There is much confusion and conflicting evidence, mainly from observational studies, on the interaction between oestrogen and/or oestrogen and progesterone on coronary heart disease. Many lines of evidence suggest that oestrogen is cardioprotective. Multiple possible mechanisms have been observed, including improvements in LDL and HDL cholesterol, vasoreactivity, Lp(a), fibrinogen, fasting blood glucose, homocysteine, and nitric oxide. Data from more than 30 epidemiological studies showed a 30 – 50% reduced risk of heart disease in women using oestrogen compared to non-users. On the basis of this evidence, oestrogen has been promoted for the prevention of heart disease. Results were similar in a recent meta-analysis restricted to 18 “good quality” observational studies, but no significant reduction in coronary heart disease incidence was observed in studies that controlled for socioeconomic status.
The first clinical trial evidence that hormone replacement therapy might be harmful came from a 1997 review of adverse events associated with oestrogen therapy in 22 small, short trials; this pooled analysis showed an increased cardiovascular risk in women without heart disease. This study was largely ignored.
In 1998, HERS, the first large clinical trial of hormone replacement therapy with coronary heart disease as the primary outcome, reported a 50% increased risk of coronary events during the first year and no overall reduction in the risk of fatal and non-fatal coronary disease or stroke after 4 years in women assigned to Premarin plus medroxyprogesterone versus placebo. The early harm was not offset by later protection, as shown in a nearly 3-year extension of the HERS trial. An extensive search for subgroups of women who might have been helped or harmed in HERS has not produced any convincing explanation. Women in HERS all had heart disease at baseline and it was suggested that hormone replacement therapy increased the risk of cardiovascular events only in such women.
In 2002, the Women’s Health Initiative trial of more than 27 500 healthy US women (less than 10% of whom had heart disease at baseline) also informed participants of an excess risk of cardiovascular disease. The Women’s Health Initiative Premarin plus medroxyprogesterone acetate (Prempro) part of the trial, with 16 608 women, was stopped early based on an excess global risk largely due to a 29% increased risk of coronary heart disease, a 26% increase of invasive breast cancer, a 41% excess stroke, and a twofold greater risk of pulmonary embolism. The excess of myocardial infarction and venous clotting appeared early in the trial. The investigators calculated that there was only a 10% chance that this cardiovascular harm would reverse itself if the trial were continued longer. Women’s Health Initiative women taking Prempro were told to stop their medication.
The Premarin-only part of the Women’s Health Initiative trial with 10 739 women has not been stopped because the risk – benefit ratio is uncertain at this time (Writing Group for the Women’s Health Initiative Investigators 2002). At this writing, WISDOM, a large clinical trial based in the United Kingdom, of the same hormone regimen used in Women’s Health Initiative, has stopped recruiting new subjects.
Several other smaller trials, some using oral or transdermal oestradiol, also found no protection against coronary atherosclerosis or stroke. Thus, there is no evidence that hormone replacement therapy prevents cardiovascular disease, and it should not be prescribed for this reason.