Action Of Dehydroepiandrosterone Sulfate Research Articles

Involvement of serum dehydroepiandrosterone sulfate in erythropoietic activity

Purpose The aim of the present study was to determine how age-related decreases in serum dehydroepiandrosterone sulfate (DHEAS) levels affect various physiological processes. Methods We retrospectively reviewed the medical records of patients in whom serum DHEAS levels were measured in our department and assessed the relationships between serum DHEAS levels and various patient characteristics. Results Among the 149 patients included in our analysis (mean age: 52.7 ± 17.6 years, range: 15–84 years), 54 (36.2%) were men. Serum DHEAS levels inversely correlated with age in men (R = −0.810, p < .01) and to a lesser extent in women (R = −0.391, p < .01). Of note, there were significant positive associations between DHEAS levels and hemoglobin (R = 0.317, p ≤ .01) and hematocrit (R = 0.324, p ≤ .01) levels, which were observed in men, but not in women. Conclusions Our study suggests that reduced DHEAS secretion inhibits erythropoietic activity in aging men, perhaps owing to the erythropoietic androgenic actions of DHEAS. Importantly, it suggests that the age-associated decline in DHEAS secretion might decrease erythropoietic activity in aging men. It is also possible that the adrenal cortex, the source of DHEAS, is dysfunctional in anemic men.

Neuroprotective Effects of Dehydroepiandrosterone Sulfate Through Inhibiting Expression of Matrix Metalloproteinase-9 from Bradykinin-Challenged Astroglia.

Dehydroepiandrosterone sulfate (DHEAS), one of the most important neuroactive steroids, is produced in the adrenals and the brain. DHEAS is believed to play a critical role in modulating different forms of cellular control, including processes associated with human neural systems. Its production rate and level in serum, adrenals, and brain gradually decrease with advancing age. The decline of DHEAS level was associated with age-related neuronal dysfunction and degeneration, most probably because the steroids protect the central nervous system (CNS) neurons against neurotoxic challenges. Moreover, increasing studies show that matrix metalloproteinases (MMPs), MMP-9 especially, are upregulated by proinflammatory mediators in the CNS disorders. The increased MMP-9 as an inflammatory biomarker of several CNS disorders that may participate in the CNS inflammation and neurodegeneration. Herein, we investigate the effects of DHEAS on brain inflammation by the model we have defined of bradykinin (BK)-induced MMP-9 expression in rat brain astrocyte (RBA) and its mechanism. The results showed that DHEAS significantly reduce MMP-9 induced by BK. Pretreatment with DHEAS can inhibit BK-stimulated phosphorylation of c-Src and PYK2. Moreover, DHEAS attenuated BK-stimulated NADPH oxidase (Nox)-derived reactive oxygen species (ROS) production, suggesting that DHEAS has an antioxidative effect. We further demonstrated that DHEAS blocked activation of ERK1/2, Akt, and c-Fos/AP-1 by BK. Finally, DHEAS decreased MMP-9-related events including RBA migration and neuronal apoptosis. The results will provide new insights into the anti-inflammatory action of DHEAS, supporting that DHEAS may have a neuroprotective effect in the improvement of the CNS disorders by reducing neuroinflammation.

The neurosteroid dehydroepiandrosterone sulfate, but not androsterone, enhances the antidepressant effect of cocaine examined in the forced swim test — Possible role of serotonergic neurotransmission

One of the mechanisms of cocaine's actions in the central nervous system is its antidepressant action. This effect might be responsible for increased usage of the drug by individuals with mood disorders. Higher endogenous levels of the excitatory neurosteroid dehydroepiandrosterone sulfate (DHEAS) were reported to correlate with successful abstinence from cocaine use in addicts, but a clinical trial showed that supplementation with a high dose of DHEA increased cocaine usage instead. Such ambiguous effects of DHEA(S) could potentially be linked to its influence on the antidepressant effect of cocaine. In this study we tested DHEAS and its metabolite, androsterone, for interactions with cocaine in animal model of depression (forced swim test) and examined the effects of both steroids and cocaine on serotoninergic neurotransmission. All substances were also tested for influence on locomotor activity. A cocaine dose of 5mg/kg, which had no significant effect on locomotor activity, was chosen for the forced swim test. Neither DHEAS nor androsterone showed any antidepressant action in this test, while cocaine manifested a clear antidepressant effect. Androsterone slightly reduced the antidepressant influence of cocaine while DHEAS markedly, dose-dependently enhanced it. Such an effect might be caused by the influence of DHEAS on serotonin neurotransmission, as this steroid decreased serotonin concentration and turnover in the striatum. When DHEAS and cocaine were administered together, the levels of serotonin in the striatum and hippocampus remained unchanged. This phenomenon may explain the additive antidepressant action of DHEAS and cocaine and why co-administration of DHEAS and cocaine increases drug use.

