Consequences of long-term hormone replacement therapy

Consequences of long-term hormone replacement therapy David W Purdie Centre for Metabolic Bone Disease, Hull Royal Infirmary, Hull, UK The use of oes...
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Consequences of long-term hormone replacement therapy David W Purdie Centre for Metabolic Bone Disease, Hull Royal Infirmary, Hull, UK

The use of oestrogens in the longer term is an area of considerable current scientific and clinical debate. The extra-reproductive range of oestrogen actions is broad, with these steroid hormones and their receptors (ERs) being intimately involved in the normal function of, inter alia, the adult female skeleton, the cardiovascular system and the brain. Desirable as the restoration of normal circulating oestrogen may be after menopause, HRT use is compromised by the engagement of the reproductive sites of breast and uterus. This may cause concern to patient and physician alike due to the consequent imposition of cyclical bleeding and risk of breast malignancy. In the individual patient, therefore, a balance of risk against benefit has to be struck so that the patient may be precisely advised of the type and duration of oestrogen replacement which may be indicated in her own case. The advent of selective oestrogen receptor modulation with its ability to delete adverse effects in breast and endometrium, is a substantial pharmacological and clinical advance.

Correspondence to Prof. David W Purdie, Centre for Metabolic Bone Disease, H S Brocklehurst Building, Hull Royal Infirmary, 220-236 Anlaby Road, Hull HU3 2RW, UK

The long-term replacement of the oestrogenic hormones of the ovary is an area of intense lay and professional medical interest and of scientific enquiry. Alone among the endocrine organs, the ovary undergoes obligatory endocrine failure long before the median life-span of the individual who may suffer, by that very failure, effects which can range from the mildly inconvenient to the clinically serious. A great debate began over three decades ago over the still unresolved issue of whether the menopause or, more precisely, climacteric ovarian failure should be regarded as physiological and hence remain untreated unless a cogent indication arose, or whether it should be classed as profoundly pathological - analogous to thyroid or adrenal failure - and treated for life unless a contra-indication arose. 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 receiving treatment for the prevention or treatment of osteoporosis or for the primary prevention of atherosclerotic cardiovascular disease.

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O The British Council 2000

Human reproduction, pharmaceutical and technical advances

Behind all the ethical and clinical debate on management, the most profound revelations have been taking place in our understanding of the mechanism of the range of action of the oestrogens, those remarkable steroid bioregulators and hormones whose production largely ends at menopause. Thanks to the elucidation by electron crystallography of the structure and function of the oestrogen receptor a (ERa)1 and the precise localisation of ERa and ER(3 in tissue by such techniques as in situ hybridisation, we now have a much clearer view of the functions which evolution has bestowed upon the oestrogens as signallers and on the oestrogen-ER complex as an instrument of signal transduction. Indeed, we now know that not all the actions of the oestrogens are receptor-mediated, with some operating - as with the peptide hormones - via surface receptors and then second messengers2. We now know that the 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, as discussed below. If to these we add the functions postulated, suspected, or displayed in the function of the ocular lens3, the gastrointestinal tract4 and the immune system5, it can be seen that, far from being solely reproductive agents as was once thought, the oestrogens range far across the physiological systems 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 which was safe, efficacious and affordable, there would be a compelling indication for them to be considered for all women at climacteric and to be offered long-term unless a personal or clinical objection were encountered. The central problems of HRT preparation to date have indeed been their unacceptability to women long-term - for a variety of reasons - despite the steady accrual of evidence supporting their beneficial action in that longer term. This paper will examine both the positive and negative effects of long-term oestrogen replacement and will, hopefully, contribute to the debate on the way ahead in the management of the postmenopause.

