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Plasma dehydroepiandrosterone and risk of myocardial infarction in 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[degrees]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 ([greater than or equal to] 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 [log.sub.e](DHEA), [log.sub.e](DHEA-S), [log.sub.e] (HDL-to-total cholesterol ratio), [log.sub.e] (CRP), [log.sub.e] (BMI), [log.sub.e](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.

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).

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.

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 [greater than or equal to] 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).

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 re-uptake, 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.

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.

Financial Disclosures: None declared.

Acknowledgment: We are grateful to the leadership and the participants of the Nurses' Health Study for their continuing dedication and commitment.

References

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John H. Page, [1] * Jing Ma, [2] Kathryn M. Rexrode, [3] Nader Rifai, [4] JoAnn E. Manson, [1,2,3] and Susan E. Hankinson [1,2]

[1] Department of Epidemiology, Harvard School of Public Health, Boston, MA; [2] Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; [3] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; [4] Department of Laboratory Medicine, Children's Hospital, Harvard Medical School, Boston, MA.

[5] Nonstandard abbreviations: DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; CRP, C-reactive protein; RR, rate ratio.

* Address correspondence to this author at: Department of Epidemiology, 677 Huntington Ave., Boston, MA 02115. Fax 617-566-7805; e-mail jpage@ hsph.harvard.edu.

Received October 20, 2007; accepted February 13, 2008.

Previously published online at DOI: 10.1373/clinchem.2007.099291
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/[m.sup.2] 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)
Postmenopausal (a) 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, 6.09 (4.74, 7.51) 5.78 (4.64, 7.12)
 mmol/L
Plasma HDL cholesterol, 1.29 (0.90, 1.83) 1.51 (1.05, 2.16)
 mmol/L
Ratio of plasma total to HDL 4.51 (3.13, 7.04) 3.83 (2.55, 5.74)
 cholesterol
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.

(a) There were 23/204/12 cases and 57/396/19 controls
of pre-/post-/uncertain menopausal status, respectively.

Table 2. Correlation between adjusted residuals of
[log.sub.e](DHEA) and [log.sub.e](DHEA-5) and residuals of
continuous covariates among control study
participants.

 Covariate DHEA DHEA-5

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.

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

 1 2

DHEA, nmol/L <9.60 9.61-16.55
 Cases/controls 58/114 53/112
 Model a 1.0 (referent) 0.97 (0.77-1.23)
 Model b 1.0 (referent) 0.92 (0.71-1.21)
 Model c 1.0 (referent) 0.93 (0.68-1.26)
 Model d 1.0 (referent) 0.92 (0.66-1.27)

DHEA-S, nmol/L <709 710-1110
 Cases/controls 43/112 61/111
 Model a 1.0 (referent) 1.23 (0.96-1.57)
 Model b 1.0 (referent) 1.38 (1.04-1.82)
 Model c 1.0 (referent) 1.44 (1.05-1.96)
 Model d 1.0 (referent) 1.43 (1.01-2.02)

 Hormone concentration
 quartile categories P value
 for
 3 4 linear
 trend

 [greater than or
 equal to] 26.34
DHEA, nmol/L 16.56-26.33
 Cases/controls 56/110 62/113
 Model a 1.01 (0.79-1.28) 1.05 (0.83-1.34) 0.06
 Model b 1.09 (0.82-1.44) 1.19 (0.90-1.57) -0.01
 Model c 1.19 (0.87-1.63) 1.27 (0.92-1.74) -0.01
 Model d 1.22 (0.88-1.68) 1.23 (0.89-1.72) 0.08

 [greater than or
DHEA-S, nmol/L 1111-1674 equal to] 1675
 Cases/controls 61/108 57/107
 Model a 1.23 (0.96-1.58) 1.26 (0.97-1.64) 0.52
 Model b 1.46 (1.08-1.96) 1.52 (1.11-2.06) 0.14
 Model c 1.56 (1.12-2.17) 1.58 (1.13-2.21) 0.06
 Model d 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 [greater than or equal to] 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).

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

 1 2

DHEA, nmol/L <9.60 9.61-16.55
Age <60, n cases/n controls 14/28 15/41
Adjusted RR (95% CI) 1.0 (referent) 1.05 (0.58-1.90)
Age [greater than or equal
 to] 60, n cases/n controls 44/86 38/71
Adjusted RR (95% CI) 1.0 (referent) 0.86 (0.60-1.23)
Estrogen negative, n cases/n
 controls (a) 35/66 32/56
Adjusted RR (95% CI) 1.0 (referent) 0.86 (0.59-1.26)
Estrogen positive, n cases/n
 controls (b) 23/48 21/56
Adjusted RR (95% CI) 1.0 (referent) 0.97 (0.60-1.57)
Fasting ([greater than or
 equal to] 10 h), n cases/n
 controls 35/65 31/69
Adjusted RR (95% CI) 1.0 (referent) 1.06 (0.71-1.57)
Nonfasting (<10 h or unknown), 23/49 22/43
 n cases/n controls
Adjusted RR (95% CI) 1.0 (referent) 0.74 (0.47-1.19)

