Low Dehydroepiandrosterone and Ischemic Heart Disease in Middle-aged Men: Prospective Results from the Massachusetts Male Aging Study

Henry A. Feldman1, Catherine B. Johannes1, Andre B. Araujo1, Beth A. Mohr1, Christopher Longcope2 and John B. McKinlay1

1 New England Research Institutes, Watertown, MA.
2 University of Massachusetts Medical School, Worcester, MA.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) have been characterized as "protective" against ischemic heart disease (IHD), especially in men, on the basis of sparse epidemiologic evidence. The authors used data from the Massachusetts Male Aging Study, a random sample prospective study of 1,709 men aged 40–70 years at baseline, to test whether serum levels of DHEA or DHEAS could predict incident IHD over a 9-year interval. At baseline (1987–1989) and follow-up (1995–1997), an interviewer-phlebotomist visited each subject in his home to obtain comprehensive health information, body measurements, and blood samples for hormone and lipid analysis. Incident IHD between baseline and follow-up was ascertained from hospital records and death registries, supplemented by self-report and evidence of medication. In the analysis sample of 1,167 men, those with serum DHEAS in the lowest quartile at baseline (<1.6 µg/ml) were significantly more likely to incur IHD by follow-up (adjusted odds ratio = 1.60, 95 percent confidence interval: 1.07, 2.39; p = 0.02), independently of a comprehensive set of known risk factors including age, obesity, diabetes, hypertension, smoking, serum lipids, alcohol intake, and physical activity. Low serum DHEA was similarly predictive. These results confirm prior evidence that low DHEA and DHEAS can predict IHD in men.

aging; androgens; cardiovascular diseases; coronary disease; dehydroepiandrosterone sulfate; myocardial ischemia; risk factors

Abbreviations: CI, confidence interval; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; IHD, ischemic heart disease; OR, odds ratio.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A low serum concentration of the adrenal steroid dehydroepiandrosterone (DHEA) has been alternately implicated and exonerated as a predictor of cardiovascular disease in general and ischemic heart disease (IHD) in particular (1GoGo–3Go). It is clear that serum levels of DHEA and its sulfate (DHEAS) decline with age more markedly than other hormone concentrations (4GoGo–6Go), corroborating the experimental evidence of their involvement in age-related health problems (7Go, 8Go). Far less clear is which of the many demonstrated biologic actions of DHEA–including effects on hemostasis, cell proliferation, lipid metabolism, stress response, and immune function–may be responsible for the apparent relation to heart disease (9GoGoGoGo–13Go). Many of the experimental results and epidemiologic relations differ between the sexes (14GoGoGo–17Go). Amid such uncertainty DHEA continues to be painted as a general marker of good health (18Go, 19Go) and sold over the counter as "anti-aging therapy" with the support of a small body of experimental evidence in humans (20GoGoGo–23Go).

Epidemiologic data on the relation of DHEA to heart disease are plentiful but largely limited to cross-sectional associations with the extent of disease (15Go, 24GoGo–26Go) or with risk factors such as smoking, alcohol intake, obesity, exercise, stress, hypertension, and nutrition (27GoGoGoGoGoGoGo–34Go). The few longitudinal studies to date are not consistent in the choice of endpoint (morbidity, mortality, extent of atherosclerosis) or in results. Only two studies have been truly prospective and of substantial duration (17Go, 35Go), the others using short follow-up (19Go, 36Go) or case-control design (37GoGoGoGo–41Go).

