HORMONES AFTER MENOPAUSE?

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1 113 HORMONES AFTER MENOPAUSE? B. Velkeniers Keywords : hormone replacement therapy, menopause, benefits-risks, narrative review ABSTRACT The average life span of a woman is increasing and the age of menopausal onset has not changed much. The length of time that a woman spends in the postmenopausal state is thus increasing. This potential estrogendeficient state may have certain physiologic and metabolic consequences. The onset of menopause is an excellent time to assess a women s overall health and to evaluate the benefit/ risk equation of hormone replacement therapy(hrt). INTRODUCTION Menopause can be viewed medically as an adultonset, potentially primary hypogonadal state with various target tissues affected. The principal areas affected are the integument, genitourinary system, neuroendocrine system, skeleton and cardiovascular system. Menopausal changes affect women differently. Constitutional factors, genetic predisposition, diet, the level of endogenous estrogen, and the level of androgen production all play a role in this variability. Alpha and beta estrogen receptors are present in differing concentrations in various tissues, which can play a role in the manifestation of hormone deficiency, as well as affect the response to various hormone formulations in individual women. Address for correspondence : Prof. Dr. Brigitte Velkeniers AZ-VUB Department of Internal Medicine Laarbeeklaan 101 B-1090 Brussels BELGIUM Tel : Fax : brigitte.velkeniers@az.vub.ac.be A well-informed decision about hormone replacement therapy (HRT), necessitates a discussion of benefits and risks of therapy. There is considerable confusion between established benefits and risks that are based on strong evidence and those that have been suggested by some evidence but have not been confirmed (1). HRT is by far the most effective therapy for treating estrogen-deficient hot flashes. Whether HRT decreases the risk of heart disease, and fracture rate needs to be confirmed. Increased risks of breast cancer, endometrial hyperplasia, thromboembolic events, gallbladder disease, related to HRT have to be considered when one outweighs its benefits. Neuroendocrine changes in the perimenopausal and postmenopausal women include vasomotor symptoms, hot flashes, or hot flushes, which can range from minor inconveniences in some women to debilitating symptoms in others. Hot flashes at night can lead to sleep disturbances with subsequent fatigue and secondary depression, therefore affecting quality of life. The physiology of hot flashes is thought to involve the hypothalamus with pulses of gonadotropin-releasing factor that may affect the autonomic nervous system. Population studies have shown that the experience of symptoms varies in different countries, and are more common and more severe after an induced menopause (2). HRT provides a well established relief of hot flashes and night sweats (3). Most studies of hot flashes have been 1 year or less in length such that the natural history of hot flashes in an untreated group has not been examined well (3). In the postmenopausal Estrogen/Progestin Interventions Trial (PEPI), the difference in hot flash symptomreporting between treated and untreated women diminished between years 1 and 3, compatible with the observed pattern of diminishing hot flashes over time in the placebo group (4).

2 114 HORMONES AFTER MENOPAUSE? Participants of this 3 year, multicenter, double blind placebo-controlled trial (875 menopausal women aged years at baseline) were assigned randomly to one of five groups : 1) placebo, 2) daily conjugated equine estrogens (CEE), 3) CEE plus cyclical medroxyprogesterone acetate (MPA), and 5) CEE plus cyclical micronized progesterone (MP). Symptoms were self-reported using a checklist at 1 and 3 years. All treated women had lower symptom levels compared with those taking placebo; there were no differences between treatments, and the effects of treatment in year 3 were weaker than those in year 1. The effect of all active treatments on vasomotor symptoms, was greater in the adherent compared to the intention-to-treat analysis. Compared with placebo, the odds of having more severe vasomotor symptoms ranged from 0.11 to 0.13 for women adherent to the active treatments in year 1 and 0.16 to 0.29 for the adherent women in year 3. Vasomotor symptoms were the sole symptom group that demonstrated differences in effects of treatment at year 1 versus year 3. Women assigned to active treatment did not differ at years 1 or 3 in the domains of cognitive-affective, anxiety, or musculoskeletal symptoms compared with placebo-assigned women. This trial confirmed a beneficial effect of estrogen on vasomotor symptoms with no additional advantage of added progestin. One important component of the assessment of benefit /risk ratio of HRT is the effect on cardiovascular benefit. Lower cardiovascular mortality is primarily responsible for the improved life expectancy in women. Before the menopausal years, women have a much lower rate of coronary heart disease (CHD) than their male counter parts. However, as