Cortisol, DHEAS, their ratio and the metabolic syndrome: evidence from the Vietnam Experience Study

in European Journal of Endocrinology
(Correspondence should be addressed to A C Phillips; Email: a.c.phillips@bham.ac.uk)

Objectives

The aim of these analyses was to examine the association of cortisol, DHEAS and the cortisol:DHEAS ratio with the metabolic syndrome (MetS) and its components.

Design

The analyses were cross-sectional.

Methods

Participants were 4255 Vietnam era US army veterans. From military service files, telephone interviews and a medical examination, occupational, socio-demographic and health data were collected. MetS was ascertained from data on body mass index; fasting blood glucose or a diagnosis of diabetes; blood pressure or a diagnosis of hypertension; high-density lipoprotein cholesterol; and triglyceride levels. Contemporary morning fasted cortisol and DHEAS concentrations were determined. The outcomes were MetS and its components. Analysis was by logistic regression, first adjusting for age and then additionally for an array of candidate confounders.

Results

Cortisol, although not in the fully adjusted analysis, and DHEAS were both related to MetS. Whereas high cortisol concentrations were associated with an increased risk of MetS, high DHEAS concentrations appeared protective. By far, the strongest associations with MetS were observed for the cortisol:DHEAS ratio; the higher the ratio, the greater the risk of having MetS. The ratio was also significantly related to four of the five MetS components.

Conclusions

The cortisol:DHEAS ratio is positively associated with MetS. Prospective analyses are needed to help untangle direction of causality, but this study suggests that the cortisol:DHEAS ratio is worthy of further study in this and other health contexts.

Abstract

Objectives

The aim of these analyses was to examine the association of cortisol, DHEAS and the cortisol:DHEAS ratio with the metabolic syndrome (MetS) and its components.

Design

The analyses were cross-sectional.

Methods

Participants were 4255 Vietnam era US army veterans. From military service files, telephone interviews and a medical examination, occupational, socio-demographic and health data were collected. MetS was ascertained from data on body mass index; fasting blood glucose or a diagnosis of diabetes; blood pressure or a diagnosis of hypertension; high-density lipoprotein cholesterol; and triglyceride levels. Contemporary morning fasted cortisol and DHEAS concentrations were determined. The outcomes were MetS and its components. Analysis was by logistic regression, first adjusting for age and then additionally for an array of candidate confounders.

Results

Cortisol, although not in the fully adjusted analysis, and DHEAS were both related to MetS. Whereas high cortisol concentrations were associated with an increased risk of MetS, high DHEAS concentrations appeared protective. By far, the strongest associations with MetS were observed for the cortisol:DHEAS ratio; the higher the ratio, the greater the risk of having MetS. The ratio was also significantly related to four of the five MetS components.

Conclusions

The cortisol:DHEAS ratio is positively associated with MetS. Prospective analyses are needed to help untangle direction of causality, but this study suggests that the cortisol:DHEAS ratio is worthy of further study in this and other health contexts.

Introduction

The metabolic syndrome (MetS) is a cluster of symptoms (obesity, high triglycerides, low high-density lipoprotein (HDL) cholesterol, raised blood pressure, and high fasting blood glucose or a diagnosis of diabetes) that increase the risk of cardiovascular and all-cause mortality (1, 2, 3, 4). It is estimated that one quarter of the world's adult population has the MetS (5). The overlap between presenting clinical features of MetS and Cushing's disease has prompted the hypothesis that elevated cortisol may have an aetiological role in the development of MetS (5, 6). Indeed, circulating cortisol concentrations are higher in individuals with MetS and its components (7, 8, 9, 10, 11). However, some studies have reported no association between cortisol and MetS (12, 13).

