Abstract
BACKGROUND
In this study we prospectively evaluated the relationships between plasma concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) and subsequent myocardial infarction in women.
METHODS
Using case-control sampling, we selected participants from the Nurses’ Health Study cohort. Blood samples were collected from 1989 to 1990 when the women were 43 to 69 years old. During follow-up through June 1998, 239 women were diagnosed with myocardial infarction (fatal and nonfatal). We matched cases 1:2 by age, cigarette smoking status, fasting status, and month of blood collection and used conditional logistic regression to adjust for potential confounders, including anthropometric factors and dietary intake.
RESULTS
Baseline median (10th, 90th percentiles) concentrations of DHEA were 17.1 (4.3, 46.7) nmol/L among women who subsequently developed myocardial infarction and 16.6 (6.1, 37.9) among controls. The risk of myocardial infarction increased with plasma concentrations of DHEA and its sulfate. Women in the highest DHEA quartile had a rate ratio (RR) of 1.27 (95% CI 0.92–1.74, P for trend = 0.008) for myocardial infarction compared with those in the lowest quartile, after adjusting for covariates. The results did not vary significantly by menopausal status, postmenopausal estrogen therapy, fasting status, or age at time of blood collection. Similar relationships between concentrations of DHEA-S and risk were observed, with an RR of 1.58 (95% CI 1.13–2.21; P for trend = 0.06) for myocardial infarction in the highest vs lowest quartile.
CONCLUSIONS
We observed a modest positive relationship between plasma concentrations of DHEA and its sulfate and the risk of subsequent myocardial infarction among predominantly postmenopausal women.
The medical literature suggests that endogenous hormones play a significant role in the etiology of coronary artery disease (1). Dehydroepiandrosterone (DHEA)5 and its sulfated form, dehydroepiandrosterone sulfate (DHEA-S), are adrenal androgens that are precursors of androgens and estrogens (2). Plasma concentrations are lowest before puberty, rapidly increase at puberty through young adulthood, and progressively decline thereafter in an age-dependent manner in both women and men (3). As such, supplemental DHEA has been promoted by some as having antiaging properties (4).
In the circulation, the predominant form is the largely inactive DHEA-S (5). The primary functions of DHEA and DHEA-S are mostly unknown (6), but they may affect cardiovascular disease risk either through direct influence on risk factors (7) or indirectly via conversion to other steroids. Data on DHEA and DHEA-S with cardiovascular risk are inconsistent, and we do not know how they affect cardiovascular risk in women. Several studies have found DHEA-S to be inversely associated with insulin sensitivity and cardiovascular outcomes. In an angiographic study, men with lower concentrations of DHEA and/or DHEA-S had more severe coronary disease (8). In a small randomized controlled trial, DHEA supplementation in elderly individuals resulted in increased insulin sensitivity and decreased abdominal fat after 6 months (9). In contrast, the concentrations of these adrenal androgens are increased in polycystic ovarian syndrome (10), a disorder associated with increased insulin resistance (11). Another randomized trial of DHEA supplementation among elderly men and women did not find statistically significant effects on body composition, quality of life, insulin sensitivity, or physical performance (12). In the Rancho Bernardo study, low DHEA-S was associated with increased cardiovascular mortality in men (13), but no such association was observed in women (who were all older than 50 years) (14). Few data are available in women, and there is a marked difference in the metabolism of DHEA-S in women relative to men. Approximately 50% of the total androgens in the prostate of adult men are derived from adrenal precursors DHEA and DHEA-S (2), whereas in women intracellular conversion of adrenal androgens to estrogens is approximately 75% before menopause and >90% after menopause (2). It has been hypothesized that DHEA and DHEA-S may exhibit antiestrogen effects in high-estrogen environments (15), but act like estrogens in low-estrogen environments (15). The true nature of the relationship between endogenous DHEA and coronary artery disease risk is not known in women. Furthermore, to our knowledge, no prospective study has evaluated the relationship between the more biologically active DHEA and the incidence of cardiovascular disease.
We conducted a nested case-control study within the Nurses’ Health Study cohort to evaluate the following questions: a) What are the relationships between circulating plasma concentrations of DHEA and DHEA-S and risk of subsequent myocardial infarction? b) Are these relationships modified by age, fasting status, menopausal status, or postmenopausal estrogen therapy at the time of blood sampling?