The Massachusetts Male Aging Study, conducted in 1987–1989 with follow-up in 1995–1997, was a random sample survey of men aged 40–70 years that included hormone levels among a comprehensive set of physiologic measurements and questions on health and aging (5Go, 42GoGoGoGo–46Go). The Massachusetts Male Aging Study baseline data showed DHEAS levels to be associated with self-reported heart disease as well as with IHD risk factors (47GoGo–49Go). Using follow-up data, we sought to test whether baseline levels of DHEA or DHEAS could predict morbidity and mortality from ischemic heart disease in the 9-year interval between waves of the Massachusetts Male Aging Study. The availability of a large number of potential confounding variables in the Massachusetts Male Aging Study data enabled us to determine whether the predictive relation was independent of the common risk factors for heart disease and the sex steroids derived from DHEA or, if not, to identify which of those factors might account for the role of DHEA.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study sample
The baseline phase of the Massachusetts Male Aging Study was conducted in 1987–1989. A two-stage, age-stratified cluster sample was drawn from the state census list in such a way that, within each age stratum (40–49, 50–59, 60–69 years), every male resident of Massachusetts had an equal probability of selection. Details of sampling and the in-home data collection protocol are published elsewhere (5Go, 45GoGo–47Go). Baseline data were obtained from 1,709 respondents, 52 percent of those eligible, of whom 1,571 were free from heart disease or definite IHD medication (see definition below). Of those, 64 lacked hormone values or risk factor data, leaving a cohort of 1,507 men eligible at baseline for this analysis.

Age in the baseline sample was uniformly distributed between 40 and 70 years by design (table 1). The cohort was predominantly Caucasian, married, employed, and college educated. The low fraction of racial minorities (5 percent) was representative of the Massachusetts population in 1987. Anthropometric and physiologic parameters closely matched those of the Second National Health and Nutrition Examination Survey. Randomly selected nonrespondents, interviewed by telephone, proved similar to respondents in general health and prevalence of chronic diseases (46Go).


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TABLE 1. Baseline dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) levels, demographic variables, and coronary risk factors in eligible cohort (1987–1989) and follow-up analysis sample (1995–1997), Massachusetts Male Aging Study cohort

 
Follow-up data were obtained in 1995–1997. Of the eligible baseline cohort of 1,507 men, 118 were confirmed deceased, 29 were unavailable for follow-up (five abroad, 24 too ill to respond), and 1,049 were reinterviewed, yielding a follow-up sample of 1,167 men, 77.4 percent of those eligible. The median interval for reinterview was 8.9 years and the range, 7.1–10.4 years. The rate of follow-up was significantly greater for men who were Caucasian, married, employed at baseline, or more highly educated (table 1) but did not vary significantly according to age, serum DHEA, or serum DHEAS. Lower participation among diabetic and hypertensive men was largely accounted for by adjustment for the demographic variables (table 1).

Data collection and coding
All protocols and procedures were approved by the institutional review board of New England Research Institutes.

A trained interviewer-phlebotomist visited each subject in his home between 8:00 and 10:00 a.m. and obtained written informed consent. Height and weight were measured by standardized methods developed for large-scale fieldwork (50Go). Obesity was defined as having a body mass index of at least 30 kg/m2 (51Go).

Health status and current treatment were ascertained by prompted self-report, using a list of nine medical conditions including heart disease, diabetes, and high blood pressure. The interviewer took inventory of all current prescription and nonprescription medications, noting the subject's stated reason for use of each. Medications were coded afterward by two pharmacoepidemiology consultants (M. B., A. H., University of Rhode Island, Providence, Rhode Island) using a classification similar to that of the American Hospital Formulary Service (52Go). "Definite IHD medication" was defined as a nitrate or dihydropyridine-type calcium channel blocker with heart disease as the given reason for use.

Hypertension was ascribed to men meeting any of four criteria: systolic blood pressure of >=140 mmHg; diastolic blood pressure of >=90 mmHg; self-report of treated high blood pressure; or antihypertensive medication with high blood pressure as the stated reason for use.

The subject's customary level of moderate to heavy physical activity was estimated from recall of the past 7 days' activites, including frequency and duration. Moderate, vigorous, and heavy physical activity were rated at 17, 25, and 42 kJ/kg/hour, respectively, as in recently published standards (53Go). Psychological instruments included the Spielberger index of anger expression (54Go) and a depression scale designed for epidemiologic use (55Go).

