Hormone replacement therapy again

Hormone replacement therapy is increasingly advocated not just for short term treatment of menopausal symptoms but as long term prophylactic therapy against heart disease, osteoporosis, even Alzheimer’s disease—indeed, as the solution to many of the problems of ageing women.¹ Should universal hormone replacement therapy be recommended in asymptomatic healthy postmenopausal women?

Many clinicians now take it as established that postmenopausal hormone therapy protects against coronary heart disease in women. However, this is not based on data from randomised trials with coronary end points. Hemminki and McPherson attempted to see whether useful information on the incidence of cardiovascular diseases and cancer could be obtained from published clinical trials which studied other outcomes of postmenopausal hormone therapy.² Despite pooling data from all the small trials they found no convincing evidence one way or the other. Most striking is the tiny size and short duration of most of the trials, which clearly had inadequate power to examine clinical events. Even the largest, the Postmenopausal Estrogens and Progestins Intervention (PEPI) trial,³ had fewer than 200 women in each treatment arm. Apart from the Nactigall study,⁴ the median duration was not much more than one year. There was substantial uncertainty about definition and ascertainment of events, which were often reported as dropouts or asides and not as the primary focus of the trials. Given the variable quality of these trials and procedures, the small difference in numbers of events could easily have arisen from biases in ascertainment and reporting. Why then, are we so convinced of the cardioprotective effect of oestrogens?

Observational prospective studies have generally shown that women taking postmenopausal exogenous oestrogens have a lower risk of coronary heart disease⁵: one meta-analysis of prospective studies suggested a relative risk of 0.56, or a 44% reduction in coronary risk.⁶ However, the lower coronary risk in hormone users in observational studies may be largely explained by selection bias.⁷ Women taking postmenopausal oestrogens, particularly in the United States, where most of the studies were conducted, tend to be healthier, with less baseline heart disease, thinner, of higher socioeconomic status, more health conscious, and have different lifestyles from women who do not take postmenopausal oestrogens. The effect of selection bias can be substantial: good compliers with placebo in trials have about 40% lower mortality than poor compliers.⁸

Nevertheless, oestrogen has biological actions that could plausibly explain cardioprotective effects.⁹ The PEPI trial has clearly shown that exogenous oestrogen administration in women raises high density lipoprotein cholesterol, lowers low density lipoprotein cholesterol, and decreases fibrinogen concentrations. Other studies indicate that oestrogens can have antioxidant effects, lower homocysteine concentrations, act as calcium channel blockers, alter vascular reactivity, and, more variably, improve glucose tolerance. The demonstrable effect on lipids, which are the strongest coronary risk factors, and the consistent strong findings for coronary heart disease in observational studies indicate a real protective effect of oestrogens, though perhaps not as great as the halving of risk observed.

In contrast, the evidence for stroke is much more equivocal. Postmenopausal hormone therapy had no effect on blood pressure in the PEPI trial,³ and observational studies indicate both increased as well as decreased stroke risks in hormone users.⁵ Randomised trials designed to examine clinical end points such as the WISDOM study in Europe and the Women’s Health Initiative in America will eventually provide more definitive answers about cardiovascular effects of postmenopausal hormone therapy but results will not be available for several years.

Nevertheless, hormone replacement therapy is also widely accepted to be protective for osteoporosis.^10–12 and possibly for Alzheimer’s disease,¹³ as well as for a variety of other menopause related conditions such as urinary symptoms and depression so why are there still reservations about universal prescription?

The concerns are over possible adverse effects and the overall risk-benefit balance of long term therapy in healthy women. The observed cardioprotective effect of oestrogen appears to be related to current use and diminishes after stopping.¹⁴ Thus, continued use is required for cardioprotection. While oestrogens undoubtedly increase bone density in women in trials, observational studies on fracture risk suggest that the protective effect is related to duration of use; as with cardiovascular disease, benefits appear to diminish rapidly after cessation (p 1858).¹⁵ Weiss reported that women have to use oestrogens for at least five years before a protective effect on hip fractures is observed.¹⁶ Unfortunately, oestrogen use increases the risk of both endometrial and breast cancer; the Nurses Health Study indicated a 30% increase in breast cancer risk in women using hormone replacement therapy who had taken it for five years or more.¹⁷ The risk of endometrial cancer is substantially mitigated, though not wholly abolished, by addition of progestins,¹⁸ but progestins do not appear to reduce, and may even increase, the risk of breast cancer.¹⁷

Various investigators have examined the risk-benefit balance of hormone replacement therapy. Roche et al have suggested that in British women there is an overall favourable balance.¹⁹ Grady estimated the potential effects of hormone replacement therapy based on estimated event rates in various categories of American women.²⁰ She concluded that major benefits would be in women at high risk of coronary heart disease, whereas those at high risk of breast cancer, such as those with a family history, would be much less likely to benefit. These theoretical estimates are supported by a more recent analysis from the Nurses Health Study, which reported that current hormone users with coronary risk factors had the largest reduction in mortality, while women at low coronary risk had substantially less benefit. The survival benefit diminished with duration of use, largely due to an increase in breast cancer.²¹

However, risk-benefit estimates and hence clinical decisions cannot be universally generalised. Studies have been done largely on women in the United States and Britain who have high absolute rates of heart disease and osteoporotic fractures. Yet even in American women an estimated 2000 women would have to take oestrogen for one year to prevent one coronary event.¹⁴ Women in countries such as Italy, Spain, or Japan, where coronary heart disease rates are substantially lower,²²,²³ would have a completely different risk-benefit balance. Additionally, the long term observational studies have largely been on oral conjugated equine oestrogens, and the effects of other preparations and modes of administration cannot be assumed to be identical.

The short term clinical use of whatever hormone preparation is pragmatically found to be effective for relieving menopausal symptoms is relatively unproblematic. However, prescription of hormone replacement therapy in asymptomatic healthy women for prevention of heart disease or osteoporosis poses more of a dilemma, and the long term risk-benefit balance is crucial. The greatest benefits are likely to be in women at high risk of these conditions in comparison with their risk of breast cancer; these are likely to be older women. The potential benefits of long term prophylactic use in perimenopausal women are more debatable. And Barrett-Connor has pointed out the importance of each individual woman’s choice based on risk pattern, fears, and quality of life.²⁴

The idea of an anti-ageing pill in the form of oestrogen therapy is certainly attractive, but it is unlikely to be the solution to healthy ageing in women. The huge international variations and secular trends in chronic disease indicate that many of these conditions are potentially preventable and not due to the menopause per se. Japanese women, who have lowest endogenous oestrogen levels, also have greatest longevity, the lowest rates of coronary heart disease, and a low prevalence of menopausal symptoms.²⁵ We already have a good understanding of some of the existing dietary and other measures we can take to improve health.²⁶,²⁷ The valuable clinical uses of oestrogens should not divert attention from identifying and acting on the major determinants of health in women.

Papers p 1858