In the last in our series on the menopause, the long-term implications for women of taking HRT are discussed
Among the endocrine organs, only the ovary undergoes an obligatory failure long before the individual reaches the end of her life. This failure may cause the individual to suffer effects which can range from the mildly inconvenient to the clinically serious.
A great debate began over three decades ago concerning the still unresolved issue of whether the menopause, or the ovarian failure that causes it, should be regarded as physiological (and hence remain untreated unless a cogent indication arose) or whether it should be classed as pathological - as in thyroid or adrenal failure - and treated for life. Hitherto, most physicians and general practitioners have adopted the middle view of utilising oestrogen replacement in those patients afflicted enough, or vocal enough, to present with a request for treatment. Hormone replacement therapy (HRT) is presently offered to a minority of the population, usually for symptomatic relief, with a lesser number of women receiving treatment for the prevention or treatment of osteoporosis.
In parallel to the ethical and clinical debate on management, major discoveries have been made in our understanding of the sheer range of action of the oestrogens, those remarkable steroid bioregulators and hormones whose production largely ends with the menopause. Thanks to the elucidation by electron crystallography of the structure and actions of oestrogen receptors (ERs)1 and our ability to locate them in tissues, we now have a much clearer view of the broad range of functions that evolution has bestowed upon the oestrogens. They are basically signallers, and the presence of the oestrogen-ER complex in the nucleus of a cell is the instrument of signal translation into protein synthesis. We now know that the main reproductive actions of the oestrogens are accompanied by significant roles in, for example, three great networks which are essential for health - the trabecular skeleton, the vascular tree and the central neural net (the central nervous system). If to these we add the functions suspected in the function of the ocular lens,2 the gastrointestinal tract3 and the immune system,4 it can be seen that, far from being solely gynaecological as was once thought, the actions of oestrogens range far across the physiological systems and play a major role in the optimal function of the adult female organism.
There is a growing but still far from general view in clinical medicine that, were the oestrogens to be made available in a format that was safe, efficacious and affordable, there would be a compelling indication for them to be considered for all climacteric women and to be offered long-term unless a personal or clinical objection were encountered.
The central problem of HRT preparations to date has been their unacceptability to women long-term, despite the steady accrual of evidence supporting their beneficial action in that longer term.
An association between oestrogen deficiency and osteoporosis was first suggested by Fuller Albright in 1941. Oestradiol, co-operating with a complex array of other hormones, growth factors and cytokines, is pivotal in maintaining the coupling or balance between the resorptive and formative actions of the bone remodelling unit.
In the absence of adequate circulating oestradiol, ie, at a plasma level below 200pmol/L, the coupling breaks and osteoclastic bone resorption outstrips osteoblastic formation. This imbalance is subjected to a multiplier effect through the loss - at the menopause - of the physiological restraint imposed by oestrogen on the recruitment of new bone remodelling units, of which some 0.5m are normally operational at any one time in the adult skeleton.
As discussed in a previous article (PJ, October 30, p712), these remodelling units operate on bone surfaces. Hence, bone loss is most significant at the trabecular sites of the femoral neck, the distal radius and the vertebrae, where bone surface areas are highest. The end result is a loss of trabecular number, thickness and degree of connection which together confer on trabecular bone its great engineering strength and its capacity for absorbing shock. Clinically, the problem is apparent in the 40,000 radial, 80,000 clinically observed vertebral and 60,000 femoral neck fractures which occur annually in England and Wales, imposing a £940m expenditure requirement on the NHS.
Oestrogen is the treatment of choice for the prevention and treatment of significant osteopenia - low bone mass not amounting to osteoporosis - and the actual disease itself. The use of an osteoprotective regime such as those shown in Panel 1 is essential to achieve a rebalancing of bone resorption and formation at the level of the bone remodelling unit and to reapply physiological restraint to the rate of recruitment of the units themselves. Thus, restoration of normal adult values of oestradiol first manifests itself in a decline in bone turnover.
|
|
Fracture risk There is a general consensus that BMD is an acceptable marker for fracture risk, with the risk of a specific fracture approximately doubling with each one standard deviation fall in BMD at the site concerned. A substantial amount of observational data attest to the ability of long-term oestrogen to reduce significantly the incidence of the main osteoporotic fractures of the spine, femoral neck and the distal radius. We have, as yet, no randomised controlled trial (RCT) data to confirm the epidemiological data in respect of hip and radial fracture. However, with regard to vertebral fracture we are on surer ground. In both the RCTs of Lindsay6 in oophorectomised women, and of Lufkin7 who studied postmenopausal women with existing osteoporotic crush fractures, the oestrogen treated women suffered significantly fewer new vertebral fractures than did the controls.
