July 9, 2002 The LACK of usefulness of HRT for the prevention of heart disease was demonstrated  with the early stopping of the estrogen+progestin arm of the WHI study

American Heart Association President Robert Bonow M.D. Responds to New Findings From Women's Health Initiative Trial

• We await the further results of the Women’s Health Initiative trial to assess the risks and benefits of women taking estrogen alone.
• Based on current evidence, the American Heart Association advises that women do not start or continue combined HRT for the prevention of coronary heart disease.”

• HRT should not be initiated for the secondary prevention of CVD.
• There are insufficient data to suggest that HRT should be initiated for the sole purpose of primary prevention of CVD.

A letter to participants in the Women's Health Initiative study notified them that the small increase in the number of heart attacks, strokes and blood clots in women taking hormones, compared with nonusers, had continued into the third year of the study. Unlike last year, no mention was made of an expectation that this trend would disappear with time.

HRT is contraindicated for the secondary prevention of coronary artery disease. There is insufficient evidence at present of benefit or harm from HRT for the primary prevention of coronary artery disease. 

Since the HERS results were published, many physicians have clutched at every hint that HRT might have benefit in preventing disease, death, and long-term disability in postmenopausal women.  More evidence brings more pessimism about the preventive benefits of HRT and ERT.  What then remains?
<major snip>
Pessimism about HRT and ERT does not mean pessimism about disease prevention in postmenopausal women.  Randomized trials that included women provide strong support for the use of [see article]

http://jama.ama-assn.org/issues/v288n1/abs/joc20521.html
Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II)

Conclusions 

Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up.  After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD.  Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.

http://jama.ama-assn.org/issues/v288n1/abs/joc20522.html
Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy:Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II)

Conclusions 

Treatment for 6.8 years with estrogen plus progestin in older women with coronary disease increased the rates of venous thromboembolism and biliary tract surgery.  Trends in other disease outcomes were not favorable and should be assessed in larger trials and in broader populations.

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http://cvm.controlled-trials.com/content/2/5/211
Do we need clinical trials to test the ability of transdermal HRT to prevent coronary heart disease? 
David Crook Department of Cardiovascular Biochemistry, St Bartholomew's and the Royal London School of Dentistry and Medicine, London, UK.
Curr Control Trials Cardiovasc Med 2001, 2 : 211-214

Conclusion:

The severe mismatch between observed and expected results for oral HRT in randomized controlled trials of CHD end-points challenges the validity of observational epidemiology, animal studies, and traditional CHD [coronary heart disease] surrogates.  Transdermal HRT is considered inferior to oral HRT for CHD prevention, because of the lack of effect on HDL [high-density lipoprotein] and PAI-1 [plasminogen activator inhibitor].  If the apparent lack of activation of CRP [C-reactive protein] by transdermal HRT can be confirmed, and if the increased CRP levels seen in oral HRT users can be linked to their adverse clinical outcomes, then an adequately powered controlled trial of transdermal HRT in the prevention of CHD would be desirable.  The lesson from recent HRT trials is that such a venture should not be started in the absence of a consensus regarding the study population (healthy women or CHD patients) and regarding the use of progestin.

The sex difference in mortality from coronary heart disease varies over time and between countries in a way that cannot be explained by endogenous oestrogen 

These trends indicate that sex differences in mortality from coronary heart disease are driven primarily by environmental factors 

Sex differences in coronary heart disease are not inevitable 

Sept 9, 2001 Extract from a preliminary study which casts further doubt on the value of HRT for cardiovascular protection. Note the neutral headline - is it coincidental that the results could be bad news for HRT? 

 Birth Control Pill, Urine Protein Link
http://dailynews.yahoo.com/h/ap/20010909/hl/hormones_heart_1.html

CHICAGO (AP) - Dutch research links birth control pills and menopause hormone supplements with small amounts of protein in the urine that may signal an increased risk of kidney and heart disease. 

 Women who used either of the estrogen-based pills faced about double the risk of developing the urine protein condition, called microalbuminuria, compared with nonusers. 
<snip>

Doctors not involved in the research stressed that the study is preliminary. 

