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PubMed1999

Relationships between dehydroepiandrosterone sulfate (DHEAS) and cortisol (CRT) plasma levels and everyday memory in Alzheimer's disease patients compared to healthy controls.

Fifty-two age-matched Alzheimer's disease (AD) patients (26 men, 26 women), mean age 76.2 years, were assessed with the Rivermead Behavioural Memory Test, a test of everyday memory, coincident with the measurement of plasma cortisol (CRT) and dehydroepiandrosterone sulfate (DHEAS) via radioimmunoassay. The AD patients were compared to a control group of age- and gender-matched healthy elderly men and women. No differences were found between the AD patients and the controls in DHEAS or CRT levels, or in the DHEAS/CRT ratio. There were no gender differences in DHEAS or CRT levels, or in the DHEAS/CRT ratio in subjects with AD. However, AD patients with higher levels of DHEAS scored better than those with lower levels on the subtests of Remembering a Name associated with a picture, Digit Span Total and Forward, and the Mini Mental Status Exam. AD patients with higher CRT levels performed worse on Delayed Route Recall than those with lower levels. These findings suggest that AD patients with higher endogenous levels of DHEAS may perform better on some memory tasks than those with lower levels, while AD patients with lower levels of CRT may perform better than those with higher CRT.

Affect↗

PubMed2003

Cortisol, DHEAS and aging: resistance to cortisol suppression in frail institutionalized elderly.

Convincing evidences has linked the hypothalamus-pituitary-adrenal (HPA) axis to aging patterns. F excess is implicated in the development of frailty characteristics whereas DHEAS is positively correlated to successful aging. We compared serum F and DHEAS levels of independent community-living (successful group, 19 M and 28 F, 69 to 87 yr) with those of institutionalized elderly (frail group, 20 M and 30 F, 65 to 95 yr). Serum F was determined at 1) baseline (08:00 h, 16:00 h and 23:00 h), 2) after 2 overnight dexamethasone (DEX) suppression tests (DST, using 0.25 and 1.0 mg doses), and 3) 60 min after ACTH stimulation (250 microg i.v. bolus); serum DHEAS was determined at 08:00 h. Basal serum F at 08:00 h, 16:00 h and 23:00 h and serum DHEAS levels were similar in both groups; however F: DHEAS ratio at 08:00 h was higher in the frail, compared to the successful group (mean +/- SD: 0.55 +/- 0.53 and 0.35 +/- 0.41, respectively; p = 0.04). In response to DST, F suppression was less effective in frail elderly after either 0.25 or 1.0 mg doses (9.0 +/- 6.0 and 2.0 +/- 0.9 microg/dl), as compared to the successful group (5.8 +/- 4.4 and 1.5 +/- 0.5 microg/dl) (p = 0.01). In addition, a significant correlation was observed between post-DEX F levels (both doses) and parameters of cognitive and physical frailty. Normal and similar F levels were observed after ACTH stimulation in both groups. Our data suggest a deficient feedback regulation of the HPA axis in frail institutionalized elderly, as demonstrated by a higher set point for F suppression. This augmented HPA tonus enforces the hypothesis that even milder F excess may be related to characteristics of frailty in the elderly.

Activities of Daily Living↗

PubMed1998

Endocrine mechanisms of stress-induced DHEA-secretion.

Acute psychological stress of a first time parachute jump stimulated DHEA and cortisol secretion in healthy volunteers. A significant shift from cortisol to DHEA occurred during this stress exposure. This effect was more pronounced in subjects receiving the beta-adrenoceptor antagonist propranolol prior to the jump. In contrast, infusion of epinephrine (0.10 microgram/kg/min) or norepinephrine (0.15 microgram/kg/min) for 20 min neither affected DHEA plasma levels nor the DHEA/cortisol ratio. However, pretreatment with propranolol resulted in a significant increase of the DHEA/cortisol ratio upon infusion of the beta-adrenoceptor agonist epinephrine. These data demonstrate that during acute psychological stress stimulation of adrenal steroid release is accompanied by a shift towards DHEA. Augmentation of this effect by beta-adrenoceptor blockade indicates a beta-adrenoceptor-dependent mechanism affecting DHEA release.

Acute Disease↗

PubMed2006

A decrease in the plasma DHEA to cortisol ratio during smoking abstinence may predict relapse: a preliminary study.

