Trials Of Hormone Replacement Therapy Research Articles

Perspectives on the Women’s Health Initiative trial of hormone replacement therapy

The premature termination of one comparison in the Women’s Health Initiative primary prevention trial due to stopping rules being reached necessitates a reconsideration of hormone replacement therapy (HRT). This part of the Women’s Health Initiative trial, however, examined only one popular HRT regimen (conjugated equine estrogen [0.625 mg] and medroxyprogesterone acetate [2.5 mg] daily) in asymptomatic postmenopausal women. To help clinicians understand this large, complex trial, we describe several pervasive biases in earlier observational studies, review the principal findings of the trial, summarize recent systematic reviews, and offer clinical suggestions for HRT. Observational studies of HRT have found consistent, powerful protection against heart disease; this now appears due to consistent, powerful selection biases. These biases have the same net effect: Women using HRT in observational studies were healthier than those not using it. The Women’s Health Initiative trial found that the overall risk-benefit ratio tipped against using HRT for prevention. Cardiovascular disease and breast cancer were increased among users, whereas colorectal cancer and osteoporotic fractures were reduced. Whether these findings relate to women with menopausal symptoms and to different HRT regimens is unknown. Hormone replacement therapy remains the best treatment for menopausal symptoms. Although estrogen has proven benefit for osteoporosis prevention, alternatives include raloxifene, alendronate, and risedronate. For women needing HRT, use of a low dose, with reassessments at least annually, appears prudent. Heart disease prevention strategies of proven value include exercise, weight control, blood pressure and lipid control, and avoidance of smoking. Hormone replacement therapy should not be used for this purpose.

The menopause, hormone replacement therapy and breast cancer

Concern exists that the reduction in breast cancer risk associated with the onset of the menopause will be negated with exposure to hormone replacement therapy (HRT). Evidence from large-scale randomised HRT trials support observational data that have shown a modest increase in breast cancer risk with long-term use (i.e. >15 years) of combined therapy, although this falls following HRT cessation suggesting a growth-promoting effect. Randomised evidence demonstrates that the efficacy of anti-estrogens, aromatase inhibitors and raloxifene in the treatment and chemoprevention of breast cancer are restricted to women with oestrogen receptor positive (ER +ve) disease; however, HRT has not been associated conclusively with a predominance of hormone sensitive breast cancer. Despite stimulating the breast cancer cell growth, HRT has not been shown to increase breast cancer recurrence or mortality when prescribed to breast cancer survivors experiencing oestrogen deficiency symptoms and randomised trials have been recommended and commenced. In conjunction with controlled breast cancer trials demonstrating a therapeutic benefit of high dose estrogens and interest in the use of additive oestrogen therapy in patients developing resistance to oestrogen deprivation, the dogma that HRT is an absolute contra-indication following diagnosis is challenged.

WISDOM: history and early demise - was it inevitable?

In 1989, the UK Medical Research Council (MRC) agreed that, if feasible, a randomized controlled trial to assess the long-term risks and benefits of hormone replacement therapy (HRT) was a priority. Feasibility work began in 1990 and demonstrated that a large-scale multicenter trial was possible. An application for funding for a main trial was submitted to MRC in 1993 and, after extensive review, funding was released in late 1996. Set-up work for the trial - the Women's International Study of long Duration Oestrogen after Menopause (WISDOM) - began in 1997 with recruitment in 1999. In October 2002, following the early discontinuation of one arm of the US Women's Health Initiative HRT trial, the MRC decided to stop the WISDOM trial. This article, by the principal UK investigators of WISDOM, sets out the background and history of the trial.

The willingness of women to participate in a long-term trial of hormone replacement therapy: A qualitative study using focus groups

The actual proportion of eligible people who participate in clinical trials is low. Consequently, a qualitative study of the willingness of women who are postmenopausal to participate in a long-term randomized control trial of hormone replacement therapy (HRT) designed to investigate the prevention of degenerative diseases was conducted. Focus group methodology was employed to explore the personal and social aspects of decision making about trial participation. Participants were randomly selected from the patient age-sex registers of four University of Adelaide general practices. Twenty-one women participated in four focus groups. The reasons for and against trial participation were examined using qualitative content analysis; ( n = 18) women were unwilling to participate in the trial. The lack of perceived individual benefit, minimal altruism, the risk of breast cancer and side effects, not wanting to take unnecessary medication, a ten-year commitment, and negative experiences of HRT use, were the main reasons given for not entering the trial. Of the few women ( n = 3) who clearly would enter the trial, free prescriptions and a positive history of using HRT were the main reasons for participation. The perceived disadvantages of clinical trials of HRT deter women from participating in a long-term clinical trial of HRT. An investment in education and information to eligible participants about both the risks and potential benefits of HRT may improve trial recruitment.

Noncardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-Up (HERS II)

Hulley, Stephen; Furberg, Curt; Barrett-Connor, Elizabeth; Cauley, Jane; Grady, Deborah; Haskell, William; Knopp, Robert; Lowery, Maureen; Satterfield, Suzanne; Schrott, Helmut; Vittinghoff, Eric; Hunninghake, Donald for the HERS Research Group

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Experience of Postmenopausal Women of Hormone Replacement Therapy

Goal: The purpose of this study was to examine and describe women's physical and psychological changes after a trial of hormone replacement therapy (HRT), so as to be able to provide accurate information about HRT to women who are preparing to undergo HRT.Methods: The study sample consisted of 10 women who were taking hormones for treatment of postmenopausal symptoms. Data were collected from September 2000 to March 2001. Interviews were recorded and transferred to written documents. The analysis of the data used the methodology described by Giogi.Results: The subjects reported that taking HRT was an excellent choice for enhancing their quality of life during menopause because they felt younger and healthier, although they expressed concern about unexpected side‐effects, after their HRT. They felt that such effects could be prevented through regular check‐ups. The participants recommended that all postmenopausal women take HRT because they believed the benefit of HRT was greater than its harmfulness. The subjects also suggested that postmenopausal women need to be educated about the physical and psychological symptoms that they feel during menopause and about how to manage the symptoms. It was concluded that accurate information about the relationship between HRT and the quality of life should be provided to postmenopausal women, in addition to providing educational programs on postmenopausal management to postmenopausal women.

Evidence from randomised trials on the long-term effects of hormone replacement therapy

Over the past few decades hormone replacement therapy (HRT) has been used increasingly by post-menopausal women in western countries. The need for objective data on long-term effects prompted the setting up of randomised trials to compare cancer and cardiovascular disease endpoints in HRT users and non-users. With the early termination of part of the Women's Health Initiative trial (JAMA 2002; 288: 321-33), it is timely to review the evidence from such studies. Four randomised trials including over 20000 women followed up for 4.9 years, on average, have now reported on the effect of HRT for major, potentially fatal, conditions. Overall, HRT users had a significantly increased incidence of breast cancer, stroke, and pulmonary embolism; a significantly reduced incidence of colorectal cancer and fractured neck of femur; but no significant change in endometrial cancer or coronary heart disease.There was no significant variation across the trials in the results for any condition. Three trials had recruited women with previous cardiovascular disease and the fourth, the Women's Health Initiative, had recruited healthy women. Combined oestrogen/progestagen HRT was used in three trials and oestrogen alone in one. Use of HRT over a 5-year period by healthy postmenopausal women in western countries is estimated to cause an extra breast cancer,stroke, or pulmonary embolus in about 6 per 1000 users aged 50-59 and 12 per 1000 aged 60-69. Over the same period, the estimated reduction in incidence of colorectal cancer or fractured neck of femur is 1.7 per 1000 users aged 50-59 and 5.5 per 1000 aged 60-69. The increased incidence of any one of these conditions is greater than any reduction, the estimated net excess over 5 years being 1 per 230 users aged 50-59, and 1 per 150 aged 60-69. Substantial new data should soon be available from randomised trials of oestrogen-alone HRT versus placebo, whereas few additional trial data on combined HRT are expected for about a decade. Existing randomised trials are too small to describe reliably the effect of HRT on important but rarer conditions, such as ovarian cancer, or on cause-specific mortality. Nor will they provide information about other types of oestrogen or progestagen. Answers to such questions will require judicious analysis and interpretation of data from observational studies.