Recent support has come from a large RCT examining the ability of raloxifene, which is a selective oestrogen receptor modulator (SERM), to prevent new vertebral fracture in postmenopausal women with and without pre-existing fractures. In both groups this agent, which is not structurally an oestrogen but which operates via the oestrogen receptor, reduced new fractures by between 30 and 50 per cent.8
There is general agreement that when oestrogen therapy is stopped and the plasma oestradiol levels decline below the normal threshold of about 200pmol/L, bone loss restarts. There is also general consensus that 10 years after HRT therapy is stopped, the BMD values at the high risk sites are back at or below the start line. However, fracture incidence is not determined by BMD alone and the influences of oestrogen on the skeleton extend not only to the density of tissue but also to its architecture.
We simply do not have adequate prospective controlled data to state to what extent the reduction in fracture risk by oestrogen endures beyond the termination of therapy.
Joints Osteoarthritis is, by far, the most important joint condition to afflict the ageing population. It is known that joint stiffness and arthralgia are prime symptoms of oestrogen deficiency9 and women treated with HRT frequently report a sensation of relubrication in their joints. However, the precise role of the oestrogen receptors, which are certainly present in articular cartilage, is unknown.
Cohort studies have found a 30 per cent reduction in symptomatic osteoarthritis in women currently on HRT. However, with such study designs, a cause and effect cannot be guaranteed, due to the unknown magnitude of biases and confounding variables. Fully randomised prospective trial data are urgently needed.
It is now generally agreed that oestrogens are intimately involved in the structure and function of the central nervous system (CNS). The identification of ERs in important areas, such as the hypothalamus, pituitary, hippocampus and basal forebrain, provides an ultrastructural basis for the recognised ability of oestrogens to modulate the hypothalamic-pituitary-ovarian axis and to influence vasomotor control and behaviour. In summary, the oestrogens are known to increase blood flow to the brain to influence neurotransmitter production and to promote neuronal interconnection. Oestrogens also act as monoamine oxidase inhibitors, which themselves have long been utilised in the treatment of depression.
Perimenopausal women frequently observe that they suffer from irritability, loss of short-term memory, mood swings and depression. The ability of oestrogen to ameliorate such symptoms in the short-term led naturally to the inquiry as to whether oestrogen might have a role in the longer-term prevention or management of the neurodegenerative disorders, including Alzheimer's disease (AD), which contribute significantly to the prevalence of dementia in the elderly.
In 1997, Tang et al10 reported from New York that, in a case-control study of 1,124 healthy elderly women, the use of oestrogen for more than one year was associated with a 60 per cent reduction in the risk of Alzheimer's disease after adjustment for potential confounding variables. A dose-duration effect was observed and none of the 23 women who were currently on HRT at entry developed Alzheimer's disease.
In the same year, Kawas et al11 reported on 472 postmenopausal women followed for 16 years in the Baltimore Longitudinal Study of Ageing. After adjustment for years spent in education, this group found that the relative risk of Alzheimer's disease among women using oestrogen was reduced by some 50 per cent. No trend in respect of treatment duration was discernible.
Recently a report from the Mayo clinic12 utilised a population-based, case-control design to examine the effect of HRT on Alzheimer's disease. The groups, 222 AD patients and a similar number of controls, were identical in age at menarche and age at menopause. Those who had taken oestrogen exhibited a significantly lower risk of AD and, in this study, there was a trend of decreasing risk with duration of oestrogen exposure.
The population-based design of this study and the collection of incident cases of AD do suggest that a valid association may be present, a conclusion supported by the meta-analysis of Yaffe et al13 who described a reduction of about 30 per cent in the risk of dementia in studies of women exposed to HRT.
