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.
Keywords: natural menopause, surgical menopause, age at menopause, cardiovascular disease, HRT, hazard ratio, pooled analysis
Introduction
Natural menopause is defined as absence of menstruation over a period of 12 months when not caused by medical treatment or surgery (Nelson, 2008), while surgical menopause refers to the removal of both ovaries (bilateral oophorectomy) prior to natural menopause (Rodriguez and Shoupe, 2015). The most significant physiological change during menopause is the decline of endogenous oestrogen and subsequent cessation of ovarian function (Bachmann, 2001). Oestrogen is cardioprotective and its decline may increase the risk of cardiovascular disease (CVD) among postmenopausal women (Mendelsohn and Karas, 1999).
Heart disease is a leading cause of illness and death for women (Benjamin et al., 2019). Previous studies have examined the links between age at natural menopause or surgical menopause separately on the risk of incident CVD (Muka et al., 2016), but few have compared their effects (Dam et al., 2019). The extent that the risk of CVD varies by the type of menopause remains unclear.
Age at menopause (natural or surgical) is an important covariate in the relationship between type of menopause and incident CVD. Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality (van der Schouw et al., 1996; Muka et al., 2016). In addition, hysterectomy in women aged 50 years or younger is known to increase the risk for CVD later in life, and surgical menopause may further add to the risk of both coronary heart disease (CHD) and stroke (Ingelsson et al., 2011; Yeh et al., 2013; Evans et al., 2016). This suggests that an interaction may exist between the type of menopause and age at menopause on the risk of incident CVD. Also, the association between menopause and risk of CVD might be modified by different HRT status.
The aim of this study is to examine the variation in risk of CVD by type of menopause (natural menopause or surgical menopause) and determine the extent that their effects interact with age at menopause and HRT use. Individual-level data were used from 10 studies that contributed to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium.
Materials and methods
Study participants
InterLACE has pooled individual-level data on reproductive health and chronic diseases from over 500 000 women from 25 observational studies across 10 countries. Most studies were of prospective longitudinal design and collected survey data on key reproductive, sociodemographic, lifestyle factors and disease outcomes. After the studies had joined InterLACE, a harmonisation process was developed to combine individual-level data. A more detailed description of the InterLACE consortium, including the study recruitment and data harmonisation process, has been published previously (Mishra et al., 2013; Mishra et al., 2016). For the present analyses, we aimed to compare the association of incident CVD for women with natural menopause and those with surgical menopause (i.e. bilateral oophorectomy). Fifteen studies in the InterLACE consortium had collected data on CVD outcomes (including CHD and stroke). Among them, 10 studies have also collected information on the number of ovaries removed for those who had oophorectomy/hysterectomy, and the age at natural menopause for those who did not experience surgery at all. Women with hysterectomy but with ovaries conserved were omitted, as their age at menopause could not be identified for certain. To examine the associations between both types of menopause and incident CVD, we excluded women who had experienced CVD events before menopause (n = 1784). Women who had missing data on key covariates were also excluded, including age at last follow-up, race/ethnicity, education level, BMI, smoking status, hypertension status, type 2 diabetes at baseline and HRT status after menopause (n = 13 304). As a result, this study was based on 10 studies with 203 767 postmenopausal women who reported their type of menopause and age at menopause, and information on CVD events. A flow chart of cohorts selection is shown in Supplementary Fig. S1.
Ethics
Each study in the InterLACE consortium has been undertaken with ethical approval from the Institutional Review Board or Human Research Ethics Committee at each participating institution, and all participants provided consent for that study.
Exposure and outcome variables
The main exposures for this study were two types of menopause, surgical menopause and natural menopause (the reference group). Natural menopause was defined as absence of menstruation over a period of 12 months and no experience of hysterectomy and/or oophorectomy prior to this. Surgical menopause was defined as removal of both ovaries. Age at menopause was categorised as <35, 35–39, 40–44, 45–49, 50–54 and ≥55 years.
The study outcome was the first non-fatal CVD event, either self-reported or ascertained from hospital medical records. CVD events were defined as either incident CHD (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). When CVD events were ascertained from hospital records, CHD events were identified using the 10th edition of the International Classification of Diseases (ICD-10) codes I21, I22, I23, I24 and I25, or using the 9th edition (ICD-9) codes 410, 411, 412 and 413. The incidence of stroke was identified using ICD-10 codes I60, I61, I63 and I64, or ICD-9 codes 430, 431, 432, 433 and 434.
