539
Endogenous Sex Hormones and
Cardiovascular Disease in Men
A Prospective Population-Based Study
Elizabeth Barrett-Connor, MD, and Kay-Tee Khaw, MRCP, MSc
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Plasma obtained and frozen in 1972-1974 from 1,009 white men (40-79 years old) who have
been followed for 12 years was examined for endogenous sex hormone levels according to
prevalent or subsequent cardiovascular disease. In these older men, no sex hormone measured
(testosterone, androstenedione, estrone, or estradiol) was significantly associated with known
cardiovascular disease at baseline or with subsequent cardiovascular mortality or ischemic
heart disease morbidity or mortality. Sex hormone-binding globulin levels were also similar by
disease status. Analyses of hormone: sex hormone-binding globulin ratios or of estrogen: androgen
ratios showed a similar lack of association with cardiovascular disease. Testosterone levels were
significantly inversely associated with levels of blood pressure, fasting plasma glucose, and
triglyceride and body mass index. In contrast, the only significant estrogen risk factor
associations were positive correlations of estrone with total plasma cholesterol, triglyceride, and
glucose. These data do not support a causal role for elevated endogenous estrogen levels and
heart disease. (Circulation 1988;78:539-545)
Among the many risk factors for cardiovascular
disease, few are more important than male
sex.1'2 Several case-control studies have
tested the hypothesis that one or more endogenous
sex hormones are related to cardiovascular disease
risk in men. Most investigators found significantly
elevated endogenous estrone and/or estradiol
levels,3-10 but some reported significantly lower
testosterone levels3 11-13 or no significant difference
in estrogens or testosterone14,15 in men who had
survived a myocardial infarction compared with
men who had not had an infarction. Based on
results of coronary angiography, some case-control
studies reported higher levels of estradiol in men
who had coronary artery stenosis compared with
men without coronary artery stenosis,16,17 but a
majority did not.6,10,18-20 One prospective study of
endogenous sex hormones and cardiovascular risk
has been published, the 6-8-year follow-up of
From the University of California, San Diego, Department of
Community and Family Medicine, La Jolla, California.
Supported in part by Grants HV-1-2160-L and HL-34591 from
the National Heart, Lung, and Blood Institute; by Grant AM
31801-02 from the National Institute of Arthritis, Diabetes, and
Digestive and Kidney Disease; by the American Heart Association; and by Grant 85-1195 from the American Heart Association, Florida Affiliate. K-T.K. had a Daland Fellowship from the
American Philosophical Society.
Address for correspondence: Elizabeth Barrett-Connor, MD,
University of California, San Diego, Department of Community
and Family Medicine, M-028, La Jolla, CA 92093.
Received February 25, 1988; revision accepted April 28, 1988.
disease-free but high-risk men recruited to the Multiple Risk Factor Intervention Trial.21 This study,
based on stored sera from 163 men who had a
definite myocardial infarction or coronary heart
disease death and 163 controls matched for age,
clinic, randomization group, and baseline cholesterol, found no significant differences between cases
and controls in baseline total or free estradiol, total
or free testosterone, or androstenedione or estrone.
Taken as a whole, the case-control studies suggest
that endogenous estrogen either is causally related
to infarction or prevents death after infarction. In
contrast, results of the prospective study do not
support a causal association unless one postulates
that an estrogen-heart disease association is
obscured in men who have high cardiovascular
disease risk for other reasons.
We report here a prospective population-based
study of 1,009 men who were followed for 12 years
after baseline evaluation for heart disease risk factors was completed and blood was obtained for sex
hormone assays.
Subjects and Methods
Between 1972 and 1974, 2,023 white men (40-79
years old) who were residents of Rancho Bernardo,
a geographically defined community in southern
California, were studied as part of a Lipid Research
Clinic prevalence study. The participation rate was
82%, and participants did not differ significantly
540
Circulation Vol 78, No 3, September 1988
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from the target population.22 All participants were
ambulatory and without acute illness at the time of
the visit. Height, weight, and blood pressure were
measured by a standard protocol; a personal history
of heart disease, hypertension, stroke, and diabetes, as well as a personal history of cigarette smoking and exogenous gonadal hormone use, was
obtained by a trained interviewer using a standardized questionnaire. Blood pressure in seated subjects was measured with a standard mercury sphygmomanometer. Height and weight were measured
with the participants wearing light clothing and no
shoes. Plasma was obtained by venipuncture
between 7:30 and 11:00 AM from fasting subjects.