Materials and Methods
STUDY POPULATION
The Nurses’ Health Study cohort was established in 1976 when 121 700 female registered nurses, 30–55 years of age, completed and returned a mailed questionnaire. The cohort continues to be followed every 2 years by questionnaire to update exposure status and to identify cases of newly diagnosed disease. Data have been collected on many coronary artery disease risk factors, including height, weight, cigarette smoking, alcohol use, physical activity, age at menopause, postmenopausal hormone use, diagnosis of hypertension and diabetes, and parental family history of myocardial infarction. Body mass index (BMI) was calculated by dividing the most recent weight before blood collection by the square of height reported in 1976.
From 1989 through 1990, blood samples were collected from 32 826 cohort members (27% of the original cohort) who were 43–69 years of age at the time. Details regarding the blood collection methods have been published (16). Briefly, each woman arranged to have her blood drawn and then shipped with an ice pack, via overnight courier, to our laboratory, where it was processed and separated into plasma, erythrocyte, and leukocyte components. Within 24 h of being drawn, 97% of the samples were received in our laboratory. The stability of estrogens and androgens in whole blood for 24–48 h has been documented (17). Since collection, samples have been archived at −130 °C or colder in continuously monitored liquid nitrogen freezers. As of 1998, follow-up of the blood study subcohort was 99.8%.
Case women were those who had provided a blood sample, reported no myocardial infarction diagnosis before blood collection, and were diagnosed with myocardial infarction after blood collection but before June 1, 1998. Overall, 239 cases of myocardial infarction (including 29 fatal) were reported during 8–9 years of follow-up among the 32 826 eligible women. For all cases of myocardial infarction, we obtained and reviewed hospital records (with 19 exceptions, which were verbally confirmed either by a nurse or by death certificate information). Myocardial infarction was classified as confirmed if symptoms met the criteria of the WHO (typical symptoms and either diagnostic electrocardiographic changes or increased cardiac enzymes). The median (10th, 90th percentiles) time from blood collection to diagnosis was 55 months (15, 91). We matched 2 control subjects per case subject by age (within 2 years), cigarette smoking status (current, past, and never smoker), month of blood collection, and fasting status (≥10 h since a meal vs <10 h or unknown) at the time of blood collection. Eighty-one percent of control matches were exact; the most relaxed match was within 3 years of age and within 6 months of blood collection. The study was approved by the Committee on Human Research at the Brigham and Women’s Hospital.
Funding agencies had no role in the design or conduct of the study or in manuscript preparation and had no rights in the approval for publication of this work.
LABORATORY ANALYSES
We measured DHEA by ELISA (Diagnostic Systems Laboratories) using the quantitative sandwich enzyme immunoassay technique (18). Based on masked quality control samples (10% of the total number of samples) inserted among the case and control blood samples, the intraassay and interassay CVs for DHEA were 7.8% and 10.1%, respectively. We measured DHEA-S by a coated-tube RIA (Diagnostic Systems Laboratories) (18); intraassay and interassay CVs were 4.3% and 3.5%, respectively.
A number of biomarkers were previously assayed in this data set and available as covariates in the current analysis. Total cholesterol was measured enzymatically (19), with an intraassay CV of 1.7%. HDL cholesterol was measured using on a Hitachi 911 analyzer (20), with an intraassay CV of 2.5%. C-reactive protein (CRP) was measured with a high-sensitivity immunoturbidimetric assay on a Hitachi 911 analyzer, with an intraassay CV of 1.4%.
DATA ANALYSIS
We estimated adjusted Spearman’s correlation coefficients of DHEA and DHEA-S to the other covariates among controls, first calculating residuals after doing linear regression with loge(DHEA), loge(DHEA-S), loge(HDL-to-total cholesterol ratio), loge(CRP), loge(BMI), loge(physical activity), and alcohol as outcome variables, and age (modeled as natural cubic splines with 4 degrees of freedom), time and fasting status at blood collection, and batch as covariates.
We used conditional logistic regression to estimate odds ratios, which were taken as direct estimates of rate ratios and 95% CIs (21).
