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1.  Trajectories of Dehydroepiandrosterone Sulfate Predict Mortality in Older Adults: The Cardiovascular Health Study 
Background
Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual’s ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging.
Methods
Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged ≥65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points.
Results
Overall, there was a slight decline in DHEAS levels over time (−0.013 μg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32–2.33) and extreme variability (HR 1.89, CI 1.47–2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88–1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001).
Conclusions
Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.
doi:10.1093/gerona/glp129
PMCID: PMC2773814  PMID: 19713299
DHEA; DHEAS; Mortality; Aging; Elderly
2.  Cardiovascular Disease Is Associated with Greater Incident Dehydroepiandrosterone Sulfate Decline in the Oldest Old: The Cardiovascular Health Study All Stars Study 
OBJECTIVES
To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age.
DESIGN
Longitudinal cohort study.
SETTING
Pittsburgh, Pennsylvania.
PARTICIPANTS
Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N =989, mean age 85.2, 63.5% women, 16.5% African American).
MEASUREMENTS
Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change.
RESULTS
Mean ± standard deviation DHEAS was 0.555 ± 0.414 μg/mL in 1996/97 and 0.482 ± 0.449 μg/mL in 2005/06 for women and 0.845 ± 0.520 μg/mL in 1996/97 and 0.658 ± 0.516 μg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (− 0.200 μg/mL) than in women (− 0.078 μg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 μg/mL (P =.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (β = − 0.04 μg/mL, P =.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio =1.46, 95% confidence interval =1.03–2.05).
CONCLUSION
DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.
doi:10.1111/j.1532-5415.2010.02724.x
PMCID: PMC2880808  PMID: 20163485
dehydroepiandrosterone sulfate; cardiovascular disease; gender; aging
3.  Concurrent Change in Dehydroepiandrosterone Sulfate and Functional Performance in the Oldest Old: Results From the Cardiovascular Health Study All Stars Study 
Introduction.
The correlation between dehydroepiandrosterone sulfate (DHEAS) decline and age led to the hypothesis that DHEAS might be a marker of primary aging, though conflicting data from observational studies of mortality do not support this. We evaluated concurrent DHEAS and functional decline in a very old cohort to test if DHEAS change tracks with functional change during aging.
Methods.
DHEAS and functional performance (gait speed, grip strength, Modified Mini-Mental State Examination [3MSE] score, and digit symbol substitution test [DSST] score) were measured in 1996–1997 and 2005–2006 in 989 participants in the Cardiovascular Health Study All Stars study (mean age 85.2 years in 2005–2006, 63.5% women and 16.5% African American). We used multivariable linear regression to test the association of DHEAS decline with functional decline.
Results.
After adjustment, each standard deviation decrease in DHEAS was associated with greater declines in gait speed (0.12 m/s, p = .01), grip strength (0.09 kg, p = .03), 3MSE score (0.13 points, p < .001), and DSST score (0.14 points, p = .001) in women only. Additional adjustment for baseline DHEAS attenuated the association with grip strength but did not alter other estimates appreciably, and baseline DHEAS was unassociated with functional decline.
Conclusions.
In this cohort of very old individuals, DHEAS decline tracked with declines in gait speed, 3MSE score, and DSST score, but not grip strength, in women independent of baseline DHEAS level. DHEAS decline might be a marker for age-associated performance decline, but its relevance is specific to women.
doi:10.1093/gerona/glq072
PMCID: PMC2920580  PMID: 20466773
Aging; Biomarker; Dehydroepiandrosterone sulfate; Function
4.  Plasma Dehydroepiandrosterone and Risk of Myocardial Infarction in Women 
Clinical Chemistry  2008;54(7):1190-1196.
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.
doi:10.1373/clinchem.2007.099291
PMCID: PMC3400530  PMID: 18451313
5.  Low dehydroepiandrosterone sulphate is associated with increased risk of ischemic stroke among women 
Stroke; a journal of cerebral circulation  2013;44(7):10.1161/STROKEAHA.111.000485.
Background and Purpose
Previous research suggests greater risk of coronary heart disease with lower levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). No studies have examined the association between DHEAS and risk for ischemic stroke. DHEAS may influence ischemic stroke risk through atherosclerotic related mechanisms (endothelial function and smooth muscle cell proliferation) or insulin resistance.
Methods
Between 1989-1990, 32,826 women without prior stroke in the Nurses’ Health Study, an observational cohort, provided blood samples and were followed for cardiovascular events. Among this sample, using a nested-case control design, 461 ischemic strokes confirmed by medical records through 2006. Cases were matched to controls free of stroke at the time of the index case and by age, ancestry, menopausal status, postmenopausal hormone use, smoking status and date of sample collection. Multivariable conditional logistic regression was utilized.
Results
Median DHEAS levels did not differ between cases (median=58.7) and controls (median=66.0; p-value=0.10). Conditional on matching factors, the lowest DHEAS quartile exhibited a relative risk (RR) of 1.30 for ischemic stroke (95% confidence interval [CI]: 0.88-1.94), compared with the highest quartile and marginally unchanged when adjusted for confounders (RR=1.33; 95%CI: 0.87-2.02). When modeled as a binary variable dichotomized at the lowest quartile, women with low DHEAS (≤the lowest quartile) had a significantly increased multivariable adjusted risk of ischemic stroke compared to those with higher levels (RR=1.41; 95%CI: 1.03-1.92).