Covariates
We included the following factors in the analyses as potential confounders according to evidence from previous studies: (Schoenaker et al., 2014; Zhu et al., 2018a,b) race/ethnicity, years of education, smoking status, BMI, hypertension status, type 2 diabetes, parity and age at menarche. Information collected at baseline was used in the analyses. Furthermore, we adjusted for HRT status in the survey following menopause. Race/ethnicity was grouped into six categories: Caucasian-European, Caucasian-Australian/New Zealand, Caucasian-American/Canadian, Asian, African American/Black and other. Years of education was categorised into ≤10, 11–12 and >12 years. Smoking status was categorised as current, former, and never smokers. BMI was categorised according to the World Health Organization criteria as <18.5 kg/m2, 18.5–24.9 kg/m2, 25–29.9 kg/m2 and ≥30 kg/m2. Hypertension or diabetes status was dichotomised as present or absent based on self-report at baseline. Parity was categorised as 0, 1, 2 and ≥3 live births. Age at menarche (self-reported) was divided into five categories as ≤11, 12, 13, 14 and 15 years or more. HRT status after menopause was defined as user or non-user.
Statistical analyses
Baseline characteristics were presented as mean and SD for continuous variables and as percentages (%) for categorical variables. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CI for the study endpoints associated with natural menopause and surgical menopause. We evaluated the proportional hazards assumption by visual inspection of figures of the Schoenfeld residuals plot and it indicated no violation. Study level variability was included in models as a random effect. As the entry age of women in each study of InterLACE varied, women who experienced menopause at a younger age (e.g. <40 years) will have a longer follow-up time than those who had later menopause. Thus, as a statistical measure to avoid left-truncation bias, the minimum age at surgical menopause (i.e. 28 years) was used as a fixed age for all women to calculate time-to-event. For women with a CVD event, follow-up time was calculated as their age at first CVD event minus 28 years; for women without a CVD event, follow-up time was defined as their age at last follow-up minus 28 years. Women with natural menopause formed the reference category. Because the time between age 28 years and menopause was unexposed person-years, we used time-dependent variable of menopausal status to deal with the issue of immortal time bias. All incident CVD was investigated first, followed by separate analyses for incident CHD and stroke. HRs (95% CI) were estimated using models which included race/ethnicity, education level, BMI, smoking status, hypertension status, type 2 diabetes, parity and HRT status after menopause.
The first analysis was to determine the association between types of menopause (the exposure) and incident CVD using natural menopause as the reference category, then the analyses were stratified by age at menopause using natural menopause at 50–54 years as the reference. In addition, age at menopause was also treated as a continuous variable to estimate the effect of 1-year decrease. HRT status might mediate the association between menopause types and incident CVD, so a further analysis examined the combined effect of types of menopause and HRT status on incident CVD.
We compared the goodness of fit of nested models using values of −2 log L and the Akaike Information Criterion (where a smaller value indicates a better fit). We also calculated χ2 statistics between nested models to assess whether the change was statistically significant after adding a parameter to the original model.
Sensitivity analysis
Five sensitivity analyses were completed. First, only those CVD cases ascertained by hospital registry data from the DNC, WHL and UK Biobank studies were included. Second, because the UK Biobank contributed over 50% of the total CVD cases, an analysis was undertaken that excluded this study. Third, the women’s characteristics in the complete dataset were compared with those in the dataset with missing values, and an analysis was conducted using data from a 10 times multiple imputation to impute missing covariates. Fourth, as age at menarche was also a potential confounder that could affect the association between menopause and incident CVD (Wilson and Mishra, 2016), it was included in a model using data from nine studies (WHITEHALL study did not collect data on age at menarche). Last, family history of CVD was included in the model using data from four studies (DNC, UKWCS, WHITEHALL and UK Biobank) that had relevant information.
Statistical analyses were performed using SAS (version 9.4, SAS Institute Inc, Cary, NC, USA). The proportional hazards regression procedure was used to perform the Cox proportional hazards regression analyses. All statistical tests were based on the two-sided 5% level of significance corresponding to two-sided 95% CI of the HR.