``These are provocative findings but they clearly need confirmation,'' said Dr. JoAnn Manson, chief of preventive medicine at Harvard University's Brigham and Women's Hospital. ``It certainly doesn't prove cause and effect."

J Am Coll Cardiol. 2001 Jul;38(1):1-7.
Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up.
Alexander KP, Newby LK, Hellkamp AS, Harrington RA, Peterson ED, Kopecky S, Langer A, O'Gara P, O'Connor CM, Daly RN, Califf RM, Khan S, Fuster V.

OBJECTIVES: 

This study explored the association between the initiation of hormone replacement therapy (HRT) and early cardiac events (<1 year) in women with a recent myocardial infarction (MI). 

Observational studies have linked postmenopausal hormone use with a reduced risk of death from heart disease. However, a recent randomized trial of HRT found no long-term benefit, primarily due to an increase in cardiac events in the first year. 

In our cohort, 28% (n = 524) used HRT at some point. <snip>....... After adjustment, new users still had a significantly higher risk of death/MI/UA than never users during follow-up (relative risk [RR] = 1.44 [1.05-1.99]). Prior/current users had no excess risk of the composite end point after adjustment. 

Users of estrogen/progestin had a lower incidence of death/MI/UA during follow-up than users of estrogen only (RR = 0.56 [0.37-0.85]).

Postmenopausal women who initiated HRT after a recent MI had an increased risk of cardiac events largely due to excess UA during follow-up.

Lower coronary event rates in women receiving hormone replacement therapy (HRT) have led to a presumption of benefit. The Heart and Estrogen/Progestin Replacement Study, a large randomized trial, observed a 1.4% first year excess of coronary events, well beyond the plausible play of chance on the expected effect. Over the duration of the study, event totals were similar, but patients treated with HRT experienced them earlier, with a net loss of patient-months of event-free survival. The point at which the lower event rate in hormone-treated patients would fully repay the first year loss, with constant rates, is almost double the trial duration (of 4.1 years). Since patients in the trial were preselected for satisfactory adherence to therapy, the net benefit in practice is likely to be even less.        <snip>

Women with or at high risk of coronary heart disease should not start HRT. There is a risk that women without coronary heart disease might experience even greater net harm from HRT. The late benefit is necessarily limited, as it cannot exceed the event rate. The mechanism of the early loss is unknown; if it were reduced proportionately less than the late benefit, considerable net harm could result. 

AMSTERDAM, Sep 05 [2000] (Reuters Health) - British researchers reported here during the XXII annual congress of the European Society of Cardiology that transdermal hormone replacement therapy (HRT) does not reduce the risk of cardiac events in postmenopausal women with existing coronary artery disease (CAD). <snip>

On intention-to-treat analysis, there was no statistical difference in the incidence of  unstable angina requiring hospitalization, MI or premature death from heart disease in women receiving HRT and women not receiving the therapy. Respectively, the average event rates were 15.6 and 12.6 per 100 patient-years. 

Results from the PHASE study also seem to indicate an increased risk of thromboembolic complications, such as stroke, with HRT. <snip>

           A new study finds that estrogen replacement therapy, which doctors have long hoped will prevent heart disease in postmenopausal women, does nothing to slow the disease's progression in those whose arteries have already been partly blocked by it. 

          The study is being reported in today's [Aug 24, 2000] issue of The New England Journal of Medicine. But another study, in the same issue, cites the hormone therapy as a factor -- along with beneficial diet,exercise and avoidance of tobacco -- in the decline of heart disease among women. An editorial accompanying the studies says women will not know whether hormone therapy protects the heart until larger studies are completed in several years. <snip>

"I was still hopeful that there would be an underlying effect on the progression of atherosclerosis," Dr. Herrington said. Now, he said, he thinks the question has been answered. 

"I think this study, coupled with the HERS trial, is a pretty compelling combination of evidence showing that estrogen replacement therapy is not effective in reducing the risk for heart attacks or heart-disease deaths, or for slowing the disease that's responsible for those heart attacks, in women with established heart disease," he said.