We additionally controlled for potential confounders that were not part of the matching scheme. Indicator variables were created for menopausal status (premenopausal, postmenopausal, unknown); parental history of myocardial infarction (a parent who had myocardial infarction before age 60); current postmenopausal hormone use (within 6 months of blood collection); a personal history of being diagnosed with diabetes, hypertension, or hypercholesterolemia; history of aspirin use; and time (1201– 0700, 0701–1100, 1101–1200) and fasting status at blood collection (since matching on this variable was not perfect). To more appropriately control for confounding by continuous covariates [plasma CRP and HDL-to-total cholesterol ratio measured at time of blood collection; mean daily alcohol intake reported in 1980, 1984, and 1986; body mass index and waist-to-hip circumference; and physical activity in metabolic equivalents (MET)-hours per week in 1988], natural cubic splines (22) with 4 degrees of freedom (3 when 4 was not feasible) were used to smooth the relationships with the log-odds of myocardial infarction. Because matching for age was not perfect, we additionally adjusted for a linear function of age. There were very few missing values in the covariates physical activity, aspirin use, CRP, and HDL-to-total cholesterol ratio (all <4%), and thus medians were used for imputation. We estimated the following conditional logistic regression models: (a) a model that controls for matching factors only; (b) a model that additionally controls for conventional nonbiomarker risk factors for myocardial infarction excluding history of hypertension, diabetes, and hypercholesterolemia; (c) a model that additionally controls for history of hypertension, diabetes, and hypercholesterolemia (considered the definitive model); and (d) a model that additionally controls for plasma lipid concentration and high-sensitivity CRP. Estimates of rate ratios for subgroups were estimated by including appropriate interaction terms in the third model above.
We conducted tests for trend by modeling the hormone concentration as a linear continuous covariate and calculating a Wald statistic (21). All P values were based on 2-sided tests. The software packages used for statistical analysis were SAS release 9 and S-plus version 6.
Results
At the time of blood sampling, the women in this study had a median (10th, 90th percentiles) age of 62 (50, 68) years. Table 1 shows the distribution of risk factors for myocardial infarction at the time of blood sampling among case women and matched controls. Both DHEA and DHEA-S were higher in cases relative to controls. As expected, median BMI, waist-to-hip ratio, total cholesterol, and CRP, as well as the proportions of those with histories of diabetes, hypertension, or having had a parent with early myocardial infarction, were higher in women who later developed myocardial infarction relative to matched controls. Similarly, the levels of physical activity, alcohol consumption, and plasma HDL cholesterol were lower in case women relative to controls.
Table 1.
Distribution of covariates in case and matched control study participants.
| Covariate | Cases | Controls |
|---|---|---|
| n | 239 | 472 |
| Dehydroepiandrosterone, nmol/L | 17.1 (4.3, 46.7) | 16.6 (6.1, 37.9) |
| Dehydroepiandrosterone sulfate, nmol/L | 1183 (465, 2389) | 1095 (484, 2483) |
| Age at blood draw, years | 62 (51, 68) | 62 (50, 68) |
| Current smokers | 78 (32.6) | 158 (33.5) |
| Body mass index, kg/m2 | 25.9 (20.4, 35.3) | 24.4 (20.7, 31.3) |
| Waist-to-hip ratio | 0.81 (0.72, 0.89) | 0.78 (0.71, 0.87) |
| Average physical activity, MET-hours per week | 8.7 (1.2, 37.2) | 9.9 (1.0, 37.7) |
| Alcohol consumption, g/day | 1.4 (0, 16.9) | 3.1 (0, 19.9) |
| Parental history of myocardial infarction | 86 (36.0) | 102 (21.6) |
| History of hypertension | 131 (54.8) | 126 (26.7) |
| History of diabetes | 44 (18.4) | 29 (6.1) |
| History of hypercholesterolemia | 25 (10.5) | 47 (10.0) |
| Use of aspirin in 1988 | ||
| None | 80 (33.5) | 149 (31.6) |
| 1–14 days per month | 88 (36.8) | 218 (46.2) |
| >14 days per month | 63 (26.4) | 93 (19.7) |
| Postmenopausala | 204 (85.4) | 396 (83.9) |
| Use of female hormones in the 3 months before blood collection | 73 (30.5) | 171 (36.2) |
| Plasma total cholesterol, mmol/L | 6.09 (4.74, 7.51) | 5.78 (4.64, 7.12) |
| Plasma HDL cholesterol, mmol/L | 1.29 (0.90, 1.83) | 1.51 (1.05, 2.16) |
| Ratio of plasma total to HDL cholesterol | 4.51 (3.13, 7.04) | 3.83 (2.55, 5.74) |
| Plasma CRP, mg/L | 3.1 (0.7, 13.7) | 2.2 (0.5, 9.2) |
Data are median (10th, 90th percentile) or n (%). Median age (range; 10th, 90th percentiles) of diagnosis of myocardial infarction was 65.8 (44.9–76.2; 54.2, 73.6) years. Median time from blood sample to diagnosis of myocardial infarction was 4.6 (0.08–8.7; 1.25, 7.6) years. Information was available for the covariates in >95% of study participants, with the exception of waist-to-hip ratio (165 cases and 334 controls). MET, metabolic equivalent.