Conclusions
Lower DHEAS levels were associated with a greater risk of ischemic stroke, even after adjustment for potential confounders. These novel observations warrant confirmation in other populations.
doi:10.1161/STROKEAHA.111.000485
PMCID: PMC3811081  PMID: 23704104
Ischemic stroke; dehydroepiandrosterone sulphate
6.  Relationship Between Low Levels of Anabolic Hormones and 6-Year Mortality in Older Men 
Archives of internal medicine  2007;167(20):2249-2254.
Background
Aging in men is characterized by a progressive decline in levels of anabolic hormones, such as testosterone, insulinlike growth factor 1 (IGF-1), and dehydroepiandrosterone sulfate (DHEA-S). We hypothesized that in older men a parallel age-associated decline in bioavailable testosterone, IGF-1, and DHEA-S secretion is associated with higher mortality independent of potential confounders.
Methods
Testosterone, IGF-1, DHEA-S, and demographic features were evaluated in a representative sample of 410 men 65 years and older enrolled in the Aging in the Chianti Area (InCHIANTI) study. A total of 126 men died during the 6-year follow-up. Thresholds for lowest-quartile definitions were 70 ng/dL (to convert to nanomoles per liter, multiply by 0.0347) for bioavailable testosterone, 63.9 ng/mL (to convert to nanomoles per liter, multiply by 0.131) for total IGF-1, and 50 μg/dL (to convert to micromoles per liter, multiply by 0.027) for DHEA-S. Men were divided into 4 groups: no hormone in the lowest quartile (reference) and 1, 2, and 3 hormones in the lowest quartiles. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis.
Results
Compared with men with levels of all 3 hormones above the lowest quartiles, having 1, 2, and 3 dysregulated hormones was associated with hazard ratios for mortality of 1.47 (95% confidence interval [CI], 0.88-2.44), 1.85 (95% CI, 1.04-3.30), and 2.29 (95% CI, 1.12-4.68), respectively (test for trend, P <.001). In the fully adjusted analysis, only men with 3 anabolic hormone deficiencies had a significant increase in mortality (hazard ratio, 2.44; 95% CI, 1.09-5.46 (test for trend, P <.001).
Conclusions
Age-associated decline in anabolic hormone levels is a strong independent predictor of mortality in older men. Having multiple hormonal deficiencies rather than a deficiency in a single anabolic hormone is a robust biomarker of health status in older persons.
doi:10.1001/archinte.167.20.2249
PMCID: PMC2646096  PMID: 17998499
7.  Higher DHEA-S (Dehydroepiandrosterone Sulfate) Levels are Associated with Depressive Symptoms during the Menopausal Transition: Results from the PENN Ovarian Aging Study 
Archives of women's mental health  2011;14(5):375-382.
Background
The influence of sex hormones on mood during menopause has been the subject of ongoing investigation. Because dehydroepiandrosterone sulfate (DHEA-S) levels have been associated with several indicators of health outcomes associated with healthy aging, this PENN Ovarian Aging study (POAS) investigation was undertaken to determine the relationship between DHEA-S levels and both depressive symptoms and major depression during the transition through menopause. The original report revealed an unexpected positive correlation between DHEA sulfate (DHEA-S) levels and depressive symptoms in the cohort at baseline. To determine whether the positive association of DHEA-S levels and depression persists in a longitudinal analysis, the cohort was studied over 11 years.
Methods
Longitudinal cohort study with 11 assessments during an 11 year interval in Philadelphia, Pennsylvania. Participants: A randomly identified, population-based sample of 436 African American and Caucasian premenopausal women aged 35 to 47 years at enrollment. Outcome Measures: Center for Epidemiologic Studies Depression Scale score and standardized diagnosis of major depression.
Results
In a multivariable model, DHEA-S levels were positively associated with depressive symptoms, when adjusted for age, menopausal stage, race, smoking status and body mass index. There was no relationship between DHEA-S levels and a diagnosis of major depression.
Conclusions
DHEA-S levels were positively associated with depressive symptoms and not with major depression during the menopausal transition.
doi:10.1007/s00737-011-0231-5
PMCID: PMC3690802  PMID: 21773816
menopausal transition; dehydroepiandrosterone sulfate; depressive symptoms; major depression; longitudinal cohort
8.  ENDOGENOUS SEX HORMONES, BLOOD PRESSURE CHANGE, AND RISK OF HYPERTENSION IN POSTMENOPAUSAL WOMEN: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Atherosclerosis  2012;224(1):228-234.
Objective
Sex steroid hormones have been postulated to involve in blood pressure (BP) regulation. We examine the association of endogenous sex hormone levels with longitudinal change of BP and risk of developing hypertension in initially normotensive postmenopausal women.
Methods
We conducted prospective analysis among 619 postmenopausal women free of hypertension at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Change of BP and development of incident hypertension were assessed during a mean of 4.8 years follow-up.
Results
After adjusting for age, race/ethnicity, and lifestyle factors, baseline serum estradiol (E2), total and bioavailable testosterone (T), dehydroepiandrosterone (DHEA) were each positively and sex- hormone binding globulin (SHBG) was inversely associated with risk of hypertension. Additional adjustment for body mass index eliminated the associations for E2 and T but only attenuated the associations for DHEA and SHBG. The corresponding multivariable hazard ratios (95% CIs) in the highest quartile were 1.28 (0.83–1.97) for E2, 1.38 (0.89–2.14) for total T, 1.42 (0.90–2.23) for bioavailable T, 1.54 (1.02–2.31) for DHEA, and 0.48 (0.30–0.76) for SHBG. Adjustment for fasting glucose, insulin, and C-reactive protein further attenuated the association for DHEA but not SHBG. Associations of sex hormones with longitudinal BP change were similar.