The skeleton The association between oestrogen deficiency and osteoporosis, first reported by Fuller Albright in 1941 6 , is now beyond scientific dispute. Oestradiol, co-operating with a complex array of calcitropic hormones, growth factors and cytokines, is pivotal in maintaining the coupling or balance between the resorptive and formative phases of the bone remodelling cycle (Fig. 1). In the absence of adequate circulating oestradiol, i.e. at a plasma level of below 200 pmol/1, the coupling breaks and osteoclastic bone resorption outstrips osteoblastic formation. This 810

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Bone remodelling in osteoporosis

Fig 1 The bone remodelling cycle.

imbalance is subjected to a multiplier effect through the loss, at menopause, of the physiological restraint imposed by oestrogen on the recruitment of new bone modelling units, of which some 0.5 million are normally operational at any one time. The net effect is bone loss which is most significant at the trabecular bone sites of femur, distal radius and vertebrae where bone surface areas are highest. The end result is a loss in the number and thickness of trabecula and in the main connection which together confer on trabecular bone its great engineering strength and shock absorptive capacity. Clinically, the problem is apparent in the 40,0000 radial, 80,000 clinically observed vertebral and 60,000 femoral neck fractures which occur annually in England and Wales, imposing about a £940 million expenditure requirement on the NHS7. Oestrogen is the treatment of choice for the prevention and treatment of significant osteopenia and established osteoporosis. In oestrogen replacement, the use of an osteoprotective regimen, such as those shown in Table 1, is essential to achieve a rebalancing of bone resorption and formation at the level of the bone remodelling unit and to re-apply physiological restraint to the rate of recruitment of the units themselves. Table 1 Osteoprotective HRT regimens

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Daily dose

Oral oestradiol-17-p Conjugated equine oestrogens Transdermal oestradiol-17-(5 Subcutaneous oestradiol-17-f) Tibolone

1 mg 0 625 mg 50 tig 50 mg (6 monthly) 2 5 mg


Human reproduction: pharmaceutical and technical advances

Restoration of normal adult values of oestradiol first manifest m a decline in bone turnover markers such as osteocalcin and bone specific alkaline phosphatase for bone formation, and urinary pyrodinoline and serum Cterminal collagen-I telopepetide for bone resorption8. Long-term, bone mineral density measurements (BMD) indicate that bone loss first becomes arrested and is then succeeded by a gain in bone mineral density, most obvious at the spine, as the resorption cavities, excavated in large numbers during the foregoing oestrogen deficiency, become refilled9. Evidence from human studies has now shown that high dose oestrogen replacement by implant therapy is anabohc to the skeleton with patients exhibiting substantial gains in BMD, while evidence of enhanced osteoblastic bone formation is manifest in the histomorphometric analysis of biopsy material10. Combination therapy in which oestrogen replacement is partnered by either an oral bisphosphonate11 or a daily subcutaneous injection of parathyroid hormone12 have been shown to be synergistic, i.e. the result in a degree of bone gain not achievable with either agent alone.

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 1 standard deviation (SD) fall in BMD at the site concerned. The World Health Organization has proposed that osteopenia be defined as a BMD of between -1 and -2.5 SD below the norm of the young normal population the numerical value of SD deviation from the mean being designated the Tscore. Similarly, osteoporosis is defined as a T-score of > -2.5. When comparing BMD results with an age-matched population rather than young normals, the standard deviation value is designated the Z-score. A substantial amount of observational data attest the ability of longterm oestrogen to reduce significantly the incidence of the prime osteoporotic fractures of the spme, femoral neck and the distal radius13"15. However, we have as yet no randomised controlled trial (RCT) data to confirm, or rather re-inforce, 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 Lindsay16 in unfractured oophorectomised women, and of Lufkin17 who studied postmenopausal women with existing osteoporotic risk fractures, the oestrogen-treated women suffered significantly fewer fractures than did the placebotreated controls. Recently, 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 fractures18. In both groups this agent, which is not structurally an oestrogen but which operates via the oestrogen receptor, reduced new fractures by 30-50%. 812

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There is general agreement that, when oestrogen therapy is stopped and the plasma levels declines below the normal threshold of -200 pmol/1, bone loss begins anew. There is also general consensus that after some 10 years of HRT therapy, the BMD values at the key sites are back at or below the gain line19. 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 whether, or to what extent, the reduction in fracture risk by oestrogen endures beyond the termination of therapy.

