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PubMed1996

Dehydroepiandrosterone (DHEA) increases production and release of Alzheimer's amyloid precursor protein.

Dehydroepiandrosterone (DHEA), the major secretory product of the human adrenal cortex, significantly declines with advanced age. We have previously demonstrated that DHEA prevents the reduction in non-amyloidogenic APP processing, following prolonged stimulation of the muscarinic receptor, in PC12 cells that express the ml acetylcholine-receptor. The present study examined whether this effect may be mediated via modulation of APP metabolism. It was found that DHEA treatment increases the content of membrane-associated APP holoprotein by 24%, and the accumulation of secreted APP in the medium by 63%. No increase in viable cell number nor in nonspecific protein production was observed in DHEA-treated cells. Thus, DHEA seems to increase specifically both APP synthesis and secretion. We propose that the age-associated decline in DHEA levels may be related to the pathological APP metabolism observed in Alzheimer's disease.

Alzheimer Disease↗

PubMed1985

Dehydroepiandrosterone (DHEA) measurements in cord blood.

Antibodies to dehydroepiandrosterone (DHEA) can be generated by coupling DHEA to carrier proteins. This report describes the use of antibodies to three different DHEA-protein complexes for the measurement of DHEA in serum and cord plasma. Each of the three antibodies produces an assay with equivalent results in serum from adults and older children. However, with cord plasma samples, two of the antibodies detected much more cross-reacting material than was detected with the third antibody. In order to determine the basis for this discrepancy, a pool of cord plasma was extracted in a manner similar to that used in the assay procedure. The steroids in the extract were separated by chromatography on a Sephadex LH-20 column and individual fractions were assayed for DHEA with each of the antibodies. There were several peaks of cross-reacting material present in cord blood that were not present in comparable amounts in serum from adults. These results indicate that assays for DHEA need to be separately validated with samples from adults and from infants.

Adult↗

PubMed2005

Effect of DHEA on endocrine functions of adipose tissue, the involvement of PPAR gamma.

Dehydroepiandrosterone (DHEA), an adrenal steroid, is known to decrease body fat. Thus, it may also alter the endocrine functions of adipose tissue. The aim of this study was to determine if administration of DHEA might influence adiponectin gene expression and secretion from adipose tissue. We demonstrate here the inducing effect of exogenously administered DHEA on adiponectin gene expression in epididymal WAT and adiponectin levels in serum of rats fed a DHEA-containing diet (0.6%, w/w) for 2 weeks, accompanied by a reduction in epididymal adipose tissue mass. A corresponding increase in peroxisome proliferator-activated receptor gamma (PPAR(gamma)) mRNA expression suggests that PPAR(gamma) may be involved in the up-regulation of adiponectin gene expression after DHEA treatment. The presented observations indicate that the positive effects of DHEA, which seems to play a protective role against insulin resistance and atherosclerosis, may be in fact indirect and due to up-regulation of adiponectin gene expression and stimulation of adiponectin secretion from adipose tissue.

Adiponectin↗

PubMed2005

Dehydroepiandrosterone (DHEA) attenuates cocaine-seeking behavior in the self-administration model in rats.

The aim of this study was to determine the possible involvement of the neurosteroid dehydroepiandrosterone (DHEA) in cocaine-seeking behavior in a self-administration model in rats. DHEA pretreatment (continued thereafter concomitantly with cocaine self-administration) attenuated cocaine-seeking behavior and elevated the levels of dopamine and serotonin in several brain regions relevant to cocaine addiction. Chronic cocaine self-administration induced elevation in brain DHEA, its sulfate ester, DHEAS, and pregnenolone. The increased brain DHEA following cocaine self-administration may serve as a compensatory protective mechanism geared to attenuate the craving for cocaine. Such anti-craving activity is further enhanced by DHEA treatment before and during cocaine self-administration.

Affect↗

PubMed2004

Dehydroepiandrosterone sulfate (DHEAS) and health: does the relationship differ by sex?

