© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
No Association Between Dehydroepiandrosterone Sulfate and Development of Atherosclerosis in a Prospective Population Study (Bruneck Study)
From the Department of Neurology (S.K., J.W.) and the Institute of General and Experimental Pathology (S.S.), University of Innsbruck, Innsbruck, Austria; the Division of Endocrinology and Metabolism (E.B.), University of Verona, Verona, Italy; and the Institute for Biomedical Aging Research (Q.X.), Austrian Academy of Science, Innsbruck, Austria.
Correspondence to Dr S. Kiechl, Department of Neurology, Innsbruck University Hospital, Anichstr. 35, A-6020 Innsbruck, Austria.
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Abstract |
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Abstract—Antiatherogenic properties of dehydroepiandrosterone (DHEA) have been postulated for >40 years. Large-scale epidemiological studies on this important issue, however, are still sparse, and those available have yielded contradictory results. The Bruneck Study involved a large random sample of men and women aged 40 to 79 years that were enrolled in 1990 and reevaluated 5 years later. Baseline DHEA sulfate (DHEAS) levels were measured in 867 subjects after an overnight fast. Development and progression of carotid atherosclerosis was monitored by high-resolution duplex ultrasound. DHEAS levels declined with advancing age (29% and 44% per decade in men and women) and showed a complex sex-specific association with various vascular risk attributes and factors conferring protection against atherosclerosis. Age- and sex-adjusted DHEAS baseline levels did not differ between subjects with or without incident/progressive atherosclerosis (geometric mean 1161 versus 1253 µg/L). After adjustment for vascular risk factors and potential confounders, the odds ratio of incident/progressive atherosclerosis comparing a 50% increase in DHEAS levels was 0.99 (95% CI 0.89 to 1.11). Lack of an association between DHEAS and atherogenesis was confirmed in sex-specific and a variety of supplementary analyses. Statistical power would be high enough to detect differences in DHEAS between outcome categories as low as 15% (
=0.05). This prospective community-based study does not
support a role for endogenous DHEA(S) in the development of
human atherosclerosis.
Key Words: dehydroepiandrosterone • atherosclerosis • aging • insulin resistance • risk factors
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Introduction |
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Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEA sulfate (DHEAS), are the most abundantly produced adrenal steroids, yet their biological significance has not been established.1 2 For >4 decades, it has been hypothesized that DHEA(S) protects the arterial wall against atherosclerosis, thus keeping the risk of cardiovascular disease low and increasing life expectancy.1 3 The beneficial action of DHEA(S) has been attributed to direct hormonal and antiproliferative mechanisms, amelioration of insulin sensitivity, inhibition of platelet aggregation, and a putative inverse association with some vascular risk factors (eg, the hypolipidemic effect).1 4 5 The clinical significance of all these potential inferences of DHEA(S) with vascular biology and coagulation, however, remains to be elucidated. Epidemiological surveys involving the effects of DHEA(S) on atherogenesis are sparse, and those available bear the disadvantages of small and selected study populations, the use of insufficient control to overcome confounding, and allowance for cross-sectional analyses.3 6 7 8 Studies involving DHEAS and cardiovascular diseases, which in most instances arise from atherosclerosis, have yielded contradictory results.6 9 10 11 12 13 14 15 16 17 In the present study, we report on the association between baseline levels of DHEAS and the 5-year incidence/progression of carotid atherosclerosis in a large random sample of men and women aged 40 to 79 years. Additional focus was on the interaction suspected to exist between DHEA(S) and insulin resistance and other vascular risk factors.
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Methods |
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Study Subjects
The Bruneck Study is a prospective population-based survey of the epidemiology and etiology of atherosclerosis.18 19 20 The survey area is located in the North of Italy (Bolzano province). At the 1990 baseline evaluation (July to November), the study population was recruited as a sex- and age-stratified random sample of all inhabitants of Bruneck aged 40 to 79 years. For each decade of age from the 5th to the 8th, 125 women and 125 men were selected for inclusion (n=1000). A total of 93.6% participated, with frozen serum specimens for the measurement of DHEAS available in a random subsample of 867 subjects. Of these subjects, 58 died between the summer of 1990 and 1995. At the first reevaluation of the study cohort in 1995, follow-up was 93% complete for sonographic reassessment of survivors (n=750). All participants gave their informed consent before entering the study.