RATIONALE: Increases in depressive symptoms during smoking cessation have been associated with risk for relapse. Several studies have linked plasma levels of cortisol and dehydroepiandrosterone (DHEA) or DHEA-sulfate (DHEAS) to depressive symptoms. OBJECTIVES: To determine whether changes in plasma cortisol, DHEA, or DHEAS levels and emergence of depressive symptoms during smoking cessation are associated with smoking relapse. MATERIALS AND METHODS: Subjects were healthy non-medicated men and women, aged 39+/-12 years, who smoked, on average, 22 cigarettes per day. Depressive symptoms, smoking withdrawal symptoms, and plasma steroid levels were measured before and after 8 days of verified smoking abstinence. Relapse status at day 15 was then determined. RESULTS: In the full sample (n=63), there was a trend for changes in depressive symptoms to be associated with relapse. In the subset of 25 subjects with plasma neuroactive steroid data, there was a significant interaction between the change in the plasma DHEA/cortisol ratio from day 0 to day 8 and relapse status at day 15. This ratio was similar before abstinence, but lower at day 8 in relapsed, compared to abstinent, subjects. Changes in the DHEA/cortisol ratio tended to predict changes in depressive symptoms in the women only. CONCLUSION: A decrease in the plasma DHEA/cortisol ratio during 8 days of smoking abstinence was associated with relapse over the following week. Further research is needed to fully characterize sex-specific relationships between abstinence-induced changes in neuroactive steroid levels, depressive or withdrawal symptoms, and relapse. Such research may lead to new interventions for refractory smoking dependence.

Adult↗

PubMed2006

Treatment with dehydroepiandrosterone (DHEA) stimulates oxidative energy metabolism in the liver mitochondria from developing rats.

Effects of treatment with DHEA (0.2 mg or 1.0 mg / kg body weight for 7 days) on oxidative energy metabolism on liver mitochondria from developing and young adult rats were examined. Treatment with DHEA resulted in a progressive dose-dependent increase in the liver weights of the developing animals without change in the body weight. In the young adult rats treatment with 1.0 mg DHEA showed increase only in the body weight. Treatment with DHEA stimulated state 3 and state 4 respiration rates in developing as well as young adult rats in dose-dependent manner with all the substrates used; magnitude of stimulation was age-dependent. In young adults the extent of simulation of state 3 respiration rates declined at higher dose (1.0 mg) of DHEA with glutamate and succinate as substrates. Stimulation of state 3 respiration rates was accompanied by increase in contents of cytochrome aa3, b and c + c1 and stimulation of ATPase and dehydrogenases activities in dose- and age-dependent manner.

Adenosine Triphosphatases↗

PubMed2002

Transformations of DHEA and its metabolites by rat liver.

Because dehydroepiandrosterone (DHEA) has a wide variety of weak beneficial effects in experimental animals and humans, we searched for metabolites of this steroid in the hope of finding more active compounds that might qualify for the title "steroid hormone." Incubation of DHEA with rat liver homogenate fortified with energy-yielding substrates resulted in rapid hydroxylation at the 7alpha-position of the molecule and subsequent conversion to other 7-oxygenated steroids in the sequence DHEA --> 7alpha-hydroxyDHEA --> 7-oxoDHEA --> 7beta-hydroxyDHEA, with branching to diols, triols, and sulfate esters. The ability of these metabolites to induce the formation of liver thermogenic enzyme activity increased from left to right in that sequence. A total of 25 different steroids were characterized, and at least six additional structures that are currently under study were produced from DHEA. 7-OxoDHEA is more effective than DHEA in enhancing memory performance in old mice and in reversing the amnesic effects of scopolamine.

Animals↗

PubMedDate not supplied

Effect of DHEA on macronutrient selection by Zucker rats.

Zucker rats are a frequently used model in obesity research. Dehydroepiandrosterone (DHEA) reduces their rate of weight gain and caloric consumption. So far, most studies have been conducted while the animals consume laboratory rodent chow, which is low in fat. In the experiments of this communication, Zucker rats were offered fat as a food choice. The goal was to determine how the consumption of fat would affect their weight gain and what effect DHEA would have on macronutrient selection. It was found that Zucker rats both male and female, lean and obese selected nearly 40% of their calories as fat when allowed to choose from nearly pure carbohydrate, protein, and fat foodstuffs. Consuming these three macronutrient diets they ate more calories and gained more weight than chow-fed controls over short periods of time. DHEA administered as an intraperitoneal injection decreased caloric intake of Zuckers. This decrement was quantitatively most important on fat intake. DHEA also prevented weight gain. It is concluded that the availability of fat food affects weight gain in Zucker rats and that DHEA modifies the selection of food such that Zucker rats eat less fat.

