Diabetes. 2004 Jan;53(1):41-52.
Dehydroepiandrosterone stimulates glucose uptake in human and murine adipocytes by inducing GLUT1 and GLUT4 translocation to the plasma membrane.

Perrini S, Natalicchio A, Laviola L, Belsanti G, Montrone C, Cignarelli A, Minielli V, Grano M, De Pergola G, Giorgino R, Giorgino F.

Department of Emergency and Organ Transplantation, Section on Internal Medicine, Endocrinology and Metabolic Diseases, Bari, Italy.

Dehydroepiandrosterone (DHEA) has been shown to modulate glucose utilization in humans and animals, but the mechanisms of DHEA action have not been clarified. We show that DHEA induces a dose- and time-dependent increase in glucose transport rates in both 3T3-L1 and human adipocytes with maximal effects at 2 h. Exposure of adipocytes to DHEA does not result in changes of total GLUT4 and GLUT1 protein levels. However, it does result in significant increases of these glucose transporters in the plasma membrane. In 3T3-L1 adipocytes, DHEA increases tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 and stimulates IRS-1- and IRS-2-associated phosphatidylinositol (PI) 3-kinase activity with no effects on either insulin receptor or Akt phosphorylation. In addition, DHEA causes significant increases of cytosolic Ca(2+) concentrations and a parallel activation of protein kinase C (PKC)-beta(2). The effects of DHEA are abrogated by pretreatment of adipocytes with PI 3-kinase and phospholipase C gamma inhibitors, as well as by inhibitors of Ca(2+)-dependent PKC isoforms, including a specific PKC-beta inhibitor. Thus, DHEA increases glucose uptake in both human and 3T3-L1 adipocytes by stimulating GLUT4 and GLUT1 translocation to the plasma membrane. PI 3-kinase, phospholipase C gamma, and the conventional PKC-beta(2) seem to be involved in DHEA effects.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14693696&dopt=Abstract DHEA




Endocr J. 2003 Dec;50(6):689-95.
The effect of physiologic hyperinsulinemia during an oral glucose tolerance test on the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) in healthy young adults born with low and with normal birth weight.

Vasarhelyi B, Bencsik P, Treszl A, Bardoczy Z, Tulassay T, Szathmari M.

Research Laboratory of Pediatrics and Nephrology, Budapest, Hungary.

Several data support that adrenal hyperandrogenism affects women with low birth weight (LBW). We also found an association between serum dehydroepiandrosterone (DHEA) and fasting insulin levels. The aim of our study was to detect the acute effects of reactive hyperinsulinemia during oral glucose tolerance test (OGTT) on DHEA(S) levels in LBW men and women. Fifty three men and 47 women (of those, 37 men and 33 women were LBW) were enrolled. DHEA, DHEAS, and insulin levels were measured before and during OGTT. Cortisol was also measured. DHEA/cortisol ratio during OGTT was calculated to analyze the acute effect of hyperinsulinemia on DHEA levels. During OGTT, DHEA and cortisol levels decreased in each individual, independently of gender and birth weight. Serum DHEAS decreased to a minor (but significant) extent only in LBW women (p<0.05). The rate of DHEA/cortisol increased in both gender, independently of birth weight. The increase of the rate of DHEA/cortisol during OGTT was associated with maximal insulin response (r = 0.45, p<0.05) and with the insulin(AUC) (r = 0.48, p<0.05) in women. Our results suggest that reactive hyperinsulinemia during OGTT might activate the androgen pathway of adrenal cortex including DHEA production. Therefore acute hyperinsulinemia might counterbalance to some extent the diurnal decrease of DHEA during OGTT.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14709839&dopt=Abstract DHEA [PubMed - in process]




FEBS Lett. 2002 Dec 18;532(3):373-8.
In vivo activation of the constitutive androstane receptor beta (CARbeta) by treatment with dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEA-S).

Fujita A, Furutama D, Tanaka T, Sakai R, Koyama A, Hanafusa T, Mitsuhashi T, Ohsawa N.