There were 23/204/12 cases and 57/396/19 controls of pre-/post-/uncertain menopausal status, respectively.
The age-, time-, fasting-, and batch-adjusted correlations between DHEA and DHEA-S concentrations and the continuous covariates were weak, except for a negative correlation with physical activity and a positive correlation with alcohol consumption (Table 2).
Table 2.
Correlation between adjusted residuals of loge(DHEA) and loge(DHEA-S) and residuals of continuous covariates among control study participants.
| Covariate | DHEA | DHEA-S |
|---|---|---|
| Body mass index | 0.01 (0.85) | 0.02 (0.66) |
| Average physical activity | −0.16 (<0.01) | −0.12 (0.01) |
| Mean alcohol consumption | 0.11 (0.02) | 0.16 (<0.01) |
| CRP | 0.00 (1.00) | 0.03 (0.55) |
| Plasma total:HDL cholesterol ratio | 0.01 (0.82) | 0.07 (0.14) |
Data are Spearman correlation coefficient (P value). Adjusted for age, time of blood collection, fasting status, and batch.
In multivariable analyses, there was a statistically significant linear trend between the risk of myocardial infarction and plasma DHEA concentration (P for trend = 0.008). Women in the highest DHEA quartile had a rate ratio (RR) of 1.27 (95% CI 0.92–1.74) (Table 3) after multivariate adjustment for nonbiomarker risk factors for myocardial infarction. Relative to the analysis for matching variables only, the association between DHEA and myocardial infarction was substantially strengthened after multivariate adjustment for confounding, although the effects were small when covariates were included in the models individually.
Table 3.
Rate ratio of myocardial infarction and 95% CI by quartile of adrenal hormone concentrations among predominantly postmenopausal women in the Nurses’ Health Study.
| Hormone concentration quartile categories |
P value for linear trend |
||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | ||
| DHEA, nmol/L | <9.60 | 9.61–16.55 | 16.56–26.33 | ≥26.34 | |
| Cases/controls | 58/114 | 53/112 | 56/110 | 62/113 | |
| Model a | 1.0 (referent) | 0.97 (0.77–1.23) | 1.01 (0.79–1.28) | 1.05 (0.83–1.34) | 0.06 |
| Model b | 1.0 (referent) | 0.92 (0.71–1.21) | 1.09 (0.82–1.44) | 1.19 (0.90–1.57) | <0.01 |
| Model c | 1.0 (referent) | 0.93 (0.68–1.26) | 1.19 (0.87–1.63) | 1.27 (0.92–1.74) | <0.01 |
| Model d | 1.0 (referent) | 0.92 (0.66–1.27) | 1.22 (0.88–1.68) | 1.23 (0.89–1.72) | 0.08 |
| DHEA-S, nmol/L | <709 | 710–1110 | 1111–1674 | ≥1675 | |
| Cases/controls | 43/112 | 61/111 | 61/108 | 57/107 | |
| Model a | 1.0 (referent) | 1.23 (0.96–1.57) | 1.23 (0.96–1.58) | 1.26 (0.97–1.64) | 0.52 |
| Model b | 1.0 (referent) | 1.38 (1.04–1.82) | 1.46 (1.08–1.96) | 1.52 (1.11–2.06) | 0.14 |
| Model c | 1.0 (referent) | 1.44 (1.05–1.96) | 1.56 (1.12–2.17) | 1.58 (1.13–2.21) | 0.06 |
| Model d | 1.0 (referent) | 1.43 (1.01–2.02) | 1.60 (1.11–2.31) | 1.58 (1.09–2.30) | 0.14 |
Data are RR (95% CI). Model a, Conditional logistic regression model controlling for matching factors only; model b, conditional logistic regression additionally controlling for age at blood draw (as a linear continuous variable), time of blood collection (1201–0700, 0701–1100, 1101–1200), fasting status at blood collection (fasting for ≥10 h vs <10 h or unknown), menopausal status (postmenopausal, uncertain status vs premenopausal), parents’ history of myocardial infarction, current postmenopausal hormone use, aspirin use, mean alcohol intake, body mass index, and physical activity in MET-hours (the latter 3 variables modeled as continuous variables with natural cubic splines); model c, conditional logistic regression additionally controlling for history of diabetes, history of hypertension, and history of hypercholesterolemia; model d, conditional logistic regression additionally controlling for plasma CRP and total-to-HDL cholesterol ratio (both modeled as continuous variables with natural cubic splines).
