Influence of oral dehydroepiandrosterone (DHEA) on urinary steroid metabolites in males and females

Oral dehydroepiandrosterone (DHEA) replacement therapy may have a multitude of potential beneficial effects and exerts its action mainly via peripheral bioconversion to androgens (and estrogens). A daily dose of 50-mg DHEA has been shown by us and others to restore low endogenous serum DHEA concentrations to normal youthful levels followed by an increase in circulating androgens and estrogens. As the hepatic first-pass effect may lead to a non physiological metabolism of DHEA after oral ingestion we studied the influence of two single DHEA doses (50 and 100 mg) on the excretion of steroid metabolites in 14 elderly males [age 58.8+/-5.1 years (mean +/- SEM)] with endogenous DHEAS levels <1500 ng/ml and in 9 healthy females (age 23.3+/-4.1 years) with transient suppression of endogenous DHEA secretion induced by dexamethasone (dex) pretreatment (4x0.5 mg/day/4 days). Urinary steroid profiles in the elderly males were compared to the steroid patterns found in 15 healthy young men (age 28.9+/-5.1 years). In the females the results were compared to their individual baseline excretion without dex pretreatment. Urinary steroid determinations were carried out by semiautomatic capillary gas-liquid chromatography. In both genders DHEA administration induced significant increases in urinary DHEA (females: baseline vs. 50 mg vs. 100 mg: 361+/-131 vs. 510+/-264 vs. 1541+/-587 microg/day; males: placebo vs. 50 mg vs. 100 mg: 434+/-154 vs. 1174+/-309 vs. 4751+/-1059 microg/day) as well as in the major DHEA metabolites androsterone (A) and etiocholanolone (Et). Fifty mg DHEA led to an excretion of DHEA and its metabolites only slightly above baseline levels found in young females and in young men, respectively, whereas 100 mg induced clearly supraphysiological values. After 50 mg DHEA the ratios of urinary DHEA metabolites (A/DHEA, Et/DHEA) were not significantly different between elderly males vs. young male volunteers and young healthy females versus their individual baseline levels. In conclusion, an oral dose of 30 to 50 mg DHEA restores a physiological urinary steroid profile in subjects with DHEA deficiency without evidence for a relevant hepatic first-pass effect on urinary metabolites.     

The effect of dehydroepiandrosterone (DHEA) on renal function and metabolism in diabetic rats

Dehydroepiandrosterone (DHEA) is an endogenous steroid hormone involved in a number of biological actions in humans and rodents, but its effects on renal tissue have not yet been fully understood. The aim of this study is to assess the effect of DHEA treatment on diabetic rats, mainly in relation to renal function and metabolism. Diabetic rats were treated with subcutaneous injections of a 10 mg/kg dose of DHEA diluted in oil. Plasma glucose and creatinine, in addition to urine creatinine, were quantified espectophotometrically. Glucose uptake and oxidation were quantified using radioactive glucose, the urinary Transforming Growth Factor β₁ (TGF-β₁) was assessed by enzyme immunoassay, and the total glutathione in the renal tissue was also measured. The diabetic rats displayed higher levels of glycemia, and DHEA treatment reduced hyperglycemia. Plasmatic creatinine levels were higher in the diabetic rats treated with DHEA, while creatinine clearance was lower. Glucose uptake and oxidation were lower in the renal medulla of the diabetic rats treated with DHEA, and urinary TGF-β₁, as well as total gluthatione levels, were higher in the diabetic rats treated with DHEA. DHEA treatment was not beneficial to renal tissue, since it reduced the glomerular filtration rate and renal medulla metabolism, while increasing the urinary excretion of TGF-β₁ and the compensatory response by the glutathione system, probably due to a mechanism involving a pro-oxidant action or a pro-fibrotic effect of this androgen or its derivatives. In conclusion, this study reports that DHEA treatment may be harmful to renal tissue, but the mechanisms of this action have not yet been fully understood.     