Joints Osteoarthritis is, by far, the most important of the arthritides which afflict the ageing population. It is known that joint-stiffness and arthralgia are prime symptoms of oestrogen deficiency20 and HRT treated women frequently report a sensation of relubncation in their joints. However, the precise role of the oestrogen receptors present in articular cartilage is unknown, although it has been reported21 that oestrogen controls interleukin-6 production in chondrocytes. Long-term, Nevitt et al,22 using a cohort design, found a 30% reduction in symptomatic osteoarthritis in women currently on HRT, RR 0.70 (0.50-0.90) while, in a case control study, Vingard et aP reported that fewer severely affected women requiring total arthroplasty had a history of taking HRT for at least one year than in controls. Spector et aP4 also reported a reduction in osteoarthritis of the knee in women currently using HRT, again in a cohort study. With such study designs, however, causality cannot be assigned due to the unknown magnitude of unrandomized biases and confounding variables. For example, osteoporosis may protect against osteoarthritis and women with osteoporosis are more likely to receive long-term oestrogen. One prospective study has been reported by Zhang et aP in which women in the Framingham study who took HRT were assessed over 8 years for the development or the progression of osteoarthritis of the knee. Compared to untreated controls these women had an RR of 0.3 (0.1-1.2) which just failed to achieve significance. Fully randomised prospective trial data are urgently needed.

Cardiovascular system Cardiovascular disease (CVD) is the major killer of postmenopausal women in the industrialised world. For many years, it had been observed that premenopausal women had a significantly lower incidence of CVD British Medical Bulletin 2000, 56 (No 3)


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than did 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 Framingham study which showed that, at all ages studied, women who were prematurely or naturally postmenopausal, had a higher mcidence of CVD then did age-matched premenopausal controls26. The means whereby oestrogens tend to protect the cardiovascular system are complex, but centre on two areas - effects on lipid profile and, more importantly, direct effects upon the vasculature itself. With regard to lipids, the postmenopausal profile exhibits an atherogenic pattern with a rise in total and in LDL-cholesterol and a fall in HDL-cholesterol. Oestrogens act by engaging ER in the liver and modulating the hepatic synthesis of apohpoproteins A, B, D and E together with lipoprotein (a). The effect of oestrogens on the lipid profile was thoroughly examined in the Prospective oEstrogen and Progestogen Interventions (PEPI)27 trial which was a 4-year double-blind, randomized placebo-controlled trial of the effect of 0.625 mg conjugated oestrogens (daily) with and without progestogens, on cardiovascular risk factors in 873 healthy postmenopausal women. There was a significant rise in HDL-cholesterol and triglycendes and a significant fall in total and in LDL-cholesterol. Raloxifene also produces lipid effects which are qualitatively similar, but quantitatively less than those found with conventional HRT28 though whether such changes are translated into clinical protection is as yet unknown. 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 patency. Activation of NO synthase also results in a inhibition of platelet aggregation29. Long-term oestrogen therapy increases coronary vasodilation in normal postmenopausal women and in those with angina and an angiographically normal coronary vasculature30. Interestingly, a man without functional oestrogen receptors has been reported to lack endothelium-based vasodilation and to have early coronary calcification31. The vascular effects of oestrogen may not be entirely genomic, i.e. receptor-mediated and consequent on gene transcription or suppression. It has been known for some time that certain effects were just too fast, too rapid in onset, to have occurred via the transcription apparatus and must, therefore, have been mediated by direct action on cells via intracellular ion fluxes. The key cell in these activities is the vascular smooth muscle cell whose influence on aggregate tone is reflected in overall peripheral vascular resistance, a key determinant of the pressure 814

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under which the blood must be discharged through the arterial tree in order to maintain tissue perfusion and oxygenation. Oestrogen has been shown to act as a calcium channel blocker in cardiac myocytes32. Very recently it has been shown by Valverde et al3i that oestradiol directly activates a tone-regulating potassium (K+) channel in vascular endothelium and smooth muscle. Oestrogen acts extracellularly by binding to a K+ channel receptor structure on the cell membrane and no intracellular signalling is required. The effect of oestrogen at physiological concentrations is to operate via the K+ channel to block the entry of Ca2+ into vascular smooth muscle cells thereby inducing their relaxation.