Clinical History and Examination
All participants underwent a clinical examination with
cardiological and neurological priority and completed standardized
questionnaires on current and past exposure to candidate vascular risk
factors.18 The average number of cigarettes smoked per day
and pack-years (as a measure of cumulative exposure) were noted for
each smoker and exsmoker. Systolic and diastolic
blood pressures were taken with a standard mercury sphygmomanometer
after at least 10 minutes of rest while the subject was in a sitting
position. The values used in the present analysis are means
of 3 measurements taken by the same investigator. Hypertension was
defined as a blood pressure 
160/95 mm Hg or the use of
antihypertensive drugs.21 A standardized oral glucose
tolerance test was performed in all subjects except those with
well-established diabetes mellitus (75 g glucose load after a 12-hour
overnight fast). Diabetes mellitus was coded as present for
subjects with fasting glucose levels >140 mg/dL and/or a 2-hour value
>200 mg/dL. Body mass index and waist-to-hip ratio were used as
obesity indices.22 Regular alcohol consumption was
quantified in terms of grams per day. The physical activity score was
calculated as the average of the scores for work (3 categories) and
sports or leisure activities (0, 
2, or >2 hours per week). The term
"chronic respiratory infections" subsumes the following conditions
(ascertained by standard clinical criteria): chronic bronchitis,
emphysema, and asthma.
Clinical End Points
Incident myocardial infarction was deemed confirmed when World
Health Organization criteria for definite disease status were
met.23 Stroke and transient ischemic attack were
classified according to the criteria of the National Survey of
Stroke.24 The diagnosis of incident peripheral
artery disease required a positive response to the Rose
Questionnaire, with the vascular nature of complaints confirmed by
standard diagnostic procedures involving the ankle/brachial
pressure index and ultrasound scans of the femoral and limb arteries
(available in all subjects) and, when appropriate, digital subtraction
angiography.
Laboratory Methods
Blood samples were taken from the antecubital vein between 7:30
and 9:30 AM after 12 hours of fasting and abstinence from
smoking.18 Triglycerides (interassay
coefficient of variation [CV] 4.3% to 5.4% for different standards)
and total and HDL cholesterol were determined enzymatically
(cholesterol oxidase-4-phenyl-2,3-dimethyl-4-amino-5-pyrazolone
and glycerol phosphate oxidase-4-phenyl-2,3-dimethyl-4-amino-pyrazalone
method, Merck; CV 2.2% to 2.4%). Lp(a) concentrations were determined
by an ELISA (Immuno; CV 3.5% to 6.3%); apolipoproteins, by a
nephelometric fixed-time method (Behring; apoA-I, CV 5.7%; apoB, CV
2.4%); serum ferritin, by fluorometric enzyme immunoassay
(Diagnostic Products Corp; CV 5.0% to 5.9%); and
antithrombin III, by chromogenic assay (CV 3.9% to 4.9%).
LDL cholesterol was calculated according to the Friedewald
formula and corrected for Lp(a) cholesterol. Fibrinogen was
assayed according to the method of Clauss.25
Hypothyroidism was defined by a thyroid-stimulating hormone level
exceeding the assay cutoff of 6.2 mIU/L (Diagnostic
Products Corp; enzyme immunoassay, CV 3.9% to 13.8%) or
previously diagnosed disease status. Albumin was assessed in an
overnight urine sample (Behring; nephelometric method, CV 4.3%).
Fasting insulin was measured according to the method of Hales
and Randle (CV 3.2% to 4.8%).22 Other
parameters were assessed by standard procedures.