Plasma DHEA-S appeared to share the same pattern of association with myocardial infarction, except that the effects were stronger and more nonlinear (Table 3). Women in the highest DHEA-S in quartile had a RR of 1.58 (95% CI 1.13–2.21) vs women in the lowest quartile (P for trend = 0.06).
Although the relationships with myocardial infarction risk appeared stronger among younger (relative to those age >60) women and for those who had provided samples after fasting ≥10 h relative to those who had not, there were no significant interactions with respect to DHEA or DHEA-S concentration by age, estrogen status (menopausal status and estrogen replacement therapy), or fasting status (P values for interactions all >0.05) (Tables 4 and 5).
Table 4.
Rate ratio of myocardial infarction by quartile of DHEA concentration and subset of age, estrogen status, and fasting status among predominantly postmenopausal women in the Nurses’ Health Study.
| Hormone concentration quartile categories |
P value for linear trend |
P value for interaction |
||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | |||
| DHEA, nmol/L | <9.60 | 9.61–16.55 | 16.56–26.33 | ≥26.34 | ||
| Age <60, n cases/n controls | 14/28 | 15/41 | 28/54 | 33/59 | 0.81 | |
| Adjusted RR (95% CI) | 1.0 (referent) | 1.05 (0.58–1.90) | 1.23 (0.72–2.11) | 1.43 (0.84–2.42) | 0.19 | |
| Age ≥60, n cases/n controls | 44/86 | 38/71 | 28/56 | 29/54 | ||
| Adjusted RR (95% CI) | 1.0 (referent) | 0.86 (0.60–1.23) | 1.21 (0.82–1.79) | 1.12 (0.75–1.68) | 0.02 | |
| Estrogen negative, n cases/n controlsa | 35/66 | 32/56 | 38/50 | 31/53 | 0.10 | |
| Adjusted RR (95% CI) | 1.0 (referent) | 0.86 (0.59–1.26) | 1.44 (0.96–2.17) | 1.13 (0.74–1.73) | 0.11 | |
| Estrogen positive, n cases/n controlsb | 23/48 | 21/56 | 18/60 | 31/60 | ||
| Adjusted RR (95% CI) | 1.0 (referent) | 0.97 (0.60–1.57) | 0.91 (0.56–1.47) | 1.37 (0.87–2.13) | 0.02 | |
| Fasting (≥10 h), n cases/n controls | 35/65 | 31/69 | 33/65 | 41/71 | 0.51 | |
| Adjusted RR (95% CI) | 1.0 (referent) | 1.06 (0.71–1.57) | 1.45 (0.96–2.20) | 1.40 (0.94–2.07) | <0.01 | |
| Nonfasting (<10 h or unknown), n cases/n controls | 23/49 | 22/43 | 23/45 | 21/42 | ||
| Adjusted RR (95% CI) | 1.0 (referent) | 0.74 (0.47–1.19) | 0.88 (0.54–1.45) | 1.08 (0.65–1.81) | 0.49 | |
Conditional logistic regression additionally controlling for age at blood draw (as a linear continuous variable), time of blood collection (1201–0700, 0701–1100, 1101–1200), fasting status at blood collection (fasting for ≥10 h vs <10 h or unknown), menopausal status (postmenopausal, uncertain status vs premenopausal), parents’ history of myocardial infarction, current postmenopausal hormone use, history of diabetes, history of hypertension, history of hypercholesterolemia, aspirin use, mean alcohol intake, body mass index, physical activity in MET-hours (the latter 3 variables modeled as continuous variables with natural cubic splines).
