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1.  DHEA metabolites activate estrogen receptors alpha and beta 
Steroids  2012;78(1):15-25.
Dehydroepiandrosterone (DHEA) levels were reported to associate with increased breast cancer risk in postmenopausal women, but some carcinogen-induced rat mammary tumor studies question this claim. The purpose of this study was to determine how DHEA and its metabolites affect estrogen receptors α or β (ERα or ERβ) -regulated gene transcription and cell proliferation. In transiently transfected HEK-293 cells, androstenediol, DHEA, and DHEA-S activated ERα. In ERβ transfected HepG2 cells, androstenedione, DHEA, androstenediol, and 7-oxo DHEA stimulated reporter activity. ER antagonists ICI 182,780 (fulvestrant) and 4-hydroxytamoxifen, general P450 inhibitor miconazole, and aromatase inhibitor exemestane inhibited activation by DHEA or metabolites in transfected cells. ERβ-selective antagonist R,R-THC (R,R-cis-diethyl tetrahydrochrysene) inhibited DHEA and DHEA metabolite transcriptional activity in ERβ-transfected cells. Expression of endogenous estrogen-regulated genes: pS2, progesterone receptor, cathepsin D1, and nuclear respiratory factor-1 was increased by DHEA and its metabolites in an ER-subtype, gene, and cell-specific manner. DHEA metabolites, but not DHEA, competed with 17β-estradiol for ERα and ERβ binding and stimulated MCF-7 cell proliferation, demonstrating that DHEA metabolites interact directly with ERα and ERβ in vitro, modulating estrogen target genes in vivo.
doi:10.1016/j.steroids.2012.10.002
PMCID: PMC3529809  PMID: 23123738
estrogen receptors; DHEA; androstendione; androstendiol; transcription
2.  Dehydroepiandrosterone (DHEA) Inhibition of Monocyte Binding by Vascular Endothelium Is Associated With Sialylation of Neural Cell Adhesion Molecule 
Reproductive Sciences  2012;19(1):86-91.
Rationale: Adhesion of monocytes to vascular endothelium is necessary for atheroma formation. This adhesion requires binding of endothelial neural cell adhesion molecule (NCAM) to monocyte NCAM. NCAM:NCAM binding is blocked by sialylation of NCAM (polysialylated NCAM; PSA-NCAM). Since estradiol (E2) and dihydrotestosterone (DHT) induced PSA-NCAM and decreased monocyte adhesion, in consideration of possible clinical applications we tested whether their prohormone dehydroepiandrosterone (DHEA) has similar effects. Experimental: (1) DHEA was administered to cultured human coronary artery endothelial cells (HCAECs) from men and women. Monocyte binding was assessed using fluorescence-labeled monocytes. (2) HCEACs were incubated with E2, DHT, DHEA alone, or with trilostane, fulvestrant or flutamide. Expression of PSA-NCAM was assessed by immunohistochemistry and Western blotting. Results: Dehydroepiandrosterone inhibited monocyte adhesion to HCAECs by ≥50% (P < .01). Fulvestrant or flutamide blockade of DHEA’s inhibition of monocyte binding appeared to be gender dependent. The DHEA-induced expression of PSA-NCAM was completely blocked by trilostane. Conclusions: In these preliminary in vitro studies, DHEA increased PSA-NCAM expression and inhibited monocyte binding in an estrogen- and androgen receptor-dependent manner. Dehydroepiandrosteroneappears to act via its end metabolites, E2 and DHT. Dehydroepiandrosterone could furnish clinical prevention against atherogenesis and arteriosclerosis.
doi:10.1177/1933719111414210
PMCID: PMC3343126  PMID: 22228741
atherosclerosis; heart disease; coronary; estrogen; androgen; adhesion; NCAM; PSA-NCAM
3.  Modulation of Receptor Phosphorylation Contributes to Activation of Peroxisome Proliferator Activated Receptor α by Dehydroepiandrosterone and Other Peroxisome Proliferators 
Molecular pharmacology  2007;73(3):968-976.
