NOTE: Since this page was first developed in 1997, beliefs about HRT have undergone a shake up and much of the earlier material has been put in doubt if not actually discredited. Nevertheless these studies are still cited as justification for various practises and the need for the use of drugs which are best sellers and thus afford great motivation for the maintenance of outdated ideas. Rather than delete them I have left them in place to show how things are changing. Hopefully, if presented with one or more of these "facts" you will recognize from whence they came...

Dec 1, 2002

This page, as well as several other hormone-oriented ones on this site, is virtually outdated, attitudes to Menopausal Hormone Therapy (in itself a significant change of name - note the abandonment of the term "Replacement") having undergone a major shift over the last few months. However, the page remains here as a record of earlier attitudes, as well as evidence against repeated claims that the WHI (E and P arm) results were a  "bombshell" and "unexpected." For more detail see the WHI page

By now, most major medical organizations have reviewed their recommendations about combination menopausal hormonal therapy and there is little to differentiate them. In general they say:

While treatment for hot flashes and other perimenopausal symptoms remains an option, a woman should be carefully counselled about the risks involved and an individual assessment made of her personal situation. Caution should be exercised about prolonged use.

Routine use of such therapy for the prevention of chronic postmenopausal conditions is not recommended;

Its use for both primary and secondary prevention of cardivascular diseas is contraindicated i.e. it should definitely not be used either before or after the development of such conditions.

Its use only for the prevention of osteoporosis should be carefully weighed against its risks, and alternative therapies such as bisphosphonates considered.

 

Until (if ever) there is evidence to the contrary, the assumption must be made that other formulations and dosages of estrogen and progestin carry the same risks as the specific ones in the study.

There is insufficient evidence as yet to decide for or against the use of unopposed estrogen as a preventive measure.

There is insufficient evidence as to whether or not phytoestrogens are protective against osteoporosis or cardiovascular disease. Many of them also list the  various herbs and supplements which are used for perimenopausal symptoms, while failing to point out that there is little or no evidence that they 'work'.

Hormone replacement therapy. An analysis of efficacy based on evidence.
Geriatrics 2002 Aug;57(8):18-20, 23-4 
Gupta G, Aronow WS. Department of Medicine, Geriatrics Division, New York Medical College, Valhalla, NY, USA.
 

Hormone replacement therapy (HRT) has long been a staple of management of the postmenopausal life phase. <snip> One of the most significant theorized benefits was protection against cardio- and cerebrovascular events. Other benefits--protection against osteoporosis, reduction in incontinence symptoms, and improved cognition--have also been linked with HRT. <snip> Nevertheless, significant clinical data refuting HRT's proposed benefits has been available for several years. 

Findings from these investigations, including new results from two very large trials, show that beyond managing traditional menopause symptoms, HRT has little or no role in protection against certain diseases or conditions associated with aging. 

Indeed, long-term use of HRT may be contraindicated in most older women with intact uteruses. 

April 16, 2002 First steps towards an official US admission that HRT isn't living up to expectations?
Hormone Replacement Therapy Falls Out of Favor With Expert Committee

Discouraging (scary?) results emerging from more recent randomized placebo-controlled studies include:

March 21, 2001 (JAMA)Women who used postmenopausal estrogens for ten years or more were at substantially increased risk of fatal ovarian cancer that persisted for many years after estrogen replacement therapy was stopped

However: shortly after (March 26, 2001National Cancer Institute at ) a further study implied that the addition of progestin mitigates the effect -though the period for increased risk from estrogens was shortened to 4 years. Article at http://washingtonpost.com/wp-dyn/health/A56737-2001Mar25.html

(April 12, 2000 WHI)"Current data from the WHI suggests that during the first two years there was a small increase in the number of heart attacks, strokes, and blood clots in women taking active hormones compared to inactive (placebo) pills."