Clinical data There is a wealth of evidence from both retrospective and prospective epidemological studies that oestrogen protects against the evolution and clinical presentation of atherosclerotic CVD. For example, in 3637 deaths from 1976-1994 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% decrease in the risk of cardiovascular death compared to untreated controls, RR 0.63 (0.56-7.0)34. The protection appeared greatest among women who exhibited clinical risk factors for coronary artery disease, whereas the benefit was substantially less for those at low apparent risk. Interestingly, this study found a relative decrease in benefit with long-term use due to an excess of deaths from breast cancer. Several meta-analyses are available which variously show a reduction of -30-50% in CVD among HRT-treated postmenopausal women35-36. All observational studies, however, suffer from the difficulties of unrandomized biases and, in particular, studies on oestrogen and CVD incur the objection that the very women likely to take up and continue with HRT are those whose personal healthcare and lifestyle is good and who are inherently less likely to develop CVD. As always, obviation of these difficulties requires randomized mterventional studies of which there are but few. One such study, the PEPI trial, vide supra, examined the effect of oestrogen and oestrogen/ progestogen combinations on risk factors for heart disease in healthy postmenopausal women. The PEPI group found that oestrogen alone or in combination with a progestogen developed a favourable lipid profile, 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 influence such endpoints and found oestrogen to be a valuable preventive agent. The failure of the progestogens studied - cyclic or continuous British Medical Bulletin 2000, 56 (No 3)


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medroxyprogesterone acetate and micronised progesterone - to block or impede the protective actions of oestrogen is encouraging, given the theoretical fear that they might do so. A recent clinical endpoint RCT, the Heart and Estrogen/progestin Replacement Study (HERS) examined the effect of oestrogen plus MPA - in a continuous combined format - versus placebo in 2763 women with established coronary disease37. It was thus a secondary and not a primary intervention study. This study found an excess of cardiovascular events, in the first year, among the HRT treated patients compared to the placebo-treated controls - relative hazard (RH) 1.52, with a neutral effect - RH 1.00 - in year two and a protective effect in years three and four - RH 0.87 and 0.67, respectively. Within year one, the excess of events was most pronounced in the first 4 months and most frequently involved non-fatal myocardial infarction. Over the whole 4 years of the study, there was no excess of cardiovascular events in the treatment group, the RH being 0.99 (0.80-1.22), but there was equally no visible evidence of protection from such events proposed on the basis of the epidemiological studies - and meta-analyses. The study also confirmed the expected HRT-associated increase in clinical venous thromboembolic events noted in observational studies,38'39 the RH being 2.89 (1.50-5.58) This study, although confined to the use of equine oestrogen and MPA, sounds a major note of caution with the accompanying editorial in the Journal of the American Medical Association40 necessarily restating, yet again, the inherent superiority of the RCT over observational studies in the determination of causality. 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, caution should be exercised in the use of HRT among women with established coronary artery disease.

Endometrium The priming of the endometrium, its proliferation and preparation for progestogenic secretory transformation 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 including complement C3, the progesterone receptor (PR) and insulin-like growth factor-141. Essential as this process is to reproduction, it is a major problem in the long-term use of HRT, the consequent return of cyclic or unscheduled bleeding being repeatedly cited by patients as a major disincentive to acceptance of, or 816

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continuation with, HRT42. The co-administration of either cyclic or continuous progestogen is necessary to, respectively, discharge or suppress the endometrium which, if subjected to chronic oestrogenic stimulation may become hyperplasdc or neoplastic. The excess of cases of endometrial cancer m non-hysterectomised women receiving oestrogen alone has been known since the mid-1970s. The association is generally accepted although in parts of the US, oestrogen monotherapy - with frequent review - is still practised. It having been generally thought that a concomitant progestogen would reduce the risk of endometrial cancer to control levels, two recent publications have raised concern. Beresford et at*3 found an excess of endometrial cancers in women receiving oestrogen plus cyclic progestogen and this has subsequently been supported by Weiderpass et at44 in a population-based case-control study from Sweden. These authors found that, after 5 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, RR 6.6 (3.1-12.6). However, women using cyclic progestogen with their oestrogen had, again after 5 years, a relative risk of 1.6 (1.1-2.4) while women using the newer continuous combined preparations there was no excess, indeed there was a protection, the RR being 0.2 (0.1-0.8). In absolute terms, the risk with cyclic progestogen is low but clinicians need to be on the lookout and should continue to entertain endometrial cancer as a differential diagnosis in women on sequential combined HRT who present with unscheduled or heavy bleeding.