Dehydroepiandrosterone (DHEA), a C19 human adrenal steroid, activates peroxisome proliferator-activated receptor α (PPARα) in vivo but does not ligand-activate PPARα in transient transfection experiments. We demonstrate that DHEA regulates PPARα action by altering both the levels and phosphorylation status of the receptor. Human hepatoma cells (HepG2) were transiently transfected with the expression plasmid encoding PPARα and a plasmid containing two copies of fatty acyl coenzyme oxidase (FACO) peroxisome-proliferator activated receptor responsive element consensus oligonucleotide in a luciferase reporter gene. Nafenopin treatment increased reporter gene activity in this system, whereas DHEA treatment did not. Okadaic acid significantly decreased nafenopin-induced reporter activity in a concentration-dependent manner. Okadaic acid treatment of primary rat hepatocytes decreased both DHEA- and nafenopin-induced FACO activity in primary rat hepatocytes. DHEA induced both PPARα mRNA and protein levels, as well as PP2A message in primary rat hepatocytes. Western blot analysis showed that the serines at positions 12 and 21 were rapidly dephosphorylated upon treatment with DHEA and nafenopin. Results using specific protein phosphatase inhibitors suggested that protein phosphatase 2A (PP2A) is responsible for DHEA action, and protein phosphatase 1 might be involved in nafenopin induction. Mutation of serines at position 6, 12, and 21 to an uncharged alanine residue significantly increased transcriptional activity, whereas mutation to negative charged aspartate residues (mimicking receptor phosphorylation) decreased transcriptional activity. DHEA action involves induction of PPARα mRNA and protein levels as well as increased PPARα transcriptional activity through decreasing receptor phosphorylation at serines in the AF1 region.
doi:10.1124/mol.107.036780
PMCID: PMC2423814  PMID: 18079279
4.  Human Prostate Stromal Cells Stimulate Increased PSA Production in DHEA-treated Prostate Cancer Epithelial Cells 
Dehydroepiandrosterone (DHEA) is commonly used as a dietary supplement and may affect prostate pathophysiology when metabolized to androgens and/or estrogens. Human prostate LAPC-4 cancer cells with a wild type androgen receptor (AR), were treated with DHEA, androgens (DHT, T, or R1881), and E2 and assayed for PSA protein and gene expression. In LAPC-4 monocultures, DHEA and E2 induced little or no increase in PSA protein or mRNA expression compared to androgen-treated cells. When prostate cancer-associated (6S) stromal cells were added in coculture, DHEA stimulated LAPC-4 cell PSA protein secretion to levels approaching induction by DHT. Also, DHEA induced 15-fold more PSA mRNA in LAPC-4 cocultures than in monocultures. LAPC-4 proliferation was increased 2–3 fold when cocultured with 6S stromal cells regardless of hormone treatment. DHEA-treated 6S stromal cells exhibited a dose- and time-dependent increase in T secretion, demonstrating stromal cell metabolism of DHEA to T. Coculture with non-cancerous stroma did not induce LAPC-4 PSA production, suggesting a differential modulation of DHEA effect in a cancer-associated prostate stromal environment. This coculture model provides a research approach to reveal detailed endocrine, intracrine, and paracrine signaling between stromal and epithelial cells that regulate tissue homeostasis within the prostate, and the role of the tumor microenvironment in cancer progression.
doi:10.1016/j.jsbmb.2008.06.008
PMCID: PMC2570207  PMID: 18621129
DHEA; stromal; prostate; PSA; coculture
5.  Inhibition of vascular inflammation by dehydroepiandrosterone sulfate in human aortic endothelial cells: roles of PPARα and NF-κB 
Vascular pharmacology  2007;48(0):76-84.