---

The virtual absence of coronary events in young menstruating women has for decades been explained by the idea that female sex hormones are the protective factor.  The new findings showing that HRT does not decrease progression of atherosclerosis in women with heart disease, and may raise the number of heart attacks in healthy postmenopausal women and in those with heart disease seriously undercut this cherished idea.

The evidence was never unanimous in favor of the "estrogen hypothesis." Awkward findings were swept under the rug under the influence of a strong paradigm (prevailing view) in favor of the hormonal explanation.  For example in the gold standard classic observational study of heart disease, The Framingham Study, women who had natural menopause, simple hysterectomy, or hysterectomy + oophorectomy all underwent a doubling in heart disease risk within 2 years after cessation of menses.  This increase in risk happened no matter what age the woman was when she stopped having periods. If only the uterus is removed in a premenopausal woman, her ovaries continue to cycle just as if the uterus was still present.  In this case, the woman continues to produce her "protective" hormones, however, according to Framingham, she suffers just as much disease increase as her sisters who have had their ovaries removed. 

There is a good bit of additional evidence against the estrogen hypothesis that remains essentially invisible when looked at from the point of view of the prevailing paradigm.  ..... read the whole article

Before, we have told you about findings from other studies that looked at how hormones may affect women’s health.  The information in this update actually comes from the WHI Hormone Program.

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.  Over time, these differences seem to get smaller and may even disappear.  In fact, overall, WHI women had fewer such events than would be expected in the general population. 

---

....."The National Women's Health Network has warned women for more than a decade that the heart benefits claimed for hormones had not been proven. <snip>

"Some news accounts have indicated that experts do not believe women and their doctors should base decisions about whether to take hormones on these findings – and if decisions were currently being made on a solid scientific basis, we would agree. If doctors recommendations to women today about hormones were always supported by reliable scientific evidence, no woman would currently be taking hormones in the belief that it would help keep her heart healthy. However, the reality – as any woman with good health insurance who has reached or is approaching menopause knows – is that doctors are routinely recommending to their menopausal patients that taking hormones will help prevent heart disease. This must stop.

---

 ...In a surprising reversal of prevailing medical wisdom, researchers conducting a nationwide study of women's hormone replacement therapy have warned subjects taking estrogen that they are slightly  more likely to have heart attacks, strokes or blood clots during the  first two years of use. 
    Researchers have long assumed that estrogen helps protect  women from cardiovascular problems. But the new findings appear  to cast doubt on that assumption...... 

http://www.washingtonpost.com/wp-dyn/articles/A3421-2000Apr3.html

...The findings are startling because most of the study's 27,000 participants do not have heart disease--and because a major goal of the multimillion-dollar study, the Women's Health Initiative, is to determine whether older women can protect their hearts by taking hormones....

In a major new study of the effects of hormone replacement therapy (HRT) on heart disease, researchers found that neither estrogen, nor estrogen combined with a progestin, slowed disease progression in 309 older women. 

ERA is the second major clinical study that calls into question the widely held belief that HRT is an effective treatment for heart disease. In 1998, HERS (the Heart and Estrogen/progestin Replacement Study) found that 2,763 women who took estrogen and a progestin for four years had just as many heart attacks as women who didn't take the treatment. 

As a result, it was recommended that women with heart disease not begin HRT to lower their risk for future heart attacks and heart disease deaths.

"ERA supports the findings of HERS. In both studies, there was no clear-cut evidence of benefit in women with established heart disease," said Herrington. He pointed out that the results don't necessarily apply to younger, healthier women.

<major snip>
Hormone replacement therapy may help prevent coronary heart disease (12, 13, 28-36). Although more than 30 observational and cross-sectional studies have reported a significant risk reduction for coronary heart disease (35% to 55%) (13, 29, 36), no large randomized trials assessing the effect of HRT in the primary prevention of coronary heart disease have been completed. 