Conclusion
In postmenopausal women, higher endogenous E2, T, and DHEA and lower SHBG were associated with higher incidence of hypertension and greater longitudinal rise in BP. The associations for E2, T, and DHEA were mostly explained by adiposity, while the association for SHBG was independent of measures of adiposity, insulin resistance, and systemic inflammation.
doi:10.1016/j.atherosclerosis.2012.07.005
PMCID: PMC3428144  PMID: 22862963
sex steroid hormones; hypertension; blood pressure; postmenopausal women; prospective study; epidemiology
9.  Salivary Cortisol and DHEA Levels in the Korean Population: Age-Related Differences, Diurnal Rhythm, and Correlations with Serum Levels  
Yonsei Medical Journal  2007;48(3):379-388.
Purpose
The primary objective of this study was to examine the changes of basal cortisol and DHEA levels present in saliva and serum with age, and to determine the correlation coefficients of steroid concentrations between saliva and serum. The secondary objective was to obtain a standard diurnal rhythm of salivary cortisol and DHEA in the Korean population.
Materials and Methods
For the first objective, saliva and blood samples were collected between 10 and 11 AM from 359 volunteers ranging from 21 to 69 years old (167 men and 192 women). For the second objective, four saliva samples (post-awakening, 11AM, 4PM, and bedtime) were collected throughout a day from 78 volunteers (42 women and 36 men) ranging from 20 to 40 years old. Cortisol and DHEA levels were measured using a radioimmunoassay (RIA).
Results
The morning cortisol and DHEA levels, and the age-related steroid decline patterns were similar in both genders. Serum cortisol levels significantly decreased around forty years of age (p < 0.001, when compared with people in their 20s), and linear regression analysis with age showed a significant declining pattern (slope = -2.29, t = -4.297, p < 0.001). However, salivary cortisol levels did not change significantly with age, but showed a tendency towards decline (slope = -0.0078, t = -0.389, p = 0.697). The relative cortisol ratio of serum to saliva was 3.4-4.5% and the ratio increased with age (slope = 0.051, t = 3.61, p < 0.001). DHEA levels also declined with age in saliva (slope = -0.007, t = -3.76, p < 0.001) and serum (slope = -0.197 t = -4.88, p < 0.001). In particular, DHEA levels in saliva and serum did not start to significantly decrease until ages in the 40s, but then decreased significantly further at ages in the 50s (p < 0.001, when compared with the 40s age group) and 60s (p < 0.001, when compared with the 50 age group). The relative DHEA ratio of serum to saliva was similar throughout the ages examined (slop = 0.0016, t = 0.344, p = 0.73). On the other hand, cortisol and DHEA levels in saliva reflected well those in serum (r = 0.59 and 0.86, respectively, p < 0.001). The highest salivary cortisol levels appeared just after awakening (about two fold higher than the 11 AM level), decreased throughout the day, and reached the lowest levels at bedtime (p < 0.001, when compared with PM cortisol levels). The highest salivary DHEA levels also appeared after awakening (about 1.5 fold higher than the 11AM level) and decreased by 11AM (p < 0.001). DHEA levels did not decrease further until bedtime (p = 0.11, when compared with PM DHEA levels).
Conclusion
This study showed that cortisol and DHEA levels change with age and that the negative slope of DHEA was steeper than that of cortisol in saliva and serum. As the cortisol and DHEA levels in saliva reflected those in serum, the measurement of steroid levels in saliva provide a useful and practical tool to evaluate adrenal functions, which are essential for clinical diagnosis.
doi:10.3349/ymj.2007.48.3.379
PMCID: PMC2628086  PMID: 17594144
Saliva cortisol; saliva DHEA; correlation; age-related changes; diurnal rhythm
10.  Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR) 
Purpose
To investigate whether androgen conversion rates after supplementation with dehydroepiandrosterone (DHEA) differ, and whether differences between patients with diminished ovarian reserve (DOR) are predictive of pregnancy chances in association with in vitro fertilization (IVF).
Methods
In a prospective cohort study we investigated 213 women with DOR, stratified for age (≤38 or >38 years) and ovarian FMR1 genotypes/sub-genotypes. All women were for at least 6 weeks supplemented with 75 mg of DHEA daily prior to IVF, between initial presentation and start of 1st IVF cycles. Levels of DHEA, DHEA-sulfate (DHEAS), total T (TT) and free T (FT) at baseline (BL) and IVF cycle start (CS) were then compared between conception and non-conception cycles.
Results
Mean age for the study population was 41.5 ± 4.4 years. Forty-seven IVF cycles (22.1 %) resulted in clinical pregnancy. Benefits of DHEA on pregnancy rates were statistically associated with efficiency of androgen conversion from DHEA to T and amplitude of T gain. Younger women converted significantly more efficiently than older females, and selected FMR1 genotypes/sub-genotypes converted better than others. FSH/androgen and AMH/androgen ratios represent promising new predictors of IVF pregnancy chances in women with DOR.