Effects of Dehydroepiandrosterone Sulfate on Anxiety and Depressive Behavior: Involvement of μ-Opioid Receptors

The effects of dehydroepiandrosterone sulfate (DEAS) on anxiety and depressive behavior were studied in animals subjected to chronic stress. Injections of DEAS (30 mg/kg) to male CBA/Lac mice decreased anxiety in submissive animals (with high levels of stress-induced anxiety formed as a result of defeats in intermale agonistic confrontations for 20 days) in the partition and plus maze tests, this being seen in control animals only in the plus maze test. In repeatedly stressed animals (shaking on a shuttle apparatus for 1 h/day for 18 days) and control Wistar rats, DEAS (30 mg/kg) decreased signs of depressive behavior in the Porsolt test. Administration of the antagonist naltrexone at doses of 0.25 mg/kg to mice and 0.1 mg/kg to rats, which are selective for μ receptors, reversed the anxiolytic and antidepressant actions of DEAS, providing evidence that μ opioid receptors play a role in these effects.

Dehydroepiandrosterone-Sulfate Modifies Human Fatty Acid Composition of Different Adipose Tissue Depots

Dehydroepiandrosterone-sulfate (DHEA-S) has been described as a protector agent against obesity-related pathologies, although the mechanism of action is still unknown. We have shown that DHEA-S acts on adipose tissue (AT), altering the fatty acid (FA) profile in rodents. Thus, we could hypothesize that some of the beneficial effects shown by DHEA-S in humans are related to a modification of the human AT-FA profile. The present study examines this question and whether this effect is tissue-dependent. Paired visceral and subcutaneous AT biopsies were obtained from 20 patients who had undergone bariatric surgery. These samples were subjected to primary adipose culture and incubated for 24 h with 1 μM DHEA-S. The FA profile of both control and treated samples were analyzed by gas chromatography. A reduction in total saturated fatty acids (SFA), the n-6 family of polyunsaturated fatty acids (PUFA) and the n-6/n-3 PUFA ratio was observed after DHEA-S treatment, whereas monounsaturated fatty acids (MUFA) increased. In addition, DHEA-S altered the percentage of several individual FA, decreasing palmitic acid and increasing vaccenic acid in both AT. All estimated desaturase activity ratios slightly increased after DHEA-S treatment, although only the increase of delta-6-desaturase index in both depots reached statistical significance. No depot-specific action of DHEA-S was found between subcutaneous and visceral AT. In vitro, DHEA-S modifies the AT-FA composition towards a better metabolic profile to a similar extent in the subcutaneous and visceral adipose depots, in both of which a decrease in SFA and increased MUFA are observed after treatment. This effect could help to explain the beneficial effects attributed to DHEA-S. Further studies, however, are required to determine whether the effect of DHEA-S on adipose tissue in vitro is conserved in vivo.

Effects of Dehydroepiandrosterone Sulfate on the Conversion of Corticosterone into 11-Dehydrocorticosterone in Stress: A Regulatory Scheme

In male rats, repeated but not single exposures to stress increased the conversion of corticosterone (CS) to 11-dehydrocorticosterone (11-DHCS), particularly on the background of administration of dehydroepiandrosterone sulfate (DHEAS). Naltrexone given 20 min before DHEAS at a dose of 0.1 mg/kg, at which it selectively blocks mu opioid receptors, prevented this effect of DHEAS, which is evidence that it is mediated by mu opioid receptors. This action of DHEAS involved endogenous ACTH and was thus mediated by central regulatory mechanisms. Our results, along with published data, lead to the first proposed scheme for the physiological regulation of the interconversion of CS and 11-DHCS in conditions of repeated stress with the involvement of DHEAS and mu opioid receptors.