Serum samples for the assessment of DHEAS concentration were stored at
-70° for an average of 6 months.26 Measurements were
performed with a radioimmunoassay (CV 5% and 8% for intra-assay and
interassay, respectively).27 Serum samples were 1:200
diluted with buffer and directly assayed. Aliquots of 0.1 mL were
incubated for 120 minutes at 4°C with 0.1 mL
[3H]DHEA (
50 pg per tube corresponding to
10 000 cpm at 37% efficacy) and 0.8 mL appropriately diluted
anti-DHEAS serum (Wien Labs). Thereafter, each radioimmunoassay tube
received 0.8 mL cold dextran-coated charcoal suspension (0.5%
[wt/vol] activated charcoal [Merck] and 0.05% dextran T-70
[Pharmacia] in assay buffer) and then was centrifuged at
800g. Supernatants (0.8 mL containing the bound
[3H]DHEA) were emulsified in liquid
scintillation cocktail (Ultima-gold, Packard) and measured in a beta
scintillation spectrometer (Tricarb 1900, Packard). Assays were
regularly controlled by an external quality-control scheme (German
Society for Clinical Chemistry) by using accuracy samples calibrated by
the gas-liquid chromatography–mass spectroscopy
reference method (gold standard).
The degree of insulin resistance was estimated by homeostasis model assessment developed by Matthews et al28 with computer-aided modeling of fasting glucose and insulin concentrations. This method was validated against the euglycemic-hyperinsulinemic clamp and found superior to other simple surrogates of insulin sensitivity, such as fasting or postglucose insulin levels.22
Scanning Protocol and Definition of Ultrasound End Points
The ultrasound protocol involves the scanning of the internal
(bulbous and distal segments) and common (proximal and distal segments)
carotid arteries of either side with a 10-MHz imaging probe and a 5-MHz
Doppler.18 Atherosclerotic lesions were defined by 2
ultrasound criteria: (1) wall surface (protrusion into the lumen or
roughness of the arterial boundary) and (2) wall texture
(echogenicity). The maximum axial diameter of plaques was assessed in
each of the 16 vessel segments, and an atherosclerosis
score was calculated by addition of all diameters. Subjects
presenting without any plaque had a score of zero. The accuracy of
this procedure has been established previously (CVs 13.5% and 15% for
intraobserver and interobserver, respectively).18 The
intima-media thickness was measured at the far wall of the common
carotid arteries. It was defined as the distance between the
lumen-intima interface and the leading edge of the media-adventitia
interface (CV 7.9% [common carotid artery] and 10.5% [internal
carotid artery]).20 Scanning was performed twice, in 1990
and 1995, by the same experienced sonographer, who was unaware of the
subjects’ clinical and laboratory characteristics. The same ultrasound
equipment was used for all scans. During the 1995 reevaluation, the
sonographer was blinded to the results of the first assessment.
Five-year changes in the atherosclerosis score were
used as an index of the progression of atherosclerosis.
Incident atherosclerosis was defined by the occurrence
of new plaques in previously normal sections of the vessels (any of the
8 segments explored), and progression of preexisting
atherosclerosis was defined by a relative increase in
the plaque diameter exceeding twice the measurement error of the method
(CVs 10% and 15% for the common and internal carotid arteries,
respectively).19 20 In the present analysis,
both processes were combined to a single outcome category for ease of
presentation and because these processes shared most of the
risk factors described. Apart from this early step in the development
of atherosclerosis, the ultrasound protocol made it
possible to define an advanced stage of atherogenesis that was shown to
originate primarily from atherothrombosis.19 20
Reproducibility of the ultrasound categories was "nearly perfect,"
as indicated by (weighted) 
coefficients >0.8 for agreements
between double measurements. This finding applies to rescannings
performed by the same and by different investigators (n=100 each).