Aino Institute for Aging Research, 3-9-25, Ohta, Ibaraki, 567-0018, Osaka, Japan.

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.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12482595&dopt=Abstract DHEA




Fertil Steril. 2004 Jan;81(1):120-5.
Glucose action and adrenocortical biosynthesis in women with polycystic ovary syndrome.

Farah-Eways L, Reyna R, Knochenhauer ES, Bartolucci AA, Azziz R.

Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.

OBJECTIVE: To determine if insulin or glucose action plays a role in adrenocortical steroidogenesis in the polycystic ovary syndrome (PCOS). DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): Nine reproductive-aged patients with PCOS and nine age-, race-, and body mass index-matched controls. MAIN OUTCOME MEASURE(S): Insulin-modified frequently sampled intravenous glucose tolerance testing and an acute 60-minute ACTH-(1-24) stimulation test. From the glucose tolerance test, glucose and insulin were measured and the insulin sensitivity index, glucose effectiveness, and acute insulin response to glucose were determined. Dehydroepiandrosterone sulfate (DHEAS) basally and 17-hydroxypregnenolone, 17-hydroxyprogesterone, DHEA, androstenedione, and cortisol during ACTH testing at 0 and 60 minute (steroid(0) and steroid(60)) were determined. The net change in steroid during the ACTH test was calculated. RESULT(S): The insulin sensitivity index had limited correlation with adrenocortical variables in both groups. In patients with PCOS, glucose effectiveness was positively associated with DHEAS, cortisol(0), cortisol(60), change in cortisol, DHEA(0), DHEA(60), change in DHEA, 17-hydroxyprenenolone(60), change in 17-hydroxypregnenolone, DHEA(0), androstenedione(0), 17-hydroxyprenenolone(0), 17-hydroxyprogesterone(0), 17-hydroxyprenenolone(60), and 17-hydroxyprogesterone(60). CONCLUSION(S): Adrenocortical biosynthesis, basally and in response to ACTH, appears to be closely associated with glucose effectiveness in PCOS. A common factor determining both the effectiveness of glucose to control its own production or uptake and adrenocortical biosynthesis may be aberrant in PCOS.





Int J Neuropsychopharmacol. 2004 Mar;7(1):71-5. Epub 2004 Jan 16.
Chronic lithium treatment affects rat brain and serum dehydroepiandrosterone (DHEA) and DHEA-sulphate (DHEA-S) levels.

Maayan R, Shaltiel G, Poyurovsky M, Ramadan E, Morad O, Nechmad A, Weizman A, Agam G.

Laboratory of Biological Psychiatry, Felsentein Medical Research Center, Beilinson Campus, Petah Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Lithium (Li) is an established effective treatment for bipolar disorder. However, the molecular mechanism of its action is still unknown. Dehydroepiandrosterone (DHEA) and its sulphate ester (DHEA-S) are adrenal hormones also synthesized de novo in the brain as neurosteroids. Recent studies have suggested that DHEA has mood-elevating properties and may demonstrate antidepressant effects. 3(2)-Phosphoadenosine 5-phosphate (PAP) phosphatase is a novel Li-inhibitable enzyme involved in sulphation processes. In the present study we examined the impact of 10 d Li treatment on serum and brain DHEA and DHEA-S levels in rats. Our results show that Li administration lowered frontal cortex and hippocampus DHEA and DHEA-S levels, in line with our hypothesis assuming that Lis inhibition of PAP phosphatase leads to elevated PAP levels resulting in inhibition of sulphation and reduction in brain DHEA-S levels. Future studies should address the involvement of neurosteroids in the mechanism of Lis mood stabilization.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14725722&dopt=Abstract DHEA