Dehydroepiandrosterone-sulfate (DHEAS) is a hormone produced by the adrenal gland and is a precursor for both androgens and estrogens. Atherosclerosis is a well characterized inflammatory disease, but little is known about the role of DHEAS in vascular inflammation. We hypothesize that DHEAS can reduce inflammation in vascular endothelial cells and the mechanism involves the peroxisome proliferator-activated receptor α (PPARα), thereby inhibiting transcription factors involved in endothelial cell inflammation. To test our hypothesis, aortic endothelial cells were pretreated for 48 hours with DHEAS, then with TNF-α. TNF-α-induced upregulation of the expression of inflammatory genes interleukin (IL)-8 and intracellular adhesion molecule (ICAM)-1 was attenuated by incubation with DHEAS. DHEAS inhibited the TNF-α-induced surface expression of vascular cell adhesion molecule (VCAM)-1. This effect was abolished by the addition of MK866, a PPARα inhibitor, indicating that PPARα is involved in the mechanism of this inhibition. The addition of the aromatase inhibitor letrozole had no effect on the inhibition of TNF-α-induced VCAM-1 expression by DHEAS. Treatment of endothelial cells with DHEAS dramatically inhibited the TNF-α-induced activation of NF-κB, an inflammatory transcription factor, and increased protein levels of the NF-κB inhibitor, IκB-α. These results signify the ability of DHEAS to directly inhibit the inflammatory process and show a potential direct effect of DHEAS on vascular inflammation that has implications for the development of atherosclerotic cardiovascular disease.
doi:10.1016/j.vph.2007.12.002
PMCID: PMC3656484  PMID: 18255343
Dehydroepiandrosterone sulfate; VCAM; PPAR; endothelial cell; inflammation
6.  In rats, oral oleoyl-DHEA is rapidly hydrolysed and converted to DHEA-sulphate 
BMC Pharmacology  2007;7:4.
Background
Dehydroepiandrosterone (DHEA) released by adrenal glands may be converted to androgens and estrogens mainly in the gonadal, adipose, mammary, hepatic and nervous tissue. DHEA is also a key neurosteroid and has antiglucocorticoid activity. DHEA has been used for the treatment of a number of diseases, including obesity; its pharmacological effects depend on large oral doses, which effect rapidly wanes in part because of its short half-life in plasma. Since steroid hormone esters circulate for longer periods, we have studied here whether the administration of DHEA oleoyl ester may extend its pharmacologic availability by keeping high circulating levels.
Results
Tritium-labelled oleoyl-DHEA was given to Wistar male and female rats by gastric tube. The kinetics of appearance of the label in plasma was unrelated to sex; the pattern being largely coincident with the levels of DHEA-sulfate only in females, and after 2 h undistinguishable from the results obtained using labelled DHEA gavages; in the short term, practically no lipophilic DHEA label was found in plasma. After 24 h only a small fraction of the label remained in the rat organs, with a different sex-related distribution pattern coincident for oleoyl- and free- DHEA gavages. The rapid conversion of oleoyl-DHEA into circulating DHEA-sulfate was investigated using stomach, liver and intestine homogenates; which hydrolysed oleoyl-DHEA optimally near pH 8. Duodenum and ileum contained the highest esterase activities. Pure hog pancreas cholesterol-esterase broke down oleoyl-DHEA at rates similar to those of oleoyl-cholesterol. The intestinal and liver esterases were differently activated by taurocholate and showed different pH-activity patterns than cholesterol esterase, suggesting that oleoyl-DHEA can be hydrolysed by a number of esterases in the lumen (e.g. cholesterol-esterase), in the intestinal wall and the liver.
Conclusion
The esterase activities found may condition the pharmacological availability (and depot effect) of orally administered steroid hormone fatty acid esters such as oleoyl-DHEA. The oral administration of oleoyl-DHEA in order to extend DHEA plasma availability has not been proved effective, since the ester is rapidly hydrolysed, probably in the intestine itself, and mainly converted to DHEA-sulfate at least in females.
doi:10.1186/1471-2210-7-4
PMCID: PMC1831771  PMID: 17346356
7.  Effects of 7-keto Dehydroepiandrosterone on Voluntary Ethanol Intake in Male Rats 
Alcohol (Fayetteville, N.Y.)  2010;45(4):349-354.