There is even less consensus about whether DHEAS, the most abundant steroid in the human circulation, is implicated in MetS. Some data suggest that lower DHEAS concentrations characterize individuals with MetS (14), but, again, this is not a universal observation (12, 13). In addition, no studies have examined the cortisol:DHEAS ratio in this context. Both cortisol and DHEAS are synthesized within the adrenal cortex, and it is conceivable that their respective relative contributions to adrenal steroid output might define observed biological action. Furthermore, the cortisol:DHEAS ratio has been found to predict health outcomes better than the level of either hormone alone (15) as well as predicting all-cause mortality (16). Given the absence of data for the cortisol:DHEAS ratio, the variable outcomes for cortisol and DHEAS, and the importance of establishing the pathways leading to MetS, the present analyses of data from a substantial cohort of Vietnam era US veterans addressed the issue of whether cortisol and DHEAS, and their ratio are associated with MetS.

Materials and methods

Sample

Participants were male Vietnam era military veterans recruited as part of the Centers for Disease Control Vietnam Experience Study (17). The effective sample size was 4255. Ethical approval for the study was given by various bodies, including the US Centers for Disease Control, and participants gave informed consent. Details of sampling at each stage of data collection are described in detail elsewhere (17). Inclusion criteria were: entered military service between January 1 1965 and December 31 1971; served only one term of enlistment and at least 16 weeks of active duty; earned a military specialty other than ‘trainee’ or ‘duty soldier’; had a military pay grade at discharge no higher than sergeant.

Data collection

Information on place of service and ethnicity was extracted from the military archives. From a telephone survey in 1985, socio-economic position was measured using household income in midlife and the grade from which participants left school. Alcohol consumption, smoking habits and marital status were ascertained using standard questions. In 1986, participants underwent a thorough medical examination. Mean age at medical examination was 38.3 years (range: 31.1–49.0). Participants fasted from 1900 h on the previous evening until blood was drawn the following morning. Cortisol and DHEAS were assessed in 1986 from serum using a double antibody RIA system (Leeco Diagnostics, Inc., Southfield, MI, USA). From the fasted blood sample, triglycerides and cholesterol fractions were assessed using a Kodak Ektachem 700 autoanalyzer (18, 19). Serum glucose level was determined with an adaptation of the glucose oxidase-peroxidase-chromogen-coupled system (18, 19). Blood pressure was measured twice in the right arm using a sphygmomanometer and an average computed. Height and weight were measured to calculate body mass index (BMI, kg/m2).

MetS and its components were defined as having at least three of the following characteristics: triglycerides ≥1.7 mmol/l (150 mg/dl); HDL cholesterol <1.036 mmol/l (40 mg/dl); blood pressure ≥130/85 mmHg or taking antihypertensive medication; BMI >30 kg/m2 (in the absence of waist circumference data, BMI at this threshold is regarded by World Health Organization and the International Diabetes Federation as an acceptable substitute in defining MetS (20)); triglycerides ≥1.7 mmol/l (150 mg/l); HDL cholesterol <1.036 mmol/l (40 mg/l); blood pressure ≥130/85 mmHg or taking antihypertensive medication; fasting glucose ≥5.6 mmol/l (100 mg/dl) or a diagnosis of diabetes. All laboratory assays were assured by using bench and blind repeat controls. In 677 randomly chosen samples, repeat sample correlations exceeded 0.98. Bench controls yielded coefficients of variation that were all <10%. Finally, current medication status was also determined at the medical examination.

Statistical analysis

Cortisol, DHEAS and cortisol:DHEAS ratio values were not normally distributed, so they were natural log-transformed. Demographic, service, health behaviour, metabolic and haemodynamic variables were compared between those with and without MetS using χ2 and ANOVAs. Logistic regression was used to examine the relationships between cortisol, DHEAS, their ratio and MetS, first in age-adjusted analyses and then in fully adjusted analyses with the additional covariates of place of service, ethnicity, marital status, alcohol consumption, smoking, household income and education grade. Further fully adjusted regression models were tested in which both cortisol and the cortisol:DHEAS ratio were entered in one case and DHEAS and the cortisol:DHEAS ratio in the other. The association between the cortisol:DHEAS ratio and the individual MetS components was examined in further fully adjusted models. Linear regression, with full adjustment, was used to test the relationship between the ratio and the number of MetS components that participants possessed.