This study uses data from a large, nationally representative sample of older Taiwanese (aged 54 and older in 2000) to investigate sex differences in the relationship between DHEAS and various health outcomes. Data collection included an individual interview, a physical examination, and samples of blood and (12-h) urine. Regression models of health outcomes on DHEAS are estimated in two steps: first, including only controls for age and sex as well as an interaction between DHEAS and sex; and second, adding covariates likely to be related to both DHEAS and health outcomes (e.g. smoking). Results reveal that higher levels of DHEAS are associated with fewer mobility limitations (especially for women), better cognitive function (among women but not men), and better self-rated health (significant only for men but of similar magnitude for women). These findings are in contrast to previous studies conducted in the US and Europe that generally find stronger associations for men than women. Also unlike previous studies, which often demonstrate a negative relationship between DHEAS and depressive symptoms at least for women, we find little evidence of such a relationship for either sex.

Aged↗

PubMed2005

Improvement of extrapyramidal symptoms following dehydroepiandrosterone (DHEA) administration in antipsychotic treated schizophrenia patients: a randomized, double-blind placebo controlled trial.

Recent investigation in schizophrenia indicated dehydroepiandrosterone (DHEA) levels to be inversely correlated with extrapyramidal symptomatology (EPS). This study thus investigates the effect of DHEA administration on medication-induced EPS. Inpatients with schizophrenia or schizoaffective disorder were randomized in double-blind fashion to receive either 100 mg DHEA or placebo in addition to a constant dosage of antipsychotic medication. Parkinsonism showed a favorable effect of DHEA with a significant time effect (p < 0.0001), as well as a significant group by time interaction (p < 0.05) and with no change noted on akathisia. Change of DHEA blood levels was negatively associated with change of Parkinsonism (p < 0.05) as well as with change of total EPS ratings (p < 0.05). DHEA appears to demonstrate a significant effect on EPS, with improvement observed particularly in Parkinsonian symptoms.

Adult↗

PubMed2007

Plasma cortisol-dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder.

Hypercortisolaemia is a feature of many severe psychiatric illnesses and has been suggested to be both a causal and exacerbating factor of clinical symptoms and neurocognitive impairment. The adrenal steroid dehydroepiandrosterone (DHEA) has antiglucocorticoid properties that may have regulatory effects on glucocorticoid action in the brain. However, there is a paucity of data on these steroids and their ratio in schizophrenia and bipolar disorder. We therefore sought to assess cortisol and DHEA levels and the cortisol-DHEA ratio in patients with schizophrenia (n=20) and bipolar disorder (n=20), on stable medication for a minimum of 6 weeks, and healthy age- and sex-matched control subjects (n=20). Steroid levels were measured from plasma samples collected at 30 min intervals from 1:00 p.m. to 4:00 p.m. Cortisol levels were found to be significantly elevated in both patient groups compared with controls. DHEA levels were elevated in schizophrenic patients compared with bipolar patients and controls, but there was no evidence of a difference in the cortisol-DHEA ratio of the groups. These data suggest that afternoon hypercortisolaemia is evident in symptomatic bipolar and schizophrenic patients compared to controls. However, an elevation in DHEA levels may represent a specific endocrine marker in schizophrenia.

Adult↗

PubMed1999

Dehydroepiandrosterone (DHEA) facilitates liver regeneration after partial hepatectomy in rats.

In this study we investigated whether or not liver regeneration is facilitated by dehydroepiandrosterone (DHEA) after partial (70%) hepatectomy in rats. Treatment with DHEA (300 mg/kg body weight) did not cause any significant increase in the expression ratio of proliferating cell nuclear antigen (PCNA) in sham-operated controls; however, in partially hepatectomized rats it caused a significant increase in the ratio in hepatocytes 24 and 36 hr after hepatectomy. In partially hepatectomized rats, DHEA treatment significantly accelerated the restoration of liver 48, 60, and 72 hr after partial hepatectomy. The restoration rate in DHEA-treated hepatectomized rats at 72 hr was 1.3-fold greater than in partially hepatectomized controls. Treatment with androstenedione (300 mg/kg body weight), the first metabolite of DHEA, did not cause any significant increase in the expression of PCNA in either sham-operated controls or partially hepatectomized rats. These results indicate that DHEA itself promotes the liver regenerative process after partial hepatectomy in rats.

Androstenedione↗

PubMedDate not supplied

DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging.