Postmenopausal and not on estrogen therapy at time of blood sampling.
Premenopausal or on estrogen therapy at time of blood sampling.
Table 5.
Rate ratio of myocardial infarction by quartile of DHEA-S concentration and subset of age, estrogen status, and fasting status among predominantly postmenopausal women in the Nurses’ Health Study.
| Hormone concentration quartile categories |
P value for linear trend |
P value for interaction |
||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | |||
| DHEA-S, nmol/L | <709 | 710–1110 | 1111–1674 | ≥1675 | ||
| Age <60, n cases/n controls | 9/24 | 20/37 | 26/57 | 35/62 | 0.89 | |
| Adjusted RR (95% CI) | 1.0 (referent) | 1.70 (0.88–3.29) | 1.70 (0.92–3.17) | 1.81 (1.01–3.24) | 0.14 | |
| Age ≥60, n cases/n controls | 34/88 | 41/74 | 35/51 | 22/45 | ||
| Adjusted RR (95% CI) | 1.0 (referent) | 1.33 (0.93–1.89) | 1.51 (1.01–2.26) | 1.40 (0.89–2.18) | 0.38 | |
| Estrogen negative, n cases/n controlsa | 28/69 | 33/49 | 37/57 | 32/46 | 0.79 | |
| Adjusted RR (95% CI) | 1.0 (referent) | 1.48 (0.98–2.22) | 1.52 (1.02–2.27) | 1.76 (1.13–2.75) | 0.10 | |
| Estrogen positive, n cases/n controlsb | 15/43 | 28/62 | 24/51 | 25/61 | ||
| Adjusted RR (95% CI) | 1.0 (referent) | 1.29 (0.80–2.06) | 1.58 (0.95–2.61) | 1.38 (0.84–2.25) | 0.26 | |
| Fasting (≥10 h), n cases/n controls | 24/71 | 44/73 | 36/62 | 32/60 | 0.18 | |
| Adjusted RR (95% CI) | 1.0 (referent) | 1.77 (1.19–2.62) | 2.14 (1.34–3.40) | 1.97 (1.25–3.11) | 0.08 | |
| Nonfasting (<10 h or unknown), n cases/n controls | 19/41 | 17/38 | 25/46 | 25/47 | ||
| Adjusted RR (95% CI) | 1.0 (referent) | 1.00 (0.58–1.70) | 1.05 (0.64–1.72) | 1.17 (0.71–1.94) | 0.32 | |
Conditional logistic regression additionally controlling for age at blood draw (as a linear continuous variable), time of blood collection (1201–0700, 0701–1100, 1101–1200), fasting status at blood collection (fasting for ≥10 h vs <10 h or unknown), menopausal status (postmenopausal, uncertain status vs premenopausal), parents’ history of myocardial infarction, current postmenopausal hormone use, history of diabetes, history of hypertension, history of hypercholesterolemia, aspirin use, mean alcohol intake, body mass index, physical activity in MET-hours (the latter 3 variables modeled as continuous variables with natural cubic splines).
Postmenopausal and not on estrogen therapy at time of blood sampling.
Premenopausal or on estrogen therapy at time of blood sampling.
Discussion
In this nested prospective study of predominantly postmenopausal women, we found a modest positive relationship between concentrations of plasma DHEA and plasma DHEA-S and later risk of myocardial infarction.
Although few data have been available in women, many have hypothesized that higher DHEA and DHEA-S would be protective for cardiovascular disease. The prevailing opinion in much of the general population is that higher DHEA is good for people and promotes healthy aging (4). Our findings clearly conflict with this opinion, and we conclude that finding a higher DHEA or DHEA-S concentration relative to another woman of similar age does not necessarily reflect better health. A number of experimental and clinical studies, primarily done in men, have suggested that DHEA might be protective against cardiovascular disease (8, 9, 13). Our results are in the same direction as another observational study in postmenopausal women. In the Multi-Ethnic Study of Atherosclerosis, higher DHEA concentration was associated with a greater odds of impaired fasting glucose, but not with diabetes risk (23). The Rancho Bernardo study did not find a statistically significant relationship between DHEA-S and subsequent cardiovascular death (14).