The in vitro observation that oestrogen is capable of inhibiting the conversion of amyloid precursor protein (APP) to b-amyloid complements the clinical observations since the deposition of amyloid is a central histo-pathological feature of AD.
No large randomised study has yet reported the effect of HRT on the clinical course of established AD and such a study is urgently required. For the moment, the ability of oestrogen to prevent Alzheimer's disease should be classed as possible rather than certain.
Other potentially useful longer term effects of oestrogen upon the CNS involve the co-ordination of balance. The issue of neuromuscular co-ordination is important not just in itself but also because it may contribute to the incidence of fracture. Osteoporotic bones do not usually fracture spontaneously but fracture as a consequence of falls. It is believed that the incidence of falls in the elderly is influenced by neuromuscular co-ordination, itself an integration of visual acuity, vestibular function and sensory stimuli from joints and muscles. Hammar et al14 have reported a prospective trial of transdermal 17-b oestradiol in healthy postmenopausal women, who acted as their own controls. Over a three-month period, oestrogen improved balance as measured by certain tests of sensory organisation involving response to sway. A control group was not examined.
Muscular function itself has long been suspected of being directly influenced by oestrogen but data have been few. Recently, however, Skelton et al15 from St Mary's Hospital, London, showed in a 12-month RCT that the power generated by the adductor pollicis muscle in the thumb was enhanced by oestrogen. These data suggest a role for oestrogen within the intrinsic actin-myosin contractile function and further exploration of such activity is required.
In summary, it is probably too soon to include use in patients at risk of Alzheimer's disease or other neurodegenerative disorders among the list of indications for HRT. Meanwhile, a perceived risk of such conditions should not deter the use of HRT while we await RCT data to refine the association proposed by the observational studies.
The major killer of postmenopausal women in the developed world is cardiovascular and cerebrovascular disease.
For many years it had been observed that premenopausal women had a significantly lower incidence of cardiovascular disease (CVD) than men of the same age and it was speculated that this relative protection was, in part, due to the presence of premenopausal plasma levels of circulating oestrogen. The increase in the incidence of CVD in postmenopausal women supported this view, as did the findings of the celebrated Framingham study in the US, which showed that women who were prematurely or naturally postmenopausal had a higher incidence of CVD than age-matched premenopausal controls.
The means whereby oestrogens tend to protect the cardiovascular system are complex but they centre on two areas - effects on lipid profile and the more important direct effects upon the vasculature itself. With regard to lipids, the postmenopausal profile exhibits an atherogenic pattern with a rise in total cholesterol and in LDL-cholesterol and a fall in HDL-cholesterol.
The effect of oestrogens on the lipid profile was recently examined thoroughly in the Prospective Oestrogen and Progestogen Interventions (PEPI) trial.16 This was a three-year, double-blind, randomised, placebo-controlled trial of the effect of conjugated oestrogens 0.625mg daily, with and without progestogens, on cardiovascular risk factors in 873 healthy postmenopausal women. There was a significant rise in HDL-cholesterol and triglycerides and a significant fall in total cholesterol and in LDL-cholesterol. Raloxifene produces lipid effects that are similar but less pronounced than those found with conventional HRT.
Many studies have addressed the effects of oestrogens on the vascular tree and a consistent picture is beginning to emerge. The oestrogen component of HRT stimulates the production of certain enzymes, including nitric oxide (NO) synthase and prostacyclin synthase, that are involved in lowering vascular tone and maintaining blood vessel patency. Long-term oestrogen therapy increases coronary vasodilatation both in healthy postmenopausal women and in those who have angina and angiographically normal coronary vessels. Interestingly, a report has been made of a man without functional oestrogen receptors, who lacks endothelium-based vasodilatation and has have early coronary calcification.
The vascular effects of oestrogen may not be entirely genomic, ie, receptor mediated and consequent on gene transcription or suppression. It has been known for some time that certain effects were just too rapid in onset to have occurred via the gene transcription apparatus and must therefore have been mediated by direct action. The main cell in these activities is the vascular smooth muscle cell. Its influence on vessel tone is reflected in peripheral vascular resistance, a major determinant of the pressure under which the blood must be discharged through the arterial tree in order to maintain tissue perfusion. Interestingly, oestrogen has been shown to act as a calcium channel blocker in heart muscle cells.