Results

Five hundred and eighty-four (14%) of the men were identified as having MetS. Aside from differing on all the components of MetS, participants with MetS were slightly older, tended to have a briefer education, were less likely to be divorced, widowed or separated and more likely to come from ethnic groups other than white or black (Table 1).

Table 1

Characteristics of participants with and without metabolic syndrome.

Metabolic syndrome (n=584)Non-metabolic syndrome (n=3671)
Means.d.Means.d.P
Metabolic syndrome markers
 BMI (kg/m2)30.734.1525.173.04<0.001
 Triglycerides (mmol/l)2.562.431.090.73<0.001
 HDL cholesterol (mmol/l)0.890.201.190.31<0.001
 SBP (mmHg)133.3312.50121.3611.11<0.001
 DBP (mmHg)91.859.2982.888.84<0.001
 Blood glucose (mmol/l)5.931.715.130.70<0.001
Predictor variables
 Cortisol (mmol/l)0.520.170.500.150.002
 DHEAS (mmol/l)5.882.496.622.73<0.001
 Cortisol:DHEAS ratio0.1020.060.0880.05<0.001
Covariates
 Age at medical examination (years)38.742.5238.262.51<0.001
 Units of alcohol per week7.2816.787.0514.010.72
n (%)n (%)P
Metabolic syndrome markers
 Obese347 (59)203 (6)<0.001
 Hypertension diagnosis169 (29)271 (7)<0.001
 Diabetes diagnosis24 (4)25 (1)<0.001
Covariates
Place of service
 Ever in Vietnam339 (58)2009 (55)0.32
 Other overseas142 (24)953 (26)
 US only103 (18)709 (19)
Ethnicity
 White473 (81)3017 (82)0.03
 Black60 (10)435 (12)
 Other51 (9)219 (6)
Household income in midlife
 <$20 000183 (31)1018 (28)0.11
 −$40 000289 (50)1840 (50)
 >$40 000112 (19)813 (22)
Years in education
 <1193 (16)419 (11)0.004
 −12218 (37)1346 (37)
 >12273 (47)1906 (52)
Smoking status
 Non-smoker146 (25)938 (26)0.96
 Ex smoker166 (28)1043 (28)
 Current smoker272 (47)1690 (46)
Marital status
 Married459 (79)2672 (73)
 Divorced/separated/widowed79 (13)688 (19)0.006
 Never married46 (8)314 (8)

In age-adjusted logistic regression analyses, men with higher morning cortisol levels were more likely to exhibit MetS, odds ratio (OR)=1.35, 95% confidence interval (CI) 1.01–1.81, P=0.04. Higher DHEAS, on the other hand, was associated with significantly reduced incidence of MetS, OR=0.55, 95% CI 0.45–0.68, P<0.001. Those with higher cortisol:DHEAS ratios were much more likely to meet the criteria for MetS, OR=1.75, 95% CI 1.47–2.09, P<0.001. This association between the cortisol:DHEAS ratio and MetS is illustrated in Fig. 1, which shows a clear dose–response relationship. In the fully adjusted analyses, the association between cortisol and MetS was no longer statistically significant at conventional levels, OR=1.31, 95% CI 0.98–1.76, P=0.07. However, higher DHEAS concentrations were still negatively, OR=0.56, 95% CI 0.46–0.69, P<0.001, and the cortisol:DHEAS ratio still positively, OR=1.72, 95% CI 1.44–2.05, P<0.001, related to MetS. In fully and mutually adjusted models, the first entering both cortisol and the cortisol:DHEAS ratio and the second entering DHEAS and the cortisol:DHEAS ratio, only the ratio emerged as a significant predictor of MetS, OR=1.83, 95% CI 1.50–2.25, P<0.001 and OR=1.46, 95% CI 1.09–1.96, P=0.01 respectively. The statistics for cortisol and DHEAS in these models were OR=0.79, 95% CI 0.57–1.11, P=0.18 and OR=0.79, 95% CI 0.57–1.11, P=0.18 respectively.

Figure 1

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Figure 1

Prevalence of MetS according to quartiles of the cortisol:DHEAS ratio (1=0.01–0.06; 2=0.01–0.08; 3=0.01–0.11; 4=0.01–0.73).