However, the Heart and Estrogen-Progestin Replacement Study (HERS) was the first randomized trial to examine the effect of HRT in secondary prevention of coronary heart disease. After 4 years of follow-up, HRT had no effect on rates of nonfatal myocardial infarction and sudden cardiac death in more than 2700 women with established coronary heart disease (44). Of interest, the HERS investigators reported a significant 52% increase in nonfatal myocardial infarction and cardiac death during the first year of HRT compared with placebo. They concluded that women with established coronary heart disease should not begin receiving HRT (44). This study did not address the use of unopposed estrogen, HRT in younger women with no preexisting coronary heart disease, or other forms or doses of estrogen or progestins. 

The apparent cardioprotection reported in observational and case-control studies may not be caused by HRT but may instead be a result of fundamental differences between women who choose to take HRT and those who do not (54, 55, 84-88). For example, women who choose to take HRT, when compared with women who choose not to use HRT, have better metabolic risk factors before menopause, have healthier lifestyles, are more educated, and are more likely to adhere to medication. These are all factors associated with overall disease risk reduction (54, 55, 84-88).

Therefore, until findings from randomized trials confirm that HRT helps to prevent coronary heart disease, this treatment should not be routinely recommended solely for this purpose.

http://www.ti.ubc.ca/pages/letter30.htm Therapeutics Letter, issue 30, June/July 1999
Levels of Evidence for Clinical Decisions: Menopausal Hormone Therapy Revisited
....What can be learned from this example?

Before the HERS trial the available evidence was from observational studies and RCTs looking at surrogate markers. Controversy was present, but many clinicians and guidelines were recommending HT for primary and secondary prevention of CHD and osteoporosis. The observational evidence (see Therapeutics Letter #14 & Therapeutics Letter #16) suggested a consistent reduction in risk of coronary heart disease with estrogens and combined HT (pooled relative risk 0.65 [0.59-0.71]). This magnitude of reduced risk (Level III evidence) is inconsistent with the HERS trial evidence and is likely due to 2 types of bias that can occur with observational studies: 

1. Selection bias - women who choose HT are healthier at baseline than those who do not, or 
2. Compliance bias - people who comply with placebo have better outcomes than those who do not. There was also RCT evidence that various regimens of HT had beneficial effects on lipid levels (possible surrogate markers for cardiovascular events, Level II evidence). The HERS trial has demonstrated that reduction in lipid levels with HT is not a valid surrogate for CHD outcomes.

In this case the risk of CHD events would be less and therefore the opportunity for benefit would be less. On the other hand the chance of adverse outcomes would most likely remain the same. It is unlikely that a drug would be beneficial in primary prevention if there is no demonstrable benefit for secondary prevention. 

Is the controversy over prescribing HT resolved by the HERS trial? Probably not. Recent publications, while including the HERS trial in their list of references, are still advising doctors to encourage use of HT for prevention of CHD and osteoporosis. It will likely take some time for the full implications of the Level I evidence from the HERS trial to be reflected in the literature and practice.

....many nonlipoprotein effects of HRT that have been so well described in the laboratory may not be of clinical significance, and it also implies that unknown negative pathways of the action of HRT still remain to be discovered..... 

For the time being, prevention of cardiovascular disease should not be considered an indication for starting HRT. As medical practitioners, we should also take a long hard look at the way we promote other apparent beneficial effects of HRT that have not yet  been confirmed in controlled trials examining clinical outcomes. As citizens, we should address the more difficult problems of social factors and aggressive marketing that foster unhealthy lifestyles, particularly for younger women. 

For the results of a new study on heart disease and gender-related differences in death rates from MI see: http://www.washingtonpost.com/wp-srv/health/digest/july99/heart0722.htm

The Post article doesn't list the journal but I think it is the NEJM. Most interesting to me is the portion which discusses the differences in symptoms of heart disease in men and women with women more likely to have "normal" EKG tracings and no chest pain to indicate heart disease or MI. 

"The researchers used various statistical methods to adjust for differences between the male and female patients. There were many. For instance,  women were less likely to have revealing EKG tracings and were more likely to have no chest pain, two conditions that make it difficult for a   physician to make a quick diagnosis. Unfortunately, women also were  more likely than men to have some problems -- notably congestive heart failure -- that increase the chance of death."