A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study

Objective To assess the possible benefit of hormone replacement therapy (HRT) in the secondary prevention of ischaemic heart disease. Design A prospective randomised trial of transdermal HRT in women with definite ischaemic heart disease. Setting A regional cardiac unit. Population Postmenopausal women with angiographically ischaemic heart disease. Methods A total of 255 postmenopausal women with angiographically proven ischaemic heart disease were recruited and randomised; 134 were treated with transdermal HRT and 121 acted as controls. The women were seen at six monthly intervals. The primary end points, which were determined by a blinded assessor, were admission to hospital with unstable angina, proven myocardial infarction or cardiac death. A total of 53 (40%) patients withdrew from the HRT group and eight (7%) from the control group. The mean duration of follow up was 30.8 months. Main outcome measures Admission to hospital with unstable angina, proven myocardial infarction or cardiac death. Results During follow up, there were 53 primary end-point events in the HRT group and 37 in the control group. Using an intention-to-treat analysis, the primary end-point event rate was 15.4 events per 100 patient years for the HRT group compared with 11.9 for the control group (event rate ratio 1.29 (95% CI 0.84–1.95, P = 0.24)). Using a per-protocol analysis, there was an event rate ratio of 1.49 (0.93–2.36, P = 0.11) for the HRT arm compared with the control arm. Particularly during the first two years of follow up, the HRT group had a higher, but not statistically significant, event rate than the control group. Conclusion Our findings suggest that transdermal HRT should not be commenced for the purpose of secondary prevention in postmenopausal women with angiographically proven ischaemic heart disease.

The choice of hormone replacement therapy or statin therapy in the treatment of hyperlipidemic postmenopausal women.

(a) Statins: the major measurable effect of these drugs is to reduce total and LDL cholesterol. In RCT trials, the Scandanavian Simvastatin Survival Study (4S), the Cholesterol and Recurrent Event (CARE) and Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID), approximately 20% of subjects were female, in whom CHD events, but not CHD or total mortality were reduced. (b) HRT: there is data available from a single RCT of continuous combined premarin and medroxyprogesterone acetate (MPA) against placebo, The Heart Estrogen Replacement Study (HERS). A study of 2763 women and mean duration of 4.1 years. This study was neutral, with no reduction in CHD events or mortality. There were more events in the first year, and fewer in years 3-5. Other studies of HRT have been observational and positive for HRT. The effects of treatment on lipoproteins with statins, HRT and combination of statin and HRT have been investigated. In secondary prevention for hyperlipidemic women to achieve cholesterol <5, low density lipoprotein (LDL)<3 mmol/l statins will be first choice, possibly with HRT additionally for its other benefits on cardiovascular risk factors.

Hormone replacement therapy trials: an update.

Recent randomized trials of hormone replacement therapy (HRT) in postmenopausal women are not consistent with the decrease in cardiovascular risk seen in observational studies of hormone therapy users compared with nonusers. Emerging evidence indicates that HRT use in some women with established coronary heart disease may be associated with prothrombotic effects or proinflammatory effects leading to adverse events. In healthy women, the decision to use HRT should be based primarily on noncardiac factors until more data becomes available that is relevant to this population. Several alternatives to HRT, including phytoestrogens and selective estrogen receptor modulators, have favorable effects on cardiovascular risk factors, but their impact on clinical outcomes remains to be determined.

Postmenopausal hormone replacement therapy as antiatherosclerotic therapy.

Cardiovascular disease remains the number one killer of women. Although important for the reduction of cardiovascular events, lipid alteration does not appear to be sufficient to obtain optimum reduction in cardiovascular risk. Women have a potential opportunity for further reduction in cardiovascular risk through postmenopausal hormone replacement therapy. More than 50 observational studies indicate that postmenopausal use of hormone replacement therapy reduces atherosclerosis and cardiovascular events. However, recently reported, randomized, controlled clinical trials have yielded mixed results as to whether hormone replacement therapy reduces cardiovascular events relative to placebo. These, as well as other randomized controlled trials of hormone replacement therapy and cardiovascular disease in postmenopausal women, are reviewed. Although conclusions concerning the specific hormones used in the specific populations studied can be offered from the completed trials, more broad conclusions concerning the use of hormone replacement therapy in the prevention of cardiovascular disease will have to await conduction and completion of other trials.

WISDOM: history and early demise – was it inevitable?

