DHEA) And Its Sulfate Ester Research Articles

Astrocyte Neuroprotection and Dehydroepiandrosterone.

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the most abundant steroid hormones in the systemic circulation of humans. Due to their abundance and reduced production during aging, these hormones have been suggested to play a role in many aspects of health and have been used as drugs for a multiple range of therapeutic actions, including hormonal replacement and the improvement of aging-related diseases. In addition, several studies have shown that DHEA and DHEAS are neuroprotective under different experimental conditions, including models of ischemia, traumatic brain injury, spinal cord injury, glutamate excitotoxicity, and neurodegenerative diseases. Since astrocytes are responsible for the maintenance of neural tissue homeostasis and the control of neuronal energy supply, changes in astrocytic function have been associated with neuronal damage and the progression of different pathologies. Therefore, the aim of this chapter is to discuss the neuroprotective effects of DHEA against different types of brain and spinal cord injuries and how the modulation of astrocytic function by DHEA could represent an interesting therapeutic approach for the treatment of these conditions.

DHEAS Levels in Obese Patients with Hashimato Thyroiditis

Introduction Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the most abundant steroid hormones in the human bloodstream. DHEAS is produced primarily in the adrenal gland, where it reflects adrenal androgen production (Labrie et al., 2005). Although it has been proposed that reduced DHEA levels contribute to increased insulin resistance, it has been shown that insulin increases DHEA clearance, suggesting that low DHEA levels may in fact be a consequence of insulin resistance (Tchernof and Labrie, 2004).

Increased serum dehydroepiandrosterone sulfate in the first episode but not in subsequent episodes in male patients with schizophrenia

BackgroundMany studies have investigated the relationship between blood levels of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S), cortisol, progesterone, and testosterone and the onset, prognosis, symptom severity, and treatment response of schizophrenia. In the present study, we assessed potential differences in blood levels of neurosteroids between drug-naïve first-episode patients with schizophrenia (FES), and drug-free patients with schizophrenia who were not in the first episode but were in a phase of acute exacerbation (DFP).Materials and methodsThe present study included 32 male FES, 28 male DFP, and 24 male healthy controls (HC). Groups were compared in terms of blood levels of adrenocorticotropic hormone (ACTH), cortisol, testosterone, progesterone, and DHEA-S.ResultsBlood levels of ACTH, cortisol, testosterone, and progesterone were similar among the groups. The mean value of serum DHEA-S was significantly different among the groups (P<0.001). The value of serum DHEA-S was higher in the FES group than in the DFP and HC groups (both P<0.001). The mean values of serum DHEA-S in the HC and DFP groups were found to be similar (P=0.33).ConclusionWe suggest that higher values of DHEA-S in the FES group compared with both the DFP and HC groups indicate that this neurosteroid response is unique to first-episode schizophrenia patients. Further studies are needed to investigate the difference in blood levels of neurosteroids in different groups in terms of age of diagnosis.

DHEA administration changes antioxidant enzymes in Wistar rat hearts

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the major circulating steroid hormones of adrenal cortex. Epidemiological studies show an inverse correlation between DHEA/DHEAS plasma concentration and mortality, with increased risks of cardiovascular disease. It is interesting to search how DHEA might act in myocardial oxidative stress, once this steroid has been largely used as a hormone of replacement therapy as well as a dietary supplement. DHEA was administrated to 3 month‐male Wistar rats (n=5 per group) in distinct doses: 1, 10 and 50 mg/kg i.p. After 6 or 24 hours, rats were killed and heart homogenates were pepared to quantify lipid peroxidation (LPO), activities and concentration of superoxide dismutase (SOD), catalase (CAT) and glutathione‐S‐transferase (GST), concentration of p‐ Akt/Akt ratio and 4‐hydroxy‐2‐nonenal (HNE). Data were evaluated by one‐way ANOVA followed by the SNK test. After 6 hours, LPO increased in groups 1 and 10 mg/kg when compared to control (69% and 98%, respectively). SOD activity was higher in all treated groups (35%, 43% and 50%, respectively). After 24 hours, SOD activity was lower (42%) in group 10 mg/kg when compared to control. Groups 10 and 50 mg/kg showed increased GST activity (55% and 43%, respectively). Akt was 48% higher after 50mg/kg dose as compared to control. Besides that acute DHEA administration induced increase in oxidative damage and reduced antioxidant defenses, after 24 h those effects were not seen and a cellular survival pathway was activated. Supported by FAPERGS and CNPq.