Citation: European Journal of Endocrinology 162, 5; 10.1530/EJE-09-1078

The cortisol:DHEAS ratio was also significantly associated with the number of components of MetS that a participant possessed, β=0.12, t=7.86, P<0.001, ΔR2=0.014. Finally, of the components of MetS, the cortisol:DHEAS ratio was positively and significantly associated with high blood pressure, OR=1.39, 95% CI 1.20–1.60, P<0.001; high blood glucose, OR=1.68, 95% CI 1.43–1.98, P<0.001; high triglycerides, OR=1.87, 95% CI 1.59–2.19, P<0.001; and low HDL, OR=1.19, 95% CI 1.04–1.35, P=0.009, in fully adjusted models. The association between the cortisol:DHEAS ratio and obesity was only a trend, OR=1.17, 95% CI 0.98–1.41, P=0.09. When these fully adjusted analyses were rerun with adjustment for obesity, the cortisol:DHEAS ratio remained significantly associated with high blood pressure, OR=1.38, 95% CI 1.19–1.59, P<0.001; high triglycerides, OR=1.88, 95% CI 1.60–2.21, P<0.001; low HDL OR=1.17, 95% CI 1.02–1.33, P=0.02; and high blood glucose, OR=1.67, 95% CI 1.41–1.97, P<0.001.

Discussion

Cortisol, although not in the fully adjusted analysis, and DHEAS were both related to MetS; whereas high cortisol concentrations were associated with an increased risk of MetS, and high DHEAS concentrations appeared protective. These outcomes, in what we believe is the largest study conducted to date, agree with some (7, 8, 9, 10, 11, 14), but not all (12, 13) of the existing literature. By far, the most robust associations with MetS were observed for the cortisol:DHEAS ratio; the higher the ratio, the greater the risk of having MetS. In mutually adjusted analyses, only the ratio emerged as a significant predictor of MetS. The cortisol:DHEAS ratio was also positively associated with the number of components of MetS as well as with four of the five MetS components. This extends previous research showing that the cortisol:DHEAS ratio was associated with all-cause mortality (16). It also predicts immune function and infectious disease susceptibility better than either hormone alone (15, 21). Thus, the cortisol:DHEAS ratio merits examination in the context of other health outcomes.

With cross-sectional analyses, it is impossible to determine causality and direction of the association. For example, it has been suggested that MetS may lead to a state of hypercortisolism, but there is also evidence that increased exposure to cortisol contributes to increased fat accumulation in the visceral depots (5). The protective effect indicated by higher DHEAS is particularly interesting, and the anti-glucocorticoid actions of its precursor, DHEA, are well documented (22, 23, 24). Higher levels of DHEA or DHEAS might lead to lower effective cortisol action, particularly at a tissue-specific level, e.g. adipose tissue and immune cells (25). Indeed, our own in vitro data have shown that DHEAS can overcome the suppressive effects of cortisol upon immune cell function, specifically the generation of superoxide by neutrophils (15), supporting the proposal that it is the ratio of these two hormones that will determine biological outcome in vivo (26). Moreover, there are no reports of MetS suppressing DHEAS production, supporting the notion that the direction of causality is from a lower ratio to MetS. Both cortisol and DHEA/DHEAS secretion are under the regulatory influence of pituitary ACTH, and excessive glucocorticoid production will lead to a down-regulation of ACTH, resulting in reduced DHEA secretion, as frequently observed in patients with an adrenal cortisol-producing adenoma. However, the circulating cortisol levels measured in this cohort are not unusually elevated. Thus, a suppressive influence of cortisol on DHEAS secretion seems unlikely. It may also be the case that both hormonal profile and susceptibility to MetS reflect programming effects in early life consequent on prenatal resource deprivation (6). However, it must be emphasized that such considerations remain speculative given the cross-sectional nature of the study; only prospective and experimental studies can resolve issues of causality.