Total plasma cholesterol and triglyceride were measured in a standardized Lipid Research Clinic laboratory; lipoprotein levels were not determined at
this visit. Fasting plasma glucose was measured in a
hospital diagnostic laboratory with a hexokinase
method for true glucose.
Specimens for the sex hormone assays were kept
frozen at - 700 C and first thawed in 1984-1986 for
hormone assays. Analyses showed no trend for
decreased hormone levels in specimens frozen for
longer periods; previous work in this laboratory had
demonstrated no hormone deterioration over 15
years when sera were frozen and stored in tightly
sealed containers. The selection of samples was
based only on the availability of frozen plasma in
the men aged 40-79 years at the baseline evaluation
who were not taking exogenous hormones. Hormone assays were performed blind to current or
subsequent disease or death in a research laboratory with a radioimmunoassay method for endogenous sex hormones.23 The sensitivity and the intraassay and interassay coefficients of variation,
respectively, were androstenedione 30 pg/ml, 4.0%
and 8.0%; testosterone 25 pg/ml, 4.1% and 10.0%;
estrone 7 pg/ml, 15.0% and 16.0%; and estradiol 5
pg/ml, 8.0% and 12.0%. Sex hormone-binding globulin, which binds testosterone and estradiol, was
determined by the method of Rosner.24
This cohort was followed yearly for vital status
for an average of 12 years, with 99.8% ascertainment. Death certificates were obtained for all decedents. Underlying cause of death was coded by a
certified nosologist according to the Eighth Revision of the ICDA; cardiovascular disease encompassed codes 400-438 and ischemic heart disease
encompassed codes 410-414. In one third of the
cohort, all death certificates with any mention of
cardiovascular disease, hypertension, or diabetes
were validated by interviews with next of kin, physicians, and hospital records. A mortality classification panel determined that these data supported
the nosologist diagnosis in 86%. Ischemic heart
disease morbidity was determined in 1983 by the
use of a postal questionnaire and in 1984-1986 by
interviews. In 1983, validation of self-reported heart
attack (by chest pain, enzyme elevation, and elec-
trocardiogram) was achieved for 72% of the 173
cases in which hospital records could be obtained.
The hormone distributions, particularly sex hormonebinding globulin, were slightly skewed. Analyses
were undertaken with both real and log-transformed
hormone values; because results were similar, the
logarithmic analyses are not shown. Both the ageadjusted partial correlation coefficients of cardiovascular risk factors with hormone levels and the
mean crude and age-adjusted hormone levels by
cardiovascular risk factor category, dichotomized
by clinical criteria, were calculated.
Mean hormone levels (age specific and age
adjusted with analysis of variance) were determined
for all men aged 40-79 years according to the
presence or absence of known cardiovascular disease (a personal history of heart attack, heart failure, or stroke) at baseline and according to subsequent cardiovascular mortality; in the latter analysis,
subjects with cardiovascular disease at baseline
were excluded to remove men whose hormone
levels might vary as a consequence of disease or its
treatment. Crude and age-adjusted (by the MantelHaenzel procedure) cardiovascular mortality rates
by tertile of each hormone were also examined. The
Cox proportional hazards model was used to determine the independent contribution of each hormone
to cardiovascular death, after age adjustment alone
and after adjusting for age and other classic cardiovascular risk factors (cigarette smoking, systolic
blood pressure, fasting plasma glucose, cholesterol,
and body mass index). To examine any possible
effect of season or year of venipuncture on measurable hormone levels, we also undertook a nested
case-control analysis for all ischemic heart disease
deaths, selecting as controls men who had no subsequent cardiovascular disease at follow-up; each
case had a control matched for age and date of visit.
Results
Table 1 shows the age, baseline, and subsequent
cardiovascular disease distribution in the 1,009
men aged 40-79 for whom hormone assays were
performed.