Animals↗

PubMed1995

Dehydroepiandrosterone (DHEA) treatment reverses the impaired immune response of old mice to influenza vaccination and protects from influenza infection.

Dehydroepiandrosterone (DHEA) is a native steroid with an immunomodulating activity. Recently it was suggested that its age-associated decline is related with immunosenescence. To examine whether DHEA administration could effectively reverse the age-associated decline of immunity against influenza vaccine, aged mice were simultaneously vaccinated and treated with DHEA. Reversal of the age-associated decline and a significant constant increase of humoral response was observed in treated mice. Increased resistance to post-vaccination intranasal challenge with live influenza virus was observed in DHEA-treated aged mice. Thus, DHEA treatment overcame the age-related defect in the immunity of old mice against influenza.

Adjuvants, Immunologic↗

PubMed2006

L-Carnitine L-tartrate (LCLT) and dehydroepiandrosterone sulfate (DHEAS) affect red and white blood cells in aged Sprague-Dawley rats.

Supplementation with either L-carnitine or DHEAS was separately suggested to counteract age-related declines. However, little is known about any interactive effects of these substances, independently promoting mitochondrial energy metabolism, in older individuals. We thus studied the effects of 3 months of daily oral combined supplementation with LCLT and DHEAS on red (RBCs) and white blood cells (WBCs) in male Sprague-Dawley rats by determining RBC and WBC counts, lymphocyte proliferation and interleukin-2 (IL-2) synthesis in spleen lymphocytes after Concanavalin A (ConA) stimulation. Supplementation with LCLT in addition to DHEAS decreased RBCs and increased platelets in the blood of 25-month-old Sprague-Dawley rats, whereas supplementation with DHEAS alone shifted the balance from segmented neutrophile granulocytes to large lymphocytes in differential WBC counts. Based on these results, interactive effects of supplementation with L-carnitine and DHEAS on RBCs and platelets are suggested.

Administration, Oral↗

PubMed2006

Effect of dehydroepiandrosterone (DHEA) treatment on oxidative energy metabolism in rat liver and brain mitochondria. A dose-response study.

OBJECTIVES: Effects of treatment with dehydroepiandrosterone (DHEA) on oxidative energy metabolism in rat liver and brain mitochondria were examined. DESIGN AND METHODS: Young adult rats were administered DHEA (0.1, 0.2, 1.0 or 2.0 mg/kg body weight) by subcutaneous route for 7 consecutive days. RESULTS: DHEA treatment resulted in general, in stimulation of state 3 respiration rates without having any uncoupling effect on ADP/O ratios. The stimulation of state 3 respiration rate for a given substrate was dose dependent in a tissue-specific manner. Parallel increases in the contents of cytochromes aa(3) and b were also noted. DHEA treatment stimulated the glutamate dehydrogenase (GDH) and succinate DCIP reductase (SDR) activities. Under the treatment conditions, mitochondrial ATPase activity was also stimulated. CONCLUSIONS: Treatment with DHEA significantly stimulated oxidative energy metabolism in liver and brain mitochondria.

Adenosine Triphosphatases↗

PubMed2007

Depressed DHEA and increased sickness response behaviors in lame dairy cows with inflammatory foot lesions.

Lameness is a multifactorial condition influenced by the environment, genetics, management and nutrition. Detection of lameness is subjective and currently limited to visual locomotion observations which lack reliability and sensitivity. The objective of this study was to search for potential biomarkers of inflammatory foot lesions that underlie most cases of lameness in dairy cows, with a focus on the sickness response and relevant endocrine, immune and behavioral changes. Serum and peripheral blood mononuclear cells (PBMC) were collected from eight sound and eight lame high-producing Holstein cows. Immune cell activation was investigated in PBMCs using a candidate gene approach in which the expression of pro-opiomelanocortin, interleukin-1beta, l-selectin, matrix metalloproteinase-9 and glucocorticoid receptor-alpha was measured via quantitative real time-RT-PCR. Endocrine changes were investigated by monitoring serum concentrations of cortisol and dehydroepiandrosterone (DHEA). Additionally, systematic behavioral observations were carried out to characterize a behavioral profile associated with a sickness response typical of this condition. Lame cows showed significantly lower eating (P=0.01) and ruminating (P=0.01) behaviors and higher incidence of self-grooming (P=0.04) compared to sound cows. Lame cows also showed a 23% decrease in serum DHEA (P=0.01) and 65% higher cortisol:DHEA ratio (P=0.06) compared to sound cows. However, no significant differences were found in candidate gene expression between lame and sound cows. In association with sickness behaviors, serum DHEA concentration and cortisol:DHEA ratio are promising objective indicators of inflammatory foot lesions in dairy cattle and may be useful as diagnostic targets for animals in need of treatment.