State and trait related predictors of serum cortisol to DHEA(S) molar ratios and hormone concentrations in schizophrenia patients

Objective: In previous studies we have demonstrated high serum molar ratios of cortisol to dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) [together abbreviated DHEA(S)], and the value of both cortisol/DHEA(S) molar ratios for prediction of responsivity to antipsychotic treatment in schizophrenia patients. The present study aimed to examine the contribution of anxiety, and severity of symptoms to the prediction of serum cortisol, DHEA(S) levels and two molar ratios across three examinations. Method: Serum concentrations of cortisol and DHEA(S)were examined in 43 schizophrenia inpatients and in 20 age matched healthy controls at baseline, and after 2 and 4 weeks. The Positive and Negative Symptom Scale and the State-Trait Anxiety Inventory scores were used as independent variables for multiple regression analysis. Results: Despite clinical improvement during the study period cortisol/DHEA(S) molar ratios were found persistently elevated as compared to healthy controls. Multiple regression analysis reveled that across three examinations cortisol/DHEA(S) molar ratios negatively associated with trait-anxiety (partial R 2 = 7–14%) rather than with negative symptoms (partial R 2 = 3–6%). Age and age of onset account for 12.7% for variability of cortisol/DHEAS ratio. Serum cortisol concentrations are predicted by trait and state-anxiety, activation symptoms and daily doses of antipsychotics. A small portion of variability in serum DHEA levels ( R 2 = 9%) is associated with symptom severity, while DHEAS levels were predicted by age at examination and age of onset. Conclusion: Elevated serum cortisol/DHEA(S) molar ratios were attributed to trait-anxiety and age rather than to clinical symptoms. The findings may indicate persistent dysfunction of the hypothalamic–pituitary–adrenal axis that is independent of the patients' clinical state.

Involvement of GABA A receptor modulating neuroactive steroids in patients with social phobia

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S), neurosteroids synthesized in the brain, are weak gamma-aminobutyric acid (GABA) A receptor allosteric antagonists that may be involved in anxiety disorders. In the present study we measured the levels of DHEA, DHEA-S, pregnenolone and cortisol in platelets of untreated patients ( n = 26) diagnosed with social phobia (SP) compared with sex- and age-matched healthy controls ( n = 21). No significant differences in neurosteroids were observed in the platelets of untreated SP patients compared with healthy controls. The findings may reflect an absence of involvement of the GABA A modulators DHEA, DHEA-S and pregnenolone in SP.

Effects of early-life stress on behavior and neurosteroid levels in the rat hypothalamus and entorhinal cortex

Recent evidence support the hypothesis that exposure to stress or trauma during early childhood may disturb the formation of functional brain pathways, in particular, of the limbic circuits. We examined the effects of exposure to early life trauma (juvenile stress) on emotional and cognitive aspects of behavior in adulthood as well as on dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) levels in relevant brain regions. Quantitative assessment of the effects of exposure to juvenile stress was made 1 month post-stress, and obtained by measuring: emotional (utilizing an open field and a startle response tests) and cognitive (Morris water-maze task) functions, as well as neurosteroids concentration (DHEA and its sulfate ester, DHEAS) in the hypothalamus and entorhinal cortex. We report here that an exposure to juvenile stress led to elevated levels of anxiety 1 month post-stress. Moreover, in a spatial learning task, the juvenile stress group performed poorer than the control group. Finally, an exposure to juvenile stress increased DHEAS but not DHEA concentrations both in the hypothalamus and the entorhinal cortex. These findings indicate that an exposure to juvenile stress has long-lasting effects on behavior and DHEAS levels in the hypothalamus and the entorhinal cortex. These effects may be of relevance to our understanding of early life stress-related disorders such as PTSD and major depression.