Age-adjusted partial correlation coefficients of
sex hormones with other cardiovascular risk factors
for all men and for those without cardiovascular
disease at baseline were similar and changed little
by further adjustment for obesity. In men without
cardiovascular disease at baseline, androstenedione
was positively and significantly (p<0.01) associated
with total cholesterol and negatively associated
with obesity (Table 2). Testosterone was negatively
and significantly (p<0.01) associated with blood
pressure, triglyceride, fasting plasma glucose, and
obesity but was not associated with total cholesterol. Estrone, but not estradiol, was positively and
significantly (p<0.01) associated with total cholesterol, triglyceride, and fasting plasma glucose. At
similar levels of statistical significance, sex hormonebinding globulin was negatively associated with
Barrett-Connor and Khaw Endogenous Sex Hormones and Cardiovascular Disease
541
TABLE 1. Distribution of Baseline and Subsequent Fatal Cardiovascular Ischemic Heart Disease by Age of Rancho
Bernardo Men 40-79 Years Old at Baseline Examination in 1972-1974
Number of deaths in 12 years
in men without cardiovascular
Number at baseline
disease at baseline
No history of
Personal history
Ischemic
cardiovascular
of cardiovascular
Cardiovascular
heart
Combined
Age (yr)
disease
disease*
disease
disease
108
40-49
106
2
2
2
50-59
178
160
18
6
6
413
353
60-69
60
44
32
310
253
57
62
70-79
42
Total
872
40-79
114
1,009
137
82
*History of cardiovascular disease includes history of heart attack, heart failure, or stroke.
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obesity, diastolic blood pressure, total cholesterol,
triglyceride, and fasting plasma glucose.
Table 3 shows the mean age-adjusted hormone
levels by categorically defined risk factors in men
without cardiovascular disease at baseline. Again,
higher androgen levels tended to be associated with
more favorable risk factor status, the exception
being cigarette smoking. In contrast, hypercholesterolemia, hyperglycemia, and cigarette smoking were
associated with significantly higher levels of estrone.
Estradiol was unrelated to categorical risk factors in
these men. Sex hormone-binding globulin was most
strongly and inversely associated with obesity.
No sex hormone measured was significantly associated with cardiovascular or ischemic heart disease
either cross-sectionally (Table 4) or prospectively
(Table 5) after excluding those with baseline cardiovascular disease from the analysis. As shown in
Table 4, the 132 men with a history of cardiovascular disease at baseline (1972-1974) had lower ageadjusted levels of androgens and higher estradiol
and sex hormone-binding globulin levels than men
without such a history, but none of these differences approached statistical significance (at p<0. 10).
Mean estrone levels were identical in men with and
without a history of cardiovascular disease. Similarly, only slightly and not significantly lower androgens and higher estrogens were seen in men free of
known heart disease at baseline who later died with
fatal cardiovascular or ischemic heart disease (Table
5). Mean baseline hormone levels were similar in
the 35 men with nonfatal myocardial infarction
compared with those with fatal ischemic heart disease cases and with men with no ischemic heart
disease (data not shown).
We also examined mean hormone levels by 12year ischemic heart disease status separately in men
less than 60 years old at baseline. Larger but not
statistically significant hormone differences between
men with and without fatal heart disease were seen
in these younger men. In the 266 men less than 60
years old who were free of known cardiovascular
disease at baseline, the eight men who subsequently
had a fatal heart attack had higher baseline estrone
levels and lower baseline testosterone and estradiol
levels than the men who did not (estrone levels,
56±18 vs. 47±17 pg/ml, respectively, p=0.22;
estradiol levels, 33 9 vs. 36 9 pg/ml, respec±
±
TABLE 2. Partial Correlation Coefficients of Cardiovascular Risk Factors With Hormone Levels in Men 40-79 Years
Old With No History of Cardiovascular Disease (n = 872)
Age-adjusted correlation coefficient (r)
Sex hormone-
Androstenedione
Testosterone
Estrone
Estradiol
binding globulin
-0.05
-0.11*
-0.01
-0.02
-0.03
-0.01
-0.10*
0.04
0.03
-0.10*
0.16*
- 0.03
0.14*
-0.02
- 0.1 lt
0.05
- 0.13*
0.1 It
0.01
-0.12*
0.05
-0.14*
0.08t
0.03
-0.11*
- 0.17*
-0.27*
0.00
-0.01
- 0.18*
Systolic blood
pressure (mm Hg)
Diastolic blood
pressure (mm Hg)
Cholesterol
(mg/dl)
Triglyceride
(mg/dl)
Fasting plasma
glucose (mg/dl)
Body mass
index
*p<0.0.
tp<0.00l.