(Feb 2000 Journal of the National Cancer Institute. ) Five years of combination therapy increased a woman's risk of breast cancer by 24%, four times as much as ERT. Though the differences were not statistically significant, sequential combination HRT appeared slightly riskier than continuous combination HRT, the investigators note. (Reuters)

(Jan. 2000 JAMA) "The researchers found that women taking combination hormone replacement therapy experienced a 40% greater risk of breast cancer than those taking no therapy; women taking oestrogen alone had a 20% greater risk. Moreover, the relative risk increased with duration of therapy, increasing by 0.01 for each year of oestrogen only use and by 0.08 a year for those taking oestrogen plus progesterone."

An editorial in JAMA (June 13, 01) at http://jama.ama-assn.org/issues/current/ffull/jed10034.html
Postmenopausal Hormone Therapy for Prevention of Fractures asks
 How Good Is the Evidence?Deborah Grady, MD, MPH; Steven R. Cummings, MD

Not that good apparently.... The article includes the statements:

....This meta-analysis highlights the fact that evidence about the efficacy of postmenopausal estrogen for prevention of osteoporotic fractures is weak.
and
.....Since women in their 50s who do not have osteoporosis have a relatively low risk of fracture, the benefit of long-term treatment with estrogen to prevent bone loss and fractures may not exceed the risks.

Apparently, though, the latest research about HRT's effects has not trickled down to many doctors who care for postmenopausal women, nor, as a result, to the women themselves.

"The problem, from our perspective, is it's still being offered to too many women with misinformation about how they can hope to benefit from taking it," says Cynthia Pearson of the National Women's Health Network, a non-profit group in Washington. "There's something deep that explains the irrational behavior around this, and I don't know what it is."

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 Oct 25, 2000 (Toronto, ON) 

 “There has been a great deal of discussion and media attention around the use of estrogen to prevent problems such as osteoporosis and heart disease in women,” says author Dr. Muhammad Mamdani, Scientist at the Institute for Clinical Evaluative Sciences. “However, we  reviewed all of the literature on ERT as a preventive therapy for cardiovascular and osteoporosis outcomes; the research studies to date don’t provide conclusive evidence of  real preventive benefit. They really represent lesser quality studies that provide ‘rough  sketches’ of the hypothesized benefits of these drugs.”

 Coupled with this lack of evidence is that more than 50 per cent of women over the age of 65  in Ontario who are taking estrogen for its potential preventive effects don’t stay on the drug  long enough to reap those benefits. However, they are on it long enough to experience  harm, adds Mamdani, who is also an Assistant Professor in the Faculty of Pharmacy at the University of Toronto. “While the potential preventive effects may require long-term use, patients may experience harmful effects in the short term. Women and their physicians need  to have frank discussions about the risks and benefits based on current research findings  before embarking on HRT as preventive therapy.”

What should I do?" Now, in my late forties, I face the same decision. Should I embark on a course of HRT as I navigate through menopause?...

.....In this issue, Keating and colleagues  report on a 1995 nationally representative survey of U.S. women 50 to 74 years of age. Their results suggest that I am not alone in my search for what to do about HRT for myself and my patients. Of 495 women with no apparent contraindications to HRT, only 20% of those with a uterus and 59% of those without a uterus were using HRT.

.....Strong epidemiologic evidence for decreasing the incidence of atherosclerotic disease with HRT is confounded by the recent results of the Heart and Estrogen/progestin Replacement Study, which suggest that HRT in women with established coronary artery disease may cause more side effects and have less impact on the course of ischemic heart disease than had been hoped.

....What can we do while we await more definitive evidence? Current recommendations suggest committing generations of women to decades of a preventive treatment that offers potentially dramatic positive effects on their health and longevity, unpleasant side effects for some, and unclear risks for breast cancer. The results of Keating and colleagues' study hint that we should turn our attention to our female patients and listen to them more carefully and systematically than we have.