It is uncertain how higher DHEA would mediate increased myocardial infarction risk. DHEA is a precursor of other adrenal sex steroids including estrogens and androgens. Among similarly aged women, in the Women’s Health Study, age-adjusted plasma DHEA-S was significantly positively correlated with plasma concentrations of estradiol and free estradiol, and even more so with testosterone and free testosterone (24). Among postmenopausal women in the same cohort, a higher molar ratio of testosterone to serum hormone binding globulin was associated with increased risk of myocardial infarction (25). Given that DHEA as well as other hormones that are derived from the adrenal cortex are under the control of adrenocorticotropic hormone, however, our finding that concentrations of DHEA correlate with the hazard of myocardial infarction may, in part, be a reflection of the actions of other adrenocortical hormones.
To our knowledge, this is the first large prospective study to have looked specifically at the relationship between plasma DHEA and myocardial infarction risk in women. Major strengths of this study are its prospective nature and its careful control of confounding factors. The major caveat of this study is that plasma concentrations of DHEA and DHEA-S may not reflect the biologically important intracellular levels of these hormones. The plasma levels result from the interplay between dietary supplementation, cellular output into the extracellular fluids (including blood), cellular reuptake, and excretion from the body. In addition, given the observational nature of the study, we cannot be sure that all unknown confounders have been adequately controlled. The size of the observed rate ratios did vary significantly with the included covariates. The single measurements of DHEA and DHEA-S used in this study may not reflect very long-term exposures to these hormones, although a previous study among postmenopausal women showed that DHEA and DHEA-S concentrations over a 3-year period were quite stable (16).
In summary, our investigations revealed that higher plasma concentration of DHEA and DHEA-S are associated with increased risk of myocardial infarction in predominantly postmenopausal women. Future studies are also needed to replicate these findings, to investigate potential mechanisms, and to better control for other aspects of adrenocortical output.
Acknowledgment
We are grateful to the leadership and the participants of the Nurses’ Health Study for their continuing dedication and commitment.
Grant/Funding Support: The work reported in this manuscript was supported by Public Health Service grants CA87969 and CA49449 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Dr. John Page was partially supported by the American Heart Association award 0475016N.
Footnotes
Nonstandard abbreviations: DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; CRP, C-reactive protein; RR, rate ratio.
Financial Disclosures: None declared.
References
- 1.Weidemann W, Hanke H. effects of androgens. Cardiovasc Drug Rev. 2002;20:175–198. doi: 10.1111/j.1527-3466.2002.tb00086.x. [DOI] [PubMed] [Google Scholar]
- 2.Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol. 2001;22:185–212. doi: 10.1006/frne.2001.0216. [DOI] [PubMed] [Google Scholar]
- 3.Nawata H, Yanase T, Goto K, Okabe T, Ashida K. Mechanism of action of anti-aging DHEA-S and the replacement of DHEA-S. Mech Ageing Dev. 2002;123:1101–1106. doi: 10.1016/s0047-6374(01)00393-1. [DOI] [PubMed] [Google Scholar]
- 4.Skolnick AA. Scientific verdict still out on DHEA. JAMA. 1996;276:1365–1367. [PubMed] [Google Scholar]
- 5.Kroboth PD, Salek FS, Pittenger AL, Fabian TJ, Frye RF. DHEA and DHEA-S: a review. J Clin Pharmacol. 1999;39:327–348. doi: 10.1177/00912709922007903. [DOI] [PubMed] [Google Scholar]
- 6.Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease. Endocr Rev. 2003;24:313–340. doi: 10.1210/er.2003-0005. [DOI] [PubMed] [Google Scholar]