princeton.edu

The hormonal control of territorial aggression in male and female vertebrates outside the breeding season is still unresolved. Most vertebrates have regressed gonads when not breeding and do not secrete high levels of sex steroids. However, recent studies implicate estrogens in the regulation of non-breeding territoriality in some bird species. One possible source of steroids during the non-breeding season could be the adrenal glands that are known to produce sex steroid precursors such as dehydroepiandrosterone (DHEA). We studied tropical, year-round territorial spotted antbirds (Hylophylax n. naevioides) and asked (1). whether both males and females are aggressive in the non-breeding season and (2). whether DHEA is detectable in the plasma at that time. We conducted simulated territorial intrusions (STIs) with live decoys to male and female free-living spotted antbirds in central Panama. Non-breeding males and females displayed robust aggressive responses to STIs, and responded more intensely to decoys of their own sex. In both sexes, plasma DHEA concentrations were detectable and higher than levels of testosterone (T) and 17beta-estradiol (E(2)). In males, plasma DHEA concentrations were positively correlated with STI duration. Next, we conducted STIs in captive non-breeding birds. Captive males and females displayed robust aggressive behavior. Plasma DHEA concentrations were detectable in both sexes, whereas T was non-detectable (E(2) was not measured). Plasma DHEA concentrations of males were positively correlated with aggressive vocalizations and appeared to increase with longer STI durations. We conclude that male and female spotted antbirds can produce DHEA during the non-breeding season and DHEA may serve as a precur

kobepharma-u.ac.jp

BACKGROUND: Since dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) have been suggested to have immunoregulatory effects, changes in the levels of these substances during and after pregnancy might affect the maternal immune system. We examined serum concentrations of DHEA and DHEAS, and cytokine production during pregnancy and after delivery. METHODS: The subjects were 73 normal pregnant, 76 normal postpartum and 30 normal non-pregnant women. Whole-blood was stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin and the levels of cytokines in the supernatant were measured using enzyme-linked immunosorbent assay (ELISA). DHEA and DHEAS were measured using ELISA and gas chromatography-mass spectrometry (GC-MS), respectively. RESULTS: The serum DHEA levels increased in the first and in the second trimesters and decreased after delivery until 11 months postpartum. DHEAS levels were decreased in the second and in the third trimesters and returned to non-pregnant levels after pregnancy. All measured cytokines (IFN-gamma, IL-2, IL-4 and IL-10) were decreased during pregnancy and subsequently increased postpartum. We found significant negative correlations between DHEA and cytokine levels. CONCLUSIONS: Increase of serum DHEA in the first and the second trimesters may suppress immune reaction during pregnancy, while a decrease of DHEA after delivery may induce postpartum enhancement of the maternal immune system. DHEA may be involved in modifying the maternal immune responses during and after pregnancy.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14734211&dopt=Abstract DHEA [PubMed - in process]




J Neurosci Res. 2004 Feb 1;75(3):391-400.
Treatment with the neurosteroid dehydroepiandrosterone promotes recovery of motor behavior after moderate contusive spinal cord injury in the mouse.

Fiore C, Inman DM, Hirose S, Noble LJ, Igarashi T, Compagnone NA.

Department of Neurological Surgery, Laboratory for Spinal cord Development and Regeneration, University of California, San Francisco, California, USA.

The neurosteroid dehydroepiandrosterone (DHEA) has neuroprotective properties after ischemic and excitatory insults to the brain. In the developing embryo, it is produced in discrete regions of the central nervous system (CNS), where it specifically promotes axonal growth of differentiated neurons. To test if DHEA could be beneficial after spinal cord injury (SCI), we used a model of moderate contusive SCI developed and characterized in the mouse. Immediately after surgery, we applied treatment with DHEA or with vehicle only and compared treatment groups (n = 12 in each group) over a 42-day period. Locomotor recovery was assessed in an open field using a standardized 21-point scale, according to gait analysis on paw print recordings and using foot fault analyses on an inclined ladder beam. The DHEA-treated group showed improved function compared to vehicle-treated animals in these tests. More strikingly, DHEA enhanced recovery of left-right coordination and fine motor control. In an attempt to correlate functional recovery with spinal cord neuropathology in the different experimental groups, we studied the area of spared white matter at the epicenter and reactive gliosis/scar formation 42 days post-injury (DPI). DHEA significantly increased the area of white matter spared at the epicenter and reduced the area of reactive gliosis surrounding the lesion. These data demonstrate the effectiveness of DHEA in promoting functional recovery in the adult murine injured spinal cord. Copyright 2003 Wiley-Liss, Inc.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14743452&dopt=Abstract DHEA