Human and some other primates are unique since their adrenals secrete large amounts of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), which are converted into androstenedione (4-dione) and then into potent androgens and estrogens in peripheral tissues, therefore providing autonomous intracrine control to target tissues that can adjust the formation and metabolism of active sex steroids according to local requirements. Knowledge in this area has recently made rapid progress with the elucidation of the structure of most of the tissue-specific cDNAs and genes that encode the steroidogenic enzymes responsible for the transformation of these inactive precursor steroids into androgens and/or estrogens. It is estimated that 30 to 50% of total androgens in men are synthesized in peripheral intracrine tissues from inactive adrenal precursors while, in women, peripheral estrogen formation is even more important, the best estimate being 75% before menopause and 100% after menopause. The marked reduction in the formation of DHEA-S by the adrenals during aging, especially before the age of 50 years, results in a dramatic fall in the formation of active sex steroids in peripheral target tissues, a situation which is thought to be associated with a long series of age-related decreases such as insulin resistance, obesity, osteoporosis, cardiovascular diseases, loss of muscle mass, cancer and other diseases. We have demonstrated for the first time a series of medically important beneficial effects of DHEA administered for 12 months to post-menopausal women. Most interestingly, the bone mineral density significantly increased. This relatively rapid change was associated with an increase in plasma osteocalcin, a marker of bone formation, while a decrease in bone resorption reflected by a decrease in urinary hydroxyproline excretion was observed in parallel. In addition, the estrogenic stimulation of vaginal cytology in the absence of any sign of stimulatory effect on the endometrium is also of potentially major interest for the prevention and management of menopause. Furthermore, the inhibitory effect of DHEA on the growth of human breast cancer xenografts in vivo in nude mice supports the beneficial use of DHEA as hormone replacement therapy in women.

Aging↗

PubMed2002

Uses of DHEA in aging and other disease states.

Dehydro-3-epiandrosterone is a steroid hormone synthesized in large quantities by the adrenal gland whose physiologic role remains unclear. The effects of DHEA could be estrogenic or androgenic, depending on the hormonal milieu. Low levels of DHEA are associated with aging, cardiovascular disease in men, and an increased risk of pre-menopausal breast and ovarian cancer. High levels of DHEA might increase the risk of postmenopausal breast cancer. Therapeutically DHEA might be useful for improving psychological well-being in the elderly, reducing disease activity in people with mild to moderate systemic lupus erythematosus and myotonic dystrophy, improving mood in those clinically depressed, and improving various parameters in women with adrenal insufficiency. Although many other claims have been made for DHEA in diverse conditions, such as aging, dementia, and AIDS, no well-designed clinical trials have clearly substantiated the utility and safety of long-term DHEA supplementation.

Aging↗

PubMed1997

IL-6, DHEA and the ageing process.

The age-related increase in circulating IL-6 levels in humans which has been attributed to a decline in DHEA production by the adrenal gland is currently attracting attention because of its possible relevance to the aetiology and management of a number of age-related clinical disorders. The potential importance of these observations and suggestions has prompted us to perform more detailed studies on the relationship between IL-6 and DHEA. Using immunoassay techniques we have found in normal healthy individuals over the age of 40 an inverse relationship between plasma DHEA levels and the presence of detectable levels of IL-6 (more than 1 pg/ml). In vitro, studies also revealed that low dose (10(-6)-10(-8) M) of DHEA and DHEAS inhibited the production of IL-6 in unstimulated human spleen cell suspension cultures whilst enhancing its release by explant cultures of the same tissue. In contrast they had no effect on immunoglobulin production. These studies suggest that there is a real, but complex relationship between IL-6 production and DHEA levels which warrants further investigation.

Adult↗

PubMed1997

Use of DHEA in a patient with advanced prostate cancer: a case report and review.

Dehydroepiandrosterone (DHEA) is being evaluated in the basic science laboratories as a potential treatment for adenocarcinomas, with some initial promise for success. However DHEA can be metabolically converted to androgenic compounds, possessing unwanted side effects. A patient with advanced prostate cancer with progressive symptomatology was treated with DHEA after other treatment regimens failed. Many of his symptoms improved on DHEA therapy, but his cancer also flared dramatically during treatment. His previous hormonally unresponsive cancer subsequently responded transiently to third-line hormonal therapy with diethylstilbestrol (DES). Adrenal precursor molecules such as DHEA may have significant therapeutic benefits in a number of diseases of the elderly, however their utility may be limited by potential androgenic side effects including endocrine epithelial cell growth. The development of analogue compounds with less conversion to androgenic metabolites should be considered, as molecules such as DHEA are more widely tested and utilized clinically.

Aged↗

PubMed1999

Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage.