Since this heart disease and the associated fatalities occur in women who are NOT YET menopausal or only beginning that change, it would seem to gum up the notion that estrogen protects women from heart disease.  But not to worry - some researchers have concluded that 

"..., it is possible that a small minority of women is innately resistant  to estrogen's beneficial effects, and that they are the ones having heart   attacks at a young age. That condition (or other, still unidentified ones)  may make them less responsive to treatments, such as aspirin, clot  dissolvers and beta-blocker drugs, that help men."  (irony mode on) When inconvenient facts present themselves, don't examine the underlying theory - twist and distort the facts to fit the theory instead. (irony mode off).

I think the findings of relatively normal EKG's in women with serious heart disease and the lack of complaints of chest pain should give doctors pause before prescribing estrogen to women - since the HERS study and a later one at the University of North Carolina Chapel Hill made it clear that estrogen, far from protecting  women with heart disease actually injured them. If we have no reliable way of diagnosing heart disease in women, maybe it would be wise to err on the side of caution. This also suggests that women at risk may already be dead before menopause and the effects of estrogen on heart disease in post menopausal  women may be nothing more than a statistical artifact.

In a study of more than 1,850 female heart attack patients that was originally designed to look at the protective effects of aspirin, more than 37% of women who began hormone replacement therapy after the study began were hospitalized with unstable angina -- chest pain not triggered by exertion, as in stable angina -- within a year.

In contrast, the hospitalization rate for women who had never used hormone replacement therapy was 17%, and the rate for those already on hormone replacement therapy prior to aspirin therapy was 21%.

The results of the first large randomized clinical trial to examine the effect of hormone replacement therapy (HRT) on women with heart disease appear in the August 19 issue of the Journal of the American Medical Association (JAMA). 

The Heart and Estrogen/Progestin Replacement Study (HERS) found that the use of estrogen plus progestin in postmenopausal women with heart disease did not prevent further heart attacks or death from coronary heart disease (CHD). This occurred despite the positive effect of treatment on lipoproteins: LDL (bad) cholesterol was reduced by 11 percent and HDL (good) cholesterol was increased by 10 percent. 

The hormone replacement regimen also increased the risk of clots in the veins (deep vein thrombosis) and lungs (pulmonary embolism).
<snip of possible explanation for the "surprising findings" above>
Despite this explanation, the HERS investigators conclude that until results from other ongoing randomized trials of HRT are available, estrogen plus progestin should not be started in women with CHD to prevent heart attacks. 

The HERS study is important since it is the first of several ongoing randomized trials looking at the effects of HRT on heart disease. The NHLBI is supporting several of these trials, including the Women's Health Initiative (WHI), the Women's Angiographic Vitamin and Estrogen (WAVE) Trial, the Women's Estrogen/Progestin and Lipid Lowering Hormone Atherosclerosis Regression Trial (WELL-HART), and the Estrogen Replacement and Atherosclerosis (ERA) Trial. [Now published -Mar 2000]

When completed, these studies, together with the results of HERS, should provide the first comprehensive evaluation of the benefits and risks of long-term hormone replacement therapy

Background: The Heart and Estrogen/Progestin Replacement Study (HERS) is the first large clinical trial designed to test the efficacy of postmenopausal estrogen/progestin therapy for secondary prevention of coronary heart disease (CHD). To examine the representativeness of the HERS cohort to the general population of postmenopausal women with CHD, we compared the baseline cardiovascular risk factor data from HERS with similar data from women presumed to have CHD from the National Health and Nutrition Examination Survey (NHANES) III.