Oestrogens and the central nervous system It is now generally agreed that the oestrogens are ultimately involved in the structure and function of the central nervous system (CNS). The identification of ER m the key areas of the hypothalamus pituitary, hippocampus and basal forebrain45, provide 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 mcrease blood flow to the brain,4* to influence neurotransmitter production,47 and to promote neuronal interconnection through dendritic growth48. Oestrogens also act as monoamine oxidase inhibitors, an effect which has long been utilised by non-steroidal agents in the treatment of depression. It is frequently observed by perimenopausal women 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 enquiry as to whether oestrogen might British Medical Bulletin 2000, 56 (No 3)


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have a role in the longer-term prevention, or management, of neurodegenerative disorders, including Alzheimer's disease, which contribute significantly to the prevalence of dementia in the elderly. It has been known for some time that Alzheimer's disease was more common among elderly women than men even when correction was made for the greater female longevity. In 1997, Tang et at*9 reported from New York that in a prospective case-control study of 1124 healthy elderly women, the use of oestrogen for more than 1 year was associated with a relative risk of Alzheimer's disease of 0.40 (0.22-0.88) after adjustment for potential confounding due to educational span, ethnicity and apohpoprotein E genotype. 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 at50 reported on 472 postmenopausal women followed for 16 years in the Baltimore Longitudinal Study of Aging. After adjustment for educational span, this group found that the relative risk of Alzheimer's disease among women using oestrogen was 0.46 (0.21-0.99). No trend in respect of treatment duration was discernible. Recently, a report from the Mayo Clinic51 utilised a population-based case-control design to examine the effect of HRT on Alzheimer's disease. The groups, 222 patients with Alzheimer's disease and a like number of controls, were identical in age at menarche , age at menopause and were adjusted for educational span. Those who had taken oestrogen exhibited a significantly lower risk of Alzheimer's disease, RR 0.42 (0.18-0.96) than the untreated controls and here there was a trend to decreased risk with duration of oestrogen exposure. It should be noted that this study did not adjust for the APO-e4 genotype which is associated with Alzheimer's disease and which was accounted for in the study of Tang et at*9. However, the population-based design and the collection of incident cases of Alzheimer's disease do suggest that a valid association may be present, a conclusion supported by the meta-analysis of Yaffe et alsl who described a - 3 0 % reduction in the risk of dementia in studies of women exposed to HRT. The in vitro observation that oestrogen at physiological concentrations is capable of inhibiting the conversion of amyloid precursor protein (APP) to P-amyloid complements the clinical results53, since the deposition of amyloid is a central histopathological feature of Alzheimer's disease54. No larger randomized study has yet reported the effect of HRT on the clinical course of established Alzheimer's disease and such a study is required. Other potentially useful longer term effects of oestrogen upon the CNS involve the co-ordination of balance and early Parkinson's disease. The issue of neuromuscular co-ordination is important not just in itself, but because it may contribute to the incidence of fracture. Osteoporotic bones do not usually fracture spontaneously, they fracture as a consequence of falls. It is believed that the incidence of falls in the elderly is influenced by 818

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neuromuscular co-ordination, itself an integration of visual acuity, vestibular function and sensory stimuli from joints and muscles. Hammar et al55 have reported a prospective trial of transdermal oestradiol-17-p1 in healthy postmenopausal women who acted as their own controls. Over a 3 month period, oestrogen increased balance as measured by certain tests of sensory organization involving response to sway. Muscular function itself has long been suspected of direct influence, but data have been few. Recently, however, Skelton et al56 from St Mary's Hospital, London, showed in a 12 month prospective, randomized controlled placebo-controlled trial that the power generated by the adductor pollicis muscle was enhanced by oestrogen, while the cross sectional area of muscle itself remained unaltered. These data suggest a role for oestrogen within the intrinsic actin-myosin contractile function and further exploration of such activity is required. With regard to Parkinson's disease, a recent study by Saunders-Pullman et al57 reports that, in a case-control study of 139 L-DOPA-untreated women with early disease, the relative risk in HRT exposed analysis revealed a multiple regression coefficient of 0.52 (P < 0.001). These authors also noted an inverse relationship between duration of oestrogen use and severity of symptoms. In summary, it is probably too soon to include risk of Alzheimer's disease or other neurodegenerative disorders among the list of indications for HRT use. 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.

