Postmenopausal Hormone Therapy a Reversal of Fortune

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Karin B. Michels and JoAnn E. MansonPostmenopausal Hormone Therapy: A Reversal of Fortune

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Postmenopausal Hormone TherapyA Reversal of Fortune

Karin B. Michels, ScD, MSc; JoAnn E. Manson, MD, DrPH

How did it become common clinical practice in past

decades to prescribe postmenopausal hormones for

the prevention of coronary heart disease (CHD)?

Postmenopausal hormone therapy (HT), although approved

by the US Food and Drug Administration for the treatment of

postmenopausal symptoms and the prevention of osteoporo-

sis, was never approved for the prevention of CHD. The

recent data from the Womens Health Initiative (WHI) and

other randomized clinical trials (RCTs) indicate that com-

bined estrogen and progestin may increase, rather than

decrease, CHD risk.1 This news has alarmed women world-

wide and has left physicians uncertain what to recommend to

their patients. Recently, the North American Menopause

Society released recommendations stating that estrogen and

progestin should not be prescribed for primary or secondary

prevention of CHD.2 The effect of unopposed estrogen and

other formulations of HT on CHD remains unclear; more

insight on the former will emerge from the still-ongoing

estrogen component of the WHI.

The surging popularity of HT use during the past few

decades was largely based on findings from observational

epidemiologic studies.3,4 Observational studies suggested

that HT may reduce the incidence of CHD, fractures, and

colorectal cancer but may increase the incidence of endo-metrial cancer, breast cancer, stroke, and venous thrombo-

embolism.4,5 Notably, except for the divergent findings

about CHD, the WHI findings were largely concordant

with the observational studies (Figure). The relative risks

for hip fractures and colorectal cancer with HT were

reduced, whereas those for breast cancer, venous throm-

boembolism, and stroke were increased. At surprising odds

with the observational studies, the WHI found a 29%

increase in CHD after an average of 5.2 years of follow-

up.1 Before the WHI, other RCTs had already begun to cast

doubt on the cardiovascular benefit of HT. The Heart and

Estrogen/progestin Replacement Study (HERS) had re-

ported an overall null result and an increased risk of CHD

in the first year among women with prior heart disease who

were randomized to HT.6 Consequently, the American

Heart Association recommended in 2001 not to initiate HT

for secondary prevention of CVD.7

What factors account for the widely divergent findings on

HT and CHD from observational studies and RCTs? This

question is particularly relevant for cardiovascular specialists

because the answers could lead to important new insights

about the pathogenesis of atherothrombotic events and could

inform future research in this area.

A cardioprotective effect of estrogen itself is still uncertain.

Several physiological effects of exogenous estrogen are

consistent with cardioprotection: Estrogen reduces LDL and

increases HDL levels; reduces Lp(a) lipoprotein, fibrinogen,

plasminogen-activator inhibitor type 1, and insulin levels;

inhibits oxidation of LDL; and improves endothelial vascular

function.8 Estrogen therapy, however, has adverse physiolog-

ical effects, including increasing triglycerides and C-reactive

protein and promoting thrombosis. Adding a progestin atten-

uates some of the lipid benefits, particularly the HDL in-

crease, but it does not seem to counter the prothrombotic

effects of estrogen.8

Currently, clinical data on HT and CHD are available from

more than 40 observational studies and from 7 RCTs (5 RCTson secondary prevention913 and 2 RCTs on primary preven-

tion1,14; Table). A meta-analysis of 40 observational studies

suggested a 50% reduction in the risk of CHD associated with

current estrogen use.3 Most of these studies include women who

used unopposed estrogen; limited data are available from obser-

vational studies on estrogen and progestin supplementation.

The first secondary prevention trial, HERS, did not find

any cardiovascular benefit of estrogen-progestin supplemen-

tation (Table).9 Subsequent trials have found either no car-

dioprotection or an increased risk of CHD events with HT

(Table).1013 Most of these trials tested oral conjugated equine

estrogen (CEE) and medroxyprogesterone acetate (MPA), but

the results with transdermal 17-estradiol with and without

norethindrone11 and estradiol valerate13 were similar (Table).

Primary prevention RCTs including clinical CHD end points

have been sparse and have also suggested an excess risk.1,14

Why then do the results from the observational studies and

the RCTs on the association between HT and CHD seem to

send different messages? There are several possible explana-

tions, both methodologically and biologically based.

