(Circulation. 1995;91:1757-1760.)
© 1995 American Heart Association, Inc.
Articles |
Dehydroepiandrosterone Sulfate Does Not Predict Cardiovascular Death in Postmenopausal Women
The Rancho Bernardo Study
From the Department of Family and Preventive Medicine, University of California, San Diego at La Jolla.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background High levels of dehydroepiandrosterone sulfate (DHEAS) appear to be associated with a reduced risk of fatal cardiovascular disease (CVD) in men. We examined the association between baseline DHEAS levels and the 19-year CVD and ischemic heart disease (IHD) mortality rates in 942 postmenopausal women free of known heart disease at baseline.
Methods and Results The 199 CVD deaths and 102 IHD deaths were not related to baseline DHEAS levels. DHEAS was not related to body mass index, fasting plasma glucose, or family history of coronary heart disease, but significantly higher DHEAS levels were found in women who had elevated total or HDL cholesterol or blood pressure, were current smokers, or were nonusers of estrogen replacement therapy. After we adjusted for age, cholesterol, blood pressure, smoking, estrogen replacement therapy, obesity, fasting plasma glucose, and family history of heart disease, the relative risk of fatal CVD and IHD was 1.11 (95% confidence interval, 0.81 to 1.23) and 0.92 (95% confidence interval, 0.85 to 1.17), respectively, for a 50-µg/dL decrease in DHEAS.
Conclusions Although higher DHEAS levels were associated with several major CVD risk factors, they were unrelated to the risk of fatal CVD in women.
Key Words: cardiovascular disease • sex • aging • risk factors
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Circulating dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), the major secretory products of the human adrenal gland, decrease with age in men and women,1 2 leading to the suggestion that low levels might be associated with diseases of aging such as atherosclerosis.3 In early case-control studies, low levels in blood or urine were associated with myocardial infarction in men.4 5 In 1986, we reported that low levels of plasma DHEAS predicted a significantly increased risk of cardiovascular death in 242 men from the Rancho Bernardo cohort who were followed for 12 years.6 Two subsequent studies confirmed this inverse association between plasma DHEAS and coronary heart disease (CHD) in men.7 8
It is well known that women have heart disease later than men. Women also have lower levels of DHEAS than men at every age. Postmenopausal women who take replacement estrogen, which may delay or prevent heart disease, have even lower DHEAS levels than untreated women.9 10 These observations suggest that DHEAS might not have a cardioprotective effect in women. This possibility was supported by a preliminary analysis of 12-year mortality in Rancho Bernardo women that revealed that a high DHEAS level actually appeared to be harmful,11 but these results were based on only 289 women and fewer than 30 cardiovascular deaths.
We report the relation of baseline DHEAS levels to 199 cardiovascular deaths that occurred over a 19-year follow-up of 942 postmenopausal women from the Rancho Bernardo cohort.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Between 1972 and 1974, 82% of a geographically defined community of older adults in Rancho Bernardo, Calif, were recruited for a study of risk factors for cardiovascular disease (CVD).12 A standardized questionnaire was completed that included questions about personal and family history of heart disease (heart attack or heart failure), smoking history, use of hormone replacement therapy, and current use of medication. Blood pressure was measured with a standard mercury sphygmomanometer after the participant had been seated for at least 5 minutes. The measurement was repeated in those in whom the initial reading was >160 mm Hg systolic or >90 mm Hg diastolic, and the lower of the two readings was recorded. Height and weight were measured with the participants in lightweight clothing without shoes. Body mass index was calculated as (kg/m2)x100. Participants were seen between 7:30 and 11:00 AM after a requested 12-hour fast. Total plasma cholesterol was measured in a standardized Lipid Research Clinics laboratory using an AutoAnalyzer.13 Fasting plasma glucose was measured in a hospital diagnostic laboratory using a hexokinase method. Plasma for DHEAS was obtained and frozen at -70°C. One third of this cohort (n=429) returned within 90 days for a second evaluation, when fasting HDL cholesterol was measured by precipitating the other lipoproteins with heparin and manganese chloride according to the standardized procedures of the Lipid Research Clinics.13
Vital status was determined annually for 99.9% of the cohort during a 19-year follow-up. Death certificates, obtained for all decedents, were coded for underlying cause of death by a certified nosologist, using the ninth revision of the International Classification of Diseases, Adapted. CVD included codes 400 to 438, and ischemic heart disease (IHD) included codes 410 to 414. A panel of cardiologists reviewed medical records in a subset and confirmed a diagnosis of definite or probable CVD in 85%.