they approach menopause, physiological changes occur that increase the risk of CHD. By the sixth decade of life, CHD rates in women approach those in men of the same age (5). Thus, it is believed, estrogen may play a role in premenopausal protection against CHD. Theoretically, HRT should decrease the CHD risk in postmenopausal women by maintaining at postmenopausal levels the metabolic factors that affect CHD. Many mechanistic studies evaluate the effect of HRT on surrogate endpoints (e.g. blood lipid levels, vascular reactivity) believed to be associated with the development of cardiovascular disease. Estrogens affect lipid metabolism, endothelial function, insulin sensitivity, vascular dilation and coagulation factors (see table 1). As menopause approaches, LDL cholesterol concentrations increase from an average of mg/dl in women less than 45 years of age to an average of 140 mg/ dl in women older than 50 (6). Postmenopausal estrogen administration has been shown to decrease LDL cholesterol by 15 % and to increase HDL cholesterol 16 %, both variables are major determinants of CHD risk. However, triglyceride levels are increased 24 % by oral estrogen replacement therapy (ERT). The effect of oral oestradiol (2 mg) was similar to that of CEE (7). Table 1 lipid-dependent mechanisms HDL-cholesterol Apolipoprotein A1 LDL-cholesterol Lipoprotein (a) nonlipid mechanisms insulin resistance, elimination fibrinogen, factor VII, PAI-1 expression of adhesion molecules vasodilatation inhibits proliferation and migration of vascular smooth muscle cells exhibit potent antioxidant properties, leading to LDL oxidation down regulates platelet and monocyte reactivity Mechanistic Evidence of Estrogen-Mediated Cardiovascular protection.

3 115 The lipid effects of estrogen depend on the route of administration, with the transdermal route having less effect on HDL cholesterol and triglycerides than the oral route (8). The effects seen with the oral administration of estrogen are related to the first-pass effect, which does not occur with transdermal administration. The beneficial effects of estrogen on circulating lipids are substantial enough that the National Education Program Expert Panel, the European Atherosclerosis Society and Belgian Lipid Club (9) have recommended hormonal therapy as a first-step approach to postmenopausal women requiring pharmacologic treatment of lipid abnormalities. The use of estrogens as a specific therapy for hypercholesterolemia in postmenopausal women was evaluated in a randomized cross-over trial (10). This trial compared the effects of a combination of CEE (up to 1.25 mg daily) along with 5 mg of MPA daily, with that of an HMG-CoA reductase inhibitor, simvastatin. Both hormone therapy and simvastatin caused significant reductions in total cholesterol (of 14 % and 26 %, resp.) and LDL cholesterol (24 % and 36 %, resp.), but simvastatin was more effective than hormone therapy. Both treatments caused a significant increase (7 %) in HDL cholesterol, with no significant difference between the two. The study noticed an increase in mean trygliceride level with hormone therapy to the limit of normal range. Since estrogen-induced hypertriglyceridemia is associated with a concomitant increase in HDL-cholesterol, the atherogenic potential of estrogen-induced hypertriglyceridemia is questionned. However, caution should clearly be used in administering oral hormone therapy to women with pre-existing hypertriglyceridemia. Progestational agents, generally, but variably, have an opposite effect on the lipid-mediated mechanisms. Therefore, the choice of the progestational agent may be a determining factor in the overall observed lipid effect. A progestin is commonly administered with estrogen in women with an intact uterus to diminish hyperplasia of the endometrium and prevent indometrial cancer (see below). MPA and levonorgestrel lower HDL cholesterol, while oral MP seems to have little or no adverse lipid effects (11). In the PEPI trial, active treatments (CEE mg/ d, CEE mg/d plus cyclic MPA 10 mg/d for 12 d/mo, CEE mg/d plus consecutive MPA 2.5 mg/ d or CEE mg/d plus cyclic MP 200 mg/d for 12d/mo), decreased mean LDL cholesterol and increased mean triglycerides compared to placebo (12). Each active treatment regimen was associated with a significantly greater increase in mean HDL-cholesterol levels than placebo. The average increases in HDLcholesterol levels were similar in women assigned to CEE alone or CEE with MP, and these women had significantly greater HDL-C elevations than women assigned to CEE with cyclic or continuous MPA. The comparative effects on lipids were further analyzed in the CHART study (13). Continuous norethindrone acetate (NA) ethinyl estradiol (E 2 ) combination and unopposed E 2 compared favorably to placebo in this 2 year, double blind / placebo controlled clinical trial. The percentage of change in the ratio of HDL-cholesterol to LDL-cholesterol was positive for all treatment groups. The increase in triglycerides associated with EE 2 was attenuated with NA-EE 2 treatment. Also, norethindrone acetate (2.5 mg or 5 mg) prevents the estrogen-induced