Administration of dehydroepiandrosterone (DHEA), a neurosteroid that can negatively modulate the GABAA receptor, has been shown to decrease voluntary intake of ethanol in rats. In vivo, DHEA can be metabolized to a variety of metabolites, including 7-keto DHEA, a metabolite without the prohormonal effects of DHEA. This study compared the effectiveness of 7-keto DHEA to DHEA for reducing ethanol intake in the same group of rats. The subjects, previously trained to drink ethanol using a saccharin-fading procedure, had access to ethanol for thirty minutes daily, and the amount consumed was recorded. Subjects were administered 10 and 56 mg/kg of DHEA or 7-keto DHEA intraperitoneally 15 minutes prior to drinking sessions. Subjects received each particular dose daily until one of two criteria was met; that is, either ethanol intake did not differ by more than 20% of the mean for three consecutive days, or for a maximum of eight days. Both 10 and 56 mg/kg of 7-keto DHEA significantly reduced the dose of ethanol consumed. While 10 mg/kg of 7-keto DHEA produced decreases similar to those found with DHEA, the 56-mg/kg dose of 7-keto DHEA was significantly more effective at decreasing the dose of ethanol consumed than the same dose of DHEA. These results show that 7-keto DHEA is comparable to, or possibly more effective than, DHEA at decreasing ethanol consumption in rats, and that 7-keto DHEA is a compound deserving further investigation as a possible clinical treatment for alcohol abuse without the prohormonal effects of DHEA.
doi:10.1016/j.alcohol.2010.08.020
PMCID: PMC3095668  PMID: 21051179
DHEA; 7-ketoDHEA; neurosteroid; GABAA receptor; ethanol intake; rats
8.  Activation of peroxisome proliferator-activated receptors by chlorinated hydrocarbons and endogenous steroids. 
Environmental Health Perspectives  1998;106(Suppl 4):983-988.
Trichloroethylene (TCE) and related hydrocarbons constitute an important class of environmental pollutants whose adverse effects on liver, kidney, and other tissues may, in part, be mediated by peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors belonging to the steroid receptor superfamily. Activation of PPAR induces a dramatic proliferation of peroxisomes in rodent hepatocytes and ultimately leads to hepatocellular carcinoma. To elucidate the role of PPAR in the pathophysiologic effects of TCE and its metabolites, it is important to understand the mechanisms whereby PPAR is activated both by TCE and endogenous peroxisome proliferators. The investigations summarized in this article a) help clarify the mechanism by which TCE and its metabolites induce peroxisome proliferation and b) explore the potential role of the adrenal steroid and anticarcinogen dehydroepiandrosterone 3beta-sulfate (DHEA-S) as an endogenous PPAR activator. Transient transfection studies have demonstrated that the TCE metabolites trichloroacetate and dichloroacetate both activate PPAR alpha, a major liver-expressed receptor isoform. TCE itself was inactive when tested over the same concentration range, suggesting that its acidic metabolites mediate the peroxisome proliferative potential of TCE. Although DHEA-S is an active peroxisome proliferator in vivo, this steroid does not stimulate trans-activation of PPAR alpha or of two other PPAR isoforms, gamma and delta/Nuc1, when evaluated in COS-1 cell transfection studies. To test whether PPAR alpha mediates peroxisomal gene induction by DHEA-S in intact animals, DHEA-S has been administered to mice lacking a functional PPAR alpha gene. DHEA-S was thus shown to markedly increase hepatic expression of two microsomal P4504A proteins associated with the peroxisomal proliferative response in wild-type mice. In contrast, DHEA-S did not induce these hepatic proteins in PPAR alpha-deficient mice. Thus, despite its unresponsiveness to steroidal peroxisome proliferators in transfection assays, PPAR alpha is an obligatory mediator of DHEA-S-stimulated hepatic peroxisomal gene induction. DHEA-S, or one of its metabolites, may thus serve as an important endogenous regulator of liver peroxisomal enzyme expression.
Images
PMCID: PMC1533341  PMID: 9703482
9.  EFFECT OF SEX STEROIDS AND INSULIN ON DEHYDROEPIANDROSTERONE SULFATE (DHEAS) PRODUCTION BY HEPG2 CELLS 
Fertility and sterility  2008;91(6):2551-2556.
OBJECTIVE
To test the hypothesis that DHEAS production from DHEA occurs in hepatic cells, and that this production is augmented by the presence of sex steroids or insulin (INS).
DESIGN
In-vitro prospective experiment
SETTING
Academic medical center.