There is a wealth of evidence from both retrospective and prospective epidemiological studies that oestrogen protects against the evolution and clinical presentation of atherosclerotic CVD. For example, in 3,637 deaths from 1976 to 1994 within the large Nurses Health Study in the US, the current use of HRT was associated, after adjustment for confounding risk factor variables such as obesity, cigarette smoking and hypertension, with a 37 per cent decrease in the risk of cardiovascular death compared with untreated controls.17 Several meta-analyses are available which variously show a reduction of about 30 to 50 per cent in CVD among HRT-treated postmenopausal women.
However, all observational studies suffer from the difficulties of biases. In particular, studies on HRT and CVD incur the objection that the very women likely to take up and continue with HRT are those whose personal health care and lifestyle is good and who are inherently less likely to develop CVD. As always, resolution of these difficulties requires RCTs, of which there are few.
In the PEPI trial it was found that oestrogen alone, or in combination with a progestogen, produced a favourable lipid profile and a reduced plasma fibrinogen and did so without observable effect upon insulin resistance or blood pressure. Although this study had no clinical endpoints, it addressed four of the central risk factors which determine such endpoints and found oestrogen to be a valuable preventive agent. The fact that the progestogens studied - cyclic or continuous medroxyprogesterone acetate (MPA) and micronised progesterone - did not block the protective actions of oestrogen is encouraging, given the theoretical fear that they might do so.
Recently, the heart and oestrogen/progestin replacement study (HERS) examined the effect of conjugated equine oestrogen plus MPA, in a continuous combined form, versus placebo in 2,763 women with established coronary disease.18 This study found an excess of cardiovascular events in the first year among the HRT-treated patients compared with the placebo-treated controls. The excess of events was most pronounced in the first four months and most frequently involved non-fatal myocardial infarction. Over the whole four years of the study, there was no excess of cardiovascular events in the treatment group, but there was, equally, no visible evidence of the protection from such events that had been expected.
The HERS study also confirmed the expected HRT-associated increase in clinical venous thromboembolic events noted in observational studies. This study, although confined to the use of equine oestrogen and MPA, sounded a major note of caution and an accompanying leading article restated the inherent superiority of the RCT over observational studies in the determination of true cause and effect.
Oestrogen has a prime function in maintaining the integrity and functional plasticity of the vascular tree. It should be replaced in the event of premature menopause and offered at natural menopause where obesity, cigarette smoking, hypertension or positive family history place the patient at additional hazard. However, until further RCT data become available, HRT should be used principally in the prevention of cardiovascular disease while caution should be exercised in women with established coronary artery disease.
The priming of the endometrium, its proliferation and preparation for secretory transformation by progesterone, is a central function of oestradiol. Oestradiol engages the ER in the stratum basalis of the endometrium and directs the synthesis of a range of proteins.
Essential as this process is to reproduction, it is a major problem in the long-term use of HRT, with the consequent return of cyclic or unscheduled bleeding being repeatedly cited by patients as a major disincentive to acceptance of, or continuation of, HRT.19 The co-administration of either cyclic or continuous progestogen is necessary, respectively, to discharge or suppress the endometrium, which, if subjected to chronic oestrogenic stimulation, may become hyperplastic or neoplastic.
It having been generally thought that concomitant progestogen would reduce the risk of endometrial cancer to control levels, two recent publications have raised concern. Beresford20 found an excess of endometrial cancers in women receiving oestrogen plus cyclic progestogen and this has subsequently been supported by a population-based case-control study from Sweden.
These authors found that, after five years of HRT, non-hysterectomised women receiving oestrogen alone had, as expected, a marked dose and duration-associated increase in endometrial cancers compared with never-users. However, women using cyclic progestogen with their oestrogen had, again after five years, a small increase in risk, while in women using the newer continuous combined preparations there was no excess - indeed there was protection.
In absolute terms, the risk with cyclic progestogen is low but clinicians and pharmacists need to be alert and should continue to think of endometrial cancer as a differential diagnosis in women on sequential combined HRT who present with unscheduled or heavy bleeding.