Conclusions
DOR at all ages appears to represent an androgen-deficient state, benefitting from androgen supplementation. Efficacy of androgen supplementation with DHEA, however, varies depending on female age and FMR1 genotype/sub-genotype. Further clarification of FMR1 effects should lead to better individualization of androgen supplementation, whether via DHEA or other androgenic compounds.
doi:10.1007/s10815-012-9890-z
PMCID: PMC3553353  PMID: 23212832
Diminished ovarian reserve; Androgens; Androgen deficiency; Androgen supplementation; Dehydroepiandrosterone (DHEA); Testosterone; FMR1 gene; Premature ovarian aging; Follicle stimulating hormone (FSH); Anti-Müllerian hormone (AMH); Pregnancy rates; In vitro fertilization (IVF); Adrenal insufficiency
11.  Association of Serum Dehydroepiandrosterone Sulfate and Cognition in Older Adults: Sex Steroid, Inflammatory, and Metabolic Mechanisms 
Neuropsychology  2013;27(3):356-363.
Objective
Dehydroepiandrosterone sulfate (DHEAS) levels and cognitive function decline with age, and a role for DHEAS in supporting cognition has been proposed. Higher DHEAS levels may be associated with better cognitive performance, although potential mechanisms for this relationship are not well established.
Method
We performed a cross-sectional study of the relationship between serum DHEAS and three aspects of cognition—executive function, working memory, and processing speed—in 49 men and 54 women, aged 60–88 years, with low serum DHEAS levels. We examined three potential mechanisms of DHEAS action—sex hormone sufficiency, inflammatory status, and glucose regulation.
Results
After adjustment for multiple covariates, higher serum DHEAS levels were associated with better working memory (standardized beta coefficient 0.50, p < .05), with a trend toward better executive function (standardized beta coefficient 0.37, p < .10) in men only. There was a nonsignificant trend toward a negative association between levels of tumor necrosis factor α (TNFα) and working memory in the combined population (standardized beta coefficient −0.22, p < .10). None of the glucoregulatory measures was associated with cognitive function.
Conclusions
The relationship between DHEAS and cognition is complex and differs by sex and cognitive domain. This study supports the need for further investigations of the sex-specific effects of DHEAS on cognition and its underlying mechanisms of action.
doi:10.1037/a0032230
PMCID: PMC4316210  PMID: 23688217
dehydroepiandrosterone; DHEAS; cognition; aging; executive function
12.  Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve? 
Critical Care  2002;6(5):434-438.
Introduction
Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic–pituitary–adrenal axis.
Materials and method
This was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-α and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death.
Results
On admission, DHEAS was extremely low in septic shock (1.2 ± 0.8 mol/l) in comparison with multiple trauma patients (2.4 ± 0.5 μmol/l; P < 0.05) and control patients (4.2 ± 1.8; P < 0.01). DHEAS had a significant (P < 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 ± 0.3 μmol/l) than did survivors (1.7 ± 1.1 μmol/l; P < 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points.
Conclusion
We identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.
doi:10.1186/cc1530
PMCID: PMC130144  PMID: 12398784
adrenal insufficiency; dehydroepiandrosterone sulphate; multiple trauma; hypothalamic–pituitary–adrenal axis; sepsis
13.  Lower Serum DHEAS levels are associated with a higher degree of physical disability and depressive symptoms in middle-aged to older African American women 
Maturitas  2007;57(4):347-360.
Background
Changes in androgen levels and associations with chronic disease, physical and neuropsychological function and disability in women over the middle to later years of life are not well understood and have not been extensively studied in African-American women.
Aims
The present cross-sectional analysis reports such levels and associations in community dwelling, African American women aged 49 – 65 years from St. Louis, Missouri.
Methods
A home-based physical examination and a health status questionnaire were administered to randomly sampled women. Body composition (DEXA), lower limb and hand-grip muscle strength, physical and neuropsychological function and disability levels were assessed. Blood was drawn and assayed for total testosterone (T), sex hormone-binding globulin (SHBG), dehydroepiandrosterone-sulfate (DHEAS), oestradiol (E2), adiponectin, leptin, triglycerides, glucose, C-reactive protein (CRP) and cytokine receptors (sIL2r, sIL6r, sTNFr1 & sTNFr2). Multiple linear regression modelling was used to identify the best predictors of testosterone, DHEAS and Free Androgen Index (T/SHBG).
Results
Seventy-four percent of women were menopausal and a quarter of these were taking oestrogen therapy. DHEAS and E2 declined between the ages of 49 and 65 years, whereas total T, SHBG and FAI remained stable. Total T and DHEAS levels were strongly correlated. In this population sample there were no independent associations of either total T or FAI with indicators of functional limitations, disability or clinically relevant depressive symptoms. Unlike total T and FAI, lower DHEAS levels was independently associated with both higher IADL scores (indicating a higher degree of physical disability) and higher CESD scores (indicating a higher degree of clinically relevant depressive symptoms).
Conclusion
There is an age-related decline in serum DHEAS in African-American women. Lower DHEAS levels appear to be associated with a higher degree of physical disability and depressive symptoms in this population.
doi:10.1016/j.maturitas.2007.03.003
PMCID: PMC2041800  PMID: 17451893
14.  Low Circulating Levels of Dehydroepiandrosterone in Histologically Advanced Nonalcoholic Fatty Liver Disease 
Hepatology (Baltimore, Md.)  2008;47(2):484-492.