It has been postulated that decreases in plasma levels of dehydroepiandrosterone (DHEA) may contribute to the development of some age-related disorders. Along with neuroprotective and memory enhancing effects, DHEA has been shown to display antioxidant properties. Moreover, oxidative stress is known to cause lipid peroxidation and degenerative changes in the hippocampus, an area involved in memory processes and especially afflicted in Alzheimer's disease (AD). Accordingly, we investigated the antioxidant effects of DHEA in models of oxidative stress using rat primary hippocampal cells and human hippocampal tissue from AD patients and age-matched controls. A pre-treatment of rat primary mixed hippocampal cell cultures with DHEA (10-100 microM) protected against the toxicity induced by H2O2 and sodium nitroprusside. Moreover, DHEA (10-100 microM) was also able to prevent H2O2/FeSO4-stimulated lipid oxidation in both control and AD hippocampal tissues. Taken together, these data suggest that DHEA may be useful in treating age-related central nervous system diseases based on its protective effects in the hippocampus.

Adjuvants, Immunologic↗

PubMedDate not supplied

Perturbations of plasma cortisol and DHEA-S following discontinuation of cocaine use in cocaine addicts.

Changes in plasma levels of cortisol and dehydroepiandrosterone sulfate (DHEA-S) following cocaine discontinuation were assessed in hospitalized chronic cocaine users. Measurements were performed after 6, 9, 18 and 21 days of abstinence. Repeated measures ANOVAs revealed significant time effects for cortisol (P<0.02) and DHEA-S (P<0.001). Changes in the two hormones did not follow the same course. Levels of cortisol were highest on day 6 and then subsequently decreased, whereas DHEA-S levels were low on day 6 and highest on day 18. Repeated measures ANCOVAs were used to test the overall effects of total duration of cocaine use, daily or weekly cocaine amounts consumed, or frequency of use on cortisol secretion. Analyses revealed a significant effect of frequency of use only (P<0.04). More sustained cocaine use was associated with higher cortisol levels and less pronounced cortisol decline after discontinuation of cocaine use, but drug intake variables had no influence on DHEA-S. The effects of presence or absence of life-long histories of aggression were also assessed. Repeated measures ANOVAs revealed a near significant group x time interaction for cortisol, which declined more dramatically in aggressive addicts than in non-aggressive addicts after day 6. DHEA-S was consistently higher in aggressive cocaine addicts, although this effect did not reach statistical significance. There was a noticeable difference in the dynamics of normalization of adrenal hormones between the two groups, with DHEA-S/cortisol ratios rising more dramatically during cocaine abstinence in aggressive than in non-aggressive addicts. In conclusion, lingering neuroendocrine perturbations persist after discontinuation of cocaine use in addicts. Some of these changes could be associated with an increased relapse risk.

Adult↗

PubMed1998

Dehydroepiandrosterone (DHEA) ameliorates the insulin sensitivity in older rats.

To evaluate whether dehydroepiandrosterone (DHEA) ameliorates the decreased insulin sensitivity in older rats, hyperinsulinemic euglycemic clamp studies were performed in rats of various age groups previously treated with DHEA. The glucose metabolic clearance rate (MCR) of the control rats showed a gradual decline with the advancing ages (MCR = 13.05 - 0.027*age (days), r2=0.683, p < 0.01, n = 18). The glucose MCR of the DHEA-treated rats also showed a gradual decline with the aging process (MCR = 12.67 - 0.011*age (days), r2=0.429, p < 0.01, n = 18). However, the MCR of the DHEA-treated rats were significantly higher than that of control rats. As glucose MCR is a parameter which indicates the insulin sensitivity in various tissues, especially in muscles and body composition, was not changed after the injection of DHEA, DHEA is considered to work on muscles to increase insulin sensitivity.

Aging↗

PubMed1997

Reciprocal size-effect relationship of the key residues in determining regio- and stereospecificities of DHEA hydroxylase activity in P450 2a5.