increase in triglyceride levels (14). Two reviews of randomized clinical trials conclude that the addition of non-androgenic progestins, in appropriate continuous or cyclic doses, to a continuous estrogen regimen, resorted in a more favourable lipoprotein profile than that seen in the woman at baseline or in untreated postmenopausal women (15,16). Moreover, different reports found that estrogen replacement, with or without concomitant progestin regimens, produced consistent reductions in Lp(a) levels (17,18). Estrogen alters various haemostatic factors that may increase an individual s risk of CHD. In the PEPI trial there was a greater increase in fibrinogen levels during the three year follow-up period among patients given placebo than among patients given either estrogen alone or estrogen combined with MPA or MP. In addition to these effects on fibrinogen, estrogen opposes platelet aggregation and increases blood flow by increasing local production of prostacyclin, which produces a favorable balance between prostacyclin and thromboxane (19). There is substantial evidence that estrogen affects vasodilatation and vascular tone (20). Estrogen and progesterone both have antioxidant effects, and estrogen is reported to favorably affect homocysteine levels in postmenopausal women (21,22). Along with the mechanistic results, there are substantial observational data (data from non-randomized

4 116 HORMONES AFTER MENOPAUSE? studies) supporting the role of HRT in preventing CHD. Different meta-analysis of these data have been performed (23,24,25). Grady and coworkers evaluated the effects of estrogen and estrogen plus progestin on CHD. They included in their analysis 30 epidemiological studies published after 1970 on the relationship between HRT and CHD. The pooled estimate of the relative risk of CHD was 0.65 (95 % CI, ) for women who had used estrogen compared with those who had never used estrogen (23). The Nurse s Health study, a large prospective cohort study that included postmenopausal women, provides estimates of the cardioprotective effects of HRT. At 16 years of follow-up, the relative risk of CHD in women who used only unopposed estrogen was 0.60 (95 % CI, ). Although the lower risk of cardiac disease in nurses could be due to the fact that users take better care of their health, the beneficial effects remain even after adjustment for cardiac risk factors such as weight and smoking(25). Because progestins attenuate the benefit of estrogen on HDL, it was considered possible that combined estrogen-progestin therapy would be less cardioprotective. In the nurse s health study, the risk of major CHD was also lower among women who reported taking estrogen with progestin (RR 0.39, 95 % CI, ) than among women who reported taking estrogen alone. In another population based control study in a cohort of women 50 to 74 years of age, without cardiovascular disease history, odds ratio s for unopposed and opposed therapy were 0.52 (95 % CI 0.35 to 0.78) and 0.79 (95 % CI, 0.59 to 1.08). The effect remained unchanged after adjusting for hypertension, hypercholesterolemia, diabetes and other risk factors (26). The protective effect was present at medium-high doses of estrogens for oral and transdermal therapy and diminished 2 to 3 years after cessation of HRT. This study did not observe an increase in risk of myocardial infarction within the first year. Nevertheless, a metaanalysis of 4124 women reported a higher incidence of cardiovascular diseases from published trials that studied other outcomes of postmenopausal therapy. The calculated odds ratios for women taking hormones versus those not taking hormones was 1.39 (95 % CI ) for cardiovascular events (27). These results concern only short term effects of HRT, and long term effects may be different. In a recent analysis of the nurse s health study the authors report on the relation among low-dose estrogen, short-term hormone use, and cardiovascular events in postmenopausal women with no previous cardiovascular disease (28). When all cardiovascular risk factors were considered, the risk of major coronary events was lower among current users of hormone therapy, including short-term users, compared with never users (RR 0.61, CI ). Among women taking oral conjugated estrogens, the risk for coronary events was similarly reduced in those currently taking mg daily (RR 0.54, CI ) and those taking 0.3 mg daily (RR 0.58, CI ), compared with never-users. However, estrogen at daily doses of mg or greater and in combination with progestin may increase risk for stroke. The lower rate of cardiovascular events among shortterm users of hormone therapy was statistically significant in this study and the upper bound of the 95 % CI was 0.80, indicating a negligible likelihood that the data would be compatible with an increased risk (28). Even though observational studies (cohort- and case control studies) help strengthen the possibility that HRT reduces the risk of CHD, study bias can influence the risk estimates. Some of the biases that need to be considered are healthy-users bias, compliance bias, surveillance bias, and healthy survivor bias. Healthy-user