The relationship between long-term oestrogen and breast cancer is of supreme interest to women considering taking HRT. Continuation studies have repeatedly shown that the two principal reasons for a patient's failure to embark, or to continue, on HRT are the return of cyclic or unscheduled bleeding and the fear of breast cancer.
It has been known for many years that late menopause and early menarche are risk factors for breast cancer. In other words, the longer the reproductive span and the longer the length of time that breast tissue is exposed to the monthly cycling of oestrogen and progesterone, the higher the risk of initiation and promotion of malignancy.
A substantial body of literature on the subject was brought together by the Collaborative Group on Hormonal Factors in Breast Cancer21 which reported, in 1997, a re-analysis of 51 epidemiological studies involving some 52,000 women with breast cancer and over 100,000 without. In summary, the group found that the relative risk of developing breast cancer increased by a factor of 1.023 per year of HRT exposure. This excess is similar to the factor of 1.028 per year imposed by increasing age of natural menopause.
After cessation of HRT use - and it should be noted that the usual duration of HRT in the UK is two years - the incidence of breast cancer is back at baseline five years later, irrespective of the duration of treatment. No major variation was noted in type of HRT with respect to breast cancer but, whatever the type, there was a definite tendency for the tumours to be less advanced at diagnosis.
This study produced useful absolute risk values for HRT and breast cancer. Since the use of relative risk with percentages is highly alarming to the majority of women who are not statistically adept, absolute values are ideal for setting risk in context. In this regard, it was found that, if 1,000 European women are followed for 20 years between the ages of 50 and 70 and take no HRT, then 45 cases of breast cancer will develop among them. If all of that same cohort of 1,000 were to take HRT for five years the excess would be two cases (ie, 47). For 10 and 15 years exposure to HRT, the cumulative excess is six and 12, respectively.
Women taking HRT for the UK standard period of about two years can, therefore, be advised that their risk of breast cancer will be increased but only by about two per 1,000 over 20 years. Many women will find such a rate acceptable, although many still will not. No significant difference in respect of breast cancer incidence was found in respect of oestrogen-only HRT preparations and those containing oestrogen and a progestogen.
Recently, the data have been published on the effect of the first licensed SERM - raloxifene - on breast cancer. In an RCT of 7,704 women followed up for 40 months, Cummings et al22 reported a reduction in the risk of breast cancer of some 76 per cent. This is a striking reduction in risk, especially since the breast cancer rate in the placebo-treated control group was normal. A follow-up study of high-risk women, in which raloxifene is to be directly compared with tamoxifen, is presently recruiting in North America.
Thus, there is probably a true relationship between exposure to conventional HRT and breast cancer. However, the excess risk attributable to the HRT is low. In a patient taking HRT for two years in her sixth decade, the component of her overall risk of breast cancer over the next two decades attributable to the HRT will be no more than 2 or 3 per cent. In other words, it is important to advise patients that the great majority of their current and prospective risk is the risk that they would run anyway by virtue of their sex, age and other intrinsic risk factors.
The risk of breast disease in a discussion on the use of HRT should always be placed in the context of symptom control and of bone and CVD protection. Women receiving HRT should have a breast examination before starting, should be counselled on breast awareness and should be enjoined never to miss their triennial mammographic review.
This review of the long-term consequences of oestrogen therapy is not comprehensive and is limited to those areas in which the positive and adverse effects of oestrogen therapy are supported by substantial literature. For a full survey, the interested reader is commended to a review of the non-reproductive actions of the oestrogens. Female longevity now requires women to spend nearly half of their adult lives in a state of profound oestrogen deficiency. It is for researchers now to determine the true consequences of that deficiency, system by system, and for the physician to determine, in the individual patient, whether or not the evidence suggests that the deficiency should be made good and, if so, by what means and for how long.
Women conceive and bear children and then play the major role in the supervision of childhood and education. It is right that, when these duties are ended, a woman should be able to look forward, with confidence, to an erect and robust older age.
HRT is not for all women, nor is it for no women - it is for some women. Thus a clear duty of care is encumbent on health professionals to determine whether or not a woman is likely to benefit from HRT. If so, it should be offered to her, with the woman exercising, as always, her right to determine whether she will take it or whether she will not.