Breast The relationship between long-term oestrogen and breast cancer is of supreme interest to women considering an offer of HRT. Continuation studies42'58 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. It appears that the longer the reproductive span, and hence the length of time that breast tissue is exposed to the obligatory cycling of oestrogen and progesterone, the higher the risk of initiation and promotion of malignancy. A very substantial body of literature on the subject was brought together by the Collaborative Group on Hormonal Factors in Breast Cancer59 who reported a re-analysis of 51 epidemiological studies embodying some 52,000 women with breast cancer and over 100,000 without. Estimates of the relative risk of breast cancer following HRT exposure were obtained after stratifying the data for such variables as age at diagnosis, British Medical Bulletin 2000, 56 (No 3)


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BMI, parity and age at first delivery. 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 modal duration of HRT in the UK is 2 years - the incidence of breast cancer is back at baseline 5 years later, irrespective of duration of exposure. No association 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 most 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 most useful for setting risk in context. In this regard, Beral et al59 found that if 1000 European or North American women are followed for 20 years from age 50-70 years and take no HRT, then 45 cases of breast cancer will develop among them. If that same cohort of 1000 all take HRT for 5 years the cumulative excess is two cases (95% CI, 1-3). For 10 and for 15 years exposure, the cumulative excess is 6 (3-9) and 12 (5-20), respectively. Women taking HRT for the UK standard period of - 2 years can, therefore, be advised that their risk of breast cancer will be increased but only by about 2 per 1000 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. It should be noted that the majority of the above data are of North American origin. They reflect that continent's different use of HRT when compared to Europe the preference for equine oestrogen and the frequent use of oestrogen alone in non-hysterectomised women. Recently, the data have been published on the effect of the Selective oEstrogen Receptor Modulator (SERM), raloxifene, on breast cancer incidence. In an RCT of 7704 women followed up for 40 months, Cummings et al60 reported an relative risk of breast cancer of 0.24 (0.13-0.44), the reduction being confined to ER positive tumours. This is a striking reduction in risk especially since the breast cancer rate in the control group was that expected in the population concerned. A follow-up study of high-risk women in which raloxifene is to be compared to 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 2 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 - 3 % . In other words, it is important to advise patients that the great majority of their current and prospective risk is the risk which they would run anyway by virtue of their 820

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sex, age and 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 by the physician. Women receiving HRT should be examined before starting, should be counselled on breast awareness and should be enjoined never to miss their triennial mammographic review.

Conclusions 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 the oestrogen therapy have a substantial literature. For a full survey, the interested reader is commended to a review of the nonreproductive actions of the oestrogens61 and specifically to discussions of their activities in the gastrointestinal, the ocular and the immune systems3"5. 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. References Brzozowski AM, Pike ACW, Dauter Z et al Molecular basis of agomsm and antagonism in the oestrogen receptor. Lancet 1997; 389: 753-8 Brubaker KD, Gay CV Evidence for plasma membrane-mediated effects of estrogen. Calctf Tissue Int 1999; 64 459-62 Hales AM, Chamberlain CG, Murphy CR et al. Estrogen protects lenses against cataract induced by transforming growth factor-p1 / Exp Med 1997; 185 273-80 Grodstein F, Newcombe PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999, 106 574-81 Jansson L, Holmdahl R. Estrogen-mediated lmmunosuppression in autoimmune diseases. Inflamm Res 1998, 47: 290-301 Albright F, Burnett CH, Cope O et al. Acute atrophy of bone (osteoporosis) simulating hyperparathyroidism. / Cltn Endocnnol Metab 1941, 1 711-6 Anon Osteoporosis: Clinical Guidelines for Prevention and Treatment. London: Royal College of Physicians of London, 1999; 18-9 Prestwood KM, Pilbeam CC, Burleson JA et al. The short term effects of conjugated estrogen on bone turnover in older women. / Chn Endocnnol Metab 1994, 79 366-71 Marx (JVC, Dailey 3rd GE, Cheney C et al. Do estrogens improve bone mineral density in osteoporotic women over age 65? / Bone Miner Res 1992; 7: 1275-9 10 Vedi S, Purdie DW, Ballard P et al. Bone remodeling and structure in postmenopausal women treated with long-term, high-dose estrogen therapy. Osteoporos Int 1999; 10: 52-8 11 Wimalawansa SJ. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med 1998,104: 219-26

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Human reproduction, pharmaceutical and technical advances

