Hormone replacement therapy and cardioprotection: the end of the tale?

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in women after the age of 50 years in most developed countries. Estrogen deficiency plays a key role in causing CVD in women. Apart from the direct effect of ovarian hormones on the vessel wall, cessation of ovarian function and the consequent reduction of sex steroid hormone levels have important metabolic and pathological implications that negatively influence the cardiovascular system. Therefore, the increased incidence of CVD observed in women after menopause should be considered on a multifactorial basis. Data available for the effects of ERT and HRT in the primary prevention of CVD are mainly observational. However, despite limitations related to this kind of study, it must be noted that their results consistently show a reduction in cardiovascular events in hormone users. Meta-analysis of epidemiological studies found that women who had ever used estrogens had a 34% overall reduction in the relative risk of cardiovascular events compared to those who had never used hormones. Most of the early epidemiological studies were conducted using unopposed estrogen replacement therapy. The number of studies evaluating the effects of estrogen-progestin replacement therapy is limited. Recently, the estrogen-progestin arm of the Women's Health Initiative (WHI) study has been stopped because of an increased incidence of breast cancer, and too early on to give any insight into possible cardiovascular effects. Comments on the cardiovascular effects of HRT from the results of the WHI study are therefore not warranted, as the study did not continue for a duration long enough to enable a calculation of cardiovascular end points. The WHI study included only one single type of estrogen-progestin association; whether different estrogen-progestin combinations, more commonly used outside the United States, may have a different effect is still a matter of speculation. A major difference between observational and randomized studies on the effect of ovarian hormones on cardiovascular function is the time of HRT initiation since menopause, which is significantly shorter in observational studies. In conclusion, the average 35-50% risk reduction in CVD with HRT in primary prevention in postmenopausal women is based on nonrandomized observational data.