542
Circulation Vol 78, No 3, September 1988
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TABLE 3. Mean Age-Adjusted Hormone Levels by Risk Factor Category in Rancho Bernardo Men 40-79 Years Old
in 1972-1974 With No Personal History of Cardiovascular Disease
Sex hormoneAndrostenedione
Testosterone
Estrone
Estradiol
binding globulin
(pg/ml)
(pg/ml)
(pg/ml)
(pg/ml)
(x 10-6 M)
Systolic blood pressure
<140 mm Hg
851
48
37
5,587
333
>140 mm Hg
820
49
37
5,212
311
0.22
p value
<0.01
0.39
0.95
0.10
Diastolic blood pressure
828
<95 mm Hg
48
37
5,502
330
850
>95 mm Hg
50
37
5,144
304
0.36
0.08
p value
<0.01
0.78
0.05
Cholesterol
821
<240 mg/dl
48
37
5,419
327
910
52
>240 mg/dl
36
5,226
294
<0.01
0.2
p value
<0.01
0.65
0.05
Fasting plasma glucose
<140 mg/dl
826
48
37
5,418
325
957
>140 mg/dl
54
4,892
38
279
p value
0.01
0.06
0.05
0.48
0.09
Body mass index
<27 kg/m2
863
49
37
5,690
339
>27 kg/m2
294
49
37
4,857
292
<0.001
p value
<0.001
0.94
0.67
<0.001
Smoking history
Nonsmoker
Smoker
p value
784
1.057
<0.001
tively, p = 0.41; and testosterone levels, 4,761 ± 1,270
vs. 5,370± 1,657 pg/ml, respectively, p = 0.23).
In men free of known heart disease at baseline,
the age-adjusted 12-year cardiovascular and ischemic death rates were also examined by tertile of
each hormone. Rates did not vary significantly or
consistently by tertile, either in the whole cohort
(Table 6) or in men less than 60 years old (not
shown). There was also no effect of season or year
of venipuncture on hormone levels, based on a
nested case-control comparison of men who died
with ischemic heart disease and their controls
matched for age, sex, and date of visit.
A Cox proportional hazards analysis adjusting for
the classic heart disease risk factors (including
blood pressure, plasma lipids and glucose, cigarette
smoking, and obesity) did not materially alter the
absent association of endogenous hormone levels
with outcome. For example, the age- and risk
factor-adjusted relative risks of testosterone for
cardiovascular death were 0.94 (confidence limits,
0.08-1.4) and for ischemic heart disease death were
1.05 (confidence limits, 0.84-1.31). Multivariate analyses were also performed after adjusting for sex
hormone-binding globulin (with the testosterone: sex
hormone-binding globulin or estradiol: sex hormonebinding globulin ratio as a surrogate for free testosterone or estradiol) with similar results. In contrast,
5,330
5,664
0.04
47
50
<0.001
36
38
0.07
322
321
0.94
both age and systolic blood pressure independently
predicted fatal cardiovascular and fatal ischemic
heart disease in this cohort (p<0.001 for age and
blood pressure; data not shown).
Discussion
In this prospective population-based study of
older men, none of the androgens or estrogens
measured in frozen plasma were significantly associated with the risk of subsequent death from cardiovascular disease or myocardial infarction. Why
are these results at variance with a majority of
case-control studies of survivors of myocardial
infarction but similar to the absent association
reported in most angiographic studies of men with
coronary artery disease and in the prospective
study of high-risk men studied in the Multiple Risk
Factor Intervention Triall-21 ?
The limitations of a single measurement of any
biological variable for epidemiological studies are
well known. This limitation should apply equally to
the published cross-sectional and to prospective
studies such as this one, however. Though only a
single hormone estimation was used, several studies have suggested that the error in a single estimation is no worse than that of other biological variables, including cholesterol; the interindividual
variation is greater than intraindividual variation,25
Barrett-Connor and Khaw Endogenous Sex Hormones and Cardiovascular Disease
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TABLE 4. Mean Crude and Age-Adjusted* Hormone Levels by
Personal History of Cardiovascular Disease in Rancho Bernardo
Men 40-79 Years Old in 1972-1974
Mean (SD)
No history of
History of
cardiovascular cardiovascular
disease
disease
(n = 872)
Hormone
(n = 137)
p value
Androstenedione
(pg/ml)
Crude
836 (345)
761 (241)
0.24
Age-adjusted
831
796
Testosterone (pg/ml)
Crude
5,361 (1,824) 5,350 (1,833) 0.95
Age-adjusted
5,355
5,345
Estrone (pg/ml)
49 (18)
Crude
50 (21)
0.83
Age-adjusted
49
49
Estradiol (pg/ml)
37 (11)
Crude
38 (13)
0.31
37
38
Age-adjusted
Sex hormone-binding
globulin (x 10-6 M)
Crude
321 (184)
344 (242)
0.91
324
326
Age-adjusted
*Age adjusted by analysis of variance.
and
a
single morning specimen is reportedly ade-
quate to characterize the testosterone of individuals.26 In the present study, all blood was
obtained from fasting subjects in the morning to
control for circadian variation in hormone levels.27
In addition, matching on season of sampling and on
date of visit did not alter the results, so the lack of
associations are unlikely to be attributable to seasonal variation in endogenous hormone levels.