Age-dependent regulation of chromaffin cell proliferation by growth factors, dehydroepiandrosterone (DHEA), and DHEA sulfate

The adrenal gland comprises two endocrine tissues of distinct origin, the catecholamine-producing medulla and the steroid-producing cortex. The inner adrenocortical zone, which is in direct contact with the adrenomedullary chromaffin cells, produces dehydroepiandrostendione (DHEA) and DHEA sulfate (DHEAS). These two androgens exhibit potential effects on neurogenesis, neuronal survival, and neuronal stem cell proliferation. Unlike the closely related sympathetic neurons, chromaffin cells are able to proliferate throughout life. The aim of this study was to investigate the effect of DHEA and DHEAS on proliferation of bovine chromaffin cells from young and adult animals. We demonstrated that graded concentrations of leukemia inhibitory factor induced proliferation of chromaffin cells from young animals, whereas EGF had no effect. On the contrary, EGF increased the cell proliferation in cells from adult animals, whereas leukemia inhibitory factor was inactive. In both cases, DHEA decreased the proliferative effect induced by the growth factors. Surprisingly, DHEAS enhanced, in a dose-dependent-manner, the effect of growth factors on proliferation in cells from adult animals but not from young animals. Flutamide, ICI 182,780, and RU 486 had no effect on the action of DHEA or DHEAS on chromaffin cell proliferation. These data show that DHEA and its sulfated form, DHEAS, differentially regulate growth-factor-induced proliferation of bovine chromaffin cells. In addition, the sensitivity of chromaffin cells to different growth factors is age-dependent. Furthermore, these two androgens may act through a receptor other than the classical steroid receptors.

Chronic administration of dehydroepiandrosterone sulfate (DHEAS) primes for facilitated induction of long-term potentiation via sigma 1 (σ 1) receptor: Optical imaging study in rat hippocampal slices

Dehydroepiandrosterone sulfate (DHEAS), one of the most abundant neurosteroids synthesized de novo in the nervous system, has well characterized effects on memory and cognitive performances. However, little is known about the underlying synaptic mechanisms. In this study, we investigated the effects of chronic administration of DHEAS (20 mg/kg for 7 days) on the plasticity of Schaffer collateral-CA1 synapses by applying an optical recording technique on the hippocampal slices stained with voltage-sensitive dyes. We report here that chronically administered DHEAS significantly facilitated the induction of frequency-dependent LTP, termed DHEAS-facilitated LTP. While tetanus of at least 50 pulses (at 100 Hz) were required to induce LTP in control rats, only 20 pulses were needed in DHEAS-treated animals. In contrast DHEA, the non-sulfated form of DHEAS, had no facilitating effect on the induction of LTP. We found that chronically administered DHEAS did not alter the presynaptic glutamate release in response to both single pulse and tetanic stimulation, suggesting that certain alterations happened in postsynaptic neurons. Co-administration of the sigma 1 (σ 1) receptor antagonists, haloperidol or NE100, with DHEAS completely inhibited the DHEAS-facilitated LTP. However, acute administration of σ 1 receptor antagonists to the slices did not affect the induction of DHEAS-facilitated LTP, suggesting that σ 1 receptor is a key target of chronic actions of DHEAS but is not involved in the induction of DHEAS-facilitated LTP. Our findings provide evidence that chronically administered DHEAS plays a priming role in inducing a facilitated synaptic plasticity probably via a chronic activation of σ 1 receptor in rat hippocampal CA1 pyramidal cells.