Fecal dehydroepiandrosterone (DHEA) immunoreactivity as a noninvasive index of circulating DHEA activity in young male laboratory rats

Evidence suggests that dehydroepiandrosterone (DHEA) plays a key role in stress and coping responses. Fecal sampling permits assessment of hormone-behavior interactions reliably and effectively, but no previous study has compared circadian- or stress-dependent alterations between serum DHEA and its fecal metabolites. In the current study, young (28 d of age) male rats were assigned to either an experimental (n = 6) or control (n = 6) group. Rats in the experimental group were exposed to a forced swim test to assess their behavioral and physiologic response to an environmental stressor; blood samples were drawn before the test (baseline), immediately after the test, and at 2 later time points. Only fecal samples were collected from control animals. Fecal DHEA and corticosterone metabolites were monitored in all animals for 24 h. DHEA metabolites in control rats exhibited significant diurnal variation, showing a similar temporal pattern as that of corticosterone metabolites. In addition, fecal and serum DHEA levels were highly correlated. Significant peaks in both DHEA and corticosterone metabolite levels were detected. These data suggest that measures of fecal DHEA can provide a complementary, noninvasive method of assessing adrenal gland function in rats.     

Pharmacokinetics of oral dehydroepiandrosterone (DHEA) in the ovariectomised cynomolgus monkey

Humans and primates are unique in having adrenals that secrete large amounts of DHEA and DHEA-S in the circulation. These steroids act as precursors of active androgens and estrogen's in a long series of peripheral target intracrine tissues. The marked decline of serum DHEA and DHEA-S concentrations with age in men and women has been incriminated in the development of various pathologies. This study provides detailed information on the effect of a single 50mg oral dose of DHEA on circulating estrogen's as well as androgens and their metabolites over 10h in adult ovariectomised (OVX) Cynomolgus monkeys. Serum DHEA, DHEA-S, testosterone (Testo) and androstenedione (4-dione) concentrations increased rapidly with a maximal value at approximately 1h after DHEA administration followed by a 60-80% decrease during the next 2-6h. An important sulfatation of DHEA occurs through first hepatic pass, thus, leading to a marked increase in serum DHEA-S. Serum androst-5-ene-3beta,17beta-diol and androsterone glucuronide (ADT-G) levels remained elevated on a plateau for 6h. Androstan-3alpha,17beta-diol-glucuronide, estradiol and estrone levels remained unchanged. The present data indicate the predominant transformation of the adrenal precursor DHEA into active androgens in peripheral tissues and support the importance of measurement of circulating glucuronide derivatives as index of peripheral or intracrine androgen formation and action.     

In vivo activation of the constitutive androstane receptor beta (CARbeta) by treatment with dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEA-S)

We investigated whether dehydroepiandrosterone (DHEA) or DHEA-sulfate (S) affected the activities of nuclear receptors, with special reference to constitutive androstane receptor beta (CARbeta). Administration of DHEA or DHEA-S enhanced the DNA binding of hepatic nuclear extracts to responsive elements for the retinoic acid receptor, the retinoic acid receptor beta 2 and the peroxisome proliferator activated receptor. The bound complexes were shown to be the CARbeta-RXR heterodimer by antibody-supershift assays. The expression of a target gene of CARbeta, Cyp2b10, was increased in liver by DHEA or DHEA-S treatment, suggesting that DHEA or DHEA-S actually activated CARbeta in vivo. It was suggested that the metabolic conversion of DHEA, DHEA-S to CARbeta ligands could occur in vivo and the metabolites could regulate the expression of CARbeta target gene expression. Our results provide new insights into the in vivo relationship between DHEA/DHEA-S and CARbeta activation.     