Most of the case-control studies with positive
findings reported higher endogenous estrogen
(estrone or estradiol) levels in survivors of myocardial infarction but similar androgens. Case-control
studies are not obliged to use frozen serum or
plasma, and it is possible that endogenous estrogens
are less stable in frozen plasma than androgens,
although there is no evidence for this. A low level of
hormone, approaching the sensitivity of the assay
method, could make any loss in storage more misleading; the average estrogen levels reported here
are consistent with expected estrone and estradiol
levels in middle-aged men28,29 and well above the
assay sensitivity. The average levels of estrogen
measured in blood frozen in 1972 were no lower
than levels in blood obtained and frozen in 1974.
Therefore, loss of estrogen in frozen plasma seems
an unlikely explanation for the absence of an estrogen heart disease association in our cohort.
Published studies of higher endogenous estrogen
levels in male survivors of myocardial infarction
compared with male controls3-'0 and the much less
consistent association of endogenous estrogen levels with atherosclerosis in angiographically studied
men6'0'16-20 are compatible with the hypothesis that
543
higher estrogen levels improve survival after a heart
attack rather than cause atherosclerosis.6 In our
cohort, however, hormone levels were similar in
the men with or without known heart disease at
baseline and in the men with or without incident
nonfatal myocardial infarction. Similarly, in the
Multiple Risk Factor Intervention Trial, the sex
hormone levels did not differ in men with both fatal
and nonfatal heart disease compared with men
without.21 Thus, a survivorship benefit seems an
unlikely explanation for the differences between
case-control and prospective studies.
Though most case-control studies measured only
total hormone levels without accounting for protein
binding, it has been suggested that only the free
(i.e., unbound) hormones might be biologically significant. However, the Multiple Risk Factor Intervention Trial measured both free and bound hormones and found no association with coronary
artery disease.2' Similarly, in this cohort, hormone: sex hormone-binding globulin ratios, used as
surrogate estimates for free hormones, were also
not related to cardiovascular disease.
Hospitalization and stress after a heart attack
could mediate changes in endogenous hormones,30
but all of the published case-control studies of
myocardial infarction cited here were conducted at
least 2 months after the acute event. It is possible
that some lifestyle change or medication commonly
used after myocardial infarction caused higher estrogen levels in cases compared with controls. For
example, digitalis has been reported to raise estrogen levels.3' Another possible confounder not
excluded in most case-control studies is cigarette
smoking, which is associated with both higher estrogen levels32,33 and an increased risk for cardiovascular disease. In the present study, the proportion
of current cigarette smokers was low (19%), and
analysis controlling for smoking did not significantly change the results. Alternatively, some postinfarction behavior change in exercise or diet could
lead to altered hormone levels.34
The average age of men in this cohort was 63
years. It is possible that the estrogen heart disease
association is seen only in younger men. In this
cohort, estradiol levels were lower and estrone
levels were higher, although not significantly so, in
men less than 60 years old whose death was attributed to ischemic heart disease. Although the early
case-control studies studied younger men, significantly higher estradiol levels were reported by
Phillips et a19 in postinfarction men whose average
age was 70 years. Therefore, age of the population
studied seems unlikely to explain the lack of a
hormone-heart disease association.