The biological basis of variability in histological progression of nonalcoholic fatty liver disease (NAFLD) is unknown. Dehydroepiandrosterone(DHEA) is the most abundant steroid hormone and has been shown to influence sensitivity to oxidative stress, insulin sensitivity, and expression of peroxisome proliferator-activated receptor alpha and procollagen messenger RNA. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA. Serum samples were obtained prospectively at the time of liver biopsy in 439 patients with NAFLD (78 in an initial and 361 in validation cohorts) and in controls with cholestatic liver disease (n = 44). NAFLD was characterized as mild [simple steatosis or nonalcoholic steatohepatitis (NASH) with fibrosis stage 0–2] or advanced (NASH with fibrosis stage 3–4). Serum levels of sulfated DHEA (DHEA-S) were measured by enzyme-linked immunosorbent assay. Patients with advanced NAFLD had lower plasma levels of DHEA-S than patients with mild NAFLD in both the initial (0.25 ± 0.07 versus 1.1 ± 0.09 µg/mL, P < 0.001) and validation cohorts (0.47 ± 0.06 versus 0.99 ± 0.04 µg/mL, P < 0.001). A “dose effect” of decreasing DHEA-S and incremental fibrosis stage was observed with a mean DHEA-S of 1.03 ± 0.05, 0.96 ± 0.07, 0.83 ± 0.11, 0.66 ± 0.11, and 0.35 ± 0.06 µg/mL for fibrosis stages 0, 1, 2, 3, and 4, respectively. All patients in both cohorts in the advanced NAFLD group had low DHEA-S levels, with the majority in the hypoadrenal range. The association between DHEA-S and severity of NAFLD persisted after adjusting for age. A relationship between disease/fibrosis severity and DHEA-S levels was not seen in patients with cholestatic liver diseases.
Conclusion
More advanced NAFLD, as indicated by the presence of NASH with advanced fibrosis stage, is strongly associated with low circulating DHEA-S. These data provide novel evidence for relative DHEA-S deficiency in patients with histologically advanced NASH.
doi:10.1002/hep.22063
PMCID: PMC2906146  PMID: 18220286
15.  Inverse Associations Between Androgens and Renal Function: The Young Men Cardiovascular Association (YMCA) Study 
American journal of hypertension  2008;22(1):100-105.
BACKGROUND
Men exhibit higher risk of nondiabetic renal diseases than women. This male susceptibility to renal disease may be mediated by gender-specific factors such as sex hormones.
METHODS
We have undertaken a cross-sectional examination of associations between renal function (creatinine clearance estimated based on Cockcroft–Gault equation) and circulating levels of sex steroids (total testosterone, total estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), and dihydrotestosterone) in 928 young (mean age: 18.5 ± 1.2 years) men.
RESULTS
Both androstenedione and DHEA-S showed inverse linear associations with renal function in the crude analysis of lean men (those with body mass index (BMI) less than median). However, only DHEA-S retained its association with renal function in lean subjects after adjustment—assuming no changes in other independent variables 1 s.d. increase in DHEA-S was associated with 13%-s.d. decrease in creatinine clearance (P = 0.004). Testosterone decreased across tertiles of creatinine clearance only in the crude analysis of nonlean (BMI greater than median) subjects (P < 0.001). The adjusted regression analysis that assumed no changes in other independent variables showed that 1 s.d. increase in total testosterone was associated with 11%-s.d. decrease in creatinine clearance of nonlean men (P = 0.006). Factor analysis confirmed an inverse association of renal function with both sex steroids and a different pattern of their loadings on glomerular filtration–related factors in lean (DHEA-S) and nonlean (testosterone) subjects.
CONCLUSIONS
Our data may suggest that androgens are inversely associated with estimated renal function in apparently healthy men without history of cardiovascular disease.
doi:10.1038/ajh.2008.307
PMCID: PMC2808108  PMID: 19096379
16.  Measuring DHEA-S in saliva: time of day differences and positive correlations between two different types of collection methods 
BMC Research Notes  2010;3:204.
Background
The anabolic steroid, dehydroepiandosterone sulfate (DHEA-S), is secreted from the adrenal cortex. It plays a significant role in the body as a precursor to sex steroids as well as a lesser known role in the hypothalamic pituitary adrenal axis (HPA) response to stress. DHEA-S can be measured reliably in saliva, making saliva collection a valuable tool for health research because it minimizes the need for invasive sampling procedures (e.g., blood draws). Typical saliva collection methods include the use of plain cotton swab collection devices (e.g., Salivette®) or passive drool. There has been some speculation that the plain saliva cotton collection device may interfere with determination of DHEA-S by enzyme immunoassay (EIA) bringing this saliva collection method into question. Because of the increasing popularity of salivary biomarker research, we sought to determine whether the cotton swab interferes with DHEA-S determination through EIA techniques.
Findings
Fifty-six healthy young adult men and women aged 18-30 years came to the lab in the morning (0800 hrs; 14 men, 14 women) or late afternoon (1600 hrs; 14 men, 14 women) and provided saliva samples via cotton Salivette and passive drool. Passive drool collection was taken first to minimize particle cross contamination from the cotton swab. Samples were assayed for DHEA-S in duplicate using a commercially available kit (DSL, Inc., Webster, TX). DHEA-S levels collected via Salivette and passive drool were positively correlated (r = + 0.83, p < 0.05). Mean DHEA-S levels were not significantly different between collection methods. Salivary DHEA-S levels were significantly higher in males than in females, regardless of saliva collection method (p < 0.05), and morning DHEA-S values were higher than evening levels (p < 0.05).