The present study may have other limitations. First, the sample was exclusively male and relatively young, so the findings may not be able to be generalized to the women and older populations. However, the sex hormone binding globulin has been found to be associated with MetS in both sexes (12, 13). Nonetheless, as premenopausal women have slightly higher total cortisol values and lower circulating DHEAS (27), it would be interesting to examine the influence of the cortisol:DHEAS ratio and MetS in women where the relationship could be even stronger. The relative youth of our sample is most likely the reason for the relatively low prevalence of MetS. However, given that the prevalence of MetS is generally higher in older individuals (28), it is possible that the associations observed would be even stronger in an older sample. It is also worth noting that the cortisol:DHEAS ratio increases with age (29), thus it is likely to be an even stronger predictor of MetS in an older sample. The second possible limitation is the use of a single morning measurement of serum cortisol and DHEAS. Cortisol has a diurnal rhythm which would be best captured through multiple measurements of the free active fraction of cortisol, such as that which can be determined through saliva sampling. Furthermore, the most accurate assessment for silent hypercortisolism is an overnight dexamethasone suppression test. However, the timing of the present samples was fairly consistent across participants. Furthermore, DHEAS concentrations remain stable throughout the day and reflect the 24-h secretion of DHEA (30, 31).

In conclusion, the cortisol:DHEAS ratio was positively associated with MetS and many of its components. Prospective research is required to clarify the causal direction of this relationship and inform future intervention strategies. In addition, it would be worthwhile examining the cortisol:DHEAS ratio in the context of other health outcomes.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

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    MullerMGrobbeeDEden TonkelaarILambertsSWvan der SchouwYT. Endogenous sex hormones and metabolic syndrome in aging men. Journal of Clinical Endocrinology and Metabolism20059026182623.

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    BoscarinoJA. Psychobiologic predictors of disease mortality after psychological trauma: implications for research and clinical surveillance. Journal of Nervous and Mental Disease2008196100107.

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    KalimiMShafagojYLoriaRPadgettDRegelsonW. Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Molecular and Cellular Biochemistry199413199104.

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    KimonidesVGSpillantiniMGSofroniewMVFawcettJWHerbertJ. Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures. Neuroscience199989429436.

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    QuinklerMSinhaBTomlinsonJWBujalskaIJStewartPMArltW. Androgen generation in adipose tissue in women with simple obesity – a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5. Journal of Endocrinology2004183331342.

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    Hazeldine J Arlt W & Lord JM. Dehydroepiandrosterone as a regulator of immune cell function. Journal of Steroid Biochemistry and Molecular Biology. In press. DOI: 10.1016/j.jsbmb.2009.12.016.

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    ButcherSKLordJM. Stress responses and innate immunity: aging as a contributory factor. Aging Cell20043151160.

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    OrentreichNBrindJLRizerRLVogelmanJH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. Journal of Clinical Endocrinology and Metabolism198459551555.

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    Prevalence of MetS according to quartiles of the cortisol:DHEAS ratio (1=0.01–0.06; 2=0.01–0.08; 3=0.01–0.11; 4=0.01–0.73).

References

1

LakkaHMLaaksonenDELakkaTANiskanenLKKumpusaloETuomilehtoJSalonenJT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. Journal of the American Medical Association200228827092716.

2

IsomaaBAlmgrenPTuomiTForsenBLahtiKNissenMTaskinenMRGroopL. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care200124683689.

3

TrevisanMLiuJBahsasFBMenottiA. Syndrome X and mortality: a population-based study. Risk Factor and Life Expectancy Research Group. American Journal of Epidemiology1998148958966.

4

ThomasGNSchoolingCMMcGheeSMHoSYCheungBMWatNMJanusEDLamKSLamTH. Metabolic syndrome increases all-cause and vascular mortality: the Hong Kong Cardiovascular Risk Factor Study. Clinical Endocrinology200766666671.

5

AnagnostisPAthyrosVGTziomalosKKaragiannisAMikhailidisDP. Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. Journal of Clinical Endocrinology and Metabolism20099426922701.

6

WalkerBR. Cortisol – cause and cure for metabolic syndrome?Diabetic Medicine20062312811288.

7

PasqualiRVicennatiVCacciariMPagottoU. The hypothalamic–pituitary–adrenal axis activity in obesity and the metabolic syndrome. Annals of the New York Academy of Sciences20061083111128.