Results
Study characteristics
Of the 203 767 postmenopausal women in the 10 studies, 87.5% experienced natural menopause and 12.5% experienced surgical menopause. There were 13 460 CVD events, including 9966 CHD and 4578 stroke events. The mean (SD) age at menopause was 49.7 (5.0) years, and the mean (SD) age at last follow-up was 61.0 (6.9) years (Table I). Nearly 54% of women were born between 1940 and 1949. The median (interquartile range: Q1–Q3) age at menopause for natural menopause and surgical menopause was 50.0 (48.0–53.0) and 47.0 (42.0–52.0) years, respectively. Women with surgical menopause were more likely to be Caucasian-Australian, with lower education level, obese and non-HRT users (Table II).
Table I.
Characteristics of individual studies in the InterLACE consortium.
| Study | Country | N | Number of CVD event | Baseline survey year | Last survey year used | Age at menopause, mean (SD) | Age at last follow-up, mean (SD) | Women’s year of birth (%) |
||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| <1930 | 1930–1939 | 1940–1949 | 1950–1959 | 1960+ | ||||||||
| Australian Longitudinal Study on Women’s Health (ALSWH) | Australia | 8183 | 957 | 1996 | 2013 | 50.1 (5.3) | 62.7 (4.0) | 74.8 | 25.2 | |||
| Melbourne Collaborative Cohort Study (MCCS) | Australia | 13 387 | 1525 | 1990–1994 | 2003–2006 | 48.8 (5.5) | 67.1 (7.9) | 30.2 | 41.0 | 25.2 | 3.6 | |
| Danish Nurse Cohort Study (DNC) | Denmark | 9719 | 1484 | 1993 | 1999 | 49.0 (4.4) | 69.2 (9.0) | 26.6 | 48.8 | 24.6 | ||
| Women’s Lifestyle and Health Study (WLH) | Sweden | 10 467 | 759 | 1991–1992 | 2003–2004 | 50.1 (4.1) | 55.6 (4.0) | 72.5 | 26.7 | 0.8 | ||
| MRC National Survey of Health and Development (NSHD) | UK | 638 | 63 | 1993 | 2000 | 49.4 (4.3) | 53.9 (0.3) | 100 | ||||
| National Child Development Study (NCDS) | UK | 307 | 13 | 2008 | 2013 | 48.3 (4.5) | 54.7 (1.2) | 100 | ||||
| English Longitudinal Study of Ageing (ELSA) | UK | 1906 | 517 | 2002 | 2010–2011 | 49.2 (5.8) | 70.3 (9.8) | 21.0 | 28.1 | 37.8 | 12.9 | 0.2 |
| UK Women's Cohort Study (UKWCS) | UK | 7923 | 462 | 1995–1998 | 1999–2004 | 48.8 (5.2) | 60.3 (7.5) | 11.4 | 39.2 | 41.5 | 7.9 | 0.1 |
| Whitehall II study (WHITEHALL) | UK | 1732 | 309 | 1985–1988 | 2006 | 49.5 (4.7) | 64 (6.6) | 0.1 | 49.5 | 44.4 | 6.0 | |
| UK Biobank (UK) | UK | 149 505 | 7371 | 2006–2010 | 2013* | 49.8 (5.0) | 60.1 (5.8) | 4.3 | 56.5 | 35.5 | 3.8 | |
| All cohorts combined | 203 767 | 13 460 | 49.7 (5.0) | 61.0 (6.9) | 4.0 | 10.3 | 53.7 | 29.2 | 2.8 | |||
There were 20 000–25 000 people included in the repeated assessment.
CVD, cardiovascular disease; InterLACE, International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events.
Table II.
Baseline characteristics of women by type of menopause (n = 203 767 women).