Dehydroepiandrosterone (DHEA) increases territorial song and the size of an associated brain region in a male songbird

In many species, male territorial aggression is tightly coupled with gonadal secretion of testosterone (T). In contrast, in song sparrows (Melospiza melodia morphna), males are highly aggressive during the breeding (spring) and nonbreeding (autumn and early winter) seasons, but not during molt (late summer). In aggressive nonbreeding song sparrows, plasma T levels are basal (< or = 0.10 ng/ml), and castration has no effect on aggression. However, aromatase inhibitors reduce nonbreeding aggression, indicating a role for estrogen in wintering males. In the nonbreeding season, the substrate for brain aromatase is unclear, because plasma T and androstenedione levels are basal. Aromatizable androgen may be derived from plasma dehydroepiandrosterone (DHEA), an androgen precursor. DHEA circulates at elevated levels in wintering males (approximately 0.8 ng/ml) and might be locally converted to T in the brain. Moreover, plasma DHEA is reduced during molt, as is aggression. Here, we experimentally increased DHEA in wild nonbreeding male song sparrows and examined territorial behaviors (e.g., singing) and discrete neural regions controlling the production of song. A physiological dose of DHEA for 15 days increased singing in response to simulated territorial intrusions. In addition, DHEA treatment increased the volume of a telencephalic brain region (the HVc) controlling song, indicating that DHEA can have large-scale neuroanatomical effects in adult animals. The DHEA treatment also caused a slight increase in plasma T. Exogenous DHEA may have been metabolized to sex steroids within the brain to exert these behavioral and neural effects, and it is also possible that peripheral metabolism contributed to these effects. These are the first results to suggest that exogenous DHEA increases male-male aggression and the size of an entire brain region in adults. The data are consistent with the hypothesis that DHEA regulates territorial behavior, especially in the nonbreeding season, when plasma T is basal.     

3beta-HSD activates DHEA in the songbird brain

Dehydroepiandrosterone (DHEA) is an abundant circulating prohormone in humans, with a variety of reported actions on central and peripheral tissues. Despite its abundance, the functions of DHEA are relatively unknown because common animal models (laboratory rats and mice) have very low DHEA levels in the blood. Over the past decade, we have obtained considerable evidence from avian studies demonstrating that (1) DHEA is an important circulating prohormone in songbirds and (2) the enzyme 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD), responsible for converting DHEA into a more active androgen, is expressed at high levels in the songbird brain. Here, we first review biochemical and molecular studies demonstrating the widespread activity and expression of 3beta-HSD in the adult and developing songbird brain. Studies examining neural 3beta-HSD activity show effects of sex, stress, and season that are region-specific. Second, we review studies showing seasonal and stress-related changes in circulating DHEA in captive and wild songbird species. Third, we describe evidence that DHEA treatment can stimulate song behavior and the growth of neural circuits controlling song behavior. Importantly, brain 3beta-HSD and aromatase can work in concert to locally metabolize DHEA into active androgens and estrogens, which are critical for controlling behavior and robust adult neuroplasticity in songbirds. DHEA is likely secreted by the avian gonads and/or adrenals, as is the case in humans, but DHEA may also be synthesized de novo in the songbird brain from cholesterol or other precursors. Irrespective of its source, DHEA seems to be an important prohormone in songbirds, and 3beta-HSD is a key enzyme in the songbird brain.     

Urine volume dependency of specific dehydroepiandrosterone (DHEA) and cortisol metabolites in healthy children