 Hormone concentration
 quartile categories

 3 4

 [greater than or
DHEA, nmol/L 16.56-26.33 equal to] 26.34
Age <60, n cases/n controls 28/54 33/59
Adjusted RR (95% CI) 1.23 (0.72-2.11) 1.43 (0.84-2.42)
Age [greater than or equal
 to] 60, n cases/n controls 28/56 29/54
Adjusted RR (95% CI) 1.21 (0.82-1.79) 1.12 (0.75-1.68)
Estrogen negative, n cases/n
 controls (a) 38/50 31/53
Adjusted RR (95% CI) 1.44 (0.96-2.17) 1.13 (0.74-1.73)
Estrogen positive, n cases/n
 controls (b) 18/60 31/60
Adjusted RR (95% CI) 0.91 (0.56-1.47) 1.37 (0.87-2.13)
Fasting ([greater than or
 equal to] 10 h), n cases/n
 controls 33/65 41/71
Adjusted RR (95% CI) 1.45 (0.96-2.20) 1.40 (0.94-2.07)
Nonfasting (<10 h or unknown), 23/45 21/42
 n cases/n controls
Adjusted RR (95% CI) 0.88 (0.54-1.45) 1.08 (0.65-1.81)

 P value for P value for
 linear trend interaction

DHEA, nmol/L
Age <60, n cases/n controls 0.81
Adjusted RR (95% CI) 0.19
Age [greater than or equal
 to] 60, n cases/n controls
Adjusted RR (95% CI) 0.02
Estrogen negative, n cases/n
 controls (a) 0.10
Adjusted RR (95% CI) 0.11
Estrogen positive, n cases/n
 controls (b)
Adjusted RR (95% CI) 0.02
Fasting ([greater than or
 equal to] 10 h), n cases/n
 controls 0.51
Adjusted RR (95% CI) -0.01
Nonfasting (<10 h or unknown),
 n cases/n controls
Adjusted RR (95% CI) 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 [greater than or equal to] 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).

(a) Postmenopausal and not on estrogen therapy at time of blood
sampling.

(b) Premenopausal or on estrogen therapy at time of blood
sampling.

Table 5. Rate ratio of myocardial infarction by quartile of DHEA-5
concentration and subset of age, estrogen status, and fasting
status among predominantly postmenopausal women in the Nurses'
Health Study.

 Hormone concentration
 quartile categories

 1 2

DHEA-S, nmol/L <709 710-1110
Age <60, n cases/n controls 9/24 20/37
Adjusted RR (95% CI) 1.0 (referent) 1.70 (0.88-3.29)
Age ?60, n cases/n controls 34/88 41/74
Adjusted RR (95% CI) 1.0 (referent) 1.33 (0.93-1.89)
Estrogen negative, n cases/n 28/69 33/49
 controls (a)
Adjusted RR (95% CI) 1.0 (referent) 1.48 (0.98-2.22)
Estrogen positive, n cases/n 15/43 28/62
 controls (b)
Adjusted RR (95% CI) 1.0 (referent) 1.29 (0.80-2.06)
Fasting (?10 h), n cases/n 24/71 44/73
 controls
Adjusted RR (95% CI) 1.0 (referent) 1.77 (1.19-2.62)
Nonfasting (<10 h or unknown), 19/41 17/38
 n cases/n controls
Adjusted RR (95% CI) 1.0 (referent) 1.00 (0.58-1.70)

 Hormone concentration
 quartile categories

 3 4

 [greater than or
DHEA-S, nmol/L 1111-1674 equal to] 1675
Age <60, n cases/n controls 26/57 35/62
Adjusted RR (95% CI) 1.70 (0.92-3.17) 1.81 (1.01-3.24)
Age ?60, n cases/n controls 35/51 22/45
Adjusted RR (95% CI) 1.51 (1.01-2.26) 1.40 (0.89-2.18)
Estrogen negative, n cases/n 37/57 32/46
 controls (a)
Adjusted RR (95% CI) 1.52 (1.02-2.27) 1.76 (1.13-2.75)
Estrogen positive, n cases/n 24/51 25/61
 controls (b)
Adjusted RR (95% CI) 1.58 (0.95-2.61) 1.38 (0.84-2.25)
Fasting (?10 h), n cases/n 36/62 32/60
 controls
Adjusted RR (95% CI) 2.14 (1.34-3.40) 1.97 (1.25-3.11)
Nonfasting (<10 h or unknown), 25/46 25/47
 n cases/n controls
Adjusted RR (95% CI) 1.05 (0.64-1.72) 1.17 (0.71-1.94)

 P value for P value for
 linear trend interaction

DHEA-S, nmol/L
Age <60, n cases/n controls 0.89
Adjusted RR (95% CI) 0.14
Age ?60, n cases/n controls
Adjusted RR (95% CI) 0.38
Estrogen negative, n cases/n 0.79
 controls (a)
Adjusted RR (95% CI) 0.10
Estrogen positive, n cases/n
 controls (b)
Adjusted RR (95% CI) 0.26
Fasting (?10 h), n cases/n 0.18
 controls
Adjusted RR (95% CI) 0.08
Nonfasting (<10 h or unknown),
 n cases/n controls
Adjusted RR (95% CI) 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 [greater than or equal to] 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).

(a) Postmenopausal and not on estrogen therapy at time of blood
sampling.

(b) Premenopausal or on estrogen therapy at time of blood
sampling.
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Title Annotation:Lipids, Lipoproteins, and Cardiovascular Risk Factors
Author:Page, John H.; Ma, Jing; Rexrode, Kathryn M.; Rifai, Nader; Manson, JoAnn E.; Hankinson, Susan E.
Publication:Clinical Chemistry
Date:Jul 1, 2008
Words:5374
Previous Article:Association between ESR2 genetic variants and risk of myocardial infarction.
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