| Natural menopause, 178 304 (87.5%) | Surgical menopause, 25 463 (12.5%) | |
|---|---|---|
| Age at baseline (years), mean (SD) | 58.1 (7.1) | 57.5 (7.5) |
| Age at menopause (years), median (Q1–Q3) | 50.0 (48.0–53.0) | 47.0 (42.0–52.0) |
| Age in years at last follow-up | ||
| <55 | 28 956 (16.2) | 5178 (20.3) |
| 55–60 | 44 009 (24.7) | 5111 (20.1) |
| ≥60 | 105 329 (59.1) | 15 174 (59.6) |
| Race/ethnicity | ||
| Caucasian-Australian | 12 812 (7.2) | 3061 (12.0) |
| Caucasian-European | 159 478 (89.4) | 21 479 (84.4) |
| Caucasian-American | 541 (0.3) | 61 (0.2) |
| Asian | 2609 (1.5) | 333 (1.3) |
| Black | 1660 (0.9) | 330 (1.3) |
| Others | 1194 (0.7) | 199 (0.8) |
| Educational attainment | ||
| ≤10 years | 86 812 (48.7) | 14 278 (56.1) |
| 11–12 years | 21 119 (11.8) | 2897 (11.4) |
| >12 years | 70 363 (39.5) | 8288 (32.5) |
| BMI (kg/m2) | ||
| Underweight, <18.5 | 1896 (1.1) | 173 (0.7) |
| Normal, 18.5–24.9 | 77 971 (43.7) | 9060 (35.6) |
| Overweight, 25.0–29.9 | 63 358 (35.5) | 9433 (37.0) |
| Obese, ≥30 | 35 069 (19.7) | 6797 (26.7) |
| Smoking status | ||
| Never | 100 693 (56.5) | 14 323 (56.3) |
| Past | 57 858 (32.5) | 8186 (32.1) |
| Current | 19 743 (11.1) | 2954 (11.6) |
| Hypertension status | ||
| Yes | 133 201 (74.7) | 17 454 (68.5) |
| No | 45 093 (25.3) | 8009 (31.5) |
| Type 2 diabetes | ||
| Yes | 170 296 (95.5) | 23 824 (93.6) |
| No | 7998 (4.49) | 1639 (6.4) |
| HRT use | ||
| Yes | 106 094 (59.5) | 6571 (25.8) |
| No | 72 200 (40.5) | 18 892 (74.2) |
| Number of children | ||
| 0 | 28 905 (16.2) | 4579 (18.0) |
| 1 | 22 063 (12.4) | 3374 (13.3) |
| 2 | 76 890 (43.1) | 11 392 (44.7) |
| 3+ | 49 411 (27.7) | 7708 (30.3) |
Q1, first quartiles; Q3, third quartiles.
Types and age of menopause and incident CVD
Compared with natural menopause, the initial analysis (Model 1, Table III) showed that surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16–1.28), with similar results for the incidence of CHD and stroke. After adjusting for age at menopause (Model 2, Table III), the relationship with each outcome was attenuated. Comparison of nested models that included both type of menopause and age at menopause showed that although age at menopause explained much of the association with incident CVD, there was also an interaction between type of menopause and age at menopause (P < 0.001, Supplementary Table SI). It was found that compared with natural menopause at age 50–54 years, surgical menopause before age 35 (2.55, 2.22–2.94) and 35–39 years (1.91, 1.71–2.14) was associated with higher risk of CVD than natural menopause at the same age (1.59, 1.23–2.05 and 1.51, 1.33–1.72, respectively) (Table IV). The HRs (95% CIs) were similar between complete case analyses (Table IV) and multiple imputation-based analyses (Table V). When age at menopause was analysed as a continuous variable, each 1-year decrease was associated with an increased risk of incident CVD of 3% (1.03, 1.02–1.04) in natural menopause group, and 5% (1.05, 1.05–1.06) in surgical menopause group.
Table III.
The hazard ratio (95% CI) between type of menopause and incident CVD.*
| CVD |
CHD |
Stroke |
||||
|---|---|---|---|---|---|---|
| Model 1 | Model 2=Model 1+ age | Model 1 | Model 2=Model 1+ age | Model 1 | Model 2=Model 1+ age | |
| Menopause types | ||||||
| Natural menopause | Reference | Reference | Reference | Reference | Reference | Reference |
| Surgical menopause | 1.22 (1.16, 1.28) | 1.05 (1.00, 1.11) | 1.26 (1.19, 1.33) | 1.08 (1.02, 1.14) | 1.21 (1.11, 1.31) | 1.03 (0.94, 1.13) |
Cox proportional-hazards models were used to estimate hazard ratios (HR) and 95% CI.
Model 1 adjusted: race/ethnicity, education, BMI, smoking status, hypertension status, diabetes status, parity at baseline and postmenopausal hormone therapy status.
Model 2 adjusted: Model 1 + age at menopause.
CVD, cardiovascular disease; CHD, coronary heart disease.
Table IV.