I recommend the Discussion section of this long paper. Below are some extracted points which interested me. (Tishy)

• Another problem with selection bias in volunteer subjects is a lower-than-expected event rate in the control group. If not prospectively considered, this factor can decrease the study's power to detect the treatment effect of interest.
• Diabetic women were not explicitly excluded from HERS; however, women with the metabolic sequelae of poorly controlled diabetes (including elevated fasting glucose or triglyceride concentrations and, to a lesser extent, uncontrolled hypertension) were ineligible. This exclusion is consistent with clinical practice, where estrogen is often withheld from diabetic women with preexisting hypertriglyceridemia for fear of exacerbating their triglyceride disorder.
• The large number of diabetic women in HERS (n = 634) will provide much needed information about triglyceride metabolism and the prospects for secondary prevention in diabetic women, whose risk for MI and CHD death is among the highest of any subgroup in the population. 
• This study highlights the deficiencies in the number and quality of descriptive data on U.S. women with CHD before HERS
• Other large epidemiologic cohorts also have relatively few women with established CHD and, in some cases, such as the Nurses Health Study,they also had certain unique selection biases.
• With the exception of the most recent trials of lipid lowering and thrombolytic therapy, trials of interventions for secondary prevention of cardiovascular disease have also included very few women. Of the three major trials of medical versus surgical therapy for coronary disease, the European Cooperative Study, the Veterans Administration Study, and CASS, only CASS included women (79, or 9.7% of 780 randomly assigned subjects). The CASS registry fortunately included a larger number of women (n = 2737) with angiographically defined CHD. Much of what we know about angina, exercise treadmill testing, and angiographically defined coronary disease in women was derived from the CASS data set, which is now more than 25 years old. 
• There are also limits on the degree to which any cohort can claim to be truly representative of the entire population, regardless of the size of the cohort. An additional limitation of the NHANES III survey and other epidemiologic studies has to do with the sensitivity and specificity of classification of CHD in women.
• Women are less likely than men either to report typical angina with CHD or acute MI or to have electrocardiographically documented Q waves develop after MI. In HERS, for example, 74.6% of women with documented CHD were free of angina at baseline. 

Some studies have shown that angina is less predictive of coronary angiographic disease or subsequent CHD events in women than in men.

An important outcome from this study is the demonstration of how little data are currently available on women with CHD in the United States. Data from the HERS trial will provide a major increment in this regard. The relatively large number of diabetic subjects in the NHANES cohort highlights the need for information about the effects of hormone replacement regimens and other forms of therapy for prevention of CHD in this high-risk subgroup. HERS, with more than 600 diabetic women, will provide critical information about the risks and benefits of hormone therapy in these patients. Finally, the data from this study reveal opportunities to enhance the sensitivity and specificity of the NHANES detection of CHD, the primary cause of morbidity and death in postmenopausal women in the United States. 

Hormone Replacement Therapy: A Useful Tool in The Prevention of Coronary Artery Disease in Postmenopausal Women?

C.J. Moerman, J.C.M. Witteman, H.J.A. Collette, J.A. Gevers Leuven, C. Kluft, P. Kenemans, K. Meeter (For The Working Group on Women and Cardiovascular Disease of the Netherlands Heart Foundation*)

 [Eur Menopause J 3(2):60-68, 1996. © 1996 PMSI Bugamor B.V.] 

Contents

• Online Resources

• Related articles and abstracts
• Annotated links to other Web sites

• Introduction (numbers pointing to  references removed)
At present it is subject to debate whether or not post-menopausal hormone supplements play a role in the prevention of cardiovascular disease in women Over the last 20 years more than 30 epidemiological studies on hormone supplements and cardiovascular diseases have been conducted. The majority showed a lower morbidity and mortality from coronary artery disease among users of postmenopausal estrogens than among non-users. Recently, two meta-analyses estimated the reduction in coronary artery disease associated with estrogen use to be 35% and 44%, respectively. Authors of a third review calculated a 25% reduction in risk when the results of the studies were not weighted for study size. Results of the epidemiological studies suggest that postmenopausal estrogen use is beneficial with respect to coronary artery disease. [But note the result of ERA above -Tishy]

Attributing the whole observed reduction of symptomatic coronary artery disease to estrogen use, however, has been criticized.Apart from one small prospective randomized trial, all studies on hormonal supplementation were observational in design. It is likely that the results of the studies have been overestimated due to selection bias. 

Besides, the estimations of the meta-analyses relate to the use of estrogens alone, in particular conjugated equine estrogens. The current practice of prescribing female hormones includes various regimens: estrogens alone (unopposed regimen), estrogens in combination with progestogens (opposed regimen), and various formulations and routes of administration (Table 1). Each of these regimens, formulations and routes of administration may have differing effects on cardiovascular health. 

