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Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1094-1100

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1094.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

No Association Between Dehydroepiandrosterone Sulfate and Development of Atherosclerosis in a Prospective Population Study (Bruneck Study)

Stefan Kiechl; Johann Willeit; Enzo Bonora; Siegfried Schwarz; Qingbo Xu

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.


*    Abstract
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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% ({alpha}=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


*    Introduction
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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.


*    Methods
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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 ({approx}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) {kappa} 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


*    Results
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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 1Down). Table 1Down 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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  		Figure 1. Effects of age in 40- to 79-year-old men and women on serum concentration of DHEAS. Values given are retransformed averages±2 SEM of log-transformed DHEAS levels in age strata of 5 years each. Lines depict regression lines. {circ} indicates men; •, women.


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  		Table 1. Partial (Age-Adjusted) Correlation of DHEAS With Vascular Risk Factors, Insulin Resistance, Markers of Inflammation, and Body Composition in the Bruneck Study (1990)

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 2Down). 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 2Down). 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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  		Table 2. Association of Baseline DHEAS Levels With 5-y Incidence/Progression of Carotid AS in the Bruneck Study (1990 to 1995)

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 2Up, 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 2Down. 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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  		Figure 2. ORs of incident/progressive carotid atherosclerosis according to quintiles (Q1 to Q5) of DHEAS levels in men and women. The logistic regression analyses were adjusted for age, baseline atherosclerosis score, alcohol consumption, Lp(a), ferritin, white blood cell count, hypertension, LDL cholesterol, HDL cholesterol, hypothyroidism, smoking (pack-years), and microalbuminuria.

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 (rp>=0.09, rp>=0.14 in sex-specific analyses). A 15% difference in DHEAS levels between subjects with and without incident/progressive atherosclerosis can be detected at an {alpha}=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 ({alpha}=0.05).


*    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 1Up), 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 1Up). 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 1Up),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 2Up). 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


*    Acknowledgments
 
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.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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