Conclusions
Results suggest that DHEA-S can be measured accurately using passive drool or cotton Salivette collection methods. Results also suggest that DHEA-S levels change across the day and that future studies need to take this time of day difference into account when measuring DHEA-S.
doi:10.1186/1756-0500-3-204
PMCID: PMC2916011  PMID: 20646292
17.  Low DHEAS levels are associated with depressive symptoms in elderly Chinese men: results from a large study 
Asian Journal of Andrology  2011;13(6):898-902.
This study investigated the association between depressive symptoms in elderly Chinese men and the total testosterone, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), oestradiol and sex hormone-binding globulin (SHBG) levels, and the free androgen index. Cross-sectional data from 1147 community-dwelling elderly men, aged 65 and older, were used. Depressive symptoms were measured using the Chinese Geriatric Depression Scale (GDS). Total testosterone, free testosterone, DHEA, DHEAS, total oestradiol, the free androgen index and SHBG levels were assessed. DHEA was significantly associated with GDS score, and there was a trend towards DHEAS association, but this was not significant (β=−0.110, P=0.015; β=−0.074, P=0.055). However, no association was seen between depressive symptoms and total testosterone levels, free testosterone levels, oestradiol levels or SHBG levels. In terms of the presence of clinically relevant depressive symptoms, there were no statistically significant differences between patients in the lowest quartile of sex steroid hormone levels and those in other quartiles of sex steroid hormone levels. Similarly to Western studies, our study shows that DHEA and DHEAS levels are associated with depressive symptoms.
doi:10.1038/aja.2011.116
PMCID: PMC3739563  PMID: 21874029
Chinese; dehydroepiandrosterone; depression; elderly men; testosterone
18.  Oral dehydroepiandrosterone (DHEA) replacement in older adults: effects on central adiposity, glucose metabolism, and blood lipids 
Clinical endocrinology  2011;75(4):456-463.
Objective
The aim was to determine the effects of dehydroepiandrosterone (DHEA) therapy on changes in central adiposity, insulin action, and blood lipids. Many of the actions of DHEA in humans are thought to be mediated through its conversion to sex hormones, which are modulators of adiposity, muscularity, and insulin sensitivity. The effects of DHEA replacement on regional tissue composition, glucose metabolism, and blood lipid profile in older adults have been inconsistent.
Design
a randomized, double-blinded, placebo-controlled trial. The intervention was oral DHEA 50 mg/d or placebo for 12 months.
Participants
58 women and 61 men, aged 60–88 yr, with low serum DHEA sulfate (DHEAS) levels at study entry.
Measurements
Computed tomography measures of abdominal fat areas, thigh muscle and fat areas, DXA-derived trunk fat mass, serum glucose and insulin responses to an oral glucose challenge, and fasted serum total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides were assessed before and after the intervention.
Results
There were no significant (P > 0.05) differences between the DHEA and placebo groups in the changes in regional tissue composition or glucose metabolism. HDL-cholesterol (P =0.01) and fasted triglycerides (P =0.02) decreased in women and men taking DHEA.
Conclusion
Restoring serum DHEAS levels in older adults to young adult levels for 1 year does not appear to reduce central adiposity or improve insulin action. The benefit of DHEA on decreasing serum triglycerides must be weighed against the HDL-lowering effect.
doi:10.1111/j.1365-2265.2011.04073.x
PMCID: PMC3166648  PMID: 21521341
dehydroepiandrosterone; regional adiposity; insulin action
19.  Modulation of Higher Primate Adrenal Androgen Secretion with Estradiol or Estradiol and Progesterone Intervention 
Menopause (New York, N.Y.)  2013;20(3):10.1097/GME.0b013e318273a070.
Background
Circulating adrenal steroids rise during the menopausal transition (MT) in most mid-aged women and may contribute to differences in between-woman symptoms as well as ultimate health outcomes. However, the mechanism(s) for this shift in adrenal steroid production in mid-aged women is not known.
Objective
To determine if hormone replacement therapy (HT) for one year can modulate adrenal androgen production.
Method
Younger (9.8 +/− 0.4 y/o, n=20) and older (22.7+/−0.4 y/o, n=37) female laboratory macaques were ovariectomized (OVX), and then each group was treated with different regimens of HT for up to one year. Changes in adrenal histology and circulating adrenal androgens were monitored following estradiol treatment alone (E) or estrogen plus progesterone (E+P), and these changes were compare to the same measures in similar aged animals given vehicle (V).
Results
Zona reticularis (ZR) area and serum dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) were higher in younger compared to older V-treated animals (P< 0.02). Both E and E+P treatments decreased circulating DHEAS in the younger group (P<0.05). While E also decreased DHEAS in the older group, this was not statistically significant. In contrast, E+P treatment in the older group resulted in a rise in DHEAS over V, which was significantly higher than the results of E alone (p< 0.01). Circulating concentrations of DHEA exhibited similar trends but these changes did not reach statistical significance.
Conclusion
These data demonstrate that intervention with ovarian steroids can modulate adrenal androgen production in female higher primates and that both animal age and type of HT regimen determines the adrenal response.
doi:10.1097/GME.0b013e318273a070
PMCID: PMC3610787  PMID: 23435030
Adrenal; Steroids; Hormone Therapy; Replacement
20.  Dehydroepiandrosterone and Corticosterone Are Regulated by Season and Acute Stress in a Wild Songbird: Jugular Versus Brachial Plasma 
Endocrinology  2008;149(5):2537-2545.