INTERVENTIONS
Hepatoma (Hep) G2 cells cultured in media supplemented with: i) DHEA (10−5M) only, ii) DHEA (10−5M) + testosterone (T, 10−6M), iii) DHEA (10−5M) + estradiol (E2, 10−6M), iv) DHEA (10−5M) + dihydrotestosterone (DHT 10−6M), v) DHEA (10−5M) + insulin (INS 10 ng/mL), or vi) DHEA (10−5M) + insulin 100 ng/mL,
OUTCOME MEASURES
DHEAS levels in the media were measured at 0, 2, 4, 6, 8, 12, 24, 48, and 72 h after adding treatments at time-point 0.
RESULTS
DHEAS was first detected in the HepG2 cell culture media at 12h incubation. The cumulative production rate of DHEAS increased linearly until 72h incubation. When compared to the effect of treatment with DHEA only, treatment with DHEA plus T, DHT, or E2 delayed the cumulative DHEAS production; alternatively, the addition of INS did not alter DHEAS production.
CONCLUSION
These data suggest that while hepatic cells have the ability of converting DHEA to DHEAS, neither sex steroids nor INS result in the increased hepatic production of DHEAS.
doi:10.1016/j.fertnstert.2008.03.049
PMCID: PMC2744856  PMID: 18554595
Adrenal androgen excess; DHEA sulphotransferase; HepG2 cells; dehydroepiandrosterone; DHEAS; SULT2A1
10.  Dehydroepiandrosterone-dependent induction of peroxisomal proliferation can be reduced by aspartyl esterification without attenuation of inhibitory bone loss in ovariectomy animal model. 
Journal of Korean Medical Science  2000;15(5):533-541.
The purpose of this study was to determine whether esterification of dehydroepiandrosterone with aspartate (DHEA-aspartate) could reduce peroxisomal proliferation induced by DHEA itself, without loss of antiosteoporotic activity. Female Sprague-Dawley rats were ovariectomized, then DHEA or DHEA-aspartate was administered intraperitoneally at 0.34 mmol/kg BW 3 times a week for 8 weeks. DHEA-aspartate treatment in ovariectomized rats significantly increased trabeculae area in tibia as much as DHEA treatment. Urinary Ca excretion was not significantly increased by DHEA or DHEA-aspartate treatment in ovariectomized rats, while it was significantly increased by ovariectomy. Osteocalcin concentration and alkaline phosphatase activity in serum and cross linked N-telopeptide type I collagen level in urine were not significantly different between DHEA-aspartate and DHEA treated groups. DHEA-aspartate treatment significantly reduced liver weight and hepatic palmitoyl-coA oxidase activity compared to DHEA treatment. DHEA-aspartate treatment maintained a nearly normal morphology of peroxisomes, while DHEA treatment increased the number and size of peroxisomes in the liver. According to these results, it is concluded that DHEA-aspartate ester has an inhibitory effect on bone loss in ovariectomized rats with a marked reduction of hepatomegaly and peroxisomal proliferation compared to DHEA.
PMCID: PMC3054677  PMID: 11068990
11.  Neurosteroid Dehydroepiandrosterone Interacts with Nerve Growth Factor (NGF) Receptors, Preventing Neuronal Apoptosis 
PLoS Biology  2011;9(4):e1001051.
The neurosteroid dehydroepiandrosterone (DHEA), produced by neurons and glia, affects multiple processes in the brain, including neuronal survival and neurogenesis during development and in aging. We provide evidence that DHEA interacts with pro-survival TrkA and pro-death p75NTR membrane receptors of neurotrophin nerve growth factor (NGF), acting as a neurotrophic factor: (1) the anti-apoptotic effects of DHEA were reversed by siRNA against TrkA or by a specific TrkA inhibitor; (2) [3H]-DHEA binding assays showed that it bound to membranes isolated from HEK293 cells transfected with the cDNAs of TrkA and p75NTR receptors (KD: 7.4±1.75 nM and 5.6±0.55 nM, respectively); (3) immobilized DHEA pulled down recombinant and naturally expressed TrkA and p75NTR receptors; (4) DHEA induced TrkA phosphorylation and NGF receptor-mediated signaling; Shc, Akt, and ERK1/2 kinases down-stream to TrkA receptors and TRAF6, RIP2, and RhoGDI interactors of p75NTR receptors; and (5) DHEA rescued from apoptosis TrkA receptor positive sensory neurons of dorsal root ganglia in NGF null embryos and compensated NGF in rescuing from apoptosis NGF receptor positive sympathetic neurons of embryonic superior cervical ganglia. Phylogenetic findings on the evolution of neurotrophins, their receptors, and CYP17, the enzyme responsible for DHEA biosynthesis, combined with our data support the hypothesis that DHEA served as a phylogenetically ancient neurotrophic factor.