Statistical Analysis
In all analyses, loge-transformed
DHEAS concentrations were applied to improve the approximation to a
normal distribution. Means presented are geometric means. The
relation between DHEAS and other variables was expressed by partial
(age-adjusted) correlation coefficients. The association of DHEAS with
incident/progressive atherosclerosis was examined by
logistic regression analysis. The test procedure was based on
the maximum likelihood estimator..29 A
base model was adjusted for age, sex, and baseline
atherosclerosis only (model 1).
Multivariate equations were fitted by a forward
stepwise selection procedure (probability value for entry and removal,
0.05 and 0.10, respectively; model 2). In another equation,
determinants of DHEAS concentration identified in the correlation
analysis were additionally forced into the model (model 3). To
eliminate potentially confounding effects of age, subjects in the
various outcome categories were matched by sex and year of birth (±2
years) and analyzed by logistic regression analysis for
matched data. Mathematical background and performance of this
type of analysis are described in detail
elsewhere.29 To rule out the existence of nonlinear
associations between DHEAS and atherogenesis, 5 equally spaced
categories of DHEAS were modeled with indicator variables in
separate analyses. Trends were estimated by visual inspection
of plots of the logit against the midpoints of DHEAS categories and by
application of orthogonal polynomials.29
Logistic regression models were supplemented and confirmed by linear regression analysis that used 5-year changes in the atherosclerosis score and intima-media thickness as continuous outcome variables. Crude and adjusted hazard ratios of incident cardiovascular disease and mortality were calculated by Cox models.30
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Results |
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Serum levels of DHEAS declined with advancing age at approximately constant rates of 29% and 44% per decade in men and women, respectively (Figure 1
).
Table 1 depicts partial
(age-adjusted) correlations between DHEAS concentrations and a broad
palette of demographic, lifestyle, and laboratory variables in men
and women. Age-adjusted DHEAS levels were higher among alcohol
consumers (17% [men] and 12% [women], P<0.01),
subjects with hypertension (21% [men] and 13% [women],
P<0.05), and male smokers (9%, P<0.05) and
lower among subjects with chronic respiratory infections (-16%
[men] and -21% [women], P<0.05) and diabetic men
(-35%, P<0.01).
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indicates men; •,
women.
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Multivariate prediction models of DHEAS concentrations, built by forward stepwise regression analysis, consisted of age, body mass index, apoB, microalbuminuria, chronic infection status (inverse), and apoA-I (inverse) in women (R2=0.22) and age, diabetes (inverse), alcohol consumption, waist-to-hip ratio, hypertension, and cigarette smoking in men (R2=0.27). Notably, measures of insulin resistance did not add significantly to the fit of these models.
Age- and sex-adjusted geometric means of DHEAS were virtually identical
in subjects with and without baseline atherosclerosis
(1124 versus 1210 µg/L, respectively). Likewise, no association was
found to exist between DHEAS and the extent of carotid
atherosclerosis (atherosclerosis
score18 ; partial (age-adjusted) correlation coefficient
(rp)=0.04 and 0.00 for men and
women, respectively; P>>0.05). During follow-up, 356 of
the 750 subjects with ultrasonographic follow-up developed new
(incident) atherosclerotic lesions and/or showed extension
(progression) of the preexisting lesion, and 394 did not. Baseline
DHEAS levels did not differ between the 2 groups (Table 2). Lack of association was confirmed by
logistic regression analysis of incident/progressive
atherosclerosis on age, sex, DHEAS levels, and
variable sets of covariates (models 1 to 3 [see Methods], Table 2). These analyses considered established and putative
vascular risk factors and determinants and correlates of DHEA(S)
identified in the preceding correlation analysis. Their
potential for confounding turned out to be low, with the odds ratios
(ORs) changing after adjustment for individual covariates from between
-5.5% and 4.4% and the net effect being close to zero (-5%).
Additional analyses that focused on the advanced
stenotic stage of atherosclerosis again failed
to assess a predictive significance for DHEAS (ORs with 95% CIs in
parentheses are as follows for a 50% increase in DHEAS levels: 1.11
(0.95 to 1.30), 1.03 (0.87 to 1.23), and 1.03 (0.86 to 1.24) for models
1 to 3, respectively; P>>0.05 each).
