Postmenopausal hormone replacement therapy.

Abstract

Several comprehensive accounts of postmenopausal hormone replacement treatment have been published in the United Kingdom in the past year` so in this review we concentrate on areas which, while often controversial, are of concern to the practising physician. We discuss the effects of postmenopausal hormone replacement therapy on the risks of developing coronary heart disease, osteoporosis, and cancer and comment on the concepts of oestrogen tachyphylaxis and dependence. We conclude with our present recommendations for hormone treatment of the menopause. Certain general concepts must be kept in mind in evaluating the burgeoning literature on postmenopausal hormone replacement therapy. The first is that nearly all the reports in this field are observational rather than experimental and many are retrospective rather than prospective. Groups of women who have chosen to take hormone treatment have been followed for varying periods and their state of health has been compared with that of a control group. Matching the control to the treatment group is an obvious problem in any such study. Quite apart from questions of whether the control group is obtained from a hospital based population or from the community, is appropriately matched for age, social class, compliance with advice related to the promotion of health, etc, women who decide to take postmenopausal hormone replacement therapy may have attitudes and behaviour with respect to healthy living and the use of medical resources that are quite different from those who decide against it. For example, Barrett-Connor' recently reported that as a group such women eat healthier diets, take more exercise, and have more contacts with their practitioners than women who elect not to go on to treatment. Although considerable consistency is developing in the reports of the benefits of oestrogen treatment, the effects of these and other biases, known and unknown, erode confidence in the magnitude of the benefits claimed. Accurate answers will only come when the evaluations are made after such biases have been allocated randomly to control and treatment groups alike. We find the arguments for substantial prospectively conducted randomised controlled trials of postmenopausal hormone replacement therapy most compelling.5: Moreover the evidence is that general practitioners in the United Kingdom are keen to collaborate.The second general concept to be borne in mind conceming the evaluation of postmenopausal hormone replacement therapy is the reliance presently placed on surrogate markers of risks and benefits. Because very large trials over prolonged periods are needed to detect changes in the incidence of clinical events, attention has been focused on surrogate markers of risk such as measurements of bone density or serum concentrations of cholesterol and its subfractions. We discuss the value of this approach in more detail later; here it is necessary to recall that a distinction should be drawn between markers and mediators of risk. For example, there is agreement that a subnormal bone mineral density is both a marker and a mediator of the risk of fracture. While a low serum high density lipoprotein concentration is certainly a marker of the risk of coronary heart disease in women, there is less certainty about the extent to which it should be regarded as a mediator. Moreover, as we shall see, as new surrogates are developed conflicting results can arise. These uncertainties may prove important in the debate concerning the possible negative impact of progestogens on the cardiovascular benefits of treatment with oestrogen (see below). Whether cotreatment with progestogens does indeed reduce the cardiovascular benefits of treatment with oestrogen will therefore only be decided by a randomised controlled trial which measures clinical end points. Meanwhile the practising clinician can but keep a close eye on the shifting interpretation of surrogate measurements of risks and benefits.