12 Bradbcer JN, Arlott ME, Meuruer PJ et al.. Treatment of osteoporosis with parathyroid peptide (hPTH 1-34) and oestrogen: increase in volumetric density of iliac cancellous bone may depend on reduced trabecular spacing as well as increased thickness of packets of newly formed bone. Chn Endocnnoi 1992, 37: 282-9 13 Cauley JA, Seeley DG, Ensrud K et al. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1994; 122: 9-16 14 Hutchinson TA, Polansky JM, Feinstein AR, Postmenopausal oestrogens protect against fracture of hip and distal radius. Lancet 1979; iu 705-9 15 Johnson RE, Specht EE The risk of hip fracture in postmenopausal females with and without estrogen drug exposure Am] Public Health 1981; 71- 138-44 16 Linsday R, Hart DM, MacLean A et al Bone response to termination of oestrogen treatment. Lancet 1978;7 1325-7 17 Lufkin EG, Wahner HW, O'Fallon WM et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992; 117: 1-9 18 Ettmger B, Black DM, Mitlak BH. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA 1999; 282: 637-45 19 Michaelsson K, Baron JA, Farahmand BY et al. Swedish Hip Fracture Study Group. Hormone replacement therapy and nsk of hip fracture: population based case-control study. BMJ 1998; 316: 1858-63 20 Oldenhave A, Jaszmann JB, Everaerd Wl et al Hysterectomized women with ovanan conservation report more severe climacteric complaints than do normal climacteric women of similar age. Am J Obstet Gynecol 1993; 168: 765-71 21 Guerne PA, Carson D, Lotz M. IL-6 production by human chondrocytes: modulation of its synthesis by cytokines, growth factors and hormones in vitro. J Immunol 1990; 144: 494—505 22 Nevitt MC, Cumrngs SR, Lane NE et al. Current use of oral estrogen is associated with a decreased prevalence of radiographic hip OA in elderly white women. Arch Intern Med 1998; 156: 2073-80 23 Vingard E, Alfredsson L, Malchau H. Lifestyle factors and hip arthrosis. Ada Orthop Scand 1997; 68 216-20 24 Spector TD, Nandra D, Hart DJ et al. The Chingford Study Is hormone replacement therapy protective for hand and knee osteoarthnos in women? Ann Rheum Dis 1997, 56: 432^t 25 Zhang YQ, McAkndon TE, Hannan MT et al Estrogen replacement therapy and worsening of radiographic knee osteoarthnns. Arth Rheum 1998; 41: 1867-73 26 KanneJ WB, Hjortland MC, McNamara PM et al. The Frammgham Study. Menopause and nsk of cardiovascular group. Ann Intern Med 1976; 85: 447-52 27 The Writing Group for the PEPI Trial. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. Effects of estrogen or estrogen progestin regimens on heart disease nsk factors in postmenopausal women. JAMA 1995; 273: 199-208 28 Delmas PD, Bjarnason NH, Mitlak BH et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometnum in postmenopausal women. N Engl J Med 1997; 337: 1641-7 29 Moncada S, Higgs A The L-argunne-nitnc oxide pathway. N Engl] Med 1993; 329. 2002-12 30 Roque M, Heras M, Roig E et al. Short-term effects of transdermaJ estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pecrons and normal results on coronary angiograms. / Am Coll Cardtol 1998; 31: 139-43 31 Sudhir K, Chou TM, Chatterjee K et al. Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man. Circulation 1997, 96. 3773—7 32 Jiang C, Sarrel PM, Lindsay DC et al. Endothelium-independent relaxation of rabbit coronary artery by 17p"-oestradiol in vitro. Br J Pharmacol 1991, 104: 1033-7 33 Valverde MA, Ro)as P, Amigo J et al. Acute activation of Maxi-K channels {hSlo) by estradiol binding to the B subunit. Nature 1999; 285: 1929-30 34 Grodstein F, Stampfer MJ, Colditz GA et al. Postmenopausal hormone replacement therapy and mortality. N Engl J Med 1997; 336: 1769-75 35 Stampfer MJ, Colditz GA. Estrogen replacement and coronary heart disease: a quantitative assessment of the epidemiological evidence. Prev Med 1991, 20; 47-63 36 Grady D, Rubin SM, Peotti DB et al. Hormone therapy to prevent disease and prolong life in postmenopausal women Ann Intern Med 1992; 117 1016-37


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Consequences of long-term HRT

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