Current cigarette and cigar smoking and passive exposure to cigarette smoke were ascertained from self-report. Customary alcohol intake was estimated from self-report of beer, wine, and liquor consumption, counting 12 g of ethanol as one drink and accounting for frequency, quantity, and binge drinking according to the formula of Khavari and Farber (56Go). Nutritional intake was measured by a semiquantitative 1-year food frequency questionnaire (45Go).

Nonfasting blood samples were drawn from the antecubital space within 4 hours of the subject's awakening. Details of blood processing are published elsewhere (47Go). Serum lipids were measured by standard techniques (57Go) and androgens by radioimmunoassay (5Go, 58Go). The coefficient of variation for DHEA measurement was 2.6 percent within assay and 5.2 percent between assays; for DHEAS, it was 4.1 percent within assay and 8.9 percent between assays. Because the half-life of DHEAS in serum is about 13 hours and there is no known diurnal variation or effect of eating, a single determination can be considered representative (59GoGo–61Go).

Of the 575 men reporting hospitalization between baseline and follow-up, all but 1 percent gave written consent for examination of their medical records, of which 76 percent were abstracted, 16 percent were determined to represent outpatient admissions or nonserious medical conditions, and 7 percent could not be located. Hospitalization for IHD was defined by discharge with International Classification of Diseases, Ninth Revision, codes 410–414.

Of the cohort members confirmed dead at follow-up, 99 percent were located in the National Death Index. IHD as cause of death was again defined by International Classification of Diseases, Ninth Revision, codes 410–414.

Statistical methods
The analytical endpoint was incident IHD, defined by any of four criteria: death attributed to IHD; hospitalization for IHD between baseline and follow-up; definite IHD medication identified in the follow-up interview (see definition above); or self-report of treated heart disease at follow-up.

The independent variable was the serum concentration of DHEA or DHEAS at baseline. DHEA and DHEAS were evaluated separately because of their substantial correlation (Spearman's r = 0.46). The simple association of baseline DHEA and DHEAS with incident IHD was assessed by logistic regression, controlling for age.

Potential confounding variables included demographic variables (race, education, marital status, employment), steroid hormone levels (testosterone, estrone, androstenedione), and the common risk factors for heart disease: active and passive cigarette smoking, cigar smoking, obesity, physical activity, alcohol consumption, diabetes, hypertension, anger index, serum levels of total cholesterol and high density lipoprotein cholesterol, and dietary intake of cholesterol, fat, and fiber. Each potential confounder was tested individually as a predictor of incident IHD, controlling for DHEA or DHEAS and age.

The joint effects of age, DHEA or DHEAS, and a selected set of demographic variables and IHD risk factors were assessed by multiple logistic regression. We constructed estimates for the adjusted incidence of IHD and the adjusted odds ratio for each predictor from parameters of the multiple logistic regression model, with asymptotic 95 percent confidence intervals. Additional contrasts in log odds were contructed as needed to compare one predictor level with the mean of several others or to test for trend across ordered categories (62Go). To test whether the predictive relation varied among subgroups, we tested interaction terms (e.g., DHEAS x age) in the multiple regression model.

"Statistically significant" refers to inference based on either a 95 percent confidence interval or an asymptotic partial F test with a 5 percent type I error rate per predictor variable. SAS software was used for all computations (63Go).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Of 1,167 men in the analysis sample, 151 (12.9 percent) incurred IHD between baseline and follow-up (table 2). These included 22 deaths attributed to IHD (1.9 percent), 84 hospital discharges with IHD-related diagnosis (7.2 percent), and 45 confirmations of definite heart medication or self-reports of treated heart disease in the follow-up interview (3.9 percent).


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TABLE 2. Incidence of ischemic heart disease (IHD) in analysis sample of Massachusetts Male Aging Study cohort between baseline (1987–1989) and follow-up (1995–1997), according to successively more inclusive definitions of IHD

 
For each decade of baseline age, the odds of incident IHD increased more than twofold (table 3). Narrowing the definition of IHD to exclude self-report or to require hospitalization did not affect the estimated odds ratio. The odds of IHD mortality increased nearly fourfold for each decade of age (table 3). All further assessments of IHD predictors were consequently adjusted for age by multiple logistic regression.


