American Journal of Epidemiology
Copyright C 1996 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
143, No. 10
Health Prior to Hormone Use: Matthews et al. Reply to Grodstein
Karen A. Matthews,
Lewis H. Kuller,
Rena R. Wing,
Elaine N. Meilahn,
and Pamela Plantinga
Grodstein (1) suggests that the useful questions
raised by our paper (2) are how and to what extent the
differences in cardiovascular health of women who do
and do not use postmenopausal estrogen replacement
therapy (ERT) affect the interpretation of observa-
tional studies on the relation between ERT use and risk
for cardiovascular disease morbidity and mortality.
She argues that the relation is likely to be causal, but
we are not ready to accept that interpretation without
further clinical trial data that would document the
effect of long-term use of ERT according to the wom-
Although it is true that many observational studies
show the benefit of ERT on risk for cardiovascular
disease, they also show that the benefit of ERT is
apparent for diseases not thought to be related to
estrogen exposure. For example, among women en-
rolled in the Study of Osteoporotic Fractures, long-
term current ERT users had a lower risk of all-cause
mortality after removal of death due to breast, endo-
metrial, and colon cancer, hip fractures, stroke, and
atherosclerotic heart disease (3). Similarly, Sturgeon et
reported lowered relative risk among current users
(defined as use within 1.9 years or less) for almost all
causes of death, including cancers (4). Grodstein sug-
gests that many physicians stop ERT when women
become ill with cancer, leaving healthy women re-
maining as current users. However, this explanation is
not easily applied to mortality from injuries, which is
also reduced among ERT users (4). The ubiquitous
benefit of ERT suggests that selection factors for ERT
use are important to consider in interpreting ERT-heart
Received for publication October 16, 1995, and in final form
February 23, 1996.
Abbreviation: ERT, estrogen replacement therapy.
Department of Psychiatry, University of Pittsburgh School of
Medicine, Pittsburgh, PA.
Department of Epidemiology, Graduate School of Public
University of Pittsburgh, Pittsburgh, PA.
Reprint requests to Dr. Karen A. Matthews, Department of Psy-
chiatry, University of Pittsburgh School of Medicine, 3811 O'Hara
Street, Pittsburgh, PA 15213.
A key selection factor for ERT use is high socio-
economic status (2, 5, 6). Socioeconomic status is a
powerful predictor of rates of mortality and morbidity
from almost every disease and condition (7). For ex-
ample, Kitagawa and Hauser (8) reported a Linear
relation between mortality and years of education
among white women aged 25-64 years. The ratio of
observed to expected deaths within subgroups ranged
from 0.78 for women with a college education or
better to 1.60 for women with <4 years of education.
Although part of the association between socioeco-
nomic status and health can be accounted for by in-
termediate risk factors, attempts to control statistically
for risk factors do not eliminate the effect of socio-
economic status on coronary disease mortality (e.g., 8,
Because we do not completely understand why
socioeconomic status is related to health, we cannot
adequately introduce appropriate controls for its influ-
Grodstein suggests that the better risk factor profile
of hormone users "reflect sociologic heterogeneity,
and . . . not biologic phenomena." We maintain that
biologic variability also affects both the initiation and
maintenance of hormone use. Women who initiate use
of ERT have had a bilateral oophorectomy, report high
levels of menopausal symptoms, and are lean (2, 5, 6),
suggestive of low endogenous estrogen levels. More-
over, women who discontinue use are frequently those
who bleed intermittently, develop uterine hyperplasia,
or develop adverse symptoms in response to ERT (10).
Indeed, these sequelae of ERT use are not rare. In the
Postmenopausal Estrogen/Progestin Interventions
Trial (PEPI) (11), the cumulative percent of women
with a uterus who discontinued unopposed estrogen
therapy for any reason was 55 percent. Thus, women
who are long-term users are likely to be quite different
biologically from never or former users. Statistical
controls for the biologic as well as the sociologic
differences between ERT users and nonusers can only
be adequate if we have perfect measurement of all
relevant variables that determine the differences.
Grodstein takes issue with the argument that adher-
ence to pill-taking may account for some of the ap-
by guest on September 27, 2012http://aje.oxfordjournals.org/Downloaded from
984 Matthews et al.
parent benefit of ERT use because the data that dem-
onstrate the utility of adherence (even to placebo)
come from randomized clinical trials, and not from
observational studies "where the subjects themselves
have chosen to use medication." Clinical trial partici-
pants also choose to take medications. For unknown
reasons, the beneficial effect of adherence is about a
50 percent reduction of rate of mortality among pa-
tients who had a myocardial infarction (12), about the
same reduction of disease rates associated with ERT
Grodstein cites a series of potential mechanisms that
underlie the ERT-coronary disease associations, some
of which are based on studies of the acute effects of
estrogen exposure, often at supraphysiologic dosage.
Our concern is that long-term exposure at physiologic
dosages may have different effects than short-term
exposure. Take several illustrations. Exposure to acute
infusions of 17-beta estradiol improved endothelium-
dependent vasodilation in both the peripheral and cor-
onary circulations of postmenopausal women, whereas
3 weeks of transdermal estradiol administration did
not result in alterations of vasodilator responses (13).
Among ovariectomized cynomolgus monkeys, 30
months of a lipid-lowering diet led to improvements in
coronary and lumen size and dilator responses to ace-
tylcholine, which were not affected by simultaneous
exposure to conjugated equine estrogen alone or with
medroxyprogesterone acetate treatment (14).
In conclusion, we think it prudent to be cautious in
interpreting the ERT-cardiovascular disease associa-
tions until clinical trial data have demonstrated for
whom ERT use is beneficial and for whom it is not. It
is premature to advocate ERT as a universal or wide-
spread preventive therapy for women.
Grodstein F. Can selection bias explain the cardiovascular
benefits of hormone replacement therapy? Am J Epidemiol
Matthews KA, Kuller LH, Wing RR, et al. Prior to use of
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The Writing Group for the PEPI Trial. Effects of estrogen or
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Horwitz RI, Viscoli CM, Berkman L, et al. Treatment adher-
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