In 1989, the UK Medical Research Council (MRC) agreed that, if feasible, a randomized controlled trial to assess the long-term risks and benefits of hormone replacement therapy (HRT) was a priority. Feasibilitywork began in 1990 and demonstrated that a large-scale multicenter trial was possible. An application for funding for a main trial was submitted to MRC in 1993 and, after extensive review, funding was releasedin late 1996. Set-up work for the trial - the Women's International Study of long Duration Oestrogen after Menopause (WISDOM) - began in 1997 with recruitment in 1999.In October 2002, following theearly discontinuation of one arm of the US Women's Health Initiative HRT trial, the MRC decided to stop the WISDOM trial. This article, by the principal UK investigators of WISDOM, sets out the backgroundand history of the trial.

Relation of estrogen receptor-α gene polymorphism and hormone replacement therapy to fall risk and muscle strength in early postmenopausal women

BACKGROUND. Several factors may increase fracture risk, among them reduced bone mineral density (BMD), increased bone resorption, microarchitectural deterioration of bone, increased fall risk, and decreased muscle strength. We have previously reported that PvuII polymorphism of the estrogen receptor-α (ER α) gene is associated with bone loss rate, fracture risk, and response to hormone replacement therapy (HRT) in early postmenopausal Finnish women.METHOD. We studied the influence of the ERα genotype on fall risk and muscle strength in a 5-year randomized HRT trial of 331 early postmenopausal women (subgroup of the population-based OSTPRE study, Kuopio, Finland). A 5-year postal inquiry in May 1994 included questions on falls during the previous 12 months. Grip strength was measured with dynamometer. The ERα gene polymorphism was analysed using PCR and PvuII restriction enzyme digestion. RESULTS. In all, 97 out of the 331 women reported falls. Half of those (56%) were slip falls, mostly during the winter season. In the HRT group, the ERα genotype was associated with fall risk (P = 0.002, logistic regression). The risk of falls (RR) was higher in women with the PP genotype than in those with the Pp (RR = 5.26, 95% CI 1.98-13.94, P = 0.001) or the pp (RR = 3.84, 95% CI 1.46-10.12, P = 0.007) genotype. When the falls were divided into slip (environment-related) and non-slip (endogenous) falls, the non-slip falls were associated with the genotype (P = 0.004), but the slip falls were not so clearly (P = 0.061). When all falls and non-slip falls were adjusted to the number of chronic health disorders and the variable time-since-menopause, the difference between the genotypes persisted (P = 0.003 and P = 0.010, respectively). In the non-HRT group, the ERα genotype was not associated with fall risk. The baseline or the 5-year grip strength values were not influenced by the ERα genotype. In conclusion, ER α polymorphism is associated with fall risk, especially with non-slip falls, in early postmenopausal Finnish women during the HRT. We have previously reported that, during HRT, women with the P allele have decreased fracture risk and that they may preferentially derive benefit from the positive effect of HRT on BMD. This suggests that the influence of ERα polymorphism may depend on the target tissue (bone versus the nervous system). CONCLUSIONS. In these early postmenopausal, non-osteoporotic and relatively healthy women, the increased fall risk associated with the PP genotype was not associated with increased fracture risk, possibly due to improved bone strength during the HRT although falls generally predispose to fractures.

Changing Rationales for Longterm Hormone Replacement Therapy in America, 1960-2000

In the Spring of 2000, American newspapers reported disturbing preliminary results from the Hormone Replacement Therapy trial of the Women's Health Initiative, a study sponsored by the National Institutes of Health involving 25,000 postmenopausal women.1 Data collected from the first several years of the projected nine-year investigation indicated that women taking oestrogen had a slightly greater risk of having heart attacks, strokes and blood clots than did those assigned to a placebo. This finding cast doubt on the prevalent medical practice of advising older women to take oestrogen on a long-term basis, allegedly to prevent both osteoporosis and heart disease. Although the study did not challenge the role of oestrogen in slowing bone loss, its dispute of the indication for heart disease made a whole new generation of women begin to question the wisdom of taking hormones for the rest of their lives. I say a 'whole new generation', because a similar scenario played out some twenty-five years ago. In the mid to late 1970s, the fate of oestrogen replacement therapy was very much in question. By that time, physicians had been prescribing oestrogen for menopausal and postmenopausal women for more than thirty years. In 1975, scientific studies demonstrated that oestrogen use increased the risk of endometrial cancer. This announcement followed on the heels of several other dis-