Few areas of health care are so awash with misinformation as the menopause. The advisory role of the pharmacist is important in protecting women from exaggerated claims for untrialled products and in advocating the use of those for which advantage has been shown. At a time of uncertainty and anxiety, women look to all health professionals for sensitive and practical help. They deserve no less.
This article forms the basis of questions under the PJ/College of Pharmacy Practice Credit for Learning scheme (see p868)
Professor Purdie is head of clinical research at the Centre for Metabolic Bone Disease, University of Hull at Hull Royal Infirmary, and Mrs Crawford is a community pharmacist in Ayrshire
| 1. Brzozowski AM, Pike ACW, Dauter Z, Hubbard RE, Bonn T, Engstrom O et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Lancet 1997;389:753. [Medline reference] |
| 2. Hales AM, Chamberlain CG, Murphy CR et al. Estrogen protects lenses against cataract induced by transforming growth factor-b. J Exp Med 1997; 185:273. [Medline reference] |
| 3. Grodstein F, Newcombe PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999;106:574. [Medline reference] |
| 4. Jansson L, Holmdahl R. Estrogen-mediated immunosuppression in autoimmune diseases. Inflamm Res 1998;47:290. [Medline reference] |
| 5. Wimalawansa SJ. A four-year randomised controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med 1998;104:219. [Medline reference] |
| 6. Lindsay R, Hart DM, Forrest C, Baird C. Prevention of spinal osteoporosis in oophorectomised women. Lancet 1980;ii:1151. [Medline reference] |
| 7. Lufkin EG, Wahner HW, O'Fallon WM, Hodgson SF, Kotowicz MA, Lane AW et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992;117:1. [Medline reference] |
| 8. Ettinger B, Black DH, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results of a three year randomised controlled trial. JAMA 1999;282:637. [Medline reference] |
| 9. Oldenhave A, Jaszmann JB, Everaerd WT et al. Hysterectomized women with ovarian conservation report more severe climacteric complaints than do normal climacteric women of similar age. Am J Obstet Gynecol 1993;168:765. [Medline reference] |
| 10. Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 1996;348:429. [Medline reference] |
| 11. Kawas C, Resnick S, Morrison A et al. A prospective study of estrogen replacement therapy and risk of developing Alzheimer's disease: The Baltimore longitudinal study of ageing. Neurol 1997;48:1517. [Medline reference] |
| 12. Waring SC, Rocca WA, Petersen RC. Postmenopausal estrogen replacement therapy and risk of AD. A population-based study. Neurol 1999;52:965. [Medline reference] |
| 13. Yaffe K, Sawaya G, Leiberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998;279:688. [Medline reference] |
| 14. Hammar ML, Lindgren R, Berg GE et al. Effects of hormone replacement on the postural balance among postmenopausal women. Obset Gynecol 1996;88:955. [Medline reference] |
| 15. Skelton DA, Phillips SK, Bruce SA et al. Hormone replacement therapy increases isometric muscle strength of adductor pollicis in post-menopausal women. Cli Sci 1999;96:357. [Medline reference] |
| 16. The writing group for the PEPI trial. The postmenopausal estrogen/progestin interventions (PEPI) trial. Effects of estrogen or estrogen progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199. [Medline reference] |
| 17. Grodstein F, Stampfer MJ, Colditz GA et al. Postmenopausal hormone replacement therapy and mortality. N Eng J Med 1997;336:1769. [Medline reference] |
| 18 Hulley S, Grady D. Bush T et al. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomised trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605. [Medline reference] |
| 19 Purdie DW, Steel SA, Howey S, Doherty SM. The technical and logistical feasibility of population examination using DEXA and directed HRT intervention: with two year follow up. Osteo Int 1996;3:S31. [Medline reference] |
| 20 Beresford SA, Weiss NS, Voigt LF et al. Risk of endometrial cancer in relation to use of oestrogen combined cyclic progestagen therapy in postmenopausal women. Lancet 1997;349:458. [Medline reference] |
| 21 Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999;281:2189. [Medline reference] |
Reference 1 is incorrectly given as Lancet 1997;389:753. It should read Nature 1997;389:753.