....Can we think of another example of a medical intervention, requiring millions of patients to take daily medication for many years, in which we have an incomplete understanding of the medical science and know even less about the motivations, attitudes, perceptions, and decision-making styles of the women we want to help?

Conclusions: Sociodemographic factors, such as region and education, may be more strongly associated with use of HRT than clinical factors, such as risk for cardiovascular disease. 

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Abstract

The overall risk/benefit of estrogen replacement therapy (ERT) is strongly dependent on assumptions about the effect of ERT on coronary heart disease (CHD). The belief that ERT causes a substantial reduction in the risk of CHD is widespread. The studies that provide support for this belief are all nonexperimental ones. Three analyses of data from two randomized clinical trials of drug treatments for CHD have examined the association of compliance with total mortality in persons who complied with the taking of placebo. In these analyses, compliance with the taking of a placebo was associated with a reduction in overall mortality of the same magnitude as the reduction in the risk of CHD in users of ERT. The benefit of compliance with placebo was not reduced by adjustment for a large number of variables, both medical and sociodemographic, that might affect mortality. Users of ERT are compliers, and the possibility that compliance bias may account for some of the apparent benefit of ERT for CHD must be taken seriously.

The WHI is one of the largest preventive studies of its kind in the United States. The WHI will focus on the major causes of death, disability and frailty in postmenopausal women. The overall goal of WHI is to reduce coronary heart disease, breast and colorectal cancer, and osteoporotic-fractures among postmenopausal women via prevention/intervention strategies and risk factor identification. The WHI is a 15 year research program that comprises of three major components: 

1.      a randomized controlled clinical trial of promising but unproven approaches to prevention; 
2.      an observational study to identify predictors of disease; 
3.      a study of community approaches to developing healthful behaviors. 
Within these pages, you will find a description of the WHI, an update on the recruitment status, project goals, and a list of participating institutions. 

WHY STUDY ONLY ONE TYPE OF ESTROGEN AND PROGESTIN?

The hormone component is studying the effects of one type of estrogen (conjugated equine estrogens, Premarin) and one type of progestin (medroxyprogesterone acetate, MPA).  The choice of these hormones was made on the basis of science and public health.  The recorded experience of women who used Premarin and MPA is what prompted the need for a rigorous clinical trial, and the initial public health question to be answered is whether the hormones most commonly used by women have benefits that exceed their risks. 

Recruitment of more than 27,000 women was successful, but arduous.  For each additional therapy chosen, it would be necessary to recruit at least 14,000 additional women.  WHI investigators therefore, adopted a more feasible strategy which would not add to the cost of the study.  The WHI is obtaining a full accounting of all hormones used during the course of the study as well as in the past by the more than 161,000 women currently enrolled in the WHI.  Each variety of hormones used by the women can then be related to their future health status, and compared to the results in the clinical trial of the subset of 27,000 women.  In this manner, the effect of other hormone therapies can be estimated.

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Hormone Replacement Therapy: Weighing the Hazards and Rewards

Abstract:
Few healthcare decisions require the intricate factoring of pros and cons as the choice between prescribing hormone replacement therapy for a woman at the threshold of menopause, and foregoing this pharmacologic option. Past medical history, genetics, and alcohol intake are just a few of the factors clinicians need to consider when weighing the risks and benefits of therapy for patients. Timing choices in initiating therapy, dosing strategies, and the pharmacologic properties of various hormone replacement therapies need to be considered once the decision to prescribe estrogen has been made. This Clinical Update summarizes some of the latest studies on hormone replacement use to assist clinicians in guiding each patient toward an optimal decision based on her unique circumstances. [Clinician Reviews 7(9):53-56, 59-60, 62, 65-66, 69-72, 1997. © 1997 Clinicians Publishing Group and Williams & Wilkins.] 
 Introduction
One fourth of all postmenopausal women in the United States now take some form of estrogen replacement therapy (ERT) to relieve hot flashes, mood swings, vaginal dryness, and other effects of menopause. The use of oral estrogen, often taken in combination with progestin (a natural or synthetic progesterone), has been shown in a compelling body of research to provide other benefits -- including control of osteoporosis and cardiovascular disease (CVD). 