Urine volume should be considered as a confounder when using urinary free cortisol (UFF) and cortisone (UFE) to assess glucocorticoid (GC) status. We aimed to examine whether adrenal androgen (AA) metabolites may be also affected by urine volume in healthy children. To compare the flow dependence of GC and AA metabolites, specific GC metabolites were examined. In 24-h urine samples of 120 (60 boys) healthy children (4-10 yr), steroid profiles were determined by GC-MS analysis, UFF and UFE by radioimmunoassay. To assess daily AA and GC secretion rates, 7 quantitatively most important AA (∑C19) and GC (∑C21) metabolites were summed. Sum of DHEA and its 16α-hydroxylated metabolites were denoted as DHEA&M. Association of urine volume with AA (∑C19, DHEA&M, DHEA, 16α-hydroxy-DHEA, 3β,16α,17β-androstenetriol) and GC (∑C21, UFF, UFE, 6β-hydroxycortisol, 20α-dihydrocortisol) were examined in linear regression models. Among the examined AA metabolites, 16α-hydroxy-DHEA (β=0.56, p<0.0001) and DHEA (β=0.43, p=0.05) showed relatively strong association with urine volume. A trend was seen for ∑C19 (β=0.23, p=0.08), but not for DHEA&M (p>0.1). Regarding GC metabolites, urine volume showed a stronger association with cortisol's direct metabolites, i.e., cortisone, 6β-hydroxycortisol and 20α-dihydrocortisol (β=0.4-0.6, p<0.01) than with cortisol itself (β=0.28, p<0.05). ∑C21 was not associated with urine volume. In conclusion, like UFF and UFE, renal excretion of DHEA, 16α-hydroxy-DHEA, 6β-hydroxycortisol, and 20α-dihydrocortisol may also depend on urine volume. The intrarenal production of the latter three and cortisone might explain their relative strong water-flow-dependency. Total AA or GC secretion marker appears not to be relevantly confounded by urine volume.     

The effects of dehydroepiandrosterone (DHEA) and its metabolites on the polycystic ovarian condition (PCO): cystogenic changes of rat granulosa cells in vitro

During mammalian folliculogenesis, granulosa cells (GCs) are initially steroidogenically quiescent, later proliferate, and subsequently commence to hormonally differentiate, first producing estrogen and later, in the preovulatory stage, secreting both estrogen and progesterone. In this study and elsewhere, we have used follicle-stimulating hormone with a combination of growth factors in vitro to simulate the above in vivo conditions. In a previous study, we used dehydroepiandrosterone (DHEA) to accomplish the polycystic ovary condition (PCO) in rats. In the latter model, there were high circulating levels of DHEA and its metabolite, androstenedione. In the present study, we investigated the effects of high levels of DHEA (10⁻⁵M) and its metabolites, androstenedione, androstenediol and dehydroepiandrosterone sulfate on the quiescent, proliferative, and steroidogenically differentiating stages of GCs cultured in a serum-free medium for up to 10 days. In addition to possessing the regularly occurring organelles, when cultured with the aforementioned androgens, the GCs acquired endoplasmic reticulum of the smooth variety which is associated with steroidogenesis. The radioimmunoassay data showed that GCs cultured in the quiescent and proliferative stages in the presence of the androgens, no longer remain in these stages but proceed to differentiate in a preovulatory direction by producing both estrogen and progesterone. This study supports our hypothesis that high circulating levels of DHEA and/or its metabolites have most effect during the quiescent and proliferative stages of granulosa cells, with regard to their structure and their steroidogenic activities.     

Changes in serum DHEA and eleven of its metabolites during 12-month percutaneous administration of DHEA

Healthy postmenopausal women aged 60-65 years (n=150) were randomized to receive twice daily application on the skin of 3g of a 0.3% dehydroepiandrosterone (DHEA) or placebo emulsion for 12 months. Serum DHEA and eleven of its metabolites were measured at screening and on day 1, as well as at 1, 3, 6, 9 and 12 months to study long-term metabolism. While serum DHEA and androst-5-ene-3beta, 17beta-diol (5-diol) increased by 203% and 178%, respectively, on average, during the 12-month period, the sum of concentrations of the metabolites of androgens, namely androsterone glucuronide (ADT-G), androstane-3alpha,17beta-diol-3G and -17G increased by only 71% while usually non statistically significant changes of 30%, 17% and 20% were observed for estrone (E(1)), estradiol (E(2)) and E(1) sulfate (E(1)-S), respectively. Despite the return of serum DHEA to normal premenopausal values with the present DHEA treatment regimen, the 65% decrease in the androgen pool found in this group of postmenopausal women is in fact corrected by only 24%, thus remaining 41% below the values found in normal premenopausal women. In fact, the changes in serum DHEA observed after percutaneous DHEA administration are a 186% overestimate of the true changes in androgen formation while the overestimate of estrogen production is even much higher. On the other hand, the pharmacokinetics of the steroids are stable over the 12-month period with no significant induction or decrease of activity of the enzymatic systems transforming DHEA predominantly into androgens.     