Author Summary
Dehydroepiandrosterone (DHEA) and its sulphate ester are the most abundant steroid hormones in humans, and DHEA was described as the first neurosteroid produced in the brain. DHEA is known to participate in multiple events in the brain, including neuronal survival and neurogenesis. However, to date no specific cellular receptor has been described for this important neurosteroid. In this study, we provide evidence that DHEA exerts its neurotrophic effects by directly interacting with the TrkA and p75NTR membrane receptors of nerve growth factor (NGF), and efficiently activates their downstream signaling pathways. This activation prevents the apoptotic loss of NGF receptor positive sensory and sympathetic neurons. The interaction of DHEA with NGF receptors may also offer a mechanistic explanation for the multiple actions of DHEA in other peripheral biological systems expressing NGF receptors, such as the immune, reproductive, and cardiovascular systems.
doi:10.1371/journal.pbio.1001051
PMCID: PMC3082517  PMID: 21541365
12.  Dehydroepiandrosterone anti-atherogenesis effect is not via its conversion to estrogen 
Acta Pharmacologica Sinica  2008;30(1):42-53.
Aim:
This study was conducted to demonstrate the anti-atherosclerotic effect of dehydroepiandrosterone (DHEA) and to investigate its possible mechanisms and whether this effect is related to its conversion to estrogen.
Methods:
Forty male New Zealand White rabbits aged 3 months were divided into 5 groups (n=8 per group) and fed different diets for 10 weeks. Serum lipid levels, the area of atherosclerotic lesions and the mRNA levels of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) in aortic lesions were measured. Then cultured vascular smooth muscle cells (VSMCs) stimulated by oxidized low density lipoprotein-cholesterol (ox-LDL) were treated by DHEA. The gene and protein expression levels of MCP-1 and VCAM-1 in VSMCs was detected. The plasmid with or without the gene of cytochrome P450 aromatase (CYP19) was transient transfected into cultured VSMCs respectively. Twenty hours later, the cells were stimulated with ox-LDL and DHEA.
Results:
DHEA could obviously decrease the area of atherosclerotic lesions and the expressions of MCP-1 and VCAM-1 in aortic lesions. But all-trans retinoic acid (atRA) which was reported would limit restenosis after balloon angioplasty had no visible synergistic effect with DHEA. DHEA could also reduce ox-LDL-induced MCP-1 and VCAM-1 expression in untransfected or transfected VSMCs.
Conclusion:
The anti-atherosclerotic effect of DHEA had nothing to do with the catalysis of cytochrome P450 aromatase (CYP19), or was not related to its conversion to estrogen.
doi:10.1038/aps.2008.2
PMCID: PMC4006531  PMID: 19060916
dehydroepiandrosterone; cytochrome P450 aromatase; all-trans retinoic acid; atherosclerosis; transfection; MCP-1; VCAM-1
13.  Oral dehydroepiandrosterone (DHEA) replacement in older adults: effects on central adiposity, glucose metabolism, and blood lipids 
Clinical endocrinology  2011;75(4):456-463.
Objective
The aim was to determine the effects of dehydroepiandrosterone (DHEA) therapy on changes in central adiposity, insulin action, and blood lipids. Many of the actions of DHEA in humans are thought to be mediated through its conversion to sex hormones, which are modulators of adiposity, muscularity, and insulin sensitivity. The effects of DHEA replacement on regional tissue composition, glucose metabolism, and blood lipid profile in older adults have been inconsistent.
Design
a randomized, double-blinded, placebo-controlled trial. The intervention was oral DHEA 50 mg/d or placebo for 12 months.