Cardiovascular Trials of Estrogen Replacement Therapy

An impressive body of evidence has suggested that estrogen therapy should be helpful to slow the pathogenesis or progression of atherosclerosis. Estrogen's favorable effects on lipids and endothelial function, coupled with extensive observational epidemiology and data from animal models of atherosclerosis, persuaded many that hormone replacement therapy (HRT) would be helpful for both primary and secondary prevention of coronary disease. Recently, several randomized clinical trials of HRT have been completed, and several more are currently under way. These trials include both primary and secondary prevention cohorts and use clinical as well as anatomic manifestations of atherosclerosis as outcomes. These trials are producing surprising and controversial results that will radically alter contemporary understanding of the role of HRT for cardiovascular disease prevention. This review briefly describes the findings of the Heart and Estrogen/Progestin Replacement Study, the Estrogen Replacement and Atherosclerosis Trial, and other recently completed clinical trials. Trials that are under way are also described and discussed.

The Time Has Come to Stop Letting the HERS Tale Wag the Dogma

The premise of this commentary is simple. We believe there has been enormous overinterpretation and misinterpretation of recent clinical data (the HERS tale1) with regard to the efficacy of hormone replacement therapy (HRT) in preventing or diminishing the risk of heart disease (the dogma). Both the medical and lay press have focused on obtaining a single yes-or-no answer to the question, “Does postmenopausal HRT reduce the risk of cardiovascular disease (CVD)?” This oversimplified approach has led to unjustified generalizations with regard to the question and to the summary judgment in some circles that HRT is not beneficial for the prevention of heart disease. See p 2300 A brief review of the literature in this area reveals the source of much of the controversy and confusion. In 1992, an elegant meta-analysis by Grady and colleagues2 concluded that “there is extensive and consistent observational evidence that estrogen use reduces risks for CHD [coronary heart disease] about 35%.” This conclusion has since been supported by additional observational studies that together include several hundred thousand woman-years of follow-up. As one example, a recent update from the Nurse’s Health Study (>400 000 woman-years of follow-up) again confirmed a 40% to 60% reduction in cardiovascular events in women taking HRT.3,4 In contrast to this large body of observational data, the recent prospective Heart Estrogen/progestin Replacement Study (HERS) proved negative. HERS, the first prospective, randomized trial of HRT assessing cardiovascular end points, demonstrated that combined HRT (0.625 mg/d conjugated equine estrogens [CEE] and 2.5 mg/d of medroxyprogesterone acetate [MPA]) had no effect on fatal or nonfatal cardiac events.1 The study included 2763 women with established coronary artery disease followed up for an average of 4.1 years. It is largely the discrepancy between the results of HERS and the many prior observational studies that …

Lipid predictors of coronary heart disease and tibolone users

Tibolone reduces plasma levels of total cholesterol by approximately 5%, triglycerides by approximately 25% and lipoprotein(a) by 20–30%, with little effect on the levels of low-density lipoproteins. In contrast to these theoretical beneficial effects, there is a 20–30% fall in levels of high-density lipoproteins (HDL). The failure of recent placebocontrolled clinical trials of hormone replacement therapy to show a cardiovascular benefit with elevated HDL levels raises the possibility that hormone replacement therapy-induced plasma lipid changes may not accurately predict clinical events. Advances in our understanding of lipoprotein metabolism, especially resulting from identification of new receptors, challenge the conventional belief that reducing HDL levels will cause cardiovascular disease.

Lipid predictors of coronary heart disease and tibolone users

Tibolone reduces plasma levels of total cholesterol by approximately 5%, triglycerides by approximately 25% and lipoprotein(a) by 20-30%, with little effect on the levels of low-density lipoproteins. In contrast to these theoretical beneficial effects, there is a 20-30% fall in levels of high-density lipoproteins (HDL). The failure of recent placebo-controlled clinical trials of hormone replacement therapy to show a cardiovascular benefit with elevated HDL levels raises the possibility that hormone replacement therapy-induced plasma lipid changes may not accurately predict clinical events. Advances in our understanding of lipoprotein metabolism, especially resulting from identification of new receptors, challenge the conventional belief that reducing HDL levels will cause cardiovascular disease.

National Randomised Trial of Hormone Replacement Therapy in Women with a History of Early Stage Breast Cancer

National Randomised Trial of Hormone Replacement Therapy in Women with a History of Early Stage Breast Cancer