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To account for potential, previously postulated,9 10
sex-specific differences in the DHEA(S)-atherosclerosis
relation, all analyses were repeated after splitting the study
population by sex. As detailed in Table 2
, no direct association
whatsoever emerged.
Theoretically, DHEA(S), per se, can be unrelated to atherosclerosis progression and yet may play a role in interactions with the effects of established vascular risk factors. This issue was addressed by including interaction terms in the logistic regression models. None of these terms, however, approached a conventional level of statistical significance.
A total of 55 subjects experienced the onset of cardiovascular disease(s) during follow-up, and 58 died. When incident cardiovascular disease was substituted for the ultrasound end point, the key message of an absent association remained unchanged (hazard ratios for a 50% increase in DHEAS levels were 0.99, 0.99, and 1.00 for models 1 to 3, respectively; P>>0.05 each). Finally, cardiovascular and overall mortality tended to be somewhat lower in subjects with high DHEAS (hazard ratios 0.78 and 0.68 for both end points, P=0.21 and 0.18, respectively [model 1]).
Lack of a linear association between DHEAS and
atherosclerosis does not necessarily rule out the
existence of a quadratic (U- or J-shaped), higher order, or threshold
relation. To address this issue, separate logistic regression equations
were fitted with quintiles of DHEAS modeled with a set of 5 indicator
variables, and the lowest quintile was defined as the reference
category (OR 1.00). The results of such analysis (model 2) are
presented graphically in Figure 2. Visual inspection did not yield
evidence of a nonlinear association, which was confirmed by
mathematical means with the use of orthogonal polynomials.
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Because of the extensive correlation evident between DHEAS levels and age (r=-0.44 and -0.47 in men and women, respectively; P<0.0001 each), the actual strength of the DHEAS-atherosclerosis relation could theoretically be underestimated because of suppression effects elicited by the leading age variable. To rule out this possibility, analyses were repeated in small age strata of 10 years. In these models, ORs for a 50% increase in DHEAS ranged between 0.95 and 1.06 (model 2, P>>0.05 each). In addition, subjects with and without incident/progressive atherosclerosis were matched by sex and year of birth. In a logistic regression analysis for matched data (223 pairs), a null association was again established.
Apart from the person-based progression model of atherosclerosis developed and validated in the Bruneck Study,19 20 several other (population-based) approaches are used to monitor atherosclerosis. The one most commonly applied is the assessment of changes in intima-media thickness or atherosclerosis scores over time (continuous outcome variable). For comparison purposes, we provide the results of such analyses, thereby adopting the form of risk factor adjustment used in the original computations (models 1 to 3). Linear regression analysis failed to show a significant association between baseline DHEAS and 5-year changes in the atherosclerosis score (regression coefficients 0.093, 0.002, and 0.001 in models 1 to 3, respectively; P>>0.05 each) and intima-media thickness (regression coefficients 0.022, 0.011, and 0.010 in models 1 to 3, respectively; P>>0.05 each). When the population was split by sex, results were as follows: regression coefficients -0.148 and 0.061 for men and women, respectively (P>>0.05 each; change in atherosclerosis score, model 2), and -0.001 and 0.015 for men and women, respectively (P>>0.05 each; intima-media thickness, model 2).
Finally, power calculations are required for a valid interpretation of
negative studies. The present analysis has sufficient power
(0.8) to detect even weak correlations between DHEAS levels and 5-year
changes in the atherosclerosis score and intima-media
thickness (rp0.09,
rp0.14 in sex-specific analyses).
A 15% difference in DHEAS levels between subjects with and without
incident/progressive atherosclerosis can be detected at
an =0.05 level with a power of 0.80. Corresponding figures in
sex-specific analyses were 22% (men) and 24% (women). On
analyzing incident cardiovascular disease, the power
was comparatively low at 0.61 (0.81) when intending to detect 35%
(50%) difference in DHEAS levels between the 2 outcome categories
(=0.05).