The present article addresses the following points: what do we know from epidemiological studies about the effects of hormone supplements on coronary artery disease; which biological mechanisms are involved, and what is the relevance to the clinical practice of the cardiologist? Does in fact the prescription of hormone supplements have a role in the prevention of coronary artery disease in postmenopausal women?
 

• Biased Results in Observational Design
• Hormonal Regimen, Formulation and Pattern of Use
• Biological Mechanisms of Action
• Lipids
• Haemostasis
• Body Weight and Carbohydrate and Insulin Metabolism
• Blood Pressure
• Vascular Tone and Tissue Perfusion
• Relevance to Clinical Practice
<snip> At the moment, two randomized trials, investigating the effect of hormone supplementation on cardiovascular events, are in progress in the United States: the Heart Estrogen progestin Replacement Study (HERS) which is conducted among women with coronary artery disease and the Women's Health Initiative (WHI) among predominantly healthy women. The latter study also investigates long-term effects. The British Medical Research Council, in collaboration with centres in countries inside and outside Europe, is preparing a long-term primary prevention trial which is scheduled to begin in 1996. The Netherlands Heart Foundation is stimulating initiatives in planning a secondary prevention trial. 

Until these trials and studies on late effects provide results, claims on the usefulness of hormonal supplementation to prevent first or recurrent coronary artery events in postmenopausal women remain premature. 

• Table

References


---

The following is a review of the article:
 Title: Prior to use of estrogen replacement therapy, are users healthier than non-users?
 Author(s): Matthews K, Kuller L, Wing R, Meilahn E, Plantinga P 
 Journal:  Am J Epidemiol 1996; 143(10):971-8. 
            Please refer to the original article for complete results and information 
 Description: 

            Estrogen replacement therapy is now commonly used by postmenopausal women in order to ameliorate the symptoms of menopause and reduce the risk of heart disease. Examinations of women's hearts using angiography have shown that women who take or have taken estrogen supplements are at 44% less risk of coronary heart disease than those who have never taken them.  But does all of that benefit really come just from estrogen, or is some other  factor at play? One group of epidemiologists suspected that women who  take estrogen may already be more health-conscious and have better cardiovascular risk profiles before beginning supplementation. To find out if  their hypothesis was correct, they selected a group of premenopausal women  for rigourous physical and psychological examination, then followed them through a period of about eight years, during which most of the women passed through menopause. Comparing the women who went on to take  supplements with those who didn't, researchers found that on average those who took estrogen had been among the healthier, better-educated, leaner women to begin with. 

I wouldn't want to say that the benefits have been exaggerated, but I would say that the size of the benefit -- and the question of precisely who benefits -- remain unclear. The purpose of the paper was to raise the concern that, since we know that estrogen users are healthier to start out with, we should not be so surprised when we see studies telling us that they do better than women who don't take supplements. 

Some short studies have been done with randomized therapy, which eliminates the factor of people who do or don't take hormones being different to begin with. Perhaps the best one was the Postmenopausal Estrogen/Progestin Interventions trial, which reported about a year ago that in randomly-assigned women there was no benefit for blood pressure and no benefit for glucose, but there was a benefit on HDL cholesterol, and on the clotting factor fibrinogen

Dr McAlister: As a general gynecologist, I'm speaking for the readers because this is an area in which we all need to be more educated. Could you explain briefly what the PEPI trials are and what they're trying to do? 

Dr Barrett-Connor: The PEPI trial was a three-year, double-blind, randomized, controlled study of 875 women to compare four treatment regimens with a placebo in order to determine which had optimal effect on heart disease risk factors. We looked at four biological system outcomes--HDL cholesterol levels, systolic blood pressure, carbohydrate metabolism (two-hour serum insulin), and  clotting/coagulation (fibrinogen). We picked conjugated equine estrogen (Premarin, Wyeth-Ayerst), because it is the one most widely used in the United States, and because most of the previous epidemiologic studies suggesting that estrogen may help to prevent heart disease have been based on this estrogen. 