The –2 basepair initiation start site ACTH receptor polymorphism influences ACTH induced adrenal androgen secretion

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the most abundant steroids in human circulation. Adrenocorticotropic hormone (ACTH) is the primary secretagogue stimulating adrenal androgens (AA) secretion. Yet, genetic and environmental factors are assumed to play a determinant role in the regulation of their biosynthesis and, thus, might explain the high variability of AA levels. We recently reported a polymorphism within the transcription initiation site of the ACTH receptor promoter gene altering the consensus sequence from CTC to CCC at –2bp which results in lower promoter activity in vitro and is associated with impaired cortisol response to ACTH stimulation in vivo. Here we show that this polymorphism also affects ACTH dependent AA secretion. We studied 14 normal volunteers: 6 CCC/CCC carriers and 8 CTC/CTC carriers of the ACTH receptor polymorphism. Baseline DHEA concentrations did not differ between groups. However, in a 6 hour ACTH stimulation test with increasing ACTH1–24 doses (120 to 3860 ng/mbody surface area/h), CCC/CCC carriers showed a significantly lower DHEA response compared to CTC/CTC carriers (area under the curve: 3201±358 vs. 5586±842µg/ml*min, P<0.04). Thus, we might have identified one of the genetic factors responsible for highly intersubject differences of DHEA concentrations.

The involvement of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) in blocking the therapeutic effect of electroconvulsive shocks in an animal model of depression

Depressed patients with resistance to electroconvulsive treatment (ECT) had high basal serum levels of dehydroepiandrosterone (DHEA) sulfate (DHEAS). To clarify the role of DHEA/S in the ECT resistance, Flinder Sensitive Line (FSL) rats, which are a genetic animal model of depression, were injected i.p. with 2 mg/kg DHEA daily for 13 days to overload their serum and brain DHEA/S levels. Thereafter, rats were exposed to electroconvulsive shock (ECS), which is analogue to ECT in humans. Both ECS and DHEA displayed an antidepressive-like effect, as assessed by immobility time in forced swim test. However, combined DHEA and ECS treatment abolished these antidepressive-like effects. In addition, the levels of neurosteroids, corticosterone and adrenocorticotropin in selected brain regions were evaluated and compared to serum levels. The present study supports our assumption that high basal levels of DHEA/S play a role in the resistance to ECS and maybe ECT in humans.

Dehydroepiandrosterone regulates insulin-like growth factor-1 system in adult rat hypothalamus.

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S) exert multiple effects in rodent and human brain. Several findings suggest that insulin-like growth factor-1 (IGF-1) is involved in the actions of DHEA. In this study, we assessed whether systemic administration of DHEA regulates the IGF-1 system in the hypothalamus, hippocampus, cerebral cortex, and cerebellum of adult rats. DHEA resulted in a significant reduction in IGF-1 receptor protein levels. This effect was dose dependent and restricted to the hypothalamus. In contrast to IGF-1 receptor, IGF-1-binding protein 2 levels were unaffected by DHEA treatment. IGF-1 levels were significantly increased in the hypothalamus of the rats treated with DHEA, whereas IGF-1 serum levels were not affected by DHEA. The effects of DHEA on the hypothalamic IGF-1 system may be highly relevant to the control and maintenance of hypothalamic neuroendocrine function.

Dehydroepiandrosterone (DHEA), DHEA Sulfate, and Aging: Contribution of the DHEAge Study to a Sociobiomedical Issue

Studies showing that blood levels of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) drop markedly with advancing age led to the concept of an “adrenopause” that might conceivably impair health. One implication is that administering DHEA may confer benefit, as does administration of estrogen to postmenopausal women. Wide interest in this possibility promoted a randomized, double-blind, placebo-controlled, year-long trial of orally administered DHEA in 280 men and women aged 60 to 79 years, the DHEAge Study. Participants were seen for various reasons at a geriatric clinic but had no severe or evolving disease. Subjects took 50 mg of DHEA daily or a placebo for 1 year and were followed up at 3-month intervals. Young adult DHEAS levels were present in men after 6 months of receiving DHEA. After 1 year of treatment the levels fell significantly compared with 6-month values in men less than 70 years of age but not in older men. Estradiol levels increased significantly during the treatment year. Women had higher DHEAS levels after 6 months of treatment, exceeding young adult values, but nearly all of them had a secondary reduction after 1 year of treatment, and this was highly significant in those younger than 70 years. There were no changes in levels of gonadotropins, thyrotropin, or triiodothyronine. Testosterone levels increased to a limited extent. Bone turnover, as measured by dual-energy x-ray absorptiometry, improved in women older than 70 years. Older women also had significantly increased libido, and skin hydration improved at the same time. In addition, pigmentation of the facial skin decreased significantly, sebum production increased, and epidermal thickness was greater than in placebo recipients. Treatment for 1 year with 50 mg daily of DHEA seems to normalize some of the effects of aging without obvious harmful consequences. It does not, however, in any sense create “supermen” or “superwomen.” Those who take DHEA at this dose level, or even in smaller amounts, require appropriate follow-up at reasonable intervals. Proc Natl Acad Sci U S A 2000;97:4279–4284

