Primary Prevention of Cardiovascular Disease With HRT

Kate Maclaran; John C Stevenson


Women's Health. 2012;8(1):63-74. 

In This Article

Abstract and Introduction


Prevention of cardiovascular disease has increasingly important health implications as our population ages. Menopause is associated with the development of cardiovascular risk factors and there are many plausible biological mechanisms through which estrogen may confer cardiovascular protection. Despite a wealth of observational data to support the use of estrogen, large randomized controlled trials failed to demonstrate a benefit. It is now becoming clearer that the beneficial cardiovascular effects of estrogen are greatest in younger women and those closest to menopause. This has led to the development of the timing hypothesis. Use of age-appropriate estrogen doses is crucial to maximize cardiovascular benefits while minimizing risk of adverse effects such as venous thromboembolism and stroke.


Cardiovascular diseases (CVD), comprising coronary heart disease (CHD), stroke and venous thromboembolism (VTE), are the leading cause of mortality in women,[201] responsible for almost a third of female deaths in the UK.[202] Marked gender differences exist in the incidence of CVD with women tending to develop CVD around 10 years later than men.[1,2] It has long been suspected that estrogen may confer protection against CVD, as the premenopausal hormonal milieu is associated with low cardiovascular risk and early studies demonstrated that the incidence of CVD increases sharply after the menopause.[1] Furthermore, menopause is associated with a number of adverse changes to classical cardiovascular risk factors, and women experiencing premature loss of ovarian function have an increased risk of ischemic heart disease[3,4] and possibly stroke.[5] However, the relationship between age, menopause and cardiovascular risk is complex, with recent studies showing no apparent acceleration of heart disease mortality at menopause.[6]

The theory that HRT may be cardioprotective was well supported by observational studies and early randomized controlled trials (RCTs); however, great controversy arose following publication of the Women's Health Initiative (WHI) data.[7] Increases in CVD and breast cancer were reported along with recommendations that HRT should only be used at the lowest dose for the shortest possible duration,[203] and due to the ensuing media frenzy, large numbers of women discontinued their HRT. These studies stimulated much discussion and debate, and now, almost a decade on, our understanding of the risks and benefits of HRT has much improved.[8] Despite initial reports of excess cardiovascular harm with HRT, subsequent analyses have shown that any increased risk is largely confined to older women or those furthest from menopause.[9,10] The differing effects of estrogen on cardiovascular risk, depending on age or time since menopause, has become known as the 'timing hypothesis'.

In this article, we aim to provide an up-to-date review of the most relevant literature on CVD and HRT, to enable the reader to understand how our knowledge has progressed in the wake of the WHI.


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