Methodological explanations focus on the observation

that long-term HT users in epidemiologic studies differ in

many ways from nonusers. Women on HT in observational

studies are more health conscious, thinner, and more

physically active, and they have a higher socioeconomicstatus and better access to health care than women who are

The opinions expressed in this editorial are not necessarily those of theeditors or of the American Heart Association.

From the Obstetrics & Gynecology Epidemiology Center, Department

of Obstetrics, Gynecology, and Reproductive Biology (K.B.M.), and theDivision of Preventive Medicine, Department of Medicine (J.E.M.),

Brigham and Womens Hospital and Harvard Medical School; and theDepartment of Epidemiology, Harvard School of Public Health (K.B.M.,J.E.M.), Boston, Mass.

Correspondence to Dr Karin B. Michels, Obstetrics & GynecologyEpidemiology Center, Brigham and Womens Hospital, 221 LongwoodAve, Boston, MA 02115. E-mail [email protected]

(Circulation2003;107:1830-1833.) 2003 American Heart Association, Inc.

Circulationis available at http://www.circulationaha.orgDOI: 10.1161/01.CIR.0000064601.65196.DF

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not on HT. Self-selection of women into the HT user group

could generate uncontrollable confounding and lead to

healthy-user bias in observational studies. Moreover,

individuals who adhere to medication have been found to

be healthier than those who do not, which could produce a

compliance bias.15 The question remains, however, of

why the observational studies and RCTs are concordant for

stroke, venous thromboembolism, fracture, and cancer, all

of which have lifestyle determinants. In particular, CHD

and stroke have similar risk factor profiles. Thus, it is

unlikely that the healthy-user bias or the compliance bias

in observational studies fully explains the differences,

Relation between postmenopausal HT and various clinical end points in observational studies and in the WHI.

Results of RCTs of Postmenopausal HT and CHD

TrialStudyGroup

Age Range at

Entry (Mean),y Treatment

Mean

Duration,y Results

Secondary prevention

Heart and Estrogen/progestin

Replacement Study92763 women with

documented CHD

4479 (66.7) 0.625 mg of oral CEE plus 2.5

mg of MPA or placebo

6.8 Primary CHD events: RR0.97

(95% CI 0.821.14)

Estrogen Replacement and

Atherosclerosis Trial10309 women with CHD 4280 (65.8) 0.625 mg of oral CEE, 0.625

mg of oral CEE plus 2.5 mg of

MPA, or placebo.

3.2 No significant differences in rates

angiographic stenoses or clinical

events

Papworth HRT

Atherosclerosis Study11255 women with CHD 55 (66.5) Transdermal 17-estradiol

alone or with cyclic

norethindrone, or placebo

2.6 CHD events:

RR1.49

(95% CI 0.932.36)

Womens Angiographic

Vitamin and Estrogen Trial12423 women with CHD Mean: 65 0.625 mg of oral CEE plus 2.5

mg of MPA, or placebo

2.8 Slightly greater angiographic

progression with HT than placebo;

CVD events:

HR1.9 (95% CI 0.973.6)

Estrogen in the Prevention of

Reinfarction Trial131017 women with CHD 5069 (62.6) 2 mg estradiol valerate or

placebo

2 CHD events: RR0.99 (95% CI

0.701.41)

All-cause mortality: RR0.79

(95% CI 0.501.27)

Primary prevention

Overview of 22 HT trials14 4124 women enrolled

in RCTs of HT

Not provided Several formulations of HT or

placebo or other therapy

3 CVD events:

RR1.39 (95% CI 0.483.95)

Womens Health Initiative1 16 608 women at usual

risk of CHD

5079 (63) 0.625 mg of oral CEE plus 2.5

mg of MPA, or placebo

5.2 CHD events:

HR1.29 (95% CI 1.021.63)

CEE indicates conjugated equine estrogen; MPA, medroxyprogesterone acetate.

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although it is possible that the end point of CHD is

particularly susceptible to these biases.

Another methodological issue to consider is the potential

failure of observational studies to capture early clinical events

that occur within a year or two of initiation of HT. In

epidemiologic studies, information on HT use may not be

updated, or it may be infrequently updated during follow-up.

If a clinical event follows soon after HT initiation, it could be

wrongly classified as occurring during a nonuser interval.

This issue could be more important for CHD than for other

end points because RCTs have indicated an early and short-

term excess risk of CHD events but delayed and/or more

persistent elevated risks of stroke, deep vein thrombosis, and

breast cancer.