Dr McAlister: Do you feel this is generalizable to other types of estrogen? 

Dr Barrett-Connor : I think it is generalizable to oral estrogen. I don't think it is generalizable to estrogen by any other route. 

Dr McAlister: Can you give us a brief summary of the overall finding? 

Dr Barrett-Connor: None of the regimens had a significant effect on blood pressure or on insulin. So we can sweep those two primary end points away for the moment. All the active regimens had an equivalent effect on blocking or reducing the increase in fibrinogen that occurs in postmenopausal women. So they were all good for fibrinogen, which has been shown to be a risk factor for heart disease in both sexes. All the active regimens reduced LDL cholesterol to about 15 mg/dL lower than in the placebo group. Whether LDL cholesterol is an impressive risk factor for heart disease in women of course is a matter of some debate. But if it is, this is a goodly change and should have a goodly effect. All of the active regimens increased triglyceride levels to the same degree, which was a surprise. The micronized progesterone had significantly less negative effect on the estrogen-associated rise in HDL cholesterol levels than the other progestin regimens. If you were worried about HDL levels in a women with a uterus, you would use estrogen and micronized progesterone, according to our study.

[Much interesting discussion well worth a visit to the URL above]

Dr McAlister: We have a long way to go on that. Dr Healy, from your comments in the JAMA editorial, where do you think this brings us? Are we closer or do we still have a long way to go before we really understand? 

Dr Healy: First of all, PEPI needed to be done. It's shocking to me that we've had estrogen out there for 50 years, and women taking it for probably longer, and we haven't answered these kinds of questions before in a controlled clinical trial. We have had the ups and downs of observational data which one year tells you one thing and the next year another. And we sit here in 1995 not being able with certainty to answer questions about outcomes for osteoporosis and heart disease and still arguing about the risks of these treatments. So I think that PEPI is coming along at a time when you have to say: ``Why didn't we have these answers 20 years ago?'' The fact that it's here is critical. I think it's opening up many paths toward further controlled trials for these and other similar drugs. I would say, though, that there aren't any major surprises with PEPI. I think the biggest surprise certainly was the HDL effect of micronized progesterone. And I quite agree with Dr Barrett-Connor that any ongoing trials now, whether they be the National Heart, Lung, and Blood Institute study on estrogen in women who have known coronary disease or the Women's Health Initiative, should relook at the regimens being offered. Also, we have to find out more about micronized progesterone. Why is it so different from Provera? Physiologically, you wouldn't expect that it should be.

Book Review [ Eur Menopause J 2(3):35-38, 1995] which compares the following two books: 
I: Treatment of the Postmenopausal Woman: Basic and Clinical Aspects
Edited by Rogerio A. Lobo. New York: Raven Press 1994. Pp 463. US$ 174. ISBN 0-781701139 

II: Practical HRT
Peter Kenemans, Ronald Barentsen and Peter van de Weijer. Bussum, the Netherlands: Medicom Europe 1995. Pp 200. US$ 49. ISBN 090-5139-110-2 

Author: H.A.I.M. van Leusden, MD, PhD

 Both books do not mention that almost all cohort studies show a decrease of total cancer incidence or mortality among users of postmenopausal estrogens. It is clear that this fact implicates a selection of healthier women that use HRT.  Therefore, it is not at all clear how much of the cardioprotective effect of postmenopausal estrogens is real, a given which is crucial for practical HRT. Moreover, these effects appear to be parallel: studies with the highest cardiovascular effect also show the highest protection from cancer of all origins and vice versa. The study of Sturgeon et al. (Epidemiology 1995; 6: 227-9) gives perhaps the strongest evidence to date on the existence of selective removal. The ultimate evidence will be a randomised controlled trial of HRT, that we all hope to be developed very soon. Contribution to the debate by an outstanding scientist as a supporter of the opposing point of view-e.g. Vandenbroucke as the devil's advocate-to Section V in Lobo's book and/or to Chapter 5 in "Practical HRT" would add great academic, thus scientific impact to future editions of both books.