mail.scu.edu.tw

Dehydroepiandrosterone (DHEA) is a putative anti-stress agent and stress is associated with the secretion of catecholamine from the adrenal gland, but the effects of DHEA on catecholamine secretion are not fully understood. Using bovine chromaffin cells, we found that DHEA inhibited catecholamine secretion and cytosolic Ca(2+) ([Ca(2+)](i)) rise coupled with nicotinic acetylcholine receptor (nAChR) without exerting an effect on (3)H-nicotine binding. In the case of high K(+) stimulation, DHEA effectively suppressed secretion without affecting [Ca(2+)](i) rise. Trifluoperazine (TFP), a calmodulin inhibitor, was capable of counteracting the inhibition of DHEA on high K(+)-induced secretions. In permeabilized cells, DHEA suppressed the Ca(2+)-induced secretion. These results suggest that DHEA (a) acts as a channel blocker that suppresses Ca(2+) influx and subsequent secretions associated with nAChR, or (b) affects the intracellular secretion machinery to suppress high K(+)-induced secretions without affecting the high K(+)-induced [Ca(2+)](i) rise. Copyright 2004 National Science Council, ROC and S. Karger AG, Basel

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14966370&dopt=Abstract DHEA [PubMed - in process]




Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3202-7. Epub 2004 Feb 18.
Mitotic and neurogenic effects of dehydroepiandrosterone (DHEA) on human neural stem cell cultures derived from the fetal cortex.

Suzuki M, Wright LS, Marwah P, Lardy HA, Svendsen CN.

Department of Anatomy and the Waisman Center, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705-2280, USA.

Dehydroepiandrosterone (DHEA) is a neurosteroid with potential effects on neurogenesis and neuronal survival in humans. However, most studies on DHEA have been performed in rodents, and there is little direct evidence for biological effects on the human nervous system. Furthermore, the mechanism of its action is unknown. Here, we show that DHEA significantly increased the growth rates of human neural stem cells derived from the fetal cortex and grown with both epidermal growth factor (EGF) and leukemia inhibitory factor (LIF). However, it had no effect on cultures grown in either factor alone, suggesting a specific action on the EGF/LIF-responsive cell. Precursors of DHEA such as pregnenolone or six of its major metabolites, had no significant effect on proliferation rates. DHEA did not alter the small number (<3%) of newly formed neuroblasts or the large number (>95%) of nestin-positive precursors. However, the number of glial fibrillary acidic protein-positive cells, its mRNA, and protein were significantly increased by DHEA. We found both N-methyl-d-aspartate and sigma 1 antagonists, but not GABA antagonists, could completely eliminate the effects of DHEA on stem cell proliferation. Finally we asked whether the EGF/LIF/DHEA-responsive stem cells had an increased potential for neurogenesis and found a 29% increase in neuronal production when compared to cultures grown in EGF/LIF alone. Together these data suggest that DHEA is involved in the maintenance and division of human neural stem cells. Given the wide availability of this neurosteroid, this finding has important implications for future use.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14973190&dopt=Abstract DHEA [PubMed - in process]



Drug Metab Dispos. 2004 Mar;32(3):305-13.
Stereo- and regioselectivity account for the diversity of dehydroepiandrosterone (DHEA) metabolites produced by liver microsomal cytochromes P450.

Miller KK, Cai J, Ripp SL, Pierce WM Jr, Rushmore TH, Prough RA.

Department of Biochemistry and Molecular Biology, The University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.

