Association of menopausal characteristics and risk of coronary heart disease: a pan-European case–cohort analysis

Dam, Veerle; Schouw, Yvonne T. van der; Onland‐Moret, N. Charlotte; Groenwold, Rolf H.H.; Peters, Sanne A.E.; Burgess, Stephen; Wood, Angela; Chirlaque, María Dolores; Moons, Karel G.M.; Oliver‐Williams, Clare; Schuit, Ewoud; Tikk, Kaja; Weiderpass, Elisabete; Holm, Marianne; Tjønneland, Anne; Kühn, Tilman; Fortner, Renée T.; Trichopoulou, Antonia; Karakatsani, Anna; Vecchia, Carlo La; Ferrari, Pietro; Gunter, Marc J.; Masala, Giovanna; Sieri, Sabina; Tumino, Rosario; Panico, Salvatore; Boer, Jolanda M. A.; Verschuren, W M Monique; Salamanca-Fernández, Elena; Arriola, Larraitz; Moreno‐Iribas, Conchi; Engström, Gunnar; Melander, Olle; Nordendahl, Maria; Wennberg, Patrik; Key, Timothy J.; Colorado‐Yohar, Sandra; Matullo, Giuseppe; Overvad, Kim; Clavel‐Chapelon, Françoise; Boeing, Heiner; Quiŕos, J. Ramón; Angelantonio, Emanuele Di; Langenberg, Claudia; Sweeting, Michael; Riboli, Elio; Wareham, Nicholas J.; Danesh, John; Butterworth, Adam S.

doi:10.1093/ije/dyz016

Cited by 55 publications

(59 citation statements)

References 40 publications

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“…Trial data in younger women taking HRT (50-59 years) suggested no increased risk of cardiovascular disease, stroke or all-cause mortality 55 . In agreement with this we found no evidence to support causal associations for ANM with cardiovascular disease, lipid levels, Alzheimer’s disease, body mass or longevity ( Supplementary Table 23 ), all of which have been reported from non-genetic observational studies 60–66 . Finally, we evaluated putative modifiable determinants of ANM suggested by previously reported observational studies.…”

Section: Resultssupporting

confidence: 79%

Genetic insights into the biological mechanisms governing human ovarian ageing

Ruth¹,

Day²,

Hussain³

et al. 2021

Preprint

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Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

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Section: Resultssupporting

confidence: 79%

Genetic insights into the biological mechanisms governing human ovarian ageing

Ruth¹,

Day²,

Hussain³

et al. 2021

Preprint

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“…Overall, there was some evidence to suggest an association between early menopause and a higher risk of CVD events 5,21–24 and between late menopause and a lower risk of CVD events 5,17,20,21,23 after adjustment for age at menarche (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Duration of estrogen exposure during reproductive years, age at menarche and age at menopause, and risk of cardiovascular disease events, all‐cause and cardiovascular mortality: a systematic review and meta‐analysis

Mishra

Chung

Waller

et al. 2020

BJOG

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Background Little is known about the estrogen exposure measurement and mutual effect of age at menarche and age at menopause in the risk of cardiovascular disease (CVD) events. Objectives To evaluate estrogen exposure measurement and describe mutual effect of age at menarche and age at menopause in the risk of CVD events. Search strategy Systematic review of literature in PubMed, Embase and Web of Science for studies published up to 28 June 2020. Selection criteria Observational studies related to estrogen exposure measurement, including mutual effect of age at menarche and age at menopause and risk of CVD events. Data collection and analysis Synthesis of evidence was conducted by reviewing individual estimates, followed by meta‐analysis. The study received no external funding. Main results A total of 75 studies were included in synthesis of evidence, of which 17 studies were included in meta‐analysis. Reproductive lifespan (age at menopause – age at menarche), endogenous estrogen exposure and total estrogen exposure were used for estrogen exposure measurement. Reproductive lifespan was by far the most commonly used method for estrogen exposure measurement. A shorter reproductive lifespan was associated with a higher risk of CVD events; the pooled relative risk (95% CI) was 1.31 (1.25–1.36) for stroke events. Robust epidemiological studies with measurement of estrogen exposure and associated health risk would strengthen the evidence. Conclusions Reproductive lifespan was the most commonly used method for estrogen exposure measurement in epidemiological studies. A shorter reproductive lifespan was associated with a higher risk of CVD events, particularly stroke. Tweetable abstract A systematic review and meta‐analysis found that women with a shorter reproductive lifespan have a higher risk of stroke events.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Association of menopausal characteristics and risk of coronary heart disease: a pan-European case–cohort analysis

Cited by 55 publications

References 40 publications

Genetic insights into the biological mechanisms governing human ovarian ageing

Genetic insights into the biological mechanisms governing human ovarian ageing

Duration of estrogen exposure during reproductive years, age at menarche and age at menopause, and risk of cardiovascular disease events, all‐cause and cardiovascular mortality: a systematic review and meta‐analysis

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

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