) and surgical menopause as removal of both ovaries. The study outcome was the first non-fatal CVD (defined as either incident coronary heart disease (CHD) or stroke) event ascertained from hospital medical records or self-reported. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI for non-fatal CVD events associated with natural menopause and surgical menopause. MAIN RESULTS AND THE ROLE OF CHANCE Compared with natural menopause, surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16–1.28). After the stratified analysis by age at menopause, a graded relationship for incident CVD was observed with lower age at menopause in both types of natural and surgical menopause. There was also a significant interaction between type of menopause and age at menopause (P < 0.001). Compared with natural menopause at 50–54 years, women with surgical menopause before 35 (2.55, 2.22–2.94) and 35–39 years (1.91, 1.71–2.14) had higher risk of CVD than those with natural menopause (1.59, 1.23–2.05 and 1.51, 1.33–1.72, respectively). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CHD than those who were not users of HRT. LIMITATIONS, REASONS FOR CAUTION Self-reported data on type and age of menopause, no information on indication for the surgery (e.g. endometriosis and fibroids) and the exclusion of fatal CVD events may bias our results. WIDER IMPLICATIONS OF THE FINDINGS In clinical practice, women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures and early diagnosis of CVD. Our findings also suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. The findings on CVD lend some support to the position that elective bilateral oophorectomy (surgical menopause) at hysterectomy for benign diseases should be discouraged based on an increased risk of CVD. STUDY FUNDING/COMPETING INTEREST(S) InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). There are no competing interests.

Early and surgical menopause associated with higher Framingham Risk Scores for cardiovascular disease in the Canadian Longitudinal Study on Aging

“…However, this result needs to be interpreted with caution since CLSA does not have information about the age at hysterectomy, and as suggested in the InterLACE study the age of surgical menopause may modify the effect of HT on the FRS. 7 …”

Clinical practice guidelines on menopause: *An executive summary and recommendations: Indian menopause society 2019–2020

“…Androgen replacement may be considered for women with persistent fatigue and loss of libido, in spite of estrogen replacement. Counsel women that HT is not a contraceptive, and erratic ovulation and pregnancy may occur in POI There is no evidence that HT increases risk of breast cancer, CVD, or dementia, over and above that found in menstruating women with a normally timed menopause Women with untreated premature menopause are at increased risk of developing osteoporosis, CVD, dementia, cognitive decline, and Parkinson's and all-cause mortality[ 127 128 129 ] Women receiving chemotherapy or radiotherapy (pelvis) should be cautioned about iatrogenic premature menopause Premenopausal hysterectomy alone may cause early menopause[ 130 131 ] …”

“…Women with untreated premature menopause are at increased risk of developing osteoporosis, CVD, dementia, cognitive decline, and Parkinson's and all-cause mortality[ 127 128 129 ]…”

Incidence and Risk Factors of Cardio-Cerebrovascular Disease in Korean Menopausal Women: A Retrospective Observational Study using the Korean Genome and Epidemiology Study data

“…Our findings align with other large-scale epidemiologic studies of early menopause and cardio-cerebrovascular diseases [12,28], which reported that early menopause had a significantly higher risk of developing cardiovascular disease and stroke than natural menopause. Furthermore, not only the type of menopause but also the time since onset of menopause has been reported as a factor affecting the occurrence of CAD and cardiovascular diseases [8,10,18]. Meta-analysis showed that women with higher age of menopause and shorter periods of time after the onset of menopause had a relatively low risk of CAD [8,18].…”

“…We identified certain sociodemographic, lifestyle, and healthrelated factors as risk factors for cardio-cerebrovascular diseases based on previous studies [9,17,18]. The sociodemographic factors included age, education, and monthly income.…”