The purpose of this study was to quantify the oxidative metabolism of dehydroepiandrosterone (3beta-hydroxy-androst-5-ene-17-one; DHEA) by liver microsomal fractions from various species and identify the cytochrome P450 (P450) enzymes responsible for production of individual hydroxylated DHEA metabolites. A gas chromatography-mass spectrometry method was developed for identification and quantification of DHEA metabolites. 7alpha-Hydroxy-DHEA was the major oxidative metabolite formed by rat (4.6 nmol/min/mg), hamster (7.4 nmol/min/mg), and pig (0.70 nmol/min/mg) liver microsomal fractions. 16alpha-Hydroxy-DHEA was the next most prevalent metabolite formed by rat (2.6 nmol/min/mg), hamster (0.26 nmol/min/mg), and pig (0.16 nmol/min/mg). Several unidentified metabolites were formed by hamster liver microsomes, and androstenedione was produced only by pig microsomes. Liver microsomal fractions from one human demonstrated that DHEA was oxidatively metabolized at a total rate of 7.8 nmol/min/mg, forming 7alpha-hydroxy-DHEA, 16alpha-hydroxy-DHEA, and a previously unidentified hydroxylated metabolite, 7beta-hydroxy-DHEA. Other human microsomal fractions exhibited much lower rates of metabolism, but with similar metabolite profiles. Recombinant P450s were used to identify the cytochrome P450s responsible for DHEA metabolism in the rat and human. CYP3A4 and CYP3A5 were the cytochromes P450 responsible for production of 7alpha-hydroxy-DHEA, 7beta-hydroxy-DHEA, and 16alpha-hydroxy-DHEA in adult liver microsomes, whereas the fetal/neonatal form CYP3A7 produced 16alpha-hydroxy and 7beta-hydroxy-DHEA. CYP3A23 uniquely formed 7al

vanderbilt.edu

We previously determined that both antecedent hypoglycemia and elevated cortisol levels blunt neuroendocrine and metabolic responses to subsequent hypoglycemia in conscious, unrestrained rats. The adrenal steroid dehydroepiandrosterone sulfate (DHEA-S) has been shown in several studies to oppose corticosteroid action. The purpose of this study was to determine if DHEA-S could preserve counterregulatory responses during repeated hypoglycemia. We studied 40 male Sprague-Dawley rats during a series of 2-day protocols. Day 1 consisted of two 2-h episodes of 1) hyperinsulinemic (30 pmol. kg(-1). min(-1)) euglycemia (6.2 +/- 0.2 mmol/l; n = 12; ANTE EUG), 2) hyperinsulinemic euglycemia (6.0 +/- 0.1 mmol/l; n = 8) plus simultaneous intravenous infusion of DHEA-S (30 mg/kg; ANTE EUG + DHEA-S), 3) hyperinsulinemic hypoglycemia (2.8 +/- 0.1 mmol/l; n = 12; ANTE HYPO), or 4) hyperinsulinemic hypoglycemia (2.8 +/- 0.1 mmol/l; n = 8) with simultaneous intravenous infusion of DHEA-S (30 mg/kg; ANTE HYPO + DHEA-S). Day 2 consisted of a single 2-h hyperinsulinemic hypoglycemic (2.8 +/- 0.1 mmol/l) clamp. During the final 30 min of day 2, hypoglycemia norepinephrine levels were significantly lower in the ANTE HYPO group versus the ANTE HYPO + DHEA-S group (2.0 +/- 0.2 vs. 3.3 +/- 0.6 nmol/l; P < 0.05). In addition, epinephrine (8 +/- 1 vs. 17 +/- 2, 14 +/- 3, and 15 +/- 3 nmol/l), glucagon (91 +/- 8 vs. 273 +/- 36, 231 +/- 42, and 297 +/- 48 ng/l), and corticosterone (1,255 +/- 193 vs. 1,915 +/- 212, 1,557 +/- 112, and 1,668 +/- 119 pmol/l) were significantly lower in the ANTE HYPO group versus the ANTE EUG, ANTE EUG