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Discussion |
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DHEAS, Insulin Resistance, and Vascular Risk Factors
The present study confirms previous evaluations that documented a prominent linear decline in DHEAS levels with advancing age (Figure 1
), slightly higher levels of DHEAS among male
smokers and alcohol consumers of either
sex,1 6 7 11 31 32 33 34 and lower levels in diabetic
men.1 35 36 Low DHEAS concentrations appeared to be
related to a favorable lipid profile in women (low LDL
cholesterol and apoB, high HDL and apoA-I) and a favorable
body composition in both sexes (Table 1). Previous studies on
this special aspect yielded controversial
results.1 7 31 37 Because of the well-known influences of
infectious illness on adrenal steroid
metabolism,38 39 the emergence of lower DHEAS
levels among subjects with chronic respiratory infections, as
ascertained by clinical criteria, was not unexpected. In all, serum
levels of DHEAS showed complex and generally weak associations with
putative and established vascular risk factors and with attributes
conferring protection against vascular diseases. There is a variety of experimentally well-founded interactions between hormonal function and metabolism of insulin and DHEA(S).4 Insulin was reported to reduce DHEAS levels by inhibiting production (diminution of adrenal 17,20-lyase activity) and stimulating its clearance from the circulation.40 On the other hand, preliminary evidence suggests that experimental DHEA supplementation improves insulin sensitivity in rats and humans.41 Previous epidemiological surveys, none of which was conducted in a large random population, revealed an inverse association between serum levels of both hormones,42 43 except for 1 study.44 The hypotheses were advanced that DHEA(S) represents an important intermediate component in the relation between insulin resistance and atherosclerosis and between aging and insulin resistance.4 In the Bruneck Study, inverse partial correlations were found to exist between DHEAS levels and measures of insulin resistance and some, but not all, components of the insulin resistance syndrome. However, after multivariate adjustment, these relations did not achieve a conventional level of statistical significance. No more than 2% of the explained variability of DHEAS levels could be attributed to insulin resistance; conversely, low baseline DHEAS did not predict the development of diabetes or impaired glucose tolerance during the 5-year observation period.
How Good Is the Evidence Linking DHEA(S) and
Atherogenesis?
In 1959, Kask3 promoted the hypothesis that persons
with a high concentration of circulating DHEA(S) are relatively
protected against atherosclerotic diseases. During the past decades, 3
main lines of evidence concerning the potential effects of DHEA(S) in
atherogenesis have become available: (1) In research, conducted in
cholesterol-fed rabbits, oral administration of high
dosages of DHEA decelerated the development of coronary and
aortic atherosclerosis.45 46 47 Rodent
models, however, are not good substitutes for people because of marked
differences in adrenal metabolism and hormone levels. (2) A
few epidemiological surveys have attempted to clarify the
antiatherogenic capacity of endogenous DHEA(S) in humans.
These studies revealed inverse7 8 or null6
associations between serum levels of DHEAS and the extent of
coronary atherosclerosis as assessed by autopsy
or in vivo by coronary angiography. Interpretation of these
results is complicated by various methodological shortcomings,
including small sample size, cross-sectional analysis,
incomplete control for confounding, and the limited capacity of
angiographic techniques to identify the early stages of
atherosclerosis. (3) Numerous epidemiological surveys
have investigated the effects of DHEA(S) on
cardiovascular disease, which in most instances arise
from atherosclerosis.1 12 13 14 The weight
of case-control studies revealed an inverse association between DHEAS
levels and disease status (mainly myocardial infarction). However,
because blood samples were collected after disease onset, low DHEAS
levels among cases may be the consequence of acute
illness1 6 39 rather than a preexisting risk factor.
