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Hormone replacement therapy findings a cause for caution, not alarm.

Observational studies have suggested major health benefits of post-menopausal hormone replacement therapy (HRT), including reductions in coronary heart disease, osteoporotic fractures and colorectal cancer. Such studies have also suggested an increased risk for breast cancer and possibly stroke. Critics have said that the benefits, but not the risks, may simply reflect a healthy user bias and have insisted on randomised trials. The Women's Health Initiative is a randomised trial of these health outcomes to assess risks and benefits for one type of HRT in a post-menopausal US population (conjugated equine oestrogens 0.625 mg plus medroxy-progesterone acetate 2.5 mg daily) compared to a placebo. The trial has shown an increased risk after five years' use for cardiovascular diseases, including coronary heart disease (the primary outcome) and stroke, although it showed benefits for hip fractures and bowel cancer. The relative risks for invasive breast cancer, coronary heart disease and stroke were increased, although the absolute risks were very small. The findings may not be the same for other types of HRT than those used in this trial, or for lower doses of the regimen that was used.

One treatment arm of the trial included over 16,000 post-menopausal women with an intact uterus. This primary prevention study was due to run for 8.5 years but was halted after just 5 years because the number of cases of breast cancer had reached a pre-specified limit. The study showed that for 10,000 women taking this type of HRT each year, compared with those not taking it, there would be an additional 8 cases of invasive breast cancer, 7 heart attacks, 8 strokes and 8 pulmonary embolisms. However, there would also be 6 fewer bowel cancers and 5 fewer hip fractures. Overall mortality was not increased with HRT, although longer follow-up may be necessary to assess the impact of the incident diseases on total mortality.

Given the biological effects of oestrogen on the cardiovascular system, the lack of benefit on coronary heart disease is surprising--but other findings on coronary health disease in relation to this HRT have also not shown benefit. HRT regimens using different oestrogens and progestogens, and different routes of administration, may be similar in their effects on the breast, bowel and bones. But the metabolic effects of different regimens are clearly different, and this is likely to impact on their cardiovascular effects. Indeed the Women's Health Initiative also has an oestrogen-only arm involving women with hysterectomies. This has not been stopped, and the results are expected to be out in 2005. The stopped arm of the trial could not distinguish the effects of oestrogen from those of progestogen. The oestrogen-only findings are therefore necessary to know whether it is the medroxy-progesterone acetate causing the harm. Particularly for coronary heart disease, the dose (and possible type of) oestrogen and type of progestogen may be crucial. Similar studies using different types of HRT from the one used in this trial must be carried out. The effects of progestogen may be important for breast cancer and atherosclerotic diseases, including coronary heart disease and stroke.

The results so far indicate that treatment with this combined HRT regimen for up to 5.2 years is not beneficial overall and that there is early harm for coronary heart disease, continuing harm for stroke and venous thromboembolism, and increasing harm for breast cancer with increasing duration of treatment. The risk-benefit profile is not consistent with the requirements for a viable intervention for the primary prevention of chronic diseases.

These results, however, do not necessarily apply to other regimens, which have not yet been tested in large randomised trials, which must now become a research priority. There is no right or wrong HRT to use in the short term, but in light of the findings of this trial, the use of HRT regimens containing conjugated oestrogen 0.625 mg together with medroxy-progesterone acetate at any dose should be avoided in the longer term. Long-term HRT can still be considered for the prevention of osteoperosis and bone fractures, and for better quality of life (e.g. against hot flushes). This is the first trial with definitive data supporting the ability of post-menopausal hormones to prevent fractures at the hip, vertebrae and other sites. The effects, if any, for the prevention of dementia are still not known, although preliminary evidence is encouraging. For women starting HRT, it continues to be recommended that the starting dose of oestrogen is kept low for women over 60 [1-3].

Another study of a regimen of oestradiol and norethindrone acetate found no evidence of endometrial hyperplasia after five years of continuous combined treatment. These data are reassuring and are in agreement with case-control studies that have documented a reduction in the incidence of endometrial cancer in women taking continuous combined HRT up to five years. Again, these data apply only to the formulation used in this study; others may not have the same outcome [4,5].

[1.] Stevenson CJ. Hormone replacement therapy: findings of women's health initiative trial need not alarm users. BMJ 2002;325:113-14.

[2.] Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in health postmenopausal women: principal results from the women's health initiative randomized controlled trial. JAMA 2002; 288(3):321-33.

[3.] Ramsay S. Trial of HRT to prevent CHD halted early because of increased harm. Lancet 2002;360:146.

[4.] Archer DF. Continuous combined hormone replacement therapy and endometrial hyperplasia. BMJ 2002;325:231-32.

[5.] Wells M, Sturdee DW, Barlow DH et al. Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study. BMJ 2002;325(7358):239.
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Title Annotation:Research
Publication:Reproductive Health Matters
Geographic Code:1USA
Date:Nov 1, 2002
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