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TABLE 3. Age-adjusted prospective association of serum dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with ischemic heart disease (IHD) incident between baseline (1987–1989) and follow-up (1995–1997) of the Massachusetts Male Aging Study, according to successively narrower definitions of IHD*

 
Figure 1 shows that disproportionately more cases of incident IHD occurred among men in the lowest quartile of baseline DHEA or DHEAS, regardless of whether the definition of IHD was restricted to mortality and hospitalization or included medication and self-report. The age-adjusted incidence of IHD from all sources was 18.0 percent for the lowest quartile of DHEA and 20.2 percent for the lowest quartile of DHEAS, compared with 10–15 percent in the upper quartiles. The age-adjusted odds ratio comparing the lowest quartile with the others (table 3) was highly significant for DHEAS (odds ratio (OR) = 1.78, 95 percent confidence interval (CI): 1.22, 2.60; p = 0.003) and marginally so for DHEA (OR = 1.45, 95 percent CI: 0.98, 2.15; p = 0.06). The linear trend across quartiles showed an increase in odds just above 20 percent for each succesive downward step in DHEA or DHEAS, significant at p = 0.03 and p = 0.02, respectively.



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FIGURE 1. Incidence of ischemic heart disease (IHD) between baseline (1987–1989) and follow-up phase (1995–1997) of the Massachusetts Male Aging Study, as predicted by the baseline serum concentration of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). Left, number of cases by source of ascertainment: death, hospitalization (HOSP), medication (MED), or self-report. Right, total cases as a percentage of the analysis sample, adjusted for age by logistic regression. Extension from bar indicates 1 standard error (SE).

 
Table 3 also shows individual contrasts between the lowest quartile and the higher quartiles, the strongest being between quartiles 1 and 4, with the odds ratio near 2.0 and the confidence interval excluding unity. The 3-df hypothesis test of equal incidence among quartiles was not rejected for DHEA (p = 0.15) but was rejected for DHEAS (p = 0.02), despite the reduced statistical power of a test taking no account of the order of quartiles. Narrowing the definition of IHD to exclude self-report or to require hospitalization weakened the statistical inferences slightly (table 3) but did not substantially reduce the estimates of effect (odds ratio). Age-adjusted IHD mortality did not vary significantly across quartiles of baseline serum DHEA or DHEAS (table 3).

To determine whether the predictive relation of DHEA and DHEAS to IHD was attributable to confounding by their metabolic products or by coronary risk factors other than age, we used multiple logisic regression to test whether those factors, as measured at baseline, predicted incident IHD independently of age and DHEA or DHEAS. The risk factors listed in table 4 were significant predictors when tested individually. These included medical conditions (diabetes, hypertension, obesity), serum lipids (total cholesterol and high density lipoprotein cholesterol), and behavioral variables (smoking, alcohol consumption, physical activity). Steroid hormone levels (testosterone, estrone, androstenedione), psychological scales (anger expression, depression), and dietary intake measures (cholesterol, fat, fiber) failed to predict incident IHD and were not included in further analyses. The demographic variables (race, marital status, education, employment) were not significant predictors of IHD but, because they were significant sources of differential selection of the analysis subsample, were included in multiple regression as a precaution against bias.


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TABLE 4. Correlation of serum dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with demographic variables and risk factors for ischemic heart disease (IHD) in the analysis sample from the Massachusetts Male Aging Study cohort, 1987–1989

 
Table 4 shows that, among the IHD risk factors, the greatest potential for confounding lay with age, which had more than 30 percent correlation with DHEA and DHEAS besides being a strong predictor of IHD. Few of the other risk factors exceeded 10 percent correlation with either DHEA or DHEAS. Demographic variables, none of which significantly predicted IHD, likewise had negligible correlation with DHEA or DHEAS. Accordingly, multiple regression analysis adjusted for demographic variables and all risk factors (table 5) yielded similar results to the analysis adjusted only for age (table 3). Only physical activity, passive smoking (confounded by active smoking), and a low level of high density lipoprotein cholesterol (confounded by alcohol intake) lost significance in the full model.