Misclassification as to cause of death based on
death certificates, as used in the present study,
could be more likely than misdiagnosis based on
hospital records, as used in case-control studies. As
noted, we confirmed the death certificate diagnosis
in 86% of cardiovascular deaths for whom valida-
544
Circulation Vol 78, No 3, September 1988
TABLE 5. Mean Crude and Age-Adjusted* Hormone Levels by 12-Year Mortality in Rancho Bernardo Men 40-79 Years Old in 1972-1974
With No Personal History of Cardiovascular Disease
Ischemic heart disease death
Mean (SD)
Cardiovascular death
No (n =758)
Yes (n= 114)
p value
No (n =790)
Yes (n =82)
p value
Androstenedione (pg/ml)
848
752
<0.01
Crude
842
767
0.03
815 (278)
837 (351)
0.52
835 (349)
821 (283)
Age-adjusted
070
Testosterone (pg/ml)
Crude
0.32
5,206
5,380
5,382
5,151
0.24
0.29
0. 3
Age-adjusted
5,412 (1,839)
5,153 (1,670)
5,385 (1,840)
5,210 (1,727)
Estrone (pg/ml)
Crude
49 (18)
49 (17)
0.86
49 (18)
49 (18)
0.69
48
48
0.81
49
49
Age-adjusted
0.80
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Estradiol (pg/ml)
37 (11)
Crude
37
Age-adjusted
Sex hormone-binding globulin
(x 10-6 M)
315 (178)
Crude
321
Age-adjusted
*Age-adjusted by analysis of variance.
37 (10)
36
0.98
0.62
37 (11)
37
36 (10)
36
0.i7
0.51
353 (216)
320
0.08
0.97
317 (177)
320
354 (237)
327
0.17
0.75
tion was sought. The Multiple Risk Factor Intervention Trial,2' which also found no association of sex
hormones to subsequent cardiovascular disease,
validated all cases and used very strict definitions of
cardiovascular disease and coronary heart disease
death. Therefore, endpoint misclassification seems
unlikely to explain the lack of hormone heart disease association in these two prospective studies.
A negative study, of course, raises the question
of statistical power, but it is unlikely that a larger
study would demonstrate a statistically and clinically significant hormone-heart disease association.
There were 82 ischemic heart disease deaths in this
cohort, more cases than were reported in any
cross-sectional study except that of Goldberg et
al,20 who found no association of endogenous estrogen with coronary artery stenosis. Based on the
events rate for ischemic heart disease in this cohort,
at a power of 0.90 and a=0.05, the potentially
detectable differences are comparable with those
reported in other studies where significant differences have been found.
If a prospective study were to reveal any significant hormone-heart disease association, our data
suggest that an androgen deficit, not an estrogen
TABLE 6. Age-Adjusted 12-Year Ischeniic Heart Disease Mortality
Rates in Rancho Bernardo Men 40-79 Years Old With No History of
Cardiovascular Disease by Tertile of Hormone Distribution
Androstenedione
Testosterone
Estrone
Estradiol
Sex hormone-binding globulin
Lowest
10.5
8.8
9.9
10.3
9.0
Tertile (%)
Middle Highest
9.2
8.9
11.2
8.2
8.6
9.6
8.3
9.1
10.0
10.1
excess, would be found in men with heart disease.
The most consistent finding in the present study
was the lower level of testosterone associated with
cardiovascular risk factors and disease. Further,
the inverse association of plasma testosterone with
several major heart disease risk factors noted in the
present and other studies'7-19,35-39 makes a protective effect of testosterone biologically plausible,
whereas there is no similar mechanism (through
more favorable risk factor status) attributable to
high endogenous estrogen levels in men. Men with
lower levels of plasma testosterone also tend to
have lower levels of high-density lipoprotein
cholesterol3536 and lipoprotein lipase. 19 In nearly all
case-control studies4-7,9,13,14,16-20 that measured
testosterone, and in the prospective Multiple Risk
Factor Intervention Trial,2' testosterone levels were
lower in men with ischemic heart disease, although,
as in the present study, differences were not always
statistically significant.
Although the present study, like its predecessors, does not completely resolve the question of
whether endogenous gonadal hormones are related
to cardiovascular disease risk in men, these data
make it increasingly unlikely that higher plasma
estrogens are causally related to cardiovascular
disease in older men. In any case, if higher estrogen levels or lower testosterone levels were associated with increased cardiovascular risk, the male
preponderance in ischemic heart disease would be
even less explicable in terms of endogenous sex
hormones per se. Investigation of the sex-, age-,
and possible dose-related differences in the relation of similar hormones to cardiovascular risk
factors may be more fruitful in terms of elucidating
mechanisms for cardiovascular disease.
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KEY WORDS * estrogen * prospective studies * testosterone
* ischemic heart disease
Endogenous sex hormones and cardiovascular disease in men. A prospective
population-based study.
E Barrett-Connor and K T Khaw
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Circulation. 1988;78:539-545
doi: 10.1161/01.CIR.78.3.539
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