- 7.Barrett-Connor E, Ferrara A. Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and noninsulin-dependent diabetes in postmenopausal women: the Rancho Bernardo Study. J Clin Endocrinol Metab. 1996;81:59–64. doi: 10.1210/jcem.81.1.8550794. [DOI] [PubMed] [Google Scholar]
- 8.Herrington DM, Gordon GB, Achuff SC, Trejo JF, Weisman HF, Kwiterovich PO, Jr, Pearson TA. Plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate in patients undergoing diagnostic coronary angiography. J Am Coll Cardiol. 1990;16:862–870. doi: 10.1016/s0735-1097(10)80334-1. [DOI] [PubMed] [Google Scholar]
- 9.Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA. 2004;292:2243–2248. doi: 10.1001/jama.292.18.2243. [DOI] [PubMed] [Google Scholar]
- 10.Haning RV, Jr, Austin CW, Carlson IH, Kuzma DL, Zweibel WJ. Role of dehydroepiandrosterone sulfate as a prehormone for ovarian steroidogenesis. Obstet Gynecol. 1985;65:199–205. [PubMed] [Google Scholar]
- 11.Ciaraldi TP, el-Roeiy A, Madar Z, Reichart D, Olefsky JM, Yen SS. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab. 1992;75:577–583. doi: 10.1210/jcem.75.2.1322430. [DOI] [PubMed] [Google Scholar]
- 12.Nair KS, Rizza RA, O’Brien P, Dhatariya K, Short KR, Nehra A, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med. 2006;355:1647–1659. doi: 10.1056/NEJMoa054629. [DOI] [PubMed] [Google Scholar]
- 13.Barrett-Connor E, Khaw KT, Yen SS. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med. 1986;315:1519–1524. doi: 10.1056/NEJM198612113152405. [DOI] [PubMed] [Google Scholar]
- 14.Barrett-Connor E, Goodman-Gruen D. Dehydroepiandrosterone sulfate does not predict cardiovascular death in postmenopausal women. The Rancho Bernardo Study. Circulation. 1995;91:1757–1760. doi: 10.1161/01.cir.91.6.1757. [DOI] [PubMed] [Google Scholar]
- 15.Ebeling P, Koivisto VA. Physiological importance of dehydroepiandrosterone. Lancet. 1994;343:1479–1481. doi: 10.1016/s0140-6736(94)92587-9. [DOI] [PubMed] [Google Scholar]
- 16.Hankinson SE, Manson JE, Spiegelman D, Willett WC, Longcope C, Speizer FE. Reproducibility of plasma hormone levels in postmenopausal women over a 2–3-year period. Cancer Epidemiol Biomarkers Prev. 1995;4:649–654. [PubMed] [Google Scholar]
- 17.Hankinson SE, London SJ, Chute CG, Barbieri RL, Jones L, Kaplan LA, et al. Effect of transport conditions on the stability of biochemical markers in blood. Clin Chem. 1989;35:2313–2316. [PubMed] [Google Scholar]
- 18.Page JH, Colditz GA, Rifai N, Barbieri RL, Willett WC, Hankinson SE. Plasma adrenal androgens and risk of breast cancer in pre-menopausal women. Cancer Epidemiol Biomarkers Prev. 2004;13:1032–1036. [PubMed] [Google Scholar]
- 19.Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470–475. [PubMed] [Google Scholar]
- 20.Sugiuchi H, Uji Y, Okabe H, Irie T, Uekama K, Kayahara N, Miyauchi K. Direct measurement of high-density lipoprotein cholesterol in serum with polyethylene glycol-modified enzymes and sulfated alpha-cyclodextrin. Clin Chem. 1995;41:717–723. [PubMed] [Google Scholar]
- 21.Lachin JM. Biostatistical Methods: The Assessment of Relative Risks. New York: Wiley; 2000. p. 529. [Google Scholar]
- 22.Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York: Springer; 2000. p. 350. [Google Scholar]
- 23.Golden SH, Dobs AS, Vaidya D, Szklo M, Gapstur S, Kopp P, et al. Endogenous sex hormones and glucose tolerance status in post-menopausal women. J Clin Endocrinol Metab. 2007;92:1289–1295. doi: 10.1210/jc.2006-1895. [DOI] [PubMed] [Google Scholar]
- 24.Ding EL, Song Y, Manson JE, Rifai N, Buring JE, Liu S. Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. Diabetologia. 2007;50:2076–2084. doi: 10.1007/s00125-007-0785-y. [DOI] [PubMed] [Google Scholar]
- 25.Rexrode KM, Manson JE, Lee IM, Ridker PM, Sluss PM, Cook NR, Buring JE. Sex hormone levels and risk of cardiovascular events in postmenopausal women. Circulation. 2003;108:1688–1693. doi: 10.1161/01.CIR.0000091114.36254.F3. [DOI] [PubMed] [Google Scholar]