Hormone replacement therapy

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Editorials

Findings of women's health initiative trial need not alarm users

Observational studies have suggested a major health benefit of postmenopausal hormone replacement therapy, including reductionsin coronary heart disease, osteoporotic fractures, and colorectalcancer. Such studies have also suggested an increased risk forbreast cancer and possibly stroke. Critics have said that thebenefits, but not the risks, may simply reflect a healthy userbias and have demanded randomised trials. The women's health initiativeis a randomised trial of these health outcomes to assess risksand benefits of intervention strategies in a postmenopausal population.The trial has shown harm for cardiovascular diseases, includingcoronary heart disease (the primary outcome) and stroke, althoughit showed benefits for hip fractures and bowel cancer. The relativerisks for invasive breast cancer, coronary heart disease, andstroke were increased, although the absolute risks were very small.The findings may not be the same for types of hormone replacementtherapy other than those used in this trial, or for lower dosesof the regimen that was useda point that is acknowledged by theauthors of thestudy.

One treatment arm of the trial included over 16 000 postmenopausal women who were taking continuous combined oestrogen-progestogenhormone replacement therapy, using conjugated equine oestrogens0.625 mg plus medroxyprogesterone acetate 2.5 mg daily, testedagainst placebo.¹ This primary prevention study was due torun for 8.5 years but was halted at just over 5 years becausethe number of cases of breast cancer had reached a prespecifiedsafety limit. For 10 000 women taking hormone replacement therapyeach year, compared with those not taking it, there would be anadditional eight cases of invasive breast cancer, seven heartattacks, eight strokes, and eight pulmonary embolisms. However,there would also be six fewer bowel cancers and five fewer hipfractures. Overall mortality was not increased withtherapy.

Survival of the human species over two million years implies that female sex hormones by themselves are not dangerous to health.If harm is established, we must therefore examine the types ofsubstitutes that we use and their means of delivery. The smallincrease in the number of patients with breast cancer accordswith previous population studies,² as are the increases invenous thromboembolism and the decreases in fractures and in bowelcancer. Given the biological effects of oestrogen on the cardiovascular system, the lack of benefit on coronary heart disease is surprisingbutthese findings apply only to this particular hormone replacementtherapy regimen, and other coronary heart disease studies of thishormone replacement therapy have not shown benefit.^3-5

Hormone replacement therapy regimens using different oestrogens and progestogens, and different routes of administration,may be similar in their effects on the breast, bowel, and skeleton.But the metabolic effects of different regimens are clearly different,⁶and this is most likely to have an impact on their cardiovasculareffects. Indeed, the women's health initiative trial also has an oestrogen-alone arm for women with hysterectomies, which hasnot been stopped. We need to see these findings to know whetherthe medroxyprogesterone acetate is causing the harm. It is mostunhelpful that this point about different oestrogens and progestogenswas not appreciated by the recent recommendations of the Committeefor Safety of Medicines and the Medicines Control Agency,⁷which were inappropriate with respect to cardiovascular disease.Particularly for coronary heart disease, the dose (and possibly type) of oestrogen and the type of progestogen may be crucial. Similar studies using different types of hormone replacement therapy than the one used in this trial must be carriedout.

Women who are currently taking continuous combined oestrogen-progestogen should not panic, as it is most unlikely to havecaused considerable harm. Certainly the risk of breast canceris not appreciably increased during the first four years, so womenwishing to take this therapy for the short term relief of menopausalsymptoms should be reassured. However, they need to discuss withtheir doctor whether they should shift to a different preparation,which could theoretically have a more beneficial effect on thecardiovascularsystem.

There is no right or wrong hormone replacement therapy to use in the short term, but in the light of the findings of thistrial the use of hormone replacement therapy regimens containingconjugated oestrogens 0.625 mg together with medroxyprogesteroneacetate (at any dose) should be avoided in the long term. Thefindings of this trial may not apply to lower doses of conjugatedequine oestrogens, given with or without other progestogens. Thelong term effects of alternative hormone replacement therapy preparationshave not yet been tested in large randomised trials, and thismust become a research priority.

At present, long term hormone replacement therapy should be given only on an individual basis, depending on the needs andrisk factors of the patient. Long term therapy could still beconsidered for prevention of osteoporosis, used as part of themanagement of women with particular cardiovascular risk factors,and used for better quality of life. We do not yet know the effects,if any, for the prevention of dementia, although preliminary evidenceis encouraging. Women who are already taking long term hormonereplacement therapy should be reviewed and counselled. If theyneed further treatment, consideration should be given to switchingthem to another form of hormone replacement therapy if they aretaking a regimen of conjugated equine oestrogen and medroxyprogesteroneacetate.

For women starting hormone replacement therapy, we continue to recommend that the starting dose of oestrogen is kept low inwomen over the age of 60. For example, this would be 1 mg fororal, or 50 µg for transdermal, oestradiol 17the 0.3 mg doseof conjugated equine oestrogens is not currently available inthe United Kingdom. The risks and benefits of alternatives tohormone replacement therapy (such as tibolone and raloxifene)are still to be determined, but they are unlikely to be the sameas the regimen used in the women's health initiativetrial.

John C Stevenson, reader in metabolic medicine.

j.stevenson@ic.ac.uk, Endocrinology and Metabolic Medicine, Faculty of Medicine, Imperial College, London W2 1NY

Malcolm I Whitehead, consultant gynaecologist.

malcolmwhitehead@mrmenopause.com, Menopause Clinic, King's College Hospital, London SE5 8RX

Footnotes

JCS and MIW have been investigators in various clinical trials of hormone replacement therapy regimens. JCS is an investigatorin the MRC women's hormones intervention secondary prevention(WHISP) trial. MIW is an investigator in the UK national trialof use of hormone replacement therapy in women with early breastcancer. They have attended meetings and lectured on hormone replacementtherapy, sometimes with the support of various pharmaceuticalcompanies.

1.	Writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333.
2.	Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative re-analysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997; 350: 1047-1059[Medline].
3.	Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-613[Medline].
4.	Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000; 343: 522-529[Abstract/Full Text].
5.	Schulman SP, Thiemann DR, Ouyang P, Chandra NC, Schulman DS, Reis SE, et al. Effects of acute hormone therapy on recurrent ischemia in postmenopausal women with unstable angina. J Am Coll Cardiol 2002; 39: 231-237[Medline].
6.	Stevenson JC. Cardiovascular effects of estrogens. J Steroid Biochem Mol Biol 2000; 74: 387-393[Medline].
7.	Medicines Control Agency, Committee on Safety of Medicines. New product information for hormone replacement therapy. Curr Problems Pharmacovigilance 2002; 28: 1-2.

© BMJ 2002