Metabolism of DHEA in postmenopausal women following percutaneous administration

The marked decline in serum dehydroepiandrosterone (DHEA) with age is believed to play a role in health problems associated with aging, these health issues being potentially preventable or reversible by the exogenous administration of DHEA. In the present study, liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and gas chromatrography/mass spectrometry (GC/MS) were used to measure the serum levels of DHEA and 11 of its metabolites in seventy-five 60-65-year-old Caucasian women who received 3g of 0.1%, 0.3%, 1.0% or 2.0% DHEA cream or placebo applied twice daily on the face, upper chest, arms and legs. The serum levels of DHEA increased 574% over control at the 2.0% DHEA dose while the sum of the androgen metabolites androsterone glucuronide (ADT-G), 3alpha-androstenediol-3G (3alpha-diol-3G) and 3alpha-diol-17G increased by only 231%. On the other hand, serum testosterone and dihydrosterone were increased by 192% and 275%, respectively, above basal levels compared to 139% and 158% for estrone and estradiol. Such data show that the transformation of exogenous DHEA in postmenopausal women is preferentially into androgens rather than into estrogens. On the other hand, the present data indicate that serum DHEA measurements following DHEA supplementation in postmenopausal women are an overestimate of the formation of active androgens and estrogens and suggest a decreased efficiency of transformation of DHEA into androgens and estrogens with aging.     

Effect of intravaginal DHEA on serum DHEA and eleven of its metabolites in postmenopausal women

The primary objective of this study was measurement of the systemic bioavailability of DHEA and its metabolites following daily intravaginal application of the sex steroid precursor. Forty postmenopausal women were randomized to receive a daily dose of one ovule of the following DHEA concentrations: 0.0%, 0.5%, 1.0% or 1.8%. After only 7 days of treatment, the maturation value of the vaginal epithelial cells was significantly increased while the vaginal pH was significantly decreased at all DHEA doses. These important local effects were observed while the serum concentrations of estradiol and testosterone remained within the values found in normal postmenopausal women at all DHEA doses. Similar observations were made for serum androstenedione, estrone, estrone-sulfate and DHEA-sulfate. Even at the highest 1.8% DHEA dose, serum DHEA was increased at the levels found in normal premenopausal women. The present data show that the intravaginal administration of DHEA permits to rapidly achieve the local beneficial effects against vaginal atrophy without significant changes in serum estrogens, thus avoiding the increased risk of breast cancer associated with the current intravaginal or systemic estrogenic formulations. In addition, the recent observation that DHEA is transformed into both androgens and estrogens in the vagina permits to exert benefits on all the three layers of the vaginal wall.     

Photo-DHEA--a functional photoreactive dehydroepiandrosterone (DHEA) analog

The steroid hormone dehydroepiandrosterone (DHEA) has beneficial effects on vascular function, survival of neurons, and fatty acid metabolism. However, a specific receptor for DHEA has not been identified to date. Here, we describe the synthesis of a photoreactive DHEA derivative (Photo-DHEA). In Photo-DHEA, typical characteristics of DHEA are conserved: (i) a “planar” tetracyclic ring system with a Δ⁵ double bond, (ii) a 3β-hydroxyl group, and (iii) a keto group at C17. In cell-based assays, Photo-DHEA showed the same properties as DHEA. We conclude that Photo-DHEA is suitable for radioiodination to yield a tool for the identification of the elusive DHEA receptor.     