Low Dehydroepiandrosterone Sulfate and Heart Disease in Middle-Aged Men: Cross-Sectional Results from the Massachusetts Male Aging Study

PURPOSE: Serum concentrations of the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS), both of which decline with age more markedly than other sex hormone levels, have been alternately credited and discredited as “protective” correlates of heart disease. Baseline data from the Massachusetts Male Aging Study (MMAS), collected in 1987–89, provided a large population-based random sample (n = 1709) in which to examine cross-sectionally the relation of DHEA and DHEAS levels to heart disease, while controlling for a comprehensive set of potential confounders including serum lipid and hormone levels as well as smoking, alcohol intake, obesity, hypertension, diabetes, diet, medication, physical activity, and psychological measures.METHODS: The subjects were men aged 40–70 years, randomly sampled from the Massachusetts state census listing, measured and interviewed at home. Nonfasting blood samples were assayed for hormones and lipids.RESULTS: In all strata of age, smoking, and alcohol intake, the age-adjusted odds ratio for self-reported heart disease was between 0.55 and 0.85 per standard deviation (SD) of log DHEA and DHEAS concentration. Multiple logistic regression analysis indicated a strong independent role for DHEAS as a predictor of self-reported heart disease, controlling for age and the potential confounders listed above. The multiply-adjusted odds ratio for heart disease was 0.64 per SD log DHEAS concentration, with 95% confidence interval (CI) 0.50–0.83 (P = 0.0002). The DHEAS effect was not diminished by controlling for use of cardiac, vasodilator, antihypertensive, or lipid-lowering medication.CONCLUSIONS: These findings suggest that serum DHEAS levels bear an inverse relationship to heart disease, independently of a large set of established cardiovascular risk factors. The cross-sectional nature of this study requires that the findings be interpreted with caution.

Effects of dehydroepiandrosterone on proliferation of human aortic smooth muscle cells.

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) have been shown to be associated with the progression of coronary atherosclerosis in clinical and in vivo studies. However, the mechanisms responsible for the association have not been determined. In the present study, we found that DHEA influences the in vitro growth of vascular smooth muscle cells obtained from the human aorta (hASMC). The concentrations of DHEA ranging from 10(-8) M to 10(-6) M significantly stimulated the mitogenesis of hASMC in serum-free culture. On the other hand, 4 hrs of pretreatment with DHEA attenuated the fetal calf serum induced proliferative effect in a dose-dependent manner. However, the in vitro effects of DHEA on the mitogenesis observed in hASMC were not seen in rat-derived aortic smooth muscle cell lines (A10 cells). With respect to DHEAS, the hormone, at concentrations up to 10(-5) M did not affect the growth of either hASMC or A10 cells in vitro. The growth response of hASMC to DHEA in vitro was markedly affected by the culture conditions. The differential proliferative effects of DHEA on smooth muscle cells between rat and human are of interest. We conclude that the effects of DHEA on mitogenesis of hASMC may, at least in part, explain the association between DHEA and atherosclerosis.

Effect of ACTH and prolactin on dehydroepiandrosterone, its sulfate ester and cortisol production by normal and tumorous human adrenocortical cells

The effect of ACTH and prolactin on the synthesis of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) was studied in cell suspensions of “normal” and tumorous (adenoma) human adrenal cortex. A stimulation of DHEA and no response of DHEAS production by ACTH in “normal” adrenocortical cell suspension was observed. However ACTH stimulated both DHEA and DHEAS synthesis in tumorous adrenocortical cells. Prolactin did not influence either the basal or the ACTH stimulated DHEA and DHEAS production of adrenocortical cells irrespective of their origin. Our results are compatible with the concept that the biosynthesis of DHEA is under ACTH control, while other factor(s) regulate(s) the sulfate pathway of DHEA secretion under normal conditions. In tumorous adrenocortical cells DHEA may be regulated—at least partly-by ACTH. Prolactin seems to have no direct effect on DHEA and DHEAS synthesis. It is postulated that the relationship between serum prolactin and DHEAS (or DHEA) levels observed by several authors might be an extraadrenal effect of prolactin on adrenal androgens.