That debate was stirred to boiling point in 2002 with publication of the first results from the Women’s Health Initiative (WHI), a randomised placebo-controlled trial of combined HRT (estrogen + progestogen) and estrogen alone. More than 28,000 women took part across a wide age range of 50 to 79 years.
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John Stevenson, speaking
on Sunday at the 'Womans
heart' Symposium said
condemnation of HRT
following the Women's
Health initiative trial was
inappropriate
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Behind the design and aims of the WHI lay the epidemiological fact that CHD-related mortality rates in younger (premenopausal) women are much lower than those in men of the same age. UK figures, for example, show a death rate in 2006 of 72 per 100,000 population in men aged 45-54 years, but only 15 per 100,000 in women of the same age. Although the mortality trend is declining in both sexes (from 253 and 46 per 100,000 respectively in 1968), the figures still suggest some gender-specific protection for women in the younger age groups.
As long ago as the 1950s it was proposed that endogenous ovarian estrogen may well be that elixir which gives women their longevity, and “estrogen replacement therapy” was introduced to make women “feminine forever” after the menopause. Later, a progestogen was added to protect the endometrium in women with an intact uterus.
HRT’s cardioprotectivity seemed confirmed by the large cohort studies of the 1980s. The Nurses’ Health Study, for example, the “grandmother” of women’s health epidemiology, reported in 1985 that, when compared with non-users, the age-adjusted relative risk of coronary disease in those who had ever used hormones was 0.5, and in current users was 0.3. “These data support the hypothesis that the postmenopausal use of estrogen reduces the risk of severe coronary heart disease,” they wrote.
However, publication of the WHI – which was set up to test the hypothesis of HRT’s cardioprotectivity - changed all that. Initial results from the combined HRT arm showed a relative risk of 1.29 for CHD, the equivalent of seven additional cases per 10,000 women over the 5.2 years course of the trial. And then the controversy began, with the WHI investigators warning in a press release that “combined postmenopausal hormones . . . should not be initiated or continued for the primary prevention of CHD”. Governments followed suit with their own hazard warnings, and very soon a worldwide HRT scare was in full flow. While HRT was not withdrawn, the mantra for its prescription became the lowest possible dose for the shortest possible duration. And this, says Dr John Stevenson from the National Heart and Lung Institute in London, who yesterday addressed a Sym posium on “A woman’s heart”, proved a calamity for the menopausal health of countless women, and an inappropriate condemnation of HRT. However, in 2007 a further WHI report - "adding insult to injury," says Stevenson - showed that “women who initiated therapy closer to menopause tended to have reduced coronary heart disease risk".
But despite the apparent U-turn, HRT, says Stevenson, remains “vilified by those prescribers and regulators who accepted the initial WHI results without question.” The 2007 re-evaluation of the WHI data reported a hazard ratio for CHD of 0.76 in women less than 10 years from the onset of menopause - and of 0.93 for those aged 50-59, 0.98 for ages 60-69, and 1.26 for ages 70-79. These results, adds Stevenson, are not that much different from those of the observational studies of the 1980s, but the post-WHI restrictions on HRT remain in place.