Animals↗

PubMed2006

Basal cortisol and DHEA levels in women with borderline personality disorder.

Previous research suggests that in borderline personality disorder (BPD) normal stress regulation, with a main role for cortisol, is disturbed. However, most studies were confounded by their lack of attention to co-morbidity. Relevant patient characteristics such as depression, childhood abuse, posttraumatic stress disorder (PTSD) and copying styles were not systematically examined. Moreover, none of the studies incorporated dehydroepiandrosterone (DHEA), a hormone that can antagonize the effects of cortisol. Hence, the present pilot study investigates the basic levels of cortisol and DHEA and the ratio (CDR) between the two hormones in BPD patients. Twenty-two women with BPD and 22 healthy female controls provided two diurnal (8 a.m./8 p.m.) salivary samples. Overall cortisol levels were not significantly increased in the patient group as a whole but only in those patients diagnosed with co-morbid PTSD and a history of childhood abuse. The patients' cortisol secretions decreased relatively less steep during the day than it did in the controls. Surprisingly, morning DHEA levels were significantly higher in the patients than in the controls. Moreover, the CDR showed a significantly larger and less favourable increase in the BPD group during the day. In the patients lower levels of DHEA in the evening proved significantly related to a stronger tendency to avoid active problem solving and a lowered inclination to seek social support. The current findings underline the relevance of cortisol and DHEA assessments and the need for further scrutiny of their interplay to foster our understanding of the biological basis of stress regulation in BPD.

Adaptation, Psychological↗

PubMed2004

DHEAS improves learning and memory in aged SAMP8 mice but not in diabetic mice.

Dehydroepiandrosterone sulfate (DHEAS) has been reported to improve memory in aged animals and suggested as a treatment for age-related dementias. The SAMP8 mouse, a model of Alzheimer's disease, has an age-related impairment in learning and memory and an increase in brain levels of amyloid precursor protein (APP) and amyloid beta protein (Abeta). Male SAMP8 mice also have a decrease in testosterone, to which DHEA is a precursor. Diabetes has been suggested as a model of aging and to be linked to Alzheimer's disease. Diabetics can have memory deficits and lower DHEAS levels. Here, we examined the effects of chronic oral DHEAS on acquisition and retention for T-maze footshock avoidance in 12 mo male SAMP8 mice and in CD-1 mice with streptozocin-induced diabetes. Learning and memory were improved in aged SAMP8 mice, but not in CD-1 mice with streptozocin-induced diabetes. These findings suggest that DHEAS is more effective in reversing the cognitive impairments associated with overexpression of Abeta than with diabetes.

Alzheimer Disease↗

PubMed2004

The phosphatidylinositol/AKT/atypical PKC pathway is involved in the improved insulin sensitivity by DHEA in muscle and liver of rats in vivo.

DHEA improves insulin sensitivity and has anti-obesity effect in animal models and men. However, the molecular mechanisms by which DHEA improves insulin action have not been clearly understood. In the present study, we examined the protein levels and phosphorylation state of insulin receptor (IR), IRS-1 and IRS-2, the association between IRSs and PI3K and SHP2, the insulin-induced IRSs associated PI 3-kinase activities, and the phosphorylation status of AKT and atypical PKCzeta/lambda in the liver and the muscle of 6 month-old Wistar rats treated with DHEA. There was no change in IR, IRS-1 and IRS-2 protein levels in both tissues of treated rats analysed by immunoblotting. On the other hand, insulin-induced IRS-1 tyrosine phosphorylation was increased in both tissues while IRS-2 tyrosyl phosphorylation was increased in liver of DHEA treated group. The PI3-kinase/AKT pathway was increased in the liver and the PI3K/atypical PKCzeta/lambda pathway was increased in the muscle of DHEA treated rats. These data indicate that these regulations of early steps of insulin action may play a role in the intracellular mechanism for the improved insulin sensitivity observed in this animal model.

