Hormone replacement use and cardiovascular function and structure in postmenopausal women

The incidence of cardiovascular disease (CVD) in women increases substantially following the menopause, making CVD the leading specific cause of death in postmenopausal women. As the menopause is characterized by a lack of estrogen, the increased CVD risk was initially attributed to this phenomenon. Synthetic estrogen was first used in the 1930s for the relief of menopausal symptoms, and since then, hormone replacement therapy (HRT) grew in popularity due to observational studies that suggested potential benefits in reducing the incidence of CVD, osteoporotic fractures and colorectal cancer (1–3). However, these studies also suggested an increased incidence of endometrial cancer, breast cancer, stroke and venous thromboembolism – but this was perceived to be outweighed by the presumed benefit of CVD prevention. However, all this was soon to change. In 1998, the Heart and Estrogen/progestin Replacement Study (HERS) (4,5) showed that women with established coronary heart disease who were assigned to HRT had rates of recurrent coronary events similar to those in the placebo group. The Women’s Health Initiative study (WHI) published in 2002 (6,7), found that the rate of coronary heart disease was higher among women assigned to combination HRT than among those assigned to placebo. Thus, perhaps the bubble has burst for HRT and CVD prevention. Current CVD prevention guidelines do not even recommend HRT for primary (or secondary) prevention of CVD in postmenopausal women. However, many questions were raised after publication of HERS and WHI. For example, women with severe menopausal symptoms were dissuaded from enrolling in the study. The participants had a higher average age than those in other studies. Would the results be different had the form of administration been different? When compared to observational studies, why was there a divergence in CHD results but a concordance with the other findings? Perhaps, the route of administration and formulation could have shown a different outcome (8). Rather than answering the question of the usefulness of HRT in postmenopausal women, these trials have thrown open the doors for more debate. The so-called ‘‘cardioprotective effects’’ of HRT were based on the assumption that the longer life expectancy in women and the natural protection against CVD was due to cyclical endogenous ovarian hormonal production before menopause. Indeed, after menopause, the risk of CVD in women increases substantially (9). HRT has been shown to have a range of potentially cardioprotective effects by altering the lipid profile, vascular reactivity, hemodynamic and fibrinolytic variables (8,10). Estrogens also preserve low-density lipoproteins (LDLs) from oxidation and protect cells against cytotoxic effects of oxidized LDL, as well as raise high-density lipoprotein (HDL)-cholesterol levels. Diabetes and dyslipidemia are also deemed to be more prevalent in post-menopausal than premenopausal women (11).