bias is possible because women who take estrogen tend to be of a higher socioeconomic status, better educated, more compliant, thinner, and more likely to drink alcohol than those who do not take estrogens (29,30). Randomized trials are thus required to prove benefits in primary prevention and to define their magnitude. Data from the women s heath initiative, an ongoing randomized clinical trial of HRT are expected in A recent interim report however, documented slight excess of coronary heart disease and stroke during the first 2 years of this large randomized controlled trial in HRT users (31). The observed association between estrogen therapy and reduced CHD risk has been reported to be especially strong for secondary prevention in women with CHD (32 38). The Heart and Estrogen/Progestin Replacement Study (HERS) was the first large, randomized doubleblind, placebo controlled trial evaluating the effectiveness of estrogen plus progesterone in reducing the risk of myocardial infarction and CHD death in postmenopausal women with CHD (39). A total of women with coronary disease, younger than 80 years, and post-

5 117 menopausal with an intact uterus were randomly assigned to either mg of CEE plus MPA or a placebo (mean age = 66.7 years). Follow-up averaged 4.1 years. Overall, there were no significant differences between groups in the primary outcome (occurrence of non-fatal MI or CHD death) as in any of the secondary cardiovascular outcomes (including coronary revascularisation, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease) : revised HERS results : 179 women with primary CHD events in the estrogen plus progestin group and 182 in the placebo group (relative hazard 0.99, 95 % CI ). The lack of an overall effect occurred despite a net 11 % lower LDL cholesterol level and 10 % higher HDL cholesterol level in the hormone group compared with the placebo group. Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. The authors thought that the results might be attributable to dual effects, e.g. an immediate prothrombotic, proarrhytmic, or proischemic effect that was later outweighed by slower progression of atherosclerosis (39). Herrington et al (40) examined the short-term effects of postmenopausal hormone therapy in terms of secondary prevention in women with established CHD. A total of 309 women with previously diagnosed artery disease were randomly assigned to receive mg of CEE per day, mg of CEE plus 2.5 mg of MPA per day, or placebo and were followed for a mean of 3.2 years. The primary endpoint was the development of new coronary lesions or the progression of established lesions, as determined by quantitative coronary angiography. Neither hormone regimen altered the incidence of new lesions or the rate of progression of established lesions, as measured angiographically, as compared with the outcome with placebo. The rate of clinical cardiovascular events were similar in the two groups, although this was not a primary endpoint. In the study of Herrington et al., as in HERS, HRT was initiated late (mean age 65 years of age), and may not protect against CHD events when initiated so long after menopause. Both trials had a relatively short follow-up (3 and 4.1 years), and protective effects may become evident only later (41). Ignoring the earlier occurrence of events in the HRT group, the HERS trial results in an apparent risk reduction of 34 %, beginning 3 years after the initiation of therapy. The medical treatment of HERS women was not in accordance with current practice guidelines. Only 78 % of women were receiving acetylsalicylic acid, 22 % were on beta-blockers and only 10 % achieved LDL cholesterol targets for secondary prevention. The results may have been further confounded in that more women in placebo-group than in the active group were started on lipid-lowering agents (22 % versus 18 %). These observations, however, illustrate the need for caution in the interpretation of observational studies and suggest that hormone replacement therapy should not be initiated for women with a history of coronary heart disease. The beneficial effects of hormone replacement therapy on bone mineral density at a variety of skeletal sites, including the spine, proximal femur and radius, have been documented in numerous prospective studies (42-45). These effects are seen both when HRT is commenced at the time of menopause and when it is started years later. Oral, and transdermal formulations of estrogen are effective, and unopposed estrogen and combined estrogen progestagen replacement appear to have a similar effect. The improvement in bone mineral density is not maintained after cessation of therapy, this suggests that lifelong therapy is necessary for prevention of osteoporosis (45). However, fracture is the only important clinical outcome of osteoporosis. Any intervention should aim to reduce the fracture risk. Anti-fracture efficacy of HRT is reviewed in Best Evidence (fourth edition). Only 2 randomized controlled trials (46-47) evaluated vertebral fracture incidence on HRT. One RCT in 75 postmenopausal women (47 75 years of age with one or more vertebral fractures) evaluated