Bntuk Medical Bullttm (1992) Vol 48, No 2, pp. 469-471 © The Briluh Council 1992

Comments from the Editor Kay-Tee Khaw University of Cambridge School of Clinical Medicine

Hormone replacement therapy has been available for over forty years; however, the indications for use have gradually widened over this time from treatment of women with premature menopause, and relief of clinical symptoms associated with the menopause such as hot flushes, to prophylaxis against osteoporosis and possibly, cardiovascular disease. This has largely been because early observational studies on women taking oestrogen therapy found striking associations with several conditions including endometrial cancer, fracture and cardiovascular disease. These findings generated more detailed clinical and biological investigations into possible mechanisms. The major potential adverse effects are reproductive cancers. There is little doubt that oestrogen replacement therapy increases risk of endometrial cancer; however, the incidence of this is low and this risk is more or less abolished by adding progestogen. Evidence for increased risk of breast cancer is much less clear. Studies showing increased risk indicate that this appears after duration of use of hormone replacement therapy of five years or more. Nevertheless, even a small increase in risk is possibly of greater concern since breast cancer is substantially commoner than endometrial cancer and generally perceived as a worse disease to suffer. Progestogens do not appear to be protective for breast cancer; some studies even suggest they may compound the increased risk. Oestrogen replacement therapy undoubtedly is beneficial for bone mineral density, but it appears that therapy needs to be continued for at least 5 years or more for protection against osteoporotic fractures. There is also debate about how long this protective effect lasts after discontinuation of therapy, since if this decreases rapidly there will be little impact on fractures, the major proportion of which occur after 75 years of age, unless treatment is carried on for life. The biggest potential public health impact of hormone replace-



ment therapy is for cardiovascular disease, which is overwhelmingly the leading cause of mortality in women. A 30% reduction in cardiovascular disease would considerably outweigh, at least in numerical terms, any increased reproductive cancer risk. Though substantial evidence from observational studies indicate up to a 60% protective effect, it is not clear how much the observed reduced risk in these studies is due to the selection bias of healthier women being more likely to be users of hormone replacement therapy. It is also unclear whether the addition of progestogens abolishes or reduces any cardioprotective impact of unopposed oestrogens. Nonetheless, there is good reason to question whether there is any basis for existing cardiovascular disease to be a contraindication to use of hormone replacement therapy. Few would argue that every postmenopausal women should have the opportunity to consider hormone replacement therapy. Currently, the balance of evidence is that hormone replacement therapy appears to have considerable benefits. Though selection bias for healthy users cannot be excluded, it is reassuring that observational studies generally show reduced all cause mortality in users, thus making any large adverse effect (apart from those already observed with reproductive cancers) unlikely. However, the shift in emphasis from treatment of individual women with current specific symptoms to treatment of large numbers of asymptomatic women to prevent some possible future event such as fracture or heart attack, which may not occur for some decades hence, raises many questions. The major uncertainties are in the quantification of the overall long term benefits and risks associated with prolonged use. There may be other potentially important, but difficult to measure effects, such as dependency associated with prolonged usage. Risk-benefit analyses such as those conducted by Daly et al. {see this issue) are helpful but, as the authors indicate, estimates are very sensitive to small changes in assumptions about the size of risks and benefits, and costings. Most of the original observational studies of hormone replacement therapy were based on oral unopposed conjugated equine oestrogens. Another area for debate is how far findings from these studies can be generalised to other hormone formulations which include different oestrogenic, progestogenic and possibly androgenic compounds, as well as to different modes of administration, such as transdermal or depot preparations. Their biological effects, such as on lipids, and hence the benefits and risks may not be at all the same as for the original oestrogens which were used.



As Marsh et al. have pointed out, women and their medical practitioners thus need to be clear about their main reasons for the use of hormone replacement therapy: whether for short term relief of symptoms or for longer term prophylaxis since the potential risk-benefit balance associated with different formulations, mode of administration and duration of use may differ. At the moment there is a wide spectrum of opinion among general practitioners concerning hormone replacement therapy ranging from extreme reluctance to enthusiastic advocacy such that women get very different advice depending on whom they see. The major clinical and public health question now concerning hormone replacement therapy is: how far should it be encouraged in asymptomatic postmenopausal women in the community as a general policy? Do we need large controlled long term trials of hormone replacement therapy examining clinical endpoints including mortality before we feel comfortable about universal prophylactic use, or have we sufficient evidence to proceed? In this issue, current available data are discussed from many points of view; we hope the evidence presented here will help readers to judge for themselves.

Hormone replacement therapy. Comments from the editor.

Bntuk Medical Bullttm (1992) Vol 48, No 2, pp. 469-471 © The Briluh Council 1992 Comments from the Editor Kay-Tee Khaw University of Cambridge School...
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