Commentary: hormone replacement therapy and coronary heart disease: four lessons.

In 1991, Stampfer and Colditz,1 reviewing epidemiological studies of the effect of postmenopausal oestrogen on coronary heart disease concluded that: ‘... the bulk of evidence strongly supports a protective effect of estrogens that is unlikely to be explained by confounding factors ...’ Their best estimate of the relative risk of coronary heart disease (CHD) in postmenopausal oestrogen users was calculated using meta-analytical techniques applied to the epidemiological studies they deemed to be of high quality based on their designs—prospective studies with internal controls and angiographic studies. This estimate was 0.50. The CI was narrow 0.43 to 0.56. The Stampfer and Colditz paper was cited widely. It became a shorthand citation for the contention that the ‘epidemiologic evidence showing that hormone replacement therapy prevents coronary heart disease is overwhelming.’ In 1998, the results of the first large randomized, placebocontrolled trial of the effect of combined oestrogen/progestin hormone replacement therapy on coronary events—the Heart Progestin/Estrogen Replacement study (HERS)—reported no beneficial effect of combined therapy on morbidity or mortality from CHD in women with established coronary disease.2 In 2002, the Women’s Health Initiative (WHI) reported that combined oestrogen/progestin hormone replacement therapy did not prevent the development of CHD in women.3 Further follow-up of women in HERS,4 other randomized trials of the effect of oestrogen alone or combined oestrogen/progestin therapy on CHD endpoints or on measures of subclinical atherosclerosis,5–10 and a meta-analysis of small randomized trials of hormone replacement that provided data on cardiovascular endpoints11 all reported no overall benefit of either oestrogen alone or oestrogen plus progestin on any cardiovascular endpoint. In March 2004, the oestrogen only arm of the WHI was terminated early after showing no effect of oestrogen alone in increasing or decreasing the risk of CHD.12 What can epidemiologists learn by rereading Stampfer and Colditz in the harsh light of the experimental studies?