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TABLE 5. Prospective association of serum dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with ischemic heart disease (IHD) incident between baseline (1987–1989) and follow-up (1995–1997) in the Massachusetts Male Aging Study, adjusted for demographic variables and coronary risk factors

 
With all potential confounding factors mutually controlled, the contrast in odds of IHD between the lowest quartile of DHEA and the upper quartiles was attenuated from 1.45 (table 3) to 1.34 (table 5), losing statistical significance. The corresponding contrast for DHEAS remained significant (OR = 1.60, 95 percent CI: 1.07, 2.39; p = 0.02), as did the linear trends for both DHEA and DHEAS, which were not attentuated (OR = 1.23 and 1.21, respectively; p = 0.02).

Treating the covariates as continuous variables in multiple logistic regression did not affect the results for either DHEA or DHEAS nor did replacing the hypertension indicator by measured blood pressure and an indicator of antihypertensive medication.

Two interaction terms proved significant: DHEAS x hypertension and DHEAS x age. The contrast in the odds of IHD between the lowest DHEAS quartile and the average of the upper three quartiles, with an estimated odds ratio 5 1.60 overall, was far more pronounced for the 784 men (67 percent) who were normotensive at baseline (OR = 2.02, 95 percent CI: 1.16, 3.53; p = 0.01) than for the 383 men (33 percent) who were hypertensive (OR = 1.26, 95 percent CI: 0.71, 2.24; p = 0.43). Stratifying by age, we found the contrast between the lowest DHEAS quartile and the upper three quartiles to be insignificant in the younger men (40–49 years at baseline), most pronounced in the central age group (50–59 years) with the odds ratio 5 2.57 (95 percent CI: 1.21, 5.45; p = 0.01), and similar to the overall effect (OR = 1.60) in the oldest men (60–69 years).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In a prospective cohort study of over 1,000 randomly chosen middle-aged Massachusetts men, we found that baseline serum levels of DHEA and DHEAS predicted incident ischemic heart disease (combined morbidity and mortality) over a 9-year interval. The relation was independent of a broad set of physiologic and behavioral IHD risk factors including age, obesity, diabetes, hypertension, smoking, serum lipids, alcohol intake, and physical activity. The relation was also independent of serum levels of testosterone, estrone, and androstenedione (the other major adrenal androgen), of which DHEA and DHEAS are metabolic precursors. Mortality alone, a rare outcome in this study, was not predicted by the DHEA or DHEAS level.

The multiple logistic regression model on which we base our conclusions showed the well-established predictive relations between IHD and the other risk factors, validating the findings with respect to DHEA and DHEAS. Age, obesity, diabetes, hypertension, cigarette smoking, and serum cholesterol predicted IHD as expected. Moderate to vigorous physical activity showed a marginally significant influence, with an equivocal difference between modest amounts and substantial amounts of exercise (64Go). The coronary "protective" effect of alcohol consumption in our cohort continued beyond the commonly cited limit of one or two drinks per day (65Go), possibly because of the strong positive correlation between alcohol intake and serum high density lipoprotein cholesterol, which was present in our data as in others' (17Go, 32Go, 35Go, 48Go) and caused serum high density lipoprotein cholesterol, a significant predictor by itself, to lose significance in multiple regression.

Two prior studies resemble ours in design and scope. In the Rancho Bernardo cohort, a predominantly Caucasian and upper middle-class sample, Barrett-Connor et al. (35Go, 66Go) measured DHEAS in 1,029 men aged 39–82 years and free from heart disease at baseline. Twelve years afterward, cardiovascular mortality was associated with low baseline DHEAS. At 19 years the effect persisted, but only if fatalities from other cases were excluded from the comparison group. Schaefer et al. (17Go) conducted a 9-year prospective study of 804 men aged 60–90 years, selected randomly during routine health examinations. Incident angina and fatal ischemic heart disease were significantly related to low baseline DHEAS. No predictive association between DHEA or DHEAS and nonfatal IHD, such as we found, was reported by either prior study.