transdermal HRT (17 ß oestradiol and oral MPA) (46). After 12 months there were fewer vertebral fractures with HRT than with placebo (8 fractures in 7 women with HRT vs. 20 fractures in 12 women with placebo, (RR 0.39, 95 % CI ). The second randomized trial (100 postmenopausal women) found that, over a median of 9 years, estrogen reduced total spine score, an indirect measurement of vertebral fracture rate but had no effect on the number of women with a vertebral crush fracture (1/57 with estrogen, 5/42 with placebo, RR 0.15, 95 % CI ) (47). For non-vertebral fracture, the evidence of anti-fracture efficacy is based on observational data (48, 49), however with conflicting results. In HERS, prevention of fracture was a secondary endpoint. It was found that estrogen had no effect on the number of woman with a hip fracture (0.9 % with HRT, 0.8 % in placebo, RR 1.09, 95 % CI ) or on the number with any

6 118 HORMONES AFTER MENOPAUSE? fracture (0.9 % with HRT, 10 % with placebo, RR 0.94, 95 % CI ) (39). Another RCT randomized 464 postmenopausal women to one of four groups : HRT alone (oestradiol and cyproterone), vitamin D alone, HRT plus vitamin D, or placebo (50). At a mean of 4.3 years follow-up, comparison of the two HRT groups versus the two groups not receiving HRT showed a reduction in the number of non-vertebral fractures (RR 0.44, 95 % CI ). Also, in a population-based control study from Sweden of women with hip fracture, a greater protection against fracture was seen in current users as opposed to past users, and 5 years after the cessation of hormone replacement therapy, the risk of hip fracture in former users had reverted to that of non-users (51). Other potential but as yet unproven benefits of longterm HRT include a reduction in the risk of colon cancer (52), improved cognitive function and protection against Alzheimer s disease (53-54). Main results on the development of endometrial hyperplasia and/or carcinoma were summarized in the Cochrane database of systematic reviews (55). Unopposed moderate or high dose oestrogen therapy was associated with a significant increase in rates of endometrial hyperplasia with increasing rates at longer duration of treatment and follow-up. Odds ratios ranged from 5.4 ( ) for 6 months of treatment to 16.0 ( ) for 36 months of treatment with moderate dose oestrogen (in the PEPI trial, 62 % of those who took moderate dose oestrogen had some form of hyperplasia at 36 months compared to 2 % of those who took placebo). Irregular bleeding and non adherence to treatment were also significantly more likely under these unopposed oestrogen regimens with greater effects with higher dose therapy. The addition of progestogens, either in continuous combined or sequential regimens, helped to prevent the development of endometrial hyperplasia and improved adherence to therapy. Irregular bleeding, however, was more likely under a continuous than a sequential oestrogen-progestogen regimen. At longer duration of treatment, continuous therapy was more protective than sequential therapy in preventing endometrial hyperplasia. There was evidence of a higher incidence of hyperplasia under long cycle sequential therapy (progestogen given every 3 months) compared to monthly sequential therapy (progestogen given every month). No increase in endometrial cancer was seen in any of the treatment groups during the limited duration (maximum of 3 years) of the trials. A small increase in the risk of endometrial cancer was however reported by Beresford et al. in relation to use of estrogen combined with cyclic progestogen therapy in postmenopausal women.(56) The major concern with long-term HRT use is an increase in the risk of breast cancer. More than 50 epidemiological studies (seven cohort studies, 45 case control studies), none of them randomized, have explored the relation between HRT and breast cancer. Risk estimates for breast cancer vary (odds ratio, from 0.5 to 2). Sources of heterogeneity of results in epidemiologic studies, include different baseline risks, variety of intervention protocols, referral funnel, data collection differences, small studies with imprecise estimates. Despite uncertainty, meta-analysis agree that there is no increase in risk for breast cancer when HRT is used 5 years or less (OR 1.05, 95 % CI ). However, an increased risk for breast cancer may be seen in women who have used HRT for more than 5 years (OR 1.22, 95 % CI ) (57-63). Most epidemiologic studies have grouped together estrogen only and combination-progesteron use. In studies that have distinguished between these groups, treatment with estrogen plus progestin was associated with a higher risk of breast cancer than unopposed estrogen, although this difference was not statistically different. Based upon these data, it is estimated that treatment with HRT increases baseline incidence of invasive breast cancer (296.9 cases per annum per (64), with 5, 21 and 15 cases for resp. estrogen alone, estrogen + cyclic progesterone, estrogen + continuous progesterone. The absolute risk increase therefore per annum is extremely small. Other adverse side-effects include an increase in the risk of venous thromboembolism. Epidemiologic studies have shown a twofold to fourfold increased risk of venous thromboembolism among postmenopausal women using HRT (65-68). In healthy women, the absolute numbers of extra cases of deep venous thrombosis and pulmonary embolism attributed to HRT seem to be only 1 in 5000 users per year and 1 in users per year, respectively. The absolute increase in risk is small. In the HERS population of older women with established coronary heart disease, the group using HRT had 1 extra venous thromboembolic event per 256 users per year (NNH : 256), compared with those taking placebo (69) (RH 2.7; 1.4-