The associations between type of menopause and incident CVD by age at menopause (based on complete dataset).*
| By age at menopause, years | CVD |
CHD |
Stroke |
||||||
|---|---|---|---|---|---|---|---|---|---|
| No. of CVD events | No. of cases per 1000 person-years | Adjusted hazard ratio (95% CI) | No. of CHD events | No. of cases per 1000 person-years | Adjusted hazard ratio (95% CI) | No. of stroke events | No. of cases per 1000 person-years | Adjusted hazard ratio (95% CI) | |
| Natural menopause | |||||||||
| <35 | 59 | 3.2 | 1.59 (1.23, 2.05) | 46 | 2.5 | 1.59 (1.18, 2.13) | 18 | 1.0 | 1.41 (0.87, 2.27) |
| 35-39 | 242 | 3.1 | 1.51 (1.33, 1.72) | 179 | 2.3 | 1.49 (1.28, 1.73) | 97 | 1.2 | 1.77 (1.43, 2.18) |
| 40-44 | 1054 | 2.6 | 1.32 (1.24, 1.41) | 780 | 1.9 | 1.32 (1.23, 1.43) | 359 | 0.9 | 1.31 (1.17, 1.47) |
| 45-59 | 2887 | 2.1 | 1.13 (1.08, 1.18) | 2122 | 1.6 | 1.13 (1.07, 1.20) | 963 | 0.7 | 1.11 (1.03, 1.20) |
| 50-54 | 5424 | 1.9 | Reference | 3953 | 1.3 | Reference | 1847 | 0.6 | Reference |
| ≥55 | 1790 | 1.9 | 0.97 (0.92, 1.02) | 1304 | 1.4 | 0.96 (0.90, 1.03) | 616 | 0.7 | 0.98 (0.89, 1.08) |
| Surgical menopause | |||||||||
| <35 | 204 | 5.4 | 2.55 (2.22, 2.94) | 162 | 4.2 | 2.55 (2.17, 2.99) | 69 | 1.8 | 2.60 (2.03, 3.33) |
| 35-39 | 322 | 3.9 | 1.91 (1.71, 2.14) | 249 | 3.0 | 1.92 (1.69, 2.19) | 108 | 1.3 | 1.91 (1.56, 2.33) |
| 40-44 | 473 | 3.2 | 1.58 (1.44, 1.74) | 373 | 2.5 | 1.63 (1.46, 1.81) | 150 | 1.0 | 1.54 (1.30, 1.82) |
| 45-59 | 558 | 2.4 | 1.20 (1.10, 1.31) | 424 | 1.8 | 1.23 (1.11, 1.36) | 190 | 0.8 | 1.21 (1.04, 1.41) |
| 50-54 | 362 | 1.9 | 0.91 (0.82, 1.01) | 278 | 1.5 | 0.92 (0.81, 1.05) | 125 | 0.7 | 0.93 (0.78, 1.12) |
| ≥55 | 126 | 1.5 | 0.73 (0.61, 0.87) | 96 | 1.1 | 0.76 (0.62, 0.93) | 36 | 0.4 | 0.61 (0.44, 0.85) |
Cox proportional-hazards models were used to estimate HR and 95% CI. All HRs were adjusted for race/ethnicity, education, BMI, smoking status, hypertension status, parity and menopausal hormone therapy status.
Table V.
The associations (adjusted HR, 95% CI) between type, age of menopause and incident CVD after missing covariates were imputed. *
| CVD |
CHD |
Stroke |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| No. of CVD events | No. of cases per 1000 person-years | Adjusted HR (95% CI) | No. of CHD events | No. of cases per 1000 person-years | Adjusted HR (95% CI) | No. of stroke events | No. of cases per 1000 person-years | Adjusted HR (95% CI) | |
| Type of menopause† | |||||||||
| Natural menopause | 12646 | 1.8 | Reference | 9116 | 1.3 | Reference | 4425 | 0.6 | Reference |
| Surgical menopause | 2131 | 2.7 | 1.05 (1.03, 1.06) | 1653 | 2.1 | 1.07 (1.05, 1.09) | 717 | 0.9 | 1.05 (1.02, 1.08) |
| By age at menopause, years | |||||||||
| Natural menopause | |||||||||
| <35 | 59 | 3.2 | 1.54 (1.19, 1.99) | 46 | 2.5 | 1.55 (1.15, 2.07) | 18 | 1.0 | 1.37 (0.85, 2.21) |
| 35-39 | 240 | 3.1 | 1.47 (1.29, 1.68) | 178 | 2.3 | 1.46 (1.26, 1.7) | 96 | 1.2 | 1.69 (1.37, 2.08) |
| 40-44 | 2287 | 1.4 | 1.50 (1.42, 1.58) | 1544 | 0.9 | 1.47 (1.38, 1.56) | 901 | 0.5 | 1.57 (1.43, 1.71) |
| 45-49 | 2877 | 2.1 | 1.12 (1.07, 1.17) | 2116 | 1.6 | 1.12 (1.06, 1.19) | 959 | 0.7 | 1.1 (1.01, 1.19) |
| 50-54 | 5394 | 1.8 | Reference | 3929 | 1.3 | Reference | 1835 | 0.6 | Reference |
| ≥55 | 1789 | 1.9 | 0.98 (0.93, 1.03) | 1303 | 1.4 | 0.97 (0.91, 1.03) | 616 | 0.7 | 1 (0.91, 1.09) |
| Surgical menopause | |||||||||
| <35 | 308 | 5.7 | 2.65 (2.36, 2.97) | 249 | 4.6 | 2.69 (2.36, 3.07) | 111 | 2.0 | 2.83 (2.32, 3.45) |