Stress has well-known effects on adrenal glucocorticoid secretion, and chronic elevation of glucocorticoids can have detrimental effects on the brain. Dehydroepiandrosterone (DHEA), an androgen precursor synthesized in the adrenal glands or the brain itself, has anti-glucocorticoid properties, but little is known about the role of DHEA in the stress response, particularly in the brain. Here, we measured the effects of acute restraint on circulating corticosterone (CORT) and DHEA levels in wild song sparrows. Blood was collected from either the brachial or jugular vein. In songbirds, jugular plasma is enriched with neurally synthesized steroids, and therefore, jugular plasma is an indirect index of the neural steroidal milieu. Subjects were sampled during four times of year: breeding, molt, early nonbreeding, and mid-nonbreeding. Baseline CORT and DHEA levels showed similar seasonal changes; both steroids were elevated during the breeding season. Baseline CORT and DHEA levels were similar in jugular and brachial plasma. Acute stress had robust effects on CORT and DHEA that were season specific and vein specific. For CORT, during the molt, stress increased jugular CORT more than brachial CORT. For DHEA, during the breeding season, stress decreased jugular DHEA but not brachial DHEA. During the molt, stress increased jugular DHEA but not brachial DHEA. Acute stress did not affect brachial DHEA. These data suggest that acute stress specifically affects the balance between DHEA synthesis and metabolism in the brain. Furthermore, these results suggest that CORT and DHEA are locally synthesized in the brain during molt, when systemic levels of CORT and DHEA are low.
doi:10.1210/en.2007-1363
PMCID: PMC2878327  PMID: 18276756 CAMSID: cams343
21.  Multiple Hormonal Deficiencies in Anabolic Hormones Are Found in Frail Older Women: The Women's Health and Aging Studies 
Background
Alterations in anabolic hormones are theorized to contribute to aging and frailty, with most studies focusing on the relationship between individual hormones and specific age-associated diseases. We hypothesized that associations with frailty would most likely manifest in the presence of deficits in multiple anabolic hormones.
Methods
The relationships of serum levels of total IGF-1, DHEAS, and free testosterone (T) with frailty status (nonfrail, prefrail, or frail) were analyzed in 494 women aged 70–79 years enrolled in the Women's Health and Aging Studies I or II. Using multivariate polytomous regression, we calculated the odds of frailty for deficiency in each hormone (defined as the bottom quartile of the hormone) individually, as well as for a count of the hormones.
Results
For each hormone, in adjusted analyses, those with the deficiency were more likely to be frail than those without the deficiency, although this did not achieve statistical significance (IGF-1: odds ratio [OR] 1.82, confidence interval [CI] 0.81–4.08; DHEAS: OR 1.68, CI 0.77–3.69; free T: OR 2.03, CI 0.89–4.64). Compared with those with no hormonal deficiencies, those with one deficiency were not more likely to be frail (OR 1.15, CI 0.49–2.68), whereas those with two or three deficiencies had a very high likelihood of being frail (OR 2.79, CI 1.06–7.32), in adjusted models.
Conclusions
The absolute burden of anabolic hormonal deficiencies is a stronger predictor of frailty status than the type of hormonal deficiency, and the relationship is nonlinear. These analyses suggest generalized endocrine dysfunction in the frailty syndrome.
doi:10.1093/gerona/gln026
PMCID: PMC2655016  PMID: 19182229
Hormones; Aging; Elderly; Women; Frailty; IGF-1; DHEAS; Testosterone
22.  The Relationship between Endogenous Androgens and Body Fat Distribution in Early and Late Postmenopausal Women 
PLoS ONE  2013;8(3):e58448.
Objectives
To investigate the relationship between endogenous androgens and body fat distribution in early and late postmenopausal women.
Materials and Methods
We enrolled postmenopausal women consisting of an early group (≤5 years since menopause, n = 105) and a late group (≥10 years since menopause, n = 107). Each group was subdivided into normal weight (BMI <24 kg/m2) group, overweight and obese (BMI ≥24 kg/m2) group. Fasting total testosterone (T), dehydroepiandrosterone-sulfate (DHEA-S) and sex hormone-binding globulin (SHBG) levels were measured. Body fat distribution was evaluated by dual-energy X-ray absorptiometry (DEXA).
Results
Late postmenopausal women had a higher proportion of body fat than early postmenopausal women. The body fat of the overweight and obese women had a greater tendency to accumulate in the abdomen compared with the normal weight women both in early and late postmenopausal groups. The overweight and obese women had a higher free testosterone (FT) than the normal weight women in early postmenopausal women (P<0.05). In late postmenopausal women, the overweight and obese women had higher DHEA-S levels than normal weight women (P<0.05). No direct relationship was observed between the T levels and body fat distribution both in early and late postmenopausal groups (P>0.05).The FT in early postmenopausal women and the DHEA-S levels in late postmenopausal women correlated positively with the trunk/leg fat ratio (T/L) and the proportion of android fat whereas correlated negatively with the proportion of gynoid fat in the partial correlation and multiple linear regression analyses (all P<0.05).
Conclusions
Serum T levels do not correlate directly with body fat distribution, the FT in early postmenopausal women and DHEA-S levels in late postmenopausal women correlate positively with abdominal fat accumulation.
doi:10.1371/journal.pone.0058448
PMCID: PMC3587576  PMID: 23484029
23.  Association of Adrenal Function and Disease Severity in Community-Acquired Pneumonia 
PLoS ONE  2014;9(6):e99518.