Our secondary findings included more pronounced effects of DHEAS in normotensive men and men in their 50s. Subgroup differences, being the product of exploratory analysis, deserve to be examined skeptically. Besides type I error, one possible explanation for the lack of effect in hypertensive men is interference from medication.

The methodological merits of our study were several. The Massachusetts Male Aging Study was designed as a prospective cohort study, avoiding the biases that can affect case-control comparisons. The cohort was randomly selected and therefore representative of Massachusetts men in the baseline year, though not of the entire United States, racial minorities being minimal. The cohort experienced some selective attrition between baseline and follow-up, but our analysis is not likely to have suffered bias as a result, because the sources of selection (demographic variables) were not predictive of IHD, while the featured predictors (DHEA and DHEAS) and their major potential confounder among the IHD risk factors (age) were distributed similarly in the eligible baseline cohort and the analysis subsample. Nevertheless we controlled the analysis for demographic variables as well as IHD risk factors as an added precaution against bias.

The primary endpoint, incident ischemic heart disease, was ascertained largely from documented sources (medical record, medication inventory, and National Death Index). Self-report, which accounted for less than one fifth of incident cases, is considered particularly reliable for heart disease (67GoGo–69Go). Eliminating self-report and medication from the definition of IHD reduced statistical power but did not materially alter the effect estimates.

A limitation of the Massachusetts Male Aging Study was the fixed, moderate-length period of follow-up (mean, 8.9 years). The number of IHD deaths recorded in that interval, 22, was adequate to provide a statistically significant relation for age but not for DHEA or DHEAS. Consequently we cannot throw light on the disparate results concerning DHEA and DHEAS with respect to fatal and nonfatal IHD reported in earlier studies (17Go, 35Go, 66Go). The narrow range of follow-up interval (7.1–10.4 years), coupled with lack of information pinpointing the onset of IHD in cases of self-report, precluded any effectual application of time-to-event ("survival") analysis, which can be more powerful than logistic regression of a dichotomous outcome when appropriate data are available.

Having demonstrated that low DHEA and DHEAS predict IHD but failed to explain the effect through indirect influence on their steroid metabolites or on the conventional physiologic and behavioral coronary risk factors, we are left with the likelihood that low DHEA contributes to a later and more specific stage of the disease, for example, by exacerbating arteriosclerosis or precipitating thrombosis. Herrington et al. (70Go) found evidence consistent with such a process in 61 human heart transplant recipients, among whom those with lower serum DHEA developed vasculopathy more frequently and sooner after surgery. The great many biologic properties of DHEA demonstrated in vitro and in animal studies do include the ability to oppose low-density lipoprotein oxidation (71Go), plaque formation (72Go), cell proliferation (73Go), platelet aggregation (74Go), and plasminogen activation (75Go).

Alternatively, unmeasured confounders such as insulin resistance (76Go, 77Go), immune response (78Go), or neural phenomena (79Go) may be responsible for both the decline in DHEA and the onset of IHD. Our prospective data show at least that such a confounder would have to have affected DHEA earlier than IHD. Whether unknown confounders or later-stage actions are responsible for the role of DHEA in the progress of IHD must be decided by considerably more laboratory and epidemiologic research. It remains for experimental studies to demonstrate whether exogenous DHEA, widely sold as a "health-food" supplement, has any benefit; our prospective observational findings have no bearing on that question.


    ACKNOWLEDGMENTS
 
Supported by grants AG-04673, DK-44995, and HL-50482 from the National Institutes of Health.

The authors thank Drs. Marilyn Barbour, Ann Hume, Richard Durante, Charlene Franz, Irwin Goldstein, Diana Salvador, and Susan Yurgalevitch among other Massachusetts Male Aging Study colleagues and staff.


    NOTES
 
Reprint requests to Dr. Henry Feldman, New England Research Institutes, 9 Galen St., Watertown, MA 02472 (e-mail: henryf{at}neri.org).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication October 12, 1999. Accepted for publication January 24, 2000.