Sex hormones and risk of coronary artery disease in women

Letter

We challenge the implication of the article on coronary artery disease in women,¹ based on the Zhao analyses of 2834 postmenopausal women,² that oestradiol is cardioprotective and explains women's lower rates of cardiovascular disease, compared with men, before menopause.

We undertook an analyses of the large-scale UK Biobank, involving 57,204 women with detectable oestradiol concentrations.³ In both pre- and postmenopausal women, in unadjusted analyses, the hazard ratio (HR) (95% confidence interval) per unit higher in log-transformed oestradiol for myocardial infarction was 0.73 (0.58; 0.92), indicating that higher oestradiol was associated with a lower risk of myocardial infarction. However, after adjusting for age, this HR became 0.94 (0.75; 1.17) and the association was no longer apparent. After further adjusting for classical cardiovascular disease risk factors, the HR was 1.05 (0.83; 1.31). Furthermore, results were similar in subgroup analyses defined by age, menopausal status, socioeconomic status, contraceptive pill use and the use of hormone replacement therapy. Zhao and colleagues undertook their analyses in postmenopausal women alone, thus not allowing for the vital comparison between women pre and post menopause.

Indeed, we did observe the rates of myocardial infarction were higher with increased age, and that oestradiol concentrations were lower with increased age, although this was not necessarily a consequence of the menopause. The presumed cardioprotective effects of oestradiol seem to be largely confounded by age and further by other cardiovascular risk factors, and menopause itself does not seem to be a causal factor for coronary heart disease risk.⁴

The article also states that higher concentrations of androgens contribute to a higher risk of cardiovascular disease in women based on findings from Zhao et al.² However, there is conflicting evidence within this domain. Islam and colleagues, in an analysis of the SHOW (Sex Hormones in Older Women) sub-study of the ASPREE trial,⁵ showed that higher quarters of testosterone (Q3 vs Q1 and Q4 vs Q1) were associated with a lower risk of major adverse cardiovascular events. Sievers and colleagues also demonstrated that low baseline testosterone in women 70 years and older was associated with increased cardiovascular disease events.⁶ Studies have also demonstrated no associations with testosterone and cardiovascular disease events⁷ or cardiovascular mortality⁸ in women.

We therefore propose that the associations of oestrogen and testosterone with coronary artery disease in women are not so clear cut in light of the numerous conflicting findings.

Katie Harris
Senior research fellow and Biostatistician¹

Sanne AE Peters
Associate professor in Epidemiology and Global Health^1,2,3

Mark Woodward
Senior professorial fellow,¹ Professor of Medical Statistics,⁴ Chair of Statistics⁵

¹ The George Institute for Global Health, UNSW Sydney
² Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands
³ The George Institute for Global Health, School of Public Health, Imperial College London, UK 
⁴ Faculty of Medicine, UNSW Sydney
⁵ Faculty of Medicine, Imperial College London, UK

 

Authors' response

Natalie Montarello and Wai Ping (Alicia) Chan, the authors of the article, comment:

We agree that menopause as a cause of cardiovascular disease is not clear-cut with multiple studies showing conflicting results. However, it has been shown consistently that women develop cardiovascular disease 7 to 10 years later than men,⁹ and that early age at menopause is associated with increased risk of cardiovascular disease.¹⁰ The increased risk here is clearly not solely attributed to oestrogen depletion, as you have pointed out in the UK Biobank Study on the effect of oestradiol on cardiovascular disease, but a combination of factors including age and the transition period into menopause.

Postmenopausal women have higher total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglyceride concentrations and lower high-density lipoprotein cholesterol (HDL-C) concentrations. LDL-C and apolipoprotein B concentrations, the more ‘atherogenic’ components of the lipid profile, have been shown to be associated with menopause and not age alone.¹¹ Similarly, weight gain and loss of skeletal mass have been attributed to ovarian ageing, rather than chronological ageing alone.¹² Postmenopausal women are also more insulin-resistant, have higher blood pressure and central obesity,¹³ contributing to the development of metabolic syndrome. It is therefore possible that oestrogen depletion worsens the cardiovascular risk-factor profile, which leads indirectly to increased cardiovascular disease during the menopause transition.

Finally, in relation to androgens and cardiovascular disease in women, high and low concentrations have both been associated with cardiovascular disease, and there are even some studies that show no association. The increased events of cardiovascular disease in women with polycystic ovarian syndrome have been attributed to the increased adiposity and, possibly, an interaction with hyperandrogenism,¹⁴ although the mechanism has yet to be elucidated. The role of hyperandrogenism is likely to be due to the negative interaction with cardiovascular risk factors, as above.

We acknowledge and are aware of the complex interaction of sex hormones and cardiovascular disease in women. However, we chose not to discuss these as the paper was aimed at providing an overview of the approach and management of coronary artery disease in women.

Australian Prescriber welcomes Feedback.