| 35-39 | 323 | 3.9 | 1.83 (1.63, 2.05) | 250 | 3.0 | 1.84 (1.62, 2.10) | 108 | 1.3 | 1.84 (1.50, 2.24) |
| 40-44 | 476 | 3.2 | 1.52 (1.38, 1.67) | 376 | 2.5 | 1.56 (1.40, 1.74) | 150 | 1.0 | 1.47 (1.24, 1.74) |
| 45-49 | 556 | 2.3 | 1.14 (1.04, 1.25) | 422 | 1.8 | 1.17 (1.05, 1.29) | 189 | 0.8 | 1.16 (1.00, 1.36) |
| 50-54 | 354 | 1.9 | 0.88 (0.79, 0.98) | 270 | 1.5 | 0.88 (0.78, 1.00) | 124 | 0.7 | 0.93 (0.77, 1.11) |
| ≥55 | 114 | 1.5 | 0.72 (0.60, 0.87) | 86 | 1.1 | 0.75 (0.61, 0.93) | 35 | 0.4 | 0.63 (0.45, 0.89) |
Cox proportional-hazards models were used to estimate HR and 95% CI All HRs were adjusted for race/ethnicity, education, BMI, smoking status, hypertension status, diabetes status, parity and menopausal hormone therapy status.
Age at menopause was further adjusted.
Examining the joint effect with HRT status, we found the association between surgical menopause and incident CVD was only evident in non-users of HRT (1.12, 1.06–1.19) (Supplementary Table SII, Fig. 1). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CVD than those who were not users of HRT, while the effects of natural menopause on risk of CVD varied little by HRT status (Supplementary Table SII, Fig. 1).
Figure 1.
The associations between types of menopause and incident CVD by age at menopause and HRT status. Cox proportional-hazards models were used to estimate HRs and 95% CI. All HRs were adjusted for race/ethnicity, education, BMI, smoking status, hypertension status, diabetes status, and parity. CHD, coronary heart disease; CVD, cardiovascular disease; HR, hazard ratio.
Sensitivity analysis
When CVD cases ascertained by hospital records were analysed (Supplementary Table SIII), similar results were produced to those presented in Table V. After excluding the UK Biobank study, associations between surgical menopause and risk of CVD were remained (Supplementary Table SIV). Overall, women’s characteristics in the complete and missing datasets were comparable (Supplementary Table SV). Results remained unchanged when models were adjusted for age at menarche or family history of CVD (data not shown).
Discussion
Compared with natural menopause, surgical menopause was associated with a higher risk of incident CVD. Although this was largely attenuated after adjustment for age at menopause, there was still evidence of an interaction between type of menopause and the age at menopause. Risk of incident CVD increased with earlier age at menopause for both natural and surgical menopause, and surgical menopause was associated with an additional risk compared with women with natural menopause at the same age. For women with early surgical menopause, HRT use reduced but did not eliminate the excess risk of CVD.
Compared with women with average age at natural menopause, our previous research has shown that women with premature and early natural menopause experienced a substantially increased risk of first non-fatal CVD event (either CHD or stroke) before the age of 60 years (Zhu et al., 2019). Our findings here showed that although age at menopause largely attenuated the association of both natural and surgical menopause with incident CVD, there was a graded relationship between earlier age at menopause and incident CVD across both types of menopause. Our findings are consistent with a recent study that found each 1-year decrease in age at menopause was associated with 2% higher risk of incident CHD (Dam et al., 2019).