In addition, several biological factors could contribute to

the differences between observational studies and RCTs.

WHI participants differed in a number of ways from women

taking HT in observational studies. In an observational

setting, free-living women are studied, who make the deci-

sion together with their physicians whether to take HT,generally on reaching menopause. One important criterion for

this decision is the presence of menopausal symptoms;

women who have menopausal symptoms are more likely to

request HT. Women with such symptoms may be those who

have the lowest endogenous estrogen levels and therefore

may have the greatest benefit from exogenous estrogen

supplementation.

Furthermore, although women in the observational stud-

ies generally initiated HT use at onset of menopause, most

of the participants in the WHI started HT many years after

menopause. In fact, 67% of women in WHI were age 60

years or older.1 It is conceivable that many of these older

women already had subclinical CHD. The prothromboticeffect of estrogens may manifest itself predominantly

among women who initiate HT well into their menopause,

whereas women who start HT early after the onset of

menopause may experience cardiovascular benefit from

estrogens. This possibility derives support from nonhuman

primate data.16 However, women in the WHI who initiated

HT at 50 to 59 years of age did not have lower hazard

ratios for CHD than older women.17 Moreover, women

with prior CHD in the WHI assigned to HT had the same

hazard ratio for CHD as women without prevalent CHD.1

These data suggest that differences by age at initiation of

HT and underlying stage of atherosclerosis may not be

sufficient explanations for the observed differences be-

tween epidemiologic studies and RCTs. Another consider-

ation is that WHI participants had higher body mass than

did women taking HT in observational studies.5 Potential

modification of the HTCHD relation by body mass index,

which correlates inversely with endogenous estrogen lev-

els, is important to explore; such analyses are in progress.

Another possible explanation for the differences be-

tween epidemiologic studies and RCTs that has been

suggested is the inclusion of silent myocardial infarctions

as end points in the WHI. While observational studies

generally do not capture this end point, less than 5% of the

major CHD events in the WHI were silent myocardialinfarctions; moreover, exclusion of silent myocardial in-

farctions did not appreciably alter the findings.1 Therefore,

this could not be a plausible explanation for the differences

observed.

Differences in the formulations and doses of HT may also

have contributed to the divergent findings from observational

studies and RCTs. As previously mentioned, most women in

observational studies used unopposed estrogen. AlthoughHERS and the WHI provide important data on continuous-

combined oral CEEs (0.625 mg/d) and MPA (2.5 mg/d), the

results cannot be generalized to unopposed estrogen, sequen-

tial progestin use, or other formulations of estrogens and

progestins, other dosages, or other routes of administration.

Future research on other regimens is needed. Identifying

biomarkers and genetic factors that predispose to adverse

effects of HT may make it possible to target HT therapy more

appropriately.

In conclusion, several methodological and biological

factors may have contributed to the divergent findings

from observational studies and RCTs. Clearly, more re-

search is needed to elucidate the relative importance of

each of these factors. In the meantime, a role remains for

combined estrogen and progestin supplementation in the

treatment of severe menopausal symptoms. Such therapy,

however, should involve the lowest effective dose and the

shortest duration of treatment to relieve symptoms.2 HT

should not be initiated or continued for primary or second-

ary prevention of cardiovascular disease.

References1. Writing Group for the Womens Health Initiative Investigators. Risks and

benefits of estrogen plus progestin in healthy postmenopausal women:

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2. The North American Menopause Society (NAMS). Report from the

NAMS Advisory Panel on Postmenopausal Hormone Therapy. The North

American Menopause Society. October 3, 2002. Menopause. 2003;

10:6 12.

3. Grodstein F, Stampfer MJ. The epidemiology of postmenopausal

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PM, eds. Thrombosis and Thromboembolism. New York, NY: Marcel

Dekker, Inc; 2002.

4. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease

and prolong life in postmenopausal women.Ann Intern Med. 1992;117:

1016 1037.

5. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational

study of postmenopausal hormone therapy and primary prevention of

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menopausal women. Heart and Estrogen/progestin Replacement Study

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11. Clarke SC, Kelleher J, Lloyd-Jones H, et al. A study of hormone

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Am J Med. 1999;106:574 82.

KEYWORDS: hormone replacement therapy, postmenopausal epidemiology

trials, clinical cardiovascular disease

Michels and Manson Hormone Therapy 1833


Postmenopausal Hormone Therapy a Reversal of Fortune

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