7 ). This risk was 50 % lower in women who reported using aspirin during the trial than in those who did not. In women who have a lower-extremity fracture, recent surgery or other hospitalization, cancer, congestive heart failure, myocardial infarction, or stroke, the risk of venous thromboembolism is 2- to 30-fold, and they accounted for 75 % of all cases of venous thromboembolism in HERS. Postmenopausal estrogen also increases the risk of gallbladder disease and cholecystectomy. Epidemiologic studies have shown an increased risk of gallstones with HRT. The nurse s health study found a relative risk of 2.1 (95 % CI ) for cholecystectomy among women using postmenopausal hormones. This risk was higher in women who had used estrogen for 10 years or more (RR 2.6, CI ) and persisted for at least 5 years after last use (RR % CI ). The increase has been confirmed in the PEPI trial and the HERS study (13, 39). CONCLUSION Making decisions about whether or not to use HRT will never be easy. In the immediate postmenopausal period some women may have tremendous problems with flushing, for which estrogen replacement therapy is efficacious. Women with an intact uterus should not receive unopposed estrogen therapy. Yet, deciding to take HRT remains difficult because of conflicting long-term risks and benefits. HRT leads to small but significant risk increase of breast cancer, endometrial cancer, and thromboembolism, while decreasing risks of developing osteoporosis and hip fracture and possibly of coronary heart disease. More women die each year from heart disease than from any other cause, including breast cancer. Therefore, any prediction of benefit on coronary artery disease will offset the small risk increase related to breast cancer and endometrial cancer. Today, we do not know whether estrogen will prevent cardiovascular disease, and we will not know until the large clinical trials now underway are completed (70). A decision analysis model based on epidemiological data suggests that hormone therapy should increase average life expectancy of most postmenopausal women. The only women not expected to gain from this treatment are both at greatest risk for breast cancer and at least risk for CHD (71). Any projection of potential benefit based on observational epidemiology or surrogate variables is however highly speculative. The data are non randomized and likely to be confounded by different bias. The first of randomized trials, the HERS trial, a secondary prevention trial, failed to show a benefit on cardiovascular events in older women with coronary artery disease and reported a significant 3-fold increase of venous thromboembolism. The adverse trend may be explained by the acute prothrombotic effects predominating early on. The findings do not lend support to the use of HRT in such women. One of the shortcomings of the trial is it relatively short duration and the negative outcome of the HERS study should not be applied to younger postmenopausal women without coronary artery disease. Although the CHD risk of a typical 50-year old women exceeds the combined risks of all other conditions, hypothetical decreased all caused mortality related to the use of HRT remains to be proven. ACKNOWLEDGEMENTS We thank prof. dr. J.A. Collins (Mc Master University, Canada) for his advice and comments, during his lectures on evidence-based medicine. The author acknowledges Mrs. Ilse De Wannemacker for her assistance and secretarial help. REFERENCES 1. Sully MC Nagny. Prescribing Hormone Replacement Therapy for menopausal symptoms. Annals of Internal Medicine 1999; 131 : Poster M, Penney GC, Russel D, Russel E, Terupleton A. A population based survey of women s experience of the menopause. Br J Obstet Gynaecol 1996; 103 : Kronenberg F. Hot flashes : phenomenology, quality of life, and search for treatment options. Exp Gerontol 1994; 29 : Greendale GA, Reboussin BA, Hogan P et al. Symptom Relief and Side Effects of Postmenopausal Hormones : Results From the Postmenopausal Estrogen/Progestin Interventions trial. Obstetrics & Gynecology 1998; 92 : Sotelo MM, Johnson SR. The effects of hormone replacement therapy on coronary heart disease. Endocrinol Metab Clin North Am 1997; 26 : Kannel WB. Metabolic risk factors for coronary heart disease in women : perspective from the Framingham Study. Am Heart J 1987; 114 : Walsh BW, Schiff I, Rosner B, et al. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. 1991; 325 :

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