In previous research, a Nurses’ Health Study (NHS) study showed surgical menopause was significantly associated with incident CHD and stroke compared with women who had hysterectomy with ovarian conservation, especially for women who experienced surgery before age 45 years and those who never used HRT (Colditz et al., 1987; Parker et al., 2009). In contrast, the Women's Health Initiative (WHI) study observed no association, even after stratifying the analysis by age at menopause (<40, 40–49, 50 years and above) (Jacoby et al., 2011). Both of these studies adjusted for age at surgical menopause in the models. Their conflicting findings may be related to different ages at enrolment (mean age was 63 years for WHI versus 51 years for NHS) and different cut-points for age at menopause used for analyses. As both studies used women with hysterectomy and ovaries conserved as the reference group, the comparison with natural menopause was not considered. Using women with natural menopause as the reference and stratifying the analysis by age at menopause, we found the highest risks with incident CVD were in the earlier age at surgical menopause group. Guidelines already suggest that surgical menopause for risk reduction of diseases, such as cancer, should be balanced with the consequences of loss of ovarian hormones (American College of Obstetricians and Gynecologists (ACOG), 2008; The Royal Australian and New Zealand College of Obstetricians and Gynaecologists, 2017). Findings on CVD from our study 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 (Matthews, 2016).
There are several possible reasons why surgical menopause had a stronger association with incident CVD than natural menopause. First, oophorectomy is often part of a hysterectomy, and about 90% of hysterectomies were caused by benign disease, such as fibroids and endometriosis (Hammer et al., 2015). These benign indications might coexist with some metabolic conditions, which may increase the risk of CVD, or they might increase the risk of CVD directly. The association between uterine fibroids and serum lipids is mixed. Some studies found that women with uterine fibroids had unfavourable lipid profile (Melo et al., 2010; Uimari et al., 2016), while more studies found that women with uterine fibroids had a higher high-density lipoprotein-C level, lower low-density lipoprotein-C level and lower total cholesterol level (Sadlonova et al., 2008; Sersam, 2012; Hussam and Zwain, 2016). A recent prospective study found that the presence of fibroids was not associated with subclinical CVD (Laughlin-Tommaso et al., 2019). Thus, the presence of uterine fibroids might not explain the difference with risk of CVD between surgical menopause and natural menopause. Evidence has shown endometriosis was associated with increased risk of CHD (Mu et al., 2016; Tan et al., 2019). The strong association observed between surgical menopause and incident CVD might be confounded by endometriosis. To the best of our knowledge, however, no studies have compared the effect of surgical and natural menopause on the risk of CVD by adjusting for endometriosis. Atsma et al. (2006) compared the effect of premature menopause (<40 years) versus menopause >45 years on risk of CVD in surgical menopausal women and natural menopausal women separately, and they found the effect in surgical menopause group was higher than that in natural menopause group. This might indicate that the effect of early surgical menopause on the risk of CVD was stronger than the effect of early natural menopause. Second, endogenous oestrogen is protective against heart disease (Mendelsohn and Karas, 1999). In a review, Korse et al. concluded that oestrogen level in surgical menopausal women was lower than in women with natural menopause (Korse et al., 2009). Women with surgical menopause experience acute hormonal decline and this may have a severe impact on the vascular system. Last, genetic variations of the oestrogen receptor gene in women with hysterectomy may also be related to risk of CHD (Weel et al., 1999; Shearman et al., 2003).
HRT is recommended for women with earlier menopause to manage menopausal symptoms (Thurston and Joffe, 2011; The North American Menopause Society Hormone Therapy Position Statement Advisory Panel, 2017). The current evidence suggests that HRT is not indicated for primary or secondary prevention of CHD and it increases the risk of stroke (Boardman et al., 2015). Nevertheless, there is a ‘timing’ hypothesis, i.e. women who started HRT less than 10 years after menopause had the most favourable effects (Manson et al., 2013). We found that women who had surgical menopause before age 45 years and took HRT had a lower risk of CHD than non-users of HRT. Our findings support the evidence that for women who experienced early surgical menopause, taking HRT might reduce their risk of CHD. Several studies have shown that HRT was associated with less coronary atherosclerosis and lower mortality, while less favourable to risk of stroke (Boardman et al., 2015; Arnson et al., 2017). The North American Menopause Society has suggested that for women with early surgical menopause or primary ovarian insufficiency, HRT is recommended until at least the median age of menopause (i.e. 50–52 years) (The North American Menopause Society Hormone Therapy Position Statement Advisory Panel, 2017).