Mechanism of action of anti-aging DHEA-S and the replacement of DHEA-S

The plasma ACTH and cortisol levels do not change during aging. On the other hand, the plasma dehydroepiandrosterone sulfate (DHEA-S) changes remarkably during aging. Before puberty, the plasma DHEA-S level both in males and females is very low, however, it rapidly increases at puberty, and thereafter significantly decreases both linearly and age-dependently. Cytochrome P450c17 has two enzyme activities, 17-α-hydroxylase and 17,20-lyase. Cortisol is synthesized by 17-α-hydroxylase, and DHEA is synthesized by 17,20-lyase. The mechanism of dissociation of cortisol and DHEA synthesis in aging depends on another regulator of 17,20-lyase of cytochrome P450c17 such as cytochrome P450 reductase. We demonstrated significant decrease in cytochrome P450 reductase activity in bovine aged adrenal glands. We clarified the beneficial effects of DHEA as an anti-aging steroid based on both in vitro and in vivo experiments, such as the stimulatory effect of immune system, anti-diabetes mellitus, anti-atherosclerosis, anti-dementia (neurosteroid), anti-obesity and anti-osteoporosis. It is very important to identify the mechanism of action of DHEA. We clarified the conversion of DHEA to estrone by cytochrome P450 aromatase in primary cultured human osteoblasts. We indentified high affinity of DHEA binding with K d=6.6 nM in antigen and DHEA stimulated human T lymphocytes. We searched for the target genes that are specifically induced in activated T lymphocytes in the presence of DHEA by subtractive hybridization screening for differentially expressed transcripts. The double blind, randomized human replacement therapies utilizing DHEA are also reviewed.

Association of dehydroepiandrosterone sulfate and testosterone deficiency with bone turnover in men with inflammatory bowel disease.

We investigated the coexistence of dehydroepiandrosterone sulfate (DHEAS) and testosterone deficiency in men with inflammatory bowel disease (IBD) and their relationship with bone homeostasis. In 45 men with IBD (25 with ulcerative colitis, 20 with Crohn's disease) the testosterone and DHEAS levels were examined in relationship to bone mineral density, osteocalcin levels, and urinary deoxypyridinoline excretions. We detected osteoporosis in 10 and osteopenia in 22 patients at the lumbar spine and/or femoral neck. Lower testosterone levels were measured in 20. Lower DHEAS levels were present in 23 patients; these had higher deoxypyridinoline excretion and lower lumbar spine and femoral neck BMD T scores than patients with normal DHEAS. DHEAS and BMD were correlated at the lumbar spine and the femoral neck. Associations remained significant after adjustment for age, weight, steroid use, and inflammatory activity. No independent effect of testosterone deficiency was detected on bone parameters. DHEAS deficiency may contribute to the bone loss of men with IBD. This putative action of DHEAS on bone turnover is contrary to the common effect of testosterone deficiency and steroid therapy.

Specific binding and effects of dehydroepiandrosterone sulfate (DHEA-S) on skeletal muscle cells: Possible implication for DHEA-S replacement therapy in patients with myotonic dystrophy

Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are the most abundant steroidal products and major circulating steroids in humans. The serum concentrations of DHEA-S are lower in patients with myotonic dystrophy (DM) than normal controls, and possible improvement of myotonia and muscle weakness was recently reported following DHEA-S replacement therapy. However, the molecular mechanism of action of DHEA-S remains unknown. To understand the reported anti-DM action of DHEA-S, we investigated DHEA-S binding in skeletal muscle cells in vitro. We identified two populations of DHEA-S binding sites (Kd = 5–9 μM and 35–40 μM) in C2C12 myocytes. Similar binding sites were also identified in human skeletal muscles. The Kd value of the high-affinity site was within the range of serum concentrations of DHEA-S in adult humans. Our results suggest that DHEA-S might act directly on skeletal muscles under normal physiological conditions in humans.

Relationships of Dehydroepiandrosterone Sulfate in the Elderly With Functional, Psychological, and Mental Status, and Short-Term Mortality

Berr, Claudine; Lafont, Sylviane; Debuire, Brigitte; Dartigues, Jean-Francois; Baulieu, Etienne-Emile Author Information

DHEAS inhibits TNF production in monocytes, astrocytes and microglial cells.