Collectively, the P450 2a4/2a5 system hyrdoxylates DHEA in at least three positions (7alpha, 7beta, and 2alpha). An individual P450, however, exhibits high specificity to one of these products. Using site-directed mutagenesis of mP450 2a5 from the wild mouse Mus minutoides and bacterial expression, we have associated the function of residues 117, 209, and 481 with the respective specificity observed in each P450. Ala at position 117 determines the 7beta-hydroxylase activity, whereas Val at this position defines the 2alpha-hydroxylase activity. Leu at position 209 is essential for high DHEA 7alpha-hydroxylase activity. The substitutions of residue 481 with various hydrophobic amino acids elicited a profound alteration of the specific hydroxylation rates, but did not influence the regio- and stereospecificities at either of the three positions of DHEA. The alterations caused by residue 481 also depended on the residue identity at position 117 or 209. The results indicate that the sizes of several key residues obey a concerted reciprocal relationship whereby the substrate pocket of the P450s adjusts to accommodate DHEA. A limited molecular modeling study successfully correlates DHEA binding to experimental DHEA hydroxylase activities for a series of mutants at key positions.

Amino Acid Sequence↗

PubMed2001

Exercise training-induced triglyceride lowering negatively correlates with DHEA levels in men with type 2 diabetes.

OBJECTIVE: To investigate the effect of an exercise training program on lipid profile in correlation with DHEA level and body weight and body composition in type 2 diabetic men. DESIGN: Longitudinal, controlled clinical intervention study with exercise training consisting of an 8 week supervised program of aerobic exercise (75% VO(2) peak, 45 min), twice a week and intermittent exercise, once a week, on a bicycle ergometer. SUBJECTS: Sixteen men (age 45.4+/-7.2 y (mean+/-s.d.), HbA1c 8.15+/-1.7%, body mass index (BMI) 29.6+/-4.6 kg/m(2)) were randomly divided into two groups: trained group (n=8) and control group (n=8). MEASUREMENTS: Lipid, apo- and lipoprotein and DHEA concentrations. Cross-sectional areas of subcutaneous and visceral adipose tissue and mid-thigh muscle by magnetic resonance imaging. RESULTS: Training decreased visceral (153.25+/-38.55 vs 84.20+/-21.30 cm(2), P<0.001), subcutaneous (241.55+/-49.55 vs 198.00+/-39.99 cm(2), P<0.001) adipose tissue area and triglyceride levels (2.59+/-1.90 vs 1.79+/-1.08 nmol/l, P<0.05) and increased mid-thigh muscle cross-sectional area (148.30+/-36.10 vs 184.35+/-35.85 cm(2), P<0.001), and DHEA levels (11.00+/-3.10 vs 14.25+/-4.10 nmol/l, P<0.05) with no modification in body weight. Changes in triglycerides were negatively correlated with changes in DHEA (r=-0.81, P=0.03). This correlation was independent of changes in abdominal fat distribution. CONCLUSION: Training decreases abdominal fat depots, improves muscular mass and affects favourably triglyceride and DHEA levels. Changes in triglycerides and DHEA were inversely related.

Adipose Tissue↗

PubMed2004

An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD.

We recently found increased adrenal cortisol responses to adrenocorticotropic hormone (ACTH)1-24 and increased pituitary ACTH and adrenal cortisol responses to corticotropin-releasing factor in premenopausal women with chronic post-traumatic stress disorder (PTSD) compared to healthy nontraumatized subjects. This pattern of hypothalamic-pituitary-adrenal axis (HPA) hyper-reactivity has been previously seen in healthy individuals treated with the antiglucocorticoid mifepristone. We therefore investigated whether endogenous plasma levels of antiglucocorticoids such as dehydroepiandrosteroine (DHEA) and progesterone were increased in premenopausal women with PTSD at baseline or in response to adrenal activation by ACTH1-24. The study revealed that DHEA responses to 250 microg ACTH1-24 were increased in 13 PTSD subjects compared to 13 healthy nontraumatized subjects, while DHEA levels were generally increased in the PTSD subjects compared to seven healthy traumatized subjects. Cortisol responses to ACTH1-24 were also higher in the women with PTSD, while progesterone levels and responses were not different among the three groups. In addition, among the PTSD subjects, the peak change in DHEA in response to ACTH1-24 was negatively correlated with the total Clinician Administered PTSD Scale score, while the peak DHEA to cortisol ratio was inversely associated with negative mood symptoms measured by the Profile of Mood States scale. This work suggests that an increased capacity for DHEA release in response to extreme adrenal activation may influence the pattern of HPA axis adaptation to extreme stress, as well as mitigate the severity of PTSD and negative mood symptoms in premenopausal women with PTSD.

Adrenal Glands↗