Countering this "good news," however, are studies that challenge the use of hormone replacement therapy (HRT) for its preventive properties. Estrogen, delivered through HRT or oral contraceptives, has been implicated in breast cancer, endometrial hyperplasia, and venous thromboembolism. Certain forms of progestin, ironically, may be a factor contributing to CVD. On the basis of these conflicting studies, it is clear that controversy still surrounds the use of HRT for healthy menopausal women. 

 As public debate continues over how broadly HRT should be prescribed, researchers now are suggesting ways to identify patients who will gain the maximum benefit from such therapy. Patient history, genetics, and even alcohol intake are just a few of many factors to consider before HRT is indicated. Timing choices in initiating therapy, possible dosing strategies, and the pharmacologic properties of various HRT combinations become important considerations once the decision to prescribe estrogen has been made. 

Authors: Col N, Eckman M, Karas R, Pauker S, Goldberg R, Ross E, et al. 
Source: JAMA. 277:1140-7. April 9, 1997. 
Institutions: Tufts University School of Medicine; University of Massachusetts Medical Center; Fallon Health Care System. 
Financial support: National Library of Medicine; Agency for Health Care Policy and Research. 

Background

Current [1997] evidence suggests that postmenopausal hormone replacement therapy (HRT) decreases morbidity and mortality from coronary disease (CAD) and osteoporosis, while increasing morbidity and mortality from breast and uterine cancer. The overall risk/benefit ratio associated with HRT for a specific individual will depend on that individual's a priori risks for these conditions. Thus, a woman at high risk for CAD and osteoporosis and at low risk for breast and uterine cancer would be more likely to benefit from HRT than a woman with an opposite risk profile. 

The best way to estimate risks and benefits of a therapy is to make use of the results of randomized clinical trials, but these results are not yet available for HRT. [2002 - They are now] This study presents a <computer model designed to estimate the effect on life expectancy of HRT in women, according to their risks for coronary disease and breast cancer. 

This is a well-designed computer model of the anticipated gain in life expectancy from estrogen-progesterone therapy in post-menopausal women. As mentioned in another summary presenting a similar model applied to thyroid disease, a major benefit of reading and understanding this type of paper is in deriving a better grasp of the underlying clinical concepts. Independent of the results of the paper, the variables and issues are laid out with great clarity. 

It must be reiterated that this is not a randomized trial, or even a cohort study. It is a computer model of the anticipated gain in life expectancy associated with HRT, based on data from other, non-randomized trials. Nevertheless, the results certainly seem reasonable. 

One point should be made. The end-point of increased life-expectancy is a combined one, and can hide some important information. A year of life lost to coronary artery disease is not the same as a year of life lost to breast cancer. Not because of the difference between the diseases (which the authors allude to when they discuss quality of life issues), but because of the difference in age of onset of these two diseases.

Given the findings that hormone use is associated with reduced mortality for multiple causes of death (11) and that there are marked lifestyle differences between hormone users and nonusers, (12) there continue to be lingering questions regarding the extent to which reductions in mortality are due to hormone use itself as opposed to the characteristics of the user. Some of the unresolved issues must await the results of ongoing intervention trials of menopausal hormones. However, since these trials may not continue long enough to accrue large numbers of patients in whom cancer develops, it will also be important to evaluate data from large observational studies. If the protective effect of long-term use continues to dissipate with time and adverse effects on breast-cancer mortality are confirmed, the optimal duration of hormone-replacement therapy will need to be reconsidered. That the beneficial effects of hormones are dependent on recent use raises questions about when to initiate use. It is encouraging that hormone use begun later in life offers bone-conserving benefits nearly equal to those conferred by use initiated earlier. (13) Furthermore, it is important, as Grodstein et al. and others have pointed out, that other means of reducing the incidence of cardiovascular diseases and osteoporosis have been identified. Physical activity is one such approach, (14) of interest in that it may also reduce the incidence of breast cancer. (15) Although further research is needed to clarify the relative benefits of various interventions as compared with hormone-replacement therapy, it may now be the time to question seriously whether hormone-replacement therapy should be prescribed for life or whether for some women, it should be more restricted in duration and combined with other effective disease-prevention techniques.