We previously reported that neurosteroids, including dehydroepiandrosterone sulfate (DHEAS), inhibit the production of TNF in vitro and in vivo. In this paper we evaluated the effect of DHEAS on TNF production by cultured rat astrocytes and murine glial cell clones, and compared it with the effect on monocytic THP-1 cells. We found that DHEAS at a concentration of 10(-4)-10(-7) M inhibits TNF production induced by lipopolysaccharide (LPS, 1 microgram/ml) in these cells. Since the inhibitory effect of DHEAS is not mediated by the glucocorticoid (GC) receptor and DHEAS is an allosteric antagonist of the GABAA receptor, we investigated the possible role of GABAA receptors in this effect. The results showed that the inhibitory effect of DHEAS (10(-6) M) on TNF production by THP-1 cells was completely reversed by addition of 10(-6) M GABA. However, a GABAA receptor antagonist (bicuculline) did not mimic the action of DHEAS. In conclusion, DHEAS can inhibit TNF production in astrocytic and microglial cells suggesting it could be an endogenous regulator of TNF production in the brain.

Induction of peroxisomal β-oxidation by structural analogues of dehydroepiandrosterone in cultured rat hepatocytes: Structure-activity relationships

The structural requirements of dehydroepiandrosterone (DHEA) for the induction of peroxisomal β-oxidation were studied in cultured rat hepatocytes. The hepatocytes were incubated for 5 days with various steroids, including 3- and 17-substituted analogues and 5-hydrogenated analogues of DHEA, and the activities of peroxisomal β-oxidation and carnitine acetyltransferase were measured. Among the steroids examined, DHEA, DHEA sulfate (DHEAS), dehydroandrosterone sulfate, androstenediol 3-sulfate, epiandrosterone sulfate and androsterone sulfate significantly induced the enzymes; 4.6- to 14.2-fold for β-oxidation and 5.1- to 10.9-fold for carnitine acetyltransferase at 50 μM. All of the sulfated steroids were more effective than the corresponding unsulfated forms. DHEAS was the most potent inducer. The 3-sulfuric group was required for the marked induction of peroxisomal β-oxidation, and the 17-carbonyl group was also important. Furthermore, the relatively planar conformation of the steroidal hydrophobic backbone was crucial for inducing the enzyme. The configuration of the 3-sulfuric group (β-configuration) and the presence of a double bond at position C5 were not primary determinants for the action of DHEAS. On the other hand, the introduction of bulky substituents to position C17 or aromatization of ring A led to a loss of inducing activity. Thus, there are strict structural requirements for the DHEA induction of peroxisomal β-oxidation, suggesting the presence of a certain specific recognition site in the cell for DHEAS, which mediates the peroxisome proliferator action of DHEA.

Receptor binding and electrophysiological effects of Dehydroepiandrosterone sulfate, an antagonist of the GABA A receptor

Recently we demonstrated that [ 3H]dehydroepiandrosterone sulfate binds specifically to two populations of sites in rat brain membranes [Majewska et al. (1990) Eur. J. Pharmac. 189, 307–315]. As an extension of this work, we studied the biochemical and pharmacological properties of [ 3H]dehydroepiandrosterone sulfate binding to brain membranes and the effects of dehydroepiandrosterone sulfate on GABA-induced currents in cultured neurons. [ 3H]Dehydroepiandrosterone sulfate binding depended upon incubation time, pH, protein concentration, and incubation temperature. Thermal denaturation or pretreatment of the membranes with protease or phospholipase A 2 reduced the binding by 54–85%. The higher affinity [ 3H]dehydroepiandrosterone sulfate binding sites appeared to be associated with protein and with the GABA A receptor complex. Among substances known to interact with the GABA A receptor complex, pregnenolone sulfate, pentobarbital, and phenobarbital inhibited the binding of [ 3H]dehydroepiandrosterone sulfate. High micromolar concentrations of dehydroepiandrosterone sulfate inhibited [ 3H]muscimol and [ 3H]flunitrazepam binding to rat brain membranes, primarily by reducing the binding affinities. Dehydroepiandrosterone sulfate also produced a concentration-dependent block of GABA-induced currents in cultured neurons from ventral mesencephalon ( IC 50 = 13 ± 3μM). The results of this study are consistent with an action of dehydroepiandrosterone sulfate as a negative noncompetitive modulator of the GABA A receptor. Because concentrations of dehydroepiandrosterone sulfate in the brain undergo physiological variations, this neurosteroid may play a vital role in regulation of neuronal excitability in the central nervous system.