Introduction
Rapid and accurate risk stratification in patients with community-acquired pneumonia (CAP) is an unmet clinical need. Cortisol to dehydroepiandrosterone (DHEA) ratio was put forward as a prognostic marker in sepsis. We herein validated the prognostic value of the adrenal hormones DHEA, DHEA-Sulfate (DHEAS), cortisol/DHEA-, cortisol/DHEAS- and DHEA/DHEAS – ratios in patients with CAP.
Methods
We assessed severity of illness using the pneumonia severity index (PSI) and measured adrenal hormone concentrations in 179 serum samples of prospectively recruited patients hospitalized with CAP. We calculated spearman rank correlation, logistic regression analysis and Kaplan Meier curves to study associations of adrenal hormones and outcomes.
Results
There was a significant correlation between PSI score and total cortisol (r = 0.24, p = 0.001), DHEAS (r = −0.23, p = 0.002), cortisol/DHEA (r = 0.23, p = 0.003), cortisol/DHEAS (r = 0.32, p = <0.0001) and DHEA/DHEAS (r = 0.20, p = 0.009). In age and gender adjusted logistic regression analysis, cortisol (OR: 2.8, 95% CI: 1.48–5.28) and DHEA (OR: 2.62, 95% CI: 1.28–5.34), but not DHEAS and the different ratios were associated with all-cause mortality. The discriminatory accuracy of cortisol and DHEA in ROC analysis (area under the curve) was 0.74 and 0.61. In Kaplan Meier analysis, patients in the highest deciles of cortisol and DHEA (p = 0.005 and p = 0.015), and to a lesser extent of cortisol/DHEAS ratio (p = 0.081) had a higher risk of death.
Conclusion
Cortisol, DHEAS and their ratios correlate with CAP severity, and cortisol and DHEA predict mortality. Adrenal function in severe pneumonia may be an important factor for CAP outcomes.
doi:10.1371/journal.pone.0099518
PMCID: PMC4049821  PMID: 24910975
24.  The association between dehydroepiandosterone and frailty in older men and women 
Age and Ageing  2009;38(4):401-406.
Objectives: to evaluate the association between dehydroepiandosterone (DHEA) and physical frailty in older adults.
Design: cross-sectional analysis of baseline information from three separate studies in healthy older men, women and residents of assisted living.
Setting: academic health centre in greater Hartford, CT, USA.
Participants: eight hundred and ninety-eight adults residing in the community or assisted living facility.
Measurements: participants had measurement of frailty (weight loss, grip strength, sense of exhaustion, walking speed and physical activity) and serum DHEAS levels.
Results: overall, 6% of the individuals in the study were classified as frail, 58% intermediate frail and 35% were not frail. In the bivariate analysis, there were differences between categories of frailty across age, gender and by DHEAS levels. In an ordinal logistic regression model, with frailty as a dependent measure, we found that age, DHEAS and interactions of age and BMI and DHEAS and BMI were predictive of more frailty characteristics.
Conclusion: we found an association between frailty and DHEAS levels. Whether the association is due to similar conditions resulting in lower DHEA levels and more susceptibility to frailty or whether lower DHEA levels have an impact on increasing frailty cannot be addressed by cross-sectional analysis. Gender did not impact the association between DHEAS and frailty, but obesity (BMI > 30 kg/m2) attenuated the association between higher DHEA levels and lower frailty status.
doi:10.1093/ageing/afp015
PMCID: PMC2720687  PMID: 19276095
dehydroepiandosterone; frailty; ageing; elderly
25.  Additive benefit of higher testosterone levels and vitamin D plus calcium supplementation in regard to fall risk reduction among older men and women 
Aim
To investigate the association between sex hormone levels and the risk of falling in older men and women.
Methods
199 men and 246 women age 65 or older living at home followed for 3 years after baseline assessment of sex hormones. Analyses controlled for age, bmi, baseline 25-hydroxyvitamin D, sex hormone binding globulin, physical activity, smoking, alcohol use, number of comorbidities, maximal follow-up, and vitamin D plus calcium treatment.
Results
Compared to the lowest quartile, men and women in the highest sex-specific quartile of total testosterone had a 78% and 66% decreased risk of falling (men: OR = 0.22; 95% CI [0.07,0.72]/ women: OR = 0.34; 95% CI [0.14,0.83]); if those individuals also took calcium plus vitamin D the anti-fall effect was enhanced to 84% among men and 85% among women (men: OR = 0.16; 95% CI [0.03,0.90] / women: OR = 0.15; 95% CI [0.04,0.57]). Women in the top quartile of dihydroepiandrosterone sulfate (DHEA-S) had a significant 61% lower risk of falling compared to those in the lowest quartile (OR = 0.39; 95% CI [0.16,0.93]). Other sex hormones and SHBG did not predict falling in men or women.
Conclusion
Higher physiologic total testosterone in both genders and higher DHEA-S levels in women predicted a more than 60% lower risk of falling. The anti-fall benefit of higher physiologic testosterone levels is enhanced to over 80% by additional calcium and vitamin D supplementation.
doi:10.1007/s00198-008-0573-7
PMCID: PMC2680613  PMID: 18351428
falls; testosterone; sex hormones; older individuals

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