The (mostly) non-American view of The Nurses' Health Mortality Study
Postmenopausal hormone therapy and mortality

The editor invited the board members of the European Menopause Journal to comment on the results and conclusions of the follow-up of the Nurses' Health Study which was published in the New England Journal of Medicine earlier this year. [Eur Menopause J 4(3):77-90, 1997. © 1997 PMSI Bugamor B.V.] 

Summary
 The Study - Postmenopausal hormone therapy and mortality
 Comment by D. Aravantinos, Athens, Greece
 Comment by M. Birkhäuser, Bern, Switzerland
 Comment by J. Bonnar, Dublin, Ireland
 Comment by P.G. Crosignani, Milan, Italy
 Comment by R.U. Erkkola, Turku, Finland

Comment by M.M. Gelfand, Montreal, Canada

<snip>The selection of patients who are to be given HRT therefore becomes an important issue. Women at high risk for cardiovascular disease will definitely benefit the most. However, as a clinician, when one is sitting in the office and discussing HRT with the patient vis-a-vis her quality of life and management of her acute symptoms of menopause, such as vasomotor instability, the long-term benefits and risks seem not to be the predominant issues. To achieve benefits for osteoporosis and cardiovascular disease, one requires long-term use of HRT (10-20 years). However, the patient is aging and this process in itself takes a toll on other parameters of the patient's health. Breast cancer incidence increases whether or not HRT is used and older women are at risk for senile dementia, including Alzheimer disease. The value of HRT in Alzheimer's disease is being investigated, hence no definitive recommendations can be made at present. Think of comparing the cost-effectiveness of saving healthcare dollars on osteoporosis and cardiovascular disease and spending them on mammography and research on Alzheimer's disease. In all of the above, my feelings are that the quality of life overshadows all other parameters in choosing to place patients on HRT. Statistics are important but emotions are equally relevant to our patients in need of HRT. <snip> 

 Comment by J.C. Huber, Vienna, Austria
 Comment by P.R. Koninckx, Leuven, Belgium
 Comment by L. Lampé, Debrecen, Hungary
 Comment by J.C. Netelenbos, Amsterdam, the Netherlands
 Comment by M. Neves-e-Castro, Lisbon, Portugal
 Comment by S. Palacios, Madrid, Spain
 Comment by A. Pines, Tel Aviv, Israel
 Comment by H.P.G. Schneider, Münster, Germany
 Comment by L. Speroff, Portland, Oregon, USA

<snip>When this latest report from the Nurses' Health Study was received by the media, I was afraid that the breast cancer effect would be highlighted, and that is exactly what happened. And by the way, I hope it aggravates you as much as it aggravates me when the New England Journal of Medicine and JAMA release reports to the media before you and I have even received our journals. This catering to the media places us in the position of responding to patients (and even journalists) without having read the report; hardly a position in which it is possible to be effective (or even to be able to avoid being embarrassed!) <snip> 

<snip> In practical terms, the paper strengthens the view that each postmenopausal woman considering HRT must be assessed individually. If HRT does indeed prolong life, it is most likely to do so in women with significant risk factors for CHD or osteoporotic fracture (Col et al. JAMA 1997; 277: 1140-7). For women without such risk factors the benefits of HRT are unclear, and may be outweighed by the possible increase in breast cancer risk.  <snip>