Animals↗

PubMed1998

Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain.

Dehydroepiandrosterone sulfate (DHEAS) is the major circulating steroid in man. Pharmacologically, it exerts marked neuropsychiatric effects. Since no target receptor has been identified, we investigated whether the organic anion transporting polypeptide (OATP), a multispecific steroid carrier, transports DHEAS. Expression of the human liver OATP in Xenopus laevis oocytes resulted in high-affinity, partially Na+-dependent uptake of [3H]DHEAS (Km: 6.6 micromol/l). DHEAS transport was inhibited by bromosulfophthalein, bile acids, sulfated estrogens and dexamethasone. Northern blot analysis showed widespread expression of OATP in human brain. These data identify OATP as the first known target protein of DHEAS in human liver and brain.

Animals↗

PubMed1983

Influence of dehydroepiandrosterone (DHEA) on cholesterol metabolism in rats.

Wistar rats were fed semipurified diets containing 0.5% of dehydroepiandrosterone (DHEA) for 14 days. DHEA feeding resulted in weight loss and slight liver enlargement. It did not affect serum triglyceride levels but increased serum cholesterol levels. Liver triglyceride levels of DHEA-fed rats were significantly lower than in controls. DHEA inhibited cholesterol absorption. Liver slices from DHEA-fed rats incorporated more acetate into cholesterol than controls; there were no differences in conversion of mevalonate.

Animals↗

PubMed1997

The effect of dehydroepiandrosterone (DHEA) on Zucker rat food selection and hypothalamic neurotransmitters.

The effect of dehydroepiandrosterone (DHEA) administered as an acute intraperitoneal (IP) injection on food selection and levels of hypothalamic neurotransmitters of obese Zucker rats was investigated. Animals consumed a 'macronutrient selection' diet which consisted of three separate foodstuffs; they were nearly pure selections of fat, protein or carbohydrate. On the day before DHEA treatment, food bowls were removed at 1700 h and the animals fasted. The next morning some were treated with IP DHEA (100-200 mg/kg) while the controls received vehicle. Two hours later, their food intakes over 4 h were quantitated or, in other experiments, the animals were decapitated and hypothalamic neurotransmitter levels determined. Results showed that the administration of DHEA clearly diminished the amount of fat the animals consumed while their intakes of carbohydrate and protein were unchanged. Levels of neurotransmitters in the paraventricular nuclear region were altered. It is concluded that DHEA diminishes the fat food consumption of obese Zucker rats by altering the levels of neurotransmitters in select regions of the hypothalamus.

Animals↗

PubMed1997

Serum cortisol and DHEA concentrations during HIV infection.

The progression of HIV infection is accompanied by severe immunodepression and cachexia, particularly during advanced stages. The immune depression is due largely to a dramatic drop in the number of CD4 cells. The loss of body weight is mainly due to a reduced fat-free mass with no change in adipose tissue. We determined the serum concentrations of cortisol and DHEA and their correlations with absolute CD4 cell counts and changes in body weight of HIV-positive men. The results of five retrospective and prospective studies indicate that the serum concentrations of cortisol and DHEA in HIV-infected patients were different from those of HIV-negative controls. Serum cortisol was elevated at all stages of infection (+20 to +50%, p < .05 to p < .001) particularly in AIDS patients (stage IV C). In contrast, the serum DHEA concentrations were closely correlated with the stage of HIV-infection, being higher in the early stages (stages II and III or > 500 CD4) than in advanced stages (IV C or < 500 CD4)-in the latter being below those of HIV-negative men-or in controls (+40 to 100%, p < .01 to p < .001). There was a negative linear correlation between the CD4 cell counts and cortisol (r = -0.4, p < .02) and a positive linear correlation with DHEA (r = +0.36, p < .01). There was no significant correlation between delta body weight and serum cortisol. In contrast, there was a negative correlation between serum DHEA and delta body weight (%) (r = -0.69, p < .0001) and a positive correlation with the cortisol/DHEA ratio (r = +0.61, p < .0001). There is thus a link between the circulating concentrations of adrenal steroids and the progression of immunosuppression and cachexia during HIV-infection. This raises the question of whether there is a cause-and-effect relationship between clinical progression and circulating steroid concentrations. Further investigations into the relationship between the ratio cortisol/DHEA and the immune response and cachexia should indicate the contributions of these steroids to the etiology of HIV infection and lead to the development of new therapeutic strategies.

Adult↗