Introduction

Recent findings from several large studies, particularly the Women's Health Initiative (WHI), have shown that women taking estrogen plus progestin have a slightly increased risk of heart attack, stroke, embolism, and breast cancer (see first link below). As a result, combination hormone replacement therapy (HRT) is only recommended for short-term relief of menopause symptoms, or for preventing osteoporosis if other forms of treatment cannot be used.

Postmenopausal women have a greater risk of developing Alzheimer's disease than men, and it's been suggested that this may be due to lower estrogen levels after menopause. There were reports of improved mental performance in women without dementia who were given estrogen. Following this, several studies were done to determine if estrogen alone decreased the risk for dementia in postmenopausal women; the results of these studies have been mixed - some show a protective effect of the hormone, and the others, no effect.

Most of the clinical centers involved in the WHI study chose to take part in the Women's Health Initiative Memory Study (WHIMS), which ran between 1995 and 1999. The WHIMS was designed to evaluate the effect of estrogen- plus- progestin¹, and estrogen alone, on the incidence of dementia and mild cognitive impairment (MCI, which means mild mental decline), compared with placebo. There were roughly 2,250 women, aged 65 or older, in both the combination HRT and placebo groups, whose results form the basis for this report. (The estrogen-alone part of the study is still ongoing in about 3,000 women who have had a hysterectomy and are therefore without risk of uterine cancer.)

The combination part of the WHIMS was stopped when the results of the WHI became known (in July 2002), and it was not considered appropriate to continue using the combination treatment. Using a battery of tests and appropriate specialist physicians, all the women were determined as having "no dementia", "MCI", or "probable dementia".

What the WHIMS results show

Over a 5-year period, a total of 61 cases of probable dementia were diagnosed among the 4,500 in the study; 40 (66%) were in the HRT group, and 21 (34%) in the placebo group.

Most cases of dementia in both treatment groups were classified as probable Alzheimer's disease, with vascular dementia in second place.

There was no significant difference in the risks of development of MCI in the HRT and the placebo groups; 56 women in the HRT group developed MCI (some of whom later developed dementia), compared with 55 in the placebo group.

Different classes (subgroups) of women in the study were analyzed: 3 age sets, 4 levels of education, a previous stroke, diabetes, use of statin drugs, and use of aspirin. The increased risk for dementia remained similar with HRT in all the groupings examined.

Other recent results

In a separate report, the WHIMS investigators described their findings of another analysis, which was done to see if estrogen-plus-progestin protects 'global cognitive function' (mental function) in older postmenopausal women.² To test this, the Modified Mini-Mental State Exam was used. The average scores in each group (HRT and placebo) increased slightly over the 4-plus years of the study (i.e. the mental functioning apparently improved slightly - but this was probably a "practice effect" of repeated testing). The increase was somewhat less in the HRT group, but the difference from the placebo group could have been by chance.

The WHI study has provided additional data on the effect of HRT on stroke.³ The study design was the same as that summarized in our earlier article (first link below). There were 16,500 women assigned to either estrogen-plus-progestin or placebo. After a follow-up of 5½ years, 1.8% of the women in the HRT group and 1.3% of the placebo women had had a stroke. In effect, women taking combination HRT were about 1½ times more likely to have a stroke. This effect was not influenced by all the known factors that affect the occurrence of stroke e.g. smoking, blood pressure, etc.

Comment

The WHIMS shows that, over a 5-year period, the risk for dementia among women taking estrogen-plus-progestin as HRT was twice that of women taking the placebo. Although this may seem alarming, it must be noted that the individual risk is very small - for every 10,000 women treated with combination HRT there would be an increased risk of 23 women with dementia, i.e. two in every 700 women on HRT, as opposed to one in 700 not taking HRT.

Also, the results were obtained in women over 65 - younger ages weren't included in the study. It's feasible that younger women might not show the same effect, although three different age sets in the over 65 study population had similar results.

Taken together, the WHI and the WHIMS findings reinforce the view that the only valid reason for taking estrogen-plus-progestin HRT is the short-term control of moderate-to-severe symptoms of menopause, or the rare need to prevent osteoporosis when an alternative therapy can't be used. It's quite understandable that women will continue to search for alternative treatments with similar effects, but it's now pretty clear that such treatments should not be considered for any possible preventive benefits on cardiovascular or mental conditions.