Neuroprotective effects of dehydroepiandrosterone (DHEA) in rat model of Alzheimer's disease

The current study was undertaken to elucidate a possible neuroprotective role of dehydroepiandrosterone (DHEA) against the development of Alzheimer's disease in experimental rat model. Alzheimer's disease was produced in young female ovariectomized rats by intraperitoneal administration of AlCl(3) (4.2 mg/kg body weight) daily for 12 weeks. Half of these animals also received orally DHEA (250 mg/kg body weight, three times weekly) for 18 weeks. Control groups of animals received either DHAE alone, or no DHEA, or were not ovariectomized. After such treatment the animals were analyzed for oxidative stress biomarkers such as hydrogen peroxide, nitric oxide and malondialdehyde, total antioxidant capacity, reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase activities, antiapoptotic marker Bcl-2 and brain derived neurotrophic factor. Also brain cholinergic markers (acetylcholinesterase and acetylcholine) were determined. The results revealed significant increase in oxidative stress parameters associated with significant decrease in the antioxidant enzyme activities in Al-intoxicated ovariectomized rats. Significant depletion in brain Bcl-2 and brain-derived neurotrophic factor levels were also detected. Moreover, significant elevations in brain acetylcholinesterase activity accompanied with significant reduction in acetylcholine level were recorded. Significant amelioration in all investigated parameters was detected as a result of treatment of Al-intoxicated ovariectomized rats with DHEA. These results were confirmed by histological examination of brain sections. These results clearly indicate a neuroprotective effect of DHEA against Alzheimer's disease.     

The effects of dexamethasone and dehydroepiandrosterone (DHEA) on cytokines and receptor expression in a human osteoblastic cell line: potential steroid-sparing role for DHEA

Osteoporosis and associated fractures are the most common and debilitating complication of glucocorticoid use. The use of alternative anti-inflammatory agents without the deleterious skeletal effects of glucocorticoids is needed. Dehydroepiandrosterone (DHEA) may have immunomodulatory as well as positive effects on bone. For our further understanding of the mechanisms of action of DHEA, as a steroid-sparing agent, we investigated and compared the effects of dexamethasone (DEX) and DHEA on the regulation of the downstream effector pathway of osteoclastogenesis; RANKL/OPG and a range of inflammatory/pro-resorbing cytokines and receptors using a human clonal osteoblastic cell line. The cells were treated with DEX, DHEA, and androstenedione (ANDI). The mRNA expression of RANKL and OPG was determined by real-time PCR after overnight incubation. The regulation of a broad spectrum of cytokines by DEX and DHEA was also investigated using a human cytokine/growth factor and receptor gene array consisting of 268 cytokine-related cDNAs. To confirm some of the gene expression changes, protein production was measured by ELISA. RANKL expression and RANKL/OPG ratio were increased by DEX. This effect was reversed by co-treatment with both DHEA or ANDI. Several pro-inflammatory/resorptive cytokines including IL-6, IL-4, IFN-gamma, macrophage inhibitory factor (MIF) were down-regulated not only by DEX but also by DHEA. In contrast to DEX, DHEA did not lead to suppression of growth factors including vascular endothelial growth factor (VEGF), fibroblast growth factor-5 (FGF-5), insulin-like growth factor-binding protein3 (IGF-BP3). Several new target genes previously documented to influence bone formation were up-regulated by DHEA such as Notch 2, insulin receptor, thrombin receptor (PAR1). The data suggest that DHEA has immunomodulatory properties without the catabolic effects on bone remodeling, observed with glucocorticoid use. DHEA may thus prove useful as a steroid-sparing agent in the management of inflammatory disorders such as SLE or rheumatoid arthritis. Further in vivo studies are indicated.     

Dehydroepiandrosterone (DHEA) metabolism in the brain: identification by liquid chromatography/mass spectrometry of the delta-4-isomer of DHEA and related steroids formed from androstenedione by mouse BV2 microglia