Actually, 6 prospective evaluations failed to obtain a significant
relation between baseline DHEAS levels and the onset of nonfatal
cardiovascular diseases.6 9 11 15 16 17 A
significant trend toward higher cardiovascular
mortality and an increased number of nonvascular deaths among men with
low DHEAS was attributed to unfavorable effects of low steroid
concentrations on survival, yet the nature of such an injurious
mechanism remains obscure. As a more convincing interpretation of this
finding, low baseline DHEAS may reflect the presence of various
clinical conditions known to enhance mortality, such as diabetes,
chronic (respiratory) infections (Table 1),38 39
severe illness,39 40 disability,49 and
cancer.50 If so, low DHEA(S) is an unspecific marker of
poor health and impending death rather than a causal risk factor.
In summary, all studies presently available cannot clarify the controversies surrounding the role of DHEA(S) in atherogenesis but rather stimulate this dispute.
No Association Between DHEA(S) and Atherosclerosis
in the Bruneck Study
The Bruneck Study is the first prospective study of the effects of
DHEA(S) on the ultrasonically measured progression of
atherosclerosis that has been conducted in the general
community. DHEAS levels at baseline were found to be unrelated to the
development of carotid atherosclerosis and did not
modify the atherogenic potential of established vascular risk factors.
Emergence of a null association applied equally to men and women and to
early and advanced (atherothrombotic) stages of
atherosclerosis. Analogous findings were obtained for
incident cardiovascular disease.
When interpreting our results, 3 important issues must be addressed,
namely, those of external validity, statistical power, and confounding
by risk attributes related to DHEAS levels: (1) External validity
actually is one main strength of the present study given the random
nature of our study cohort, the high participation, and near complete
follow-up (>90%). The study population may be regarded as
representative of white populations in Central
and Western Europe. Extrapolations to other ethnic groups, however,
require caution because of the well-known race-specific differences in
DHEA(S) levels and adrenal metabolism.1 (2) In
the Bruneck Study, statistical power is high enough to detect small
differences in DHEAS levels between subjects with and without
incident/progressive atherosclerosis. Analyses
of incident cardiovascular disease, however, should be
interpreted with some caution because of the low number of outcome
events. In line with the preceding caution, for reasons of statistical
power, judgment involving DHEAS and risk of death would require a
longer follow-up period. (3) Finally, confounding is an unlikely
explanation for our results. All analyses were carefully
controlled for potential effects of age, sex, established vascular risk
factors, and the various determinants/correlates of DHEAS levels
identified (Table 2). We did so by adjusting for all these
variables in multivariate equations (standard
procedure) and performing subgroup analyses (eg, in men and
women). To rule out suppression effects by age, which is extensively
correlated with DHEAS, our results were replicated in age-matched
models.
In concordance with most previous epidemiological studies, we assessed serum concentrations of the stable sulfate ester DHEAS. In spite of the high correlation between DHEA and DHEAS levels1 and their biological linkage, it cannot be ruled out that an association exists between DHEA and atherosclerosis risk, which is missed by measuring its sulfated form in serum.
Conclusions
This large prospective study does not support a role of
endogenous DHEA(S) in the development of human
atherosclerosis. The proposed inverse association
between DHEA(S) and insulin resistance is much weaker in the general
community than expected from observations in smaller selected
populations and experimental work. Although DHEA(S) may exert
beneficial effects on certain age-related disorders, such as cognitive
impairment and dementia,51 52 the issue remains unsettled
for atherosclerosis and arterial diseases,
which are the main causes of disability and mortality in the elderly.
The promise of the media that DHEAS is a "fountain of youth" lacks
a solid scientific basis.53
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Acknowledgments |
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The Bruneck Study was supported by the "Pustertaler Verein zur Prävention von Herz- und Hirngefäßerkrankungen," the "Sanitätseinheit Ost," and the "Assessorat für Gesundheit," Province of Bozen, Italy. The expert technical assistance of Irene Gaggl is kindly acknowledged.
Received September 30, 1999; accepted December 3, 1999.
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