Strengths and limitations
The main strength of this study was the use of pooled individual-level data from 10 studies across different geographic regions and populations. This provided a large sample size and sufficient statistical power to quantify the association between natural and surgical menopause, age at menopause and specific types of incident CVD. The participant-level data in InterLACE has enabled the harmonisation of variables using common definitions, coding and cut points, which is not usually possible with meta-analyses of published results. This has also enabled the investigation of associations of surgical menopause compared with those of natural menopause, while taking into account a wide range of covariates.
Several limitations need to be acknowledged. First, self-reported oophorectomy status and age at menopause in this study may lead to some misclassifications of the exposure groups, e.g. some women who reported bilateral oophorectomy (surgical menopause) might be unilateral oophorectomy. However, previous studies found self-reported oophorectomy were in high concordance with the assessment of the surgical record (Colditz et al., 1987; Phipps and Buist, 2009), and misclassification would only make the effect of surgical menopause underestimated. Second, around 38% of postmenopausal CVD events were self-reported, but consistent findings were observed in the sensitivity analysis confined to CVD events ascertained through medical records. Third, we used variables reported at baseline (mid age) or postmenopausal single time of HRT status as covariates rather than treating them as time-varying covariates, which may lead to some bias. Nonetheless, in studies of InterLACE that included women who reported smoking status and BMI levels both before and after menopause (i.e. UK Biobank, NSHD, NCDS), the concordance was approximately 83%. In addition, for around 80% of women using HRT, the treatment would last over 6 years (Karim et al., 2011). Thus, we conclude that the bias caused by time-varying covariates is limited. Fourth, we lacked information on type (oestrogen-only or oestrogen plus progestin) and route (oral or transdermal) of HRT use, thus whether the risk for CVD varied by type and route of HRT use could not be examined in this study. Last, as the outcome of this study was non-fatal CVD events, the exclusion of fatal CVD events may bias our results. However, given that only 7.2% of individuals have a fatal event as their first CVD event (Jorstad et al., 2016) and that earlier menopause has been associated with higher CVD mortality (Muka et al., 2016), the inclusion of fatal events in the analyses would only strengthen the association between earlier age at menopause and incident CVD.
In summary, earlier surgical menopause (e.g. <45 years) poses additionally increased risk of incident CVD events, compared with women with natural menopause at the same age, and this risk increased with lower age at menopause. Although HRT use reduced the risk of CVD in women with early surgical menopause, it did not eliminate the excess risk.
Our findings may have important public health implications. First, prophylactic bilateral oophorectomy at the time of hysterectomy should be undertaken with great caution, especially in women with benign conditions and younger than 50 years. Second, in women with early surgical menopause or primary ovarian insufficiency, taking HRT might reduce their excess risk of CVD. Third, 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. Last, our findings suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. Further research is needed to assess the added value of these female-specific predictors to existing CVD models for women.
Supplementary Material
Acknowledgements
The data on which this research is based were drawn from 10 observational studies. The research included data from the ALSWH, the University of Newcastle, Australia, and the University of Queensland, Australia. We are grateful to the Australian Government Department of Health for funding and to the women who provided the survey data. The MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414 and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. DNC was supported by the National Institute of Public Health, Copenhagen, Denmark. WLH was funded by a grant from the Swedish Research Council (521-2011-2955). NSHD has core funding from the UK Medical Research Council (MC UU 12019/1). NCDS is funded by the Economic and Social Research Council. ELSA is funded by the National Institute on Aging (2RO1AG7644 and 2RO1AG017644-01A1) and a consortium of UK government departments. UKWCS was funded by the World Cancer Research Fund. The Whitehall II study has been supported by grants from the Medical Research Council (K013351) and British Heart Foundation (RG/16/11/32334). This research has been conducted using the UK Biobank resource under application 26629.
All studies would like to thank the participants for volunteering their time to be involved in the respective studies. The findings and views in this article are not necessarily those of the original studies or their respective funding agencies.
Authors’ roles
DZ conducted the literature review, statistical analyses and drafted the manuscript. HFC and NP harmonised the data and contributed to the interpretation of the results. AJD contributed to the statistical analyses and interpretation of the results. EJB, DCG, DK, RH, JEC, GGG, FB, PD, MKS, SS and EW provided study data. GDM conceived the study design and contributed to interpretation of the results. All authors contributed to critical revision of the manuscript.
Funding
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). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Conflict of interest
The authors have declared that no competing interests exist.
Disclaimer
Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization.
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