Studies to elucidate the role of dehydroepiandrosterone (DHEA) metabolism in neuroprotection have compared its relative 7-hydroxylation against estrogen formation by way of 4-androstenedione (AD) in various rodent brain cell lines. In all cases, the 7alpha- and 7beta-hydroxy epimers of DHEA were found to be the dominant products with one notable exception. BV2 mouse microglia were virtually unable to hydroxylate DHEA at C-7 and converted AD to a major unknown metabolite not observed with mouse BHc hippocampal cells. In this paper, we describe the identification of this compound based on its physical properties and analysis by TLC and HPLC. Its identity as 3beta-hydroxy-4-androstene-17-one, the Delta(4)-isomer of DHEA, was confirmed by mass spectrometry (LC/MS), as well as by reverse isotope dilution analysis involving co-crystallization with the synthetic steroid. Possible mechanisms for the formation of this isomer of DHEA by BV2 microglia are proposed, together with that of other C-19 steroids detected which include testosterone (T), 5alpha-dihydrotestosterone and 5alpha-androstanedione.     

Decoding functional metabolomics with docosahexaenoyl ethanolamide (DHEA) identifies novel bioactive signals

Neuroinflammation and traumatic brain injury involve activation of inflammatory cells and production of local pro-inflammatory mediators that can amplify tissue damage. Using LC-UV-MS-MS-based lipidomics in tandem with functional screening at the single-cell level in microfluidic chambers, we identified a series of novel bioactive oxygenated docosahexaenoyl ethanolamide- (DHEA) derived products that regulated leukocyte motility. These included 10,17-dihydroxydocosahexaenoyl ethanolamide (10,17-diHDHEA) and 15-hydroxy-16(17)-epoxy-docosapentaenoyl ethanolamide (15-HEDPEA), each of which was an agonist of recombinant CB2 receptors with EC(50) 3.9 × 10(-10) and 1.0 × 10(-10) M. In human whole blood, 10,17-diHDHEA and 15-HEDPEA at concentrations as low as 10 pM each prevented formation of platelet-leukocyte aggregates involving either platelet-monocyte or platelet-polymorphonuclear leukocyte. In vivo, 15-HEDPEA was organ-protective in mouse reperfusion second organ injury. Together these results indicate that DHEA oxidative metabolism produces potent novel molecules with anti-inflammatory and organ-protective properties.     

Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) inhibit the apoptosis in human peripheral blood lymphocytes

BACKGROUND: Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) are the major steroid hormones secreted by the adrenal gland. Administration of DHEA has been reported to have beneficial effects on aging, diabetes, and atherosclerosis. Apoptosis is a normal physiologic process that occurs during embryonic development as well as in the maintenance of tissue homeostasis. In this study, we examined the suppressive effect of DHEA(S) on staurosporine-induced apoptosis in human peripheral blood lymphocytes (PBL). METHODS: Apoptosis was induced in human PBL with staurosporine and measured by flow cytometry utilizing Annexin V and propidium iodide (PI) staining. The quantity of FITC+/PI- cells corresponded to early apoptosis, while that of FITC+/PI+ cells corresponded to late apoptosis or secondary necrosis. RESULTS: The fraction of staurosporine-induced early apoptosis but not that of secondary necrosis in PBL was reduced by the treatment with either DHEA or DHEAS. Furthermore, this apoptosis was neither associated with androgen receptor (AR) nor with estrogen receptor (ER). CONCLUSIONS: This is the first study showing that DHEA(S) inhibits apoptosis in human PBL through a mechanism independent of either ARs or ERs. DHEA(S) may be a promising chemopreventive drug for aging, diabetes, and atherosclerosis.     

Anti-lipidperoxidative role of exogenous dehydroepiendrosterone (DHEA) administration in normal ageing rat brain

Effects of exogenous dehydroepiendrosterone (DHEA) administration on the levels of lipid proxidation products, malondialdyde (MDA)-a thiobarbuteric acid reactive substance (TBARS) and 4-hydroxynonenal (4-HNE) in different brain regions viz. cerebral cortex, hippocampus cerebellum, and brain stem of 12 and 22 months old rats were studied. DHEA treatment significantly depressed TBARS and 4-HNE in all the brain regions studied, in both the age group rats. Interestingly, the magnitude of decrease was higher in the 22 months old rats than that in 12 months old rats. The results suggest that older the animal, better will be the response of exogenous DHEA administration against age-related peroxidative products.