8

ReynoldsRMSyddallHEWalkerBRWoodPJPhillipsDI. Predicting cardiovascular risk factors from plasma cortisol measured during oral glucose tolerance tests. Metabolism200352524527.

9

SenYKandemirNAlikasifogluAGoncNOzonA. Prevalence and risk factors of metabolic syndrome in obese children and adolescents: the role of the severity of obesity. European Journal of Pediatrics200816711831189.

10

VogelzangsNPenninxBW. Cortisol and insulin in depression and metabolic syndrome. Psychoneuroendocrinology200732856.

11

WeigensbergMJToledo-CorralCMGoranMI. Association between the metabolic syndrome and serum cortisol in overweight Latino youth. Journal of Clinical Endocrinology and Metabolism20089313721378.

12

MaggioMLauretaniFCedaGPBandinelliSBasariaSBleAEganJPaolissoGNajjarSJeffrey MetterEValentiGGuralnikJMFerrucciL. Association between hormones and metabolic syndrome in older Italian men. Journal of the American Geriatrics Society20065418321838.

13

MaggioMLauretaniFCedaGPBandinelliSBasariaSPaolissoGBleAEganJMMetterEJAbbatecolaAMZulianiGRuggieroCValentiGGuralnikJMFerrucciL. Association of hormonal dysregulation with metabolic syndrome in older women: data from the InCHIANTI study. American Journal of Physiology. Endocrinology and Metabolism2007292E353E358.

14

MullerMGrobbeeDEden TonkelaarILambertsSWvan der SchouwYT. Endogenous sex hormones and metabolic syndrome in aging men. Journal of Clinical Endocrinology and Metabolism20059026182623.

15

ButcherSKKillampalliVLascellesDWangKAlparEKLordJM. Raised cortisol:DHEAS ratios in the elderly after injury: potential impact upon neutrophil function and immunity. Aging Cell20054319324.

16

BoscarinoJA. Psychobiologic predictors of disease mortality after psychological trauma: implications for research and clinical surveillance. Journal of Nervous and Mental Disease2008196100107.

17

PhillipsACBattyGDGaleCRDearyIJOsbornDMacIntyreKCarrollD. Generalised anxiety disorder, major depressive disorder, and their comorbidity as predictors of all-cause and cardiovascular mortality: the Vietnam Experience Study. Psychosomatic Medicine200971395403.

18

Study. The Centers for Disease Control Vietnam Experience StudyHealth status of Vietnam veterans. I. Psychosocial characteristics. Journal of the American Medical Association198825927012707.

19

Study. The Centers for Disease Control Vietnam Experience StudyHealth status of Vietnam veterans. II. Physical Health. Journal of the American Medical Association198825927082714.

20

ZimmetPK GeorgeMMASerrano RiosM. A new international diabetes federation worldwide definition of the metabolic syndrome: the rationale and the results. Revista Española de Cardiología20055813711376.

21

ArltWHammerFSanningPButcherSKLordJMAllolioBAnnaneDStewartPM. Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock. Journal of Clinical Endocrinology and Metabolism20069125482554.

22

KalimiMShafagojYLoriaRPadgettDRegelsonW. Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Molecular and Cellular Biochemistry199413199104.

23

KimonidesVGSpillantiniMGSofroniewMVFawcettJWHerbertJ. Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures. Neuroscience199989429436.

24

QuinklerMSinhaBTomlinsonJWBujalskaIJStewartPMArltW. Androgen generation in adipose tissue in women with simple obesity – a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5. Journal of Endocrinology2004183331342.

25

Hazeldine J Arlt W & Lord JM. Dehydroepiandrosterone as a regulator of immune cell function. Journal of Steroid Biochemistry and Molecular Biology. In press. DOI: 10.1016/j.jsbmb.2009.12.016.

26

ButcherSKLordJM. Stress responses and innate immunity: aging as a contributory factor. Aging Cell20043151160.

27

OrentreichNBrindJLRizerRLVogelmanJH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. Journal of Clinical Endocrinology and Metabolism198459551555.

28

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