Between 1985 and 1986, specimens obtained at baseline were thawed, and DHEAS was measured by radioimmunoassay.14 The sensitivity for the DHEAS assay was 0.02 µg/mL, the intra-assay coefficient of variation was 5.2%, and the interassay coefficient of variation was 10.0%. Previous work in this laboratory had demonstrated no deterioration in DHEAS over 15 years.15
Data were analyzed using STATISTICAL ANALYSIS SYSTEMS
(SAS Inc). Analyses were performed with and without logarithms of DHEAS
to account for its slightly skewed distribution; results did not
differ, and only measured data are shown. The 19-year CVD and IHD
mortality rates were calculated for women with DHEAS levels below and
above 61 µg/dL (approximately 50th percentile) with adjustment for
age using the Mantel-Haenszel direct-age adjustment and
2 test for statistical significance. Mean
age-adjusted DHEAS levels were compared by high- and low-risk
categories using ANCOVA. Kaplan-Meier survival curves were used to
compare CVD and IHD mortality rates by DHEAS level above and below the
median. The independent contribution of DHEAS to the risk of fatal CVD
and IHD was assessed using the Cox proportional hazards
model.16 All P values are two-tailed.
Statistical significance was defined as P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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There were 942 women aged
50 years (mean age, 65.2 years)
without known heart disease at baseline. As shown in Table 1
,
mean DHEAS levels were significantly higher in women
with hypercholesterolemia, with hypertension, who currently smoked
cigarettes, or who were nonusers of estrogen replacement therapy. In
the 429 women whose HDL cholesterol was measured, women whose plasma
HDL was 45 mg/dL had significantly higher age-adjusted mean DHEAS
levels than women with HDL <45 mg/dL (86.6 versus 63.9 µg/dL,
P=.0001). DHEAS was not related to body mass index, fasting
plasma glucose, or family history of CHD.
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As shown in Table 2, the 199 CVD deaths and 102 IHD
deaths were unrelated to mean DHEAS levels at baseline. Age-adjusted
CVD mortality rates were 42.3% and 44.6%, respectively, comparing
women with DHEAS levels above and below the median of 61 µg/dL. The
IHD death rates for women above and below the DHEAS median were 24.0%
and 24.1%, respectively. Comparable results were found when CVD and
IHD mortality rates were compared by DHEAS quartile. Exclusion of the
291 women who reported taking estrogen replacement at baseline did not
alter these results.
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With a Cox proportional hazards model, the age-adjusted relative risk (RR) of CVD death for a 50-µg/dL decrease in DHEAS was 1.05 (95% confidence interval, 0.91 to 1.10). After an adjustment for age, cholesterol, blood pressure, smoking, estrogen replacement therapy, obesity, fasting plasma glucose, and family history of heart disease, the RR was 1.11 (95% confidence interval [CI], 0.81 to 1.23). Similar analysis for IHD death showed an age-adjusted RR of 1.01 (95% CI, 0.99 to 1.02) and a multiply adjusted RR of 0.92 (95% CI, 0.85 to 1.17). When HDL replaced cholesterol in the Cox model, the multiply adjusted RR values for CVD and IHD were similar (CVD: RR=1.03, 95% CI, 0.94 to 1.06; IHD: RR=1.16, 95% CI, 0.75 to 1.33). Exclusion of the women who reported taking estrogen replacement at baseline did not materially change any of these results.
Kaplan-Meier 19-year survival curves were calculated to evaluate the
possibility that DHEAS levels were important for only a few years after
measurement or were important only in relatively young women. For the
older women, the proportion dying of CVD (Fig 1) or IHD
(Fig 2) was nonsignificantly greater among those with
DHEAS levels above the median. The inverse, also nonsignificant, was
seen in the younger women. In both age groups, differences in mortality
by baseline DHEAS increased only slightly and not significantly with
the interval since blood hormone levels were obtained. Similar results
were found when CVD and IHD survival curves were compared by DHEAS
quartile.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In contrast to the situation in men,6 7 8 no reduced risk of CVD was observed in women who had high levels of DHEAS, before or after adjustment for other heart disease risk factors. The present study had a >95% power to detect a twofold increased risk of CVD mortality and a >90% power to detect a twofold risk of fatal IHD.
We considered several possible explanations for the absent protective effect in women. The survival curves do not suggest that there was too long an interval between measurement of DHEAS and the cardiovascular events. Although missed diagnosis and misclassification of CVD and IHD are common in clinical studies of women,17 18 19 no sex difference has been demonstrated in death certificates.20 Although women have lower levels of DHEAS than men, all women had a DHEAS level greater than the sensitivity of the assay, 0.02 µg/mL. It has been reported that the interconversion between DHEA and DHEAS is different in men than in women,21 and we cannot exclude the possibility that DHEA, but not DHEAS, is protective in women. However, we chose to measure DHEAS instead of DHEA because the latter shows great diurnal variation, limiting interpretation of data based on samples drawn as little as 4 hours apart.22
These data do not exclude the possibility that low DHEAS levels promote nonfatal CHD. If this were true, it still would not explain the sex difference, since the association in Rancho Bernardo men was much stronger for fatal than for nonfatal CVD.6
Although DHEAS was not associated with fatal CVD or IHD, before or after adjustment for all measured covariates, low DHEAS levels were associated with higher total cholesterol, blood pressure, cigarette smoking, and nonuse of postmenopausal estrogen. DHEAS was positively associated with HDL cholesterol, the major IHD risk factor with the most striking sex differences. DHEAS has been reported to be positively associated with HDL cholesterol in men but not in women.23
The observation that low plasma DHEAS levels were not associated with the risk of fatal CVD or IHD in elderly women, in contrast to the inverse association observed in studies of men,6 7 8 9 10 has interesting implications about possible mechanisms of action of DHEAS and other sex steroids. A sex difference in the association between DHEAS and CVD would make it most unlikely that the mechanism of action is due to a sex-neutral metabolic effect such as the potent noncompetitive inhibition by DHEAS of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose cycle,24 25 or inhibition of nicotinamide adenine dinucleotide phosphate,26 27 either of which could theoretically promote atherosclerosis. Instead, the apparent protective effect of DHEAS in men and the absent protection in women make it more likely that the sex difference reflects sex hormone activity for DHEAS. Although its androgenicity is weak, DHEAS is present in larger quantities than any other sex steroid. Furthermore, the presumably active component, DHEA, has the high turnover rate characteristic of a biologically active hormone. One possibility is that DHEAS is an important source of estrogen in men but not in postmenopausal women and that estrogen is the protective metabolic product. DHEAS could be a source of estrogen in men, who have higher or similar estrogen levels compared with postmenopausal women.28 Alternately, the apparent sex-specific CVD effect is compatible with the theory that DHEAS acts as an androgen and that androgens are good for men while estrogens are good for women, a teleologically attractive argument made elsewhere.29 30 31
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Acknowledgments |
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This work was supported by National Institutes of Health grant 2R01-DK31-801-09A2. Dr Goodman-Gruen is supported by grant PSA-AB00353-07.
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Footnotes |
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Reprint requests to Elizabeth Barrett-Connor, MD, Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0628.
Received August 18, 1994; revision received October 12, 1994; accepted October 30, 1994.
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