Participants
58 women and 61 men, aged 60–88 yr, with low serum DHEA sulfate (DHEAS) levels at study entry.
Measurements
Computed tomography measures of abdominal fat areas, thigh muscle and fat areas, DXA-derived trunk fat mass, serum glucose and insulin responses to an oral glucose challenge, and fasted serum total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides were assessed before and after the intervention.
Results
There were no significant (P > 0.05) differences between the DHEA and placebo groups in the changes in regional tissue composition or glucose metabolism. HDL-cholesterol (P =0.01) and fasted triglycerides (P =0.02) decreased in women and men taking DHEA.
Conclusion
Restoring serum DHEAS levels in older adults to young adult levels for 1 year does not appear to reduce central adiposity or improve insulin action. The benefit of DHEA on decreasing serum triglycerides must be weighed against the HDL-lowering effect.
doi:10.1111/j.1365-2265.2011.04073.x
PMCID: PMC3166648  PMID: 21521341
dehydroepiandrosterone; regional adiposity; insulin action
14.  Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake 
Glucocorticoids increase adipocyte proliferation and differentiation, a process underpinned by the local reactivation of inactive cortisone to active cortisol within adipocytes catalyzed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal sex steroid precursor dehydroepiandrosterone (DHEA) has been shown to inhibit 11β-HSD1 in murine adipocytes; however, rodent adrenals do not produce DHEA physiologically. Here, we aimed to determine the effects and underlying mechanisms of the potential antiglucocorticoid action of DHEA and its sulfate ester DHEAS in human preadipocytes. Utilizing a human subcutaneous preadipocyte cell line, Chub-S7, we examined the metabolism and effects of DHEA in human adipocytes, including adipocyte proliferation, differentiation, 11β-HSD1 expression, and activity and glucose uptake. DHEA, but not DHEAS, significantly inhibited preadipocyte proliferation via cell cycle arrest in the G1 phase independent of sex steroid and glucocorticoid receptor activation. 11β-HSD1 oxoreductase activity in differentiated adipocytes was inhibited by DHEA. DHEA coincubated with cortisone significantly inhibited preadipocyte differentiation, which was assessed by the expression of markers of early (LPL) and terminal (G3PDH) adipocyte differentiation. Coincubation with cortisol, negating the requirement for 11β-HSD1 oxoreductase activity, diminished the inhibitory effect of DHEA. Further consistent with glucocorticoid-opposing effects of DHEA, insulin-independent glucose uptake was significantly enhanced by DHEA treatment. DHEA increases basal glucose uptake and inhibits human preadipocyte proliferation and differentiation, thereby exerting an antiglucocorticoid action. DHEA inhibition of the amplification of glucocorticoid action mediated by 11β-HSD1 contributes to the inhibitory effect of DHEA on human preadipocyte differentiation.
doi:10.1152/ajpendo.00314.2012
PMCID: PMC3840204  PMID: 24022868
dehydroepiandrosterone; human adipogenesis; 11β-hydroxysteroid dehydrogenase type 1; insulin sensitivity
15.  The Protective Effect of Dehydroepiandrosterone on Ovarian Tissues After Torsion-Detorsion Injury: A Stereological and Histopathological Study 
Objective
Ovarian torsion is a rare problem in pre-pubescent girls that must be included in the differential diagnosis of patients with abdominal or pelvic pain. Current advice for treatment to support ovary preservation considers the macroscopic appearance of the ovary, but this is not a reliable indicator of the degree of injury in cases of ovarian torsion. The aim of this study was to determine the effects of dehydroepiandrosterone (DHEA) treatment on the rat ovary after torsion-detorsion injury using a histopathological approach and stereological methods.
Materials and Methods
Fifteen adult female Sprague Dawley rats were divided into three groups: sham operated (Control; n=5), torsion-detorsion with saline (Saline; n = 5), and torsion-detorsion with DHEA (DHEA; n = 5). Rats in the sham-operated group underwent a surgical procedure similar to the other groups, but the adnexa were not torsioned. The DHEA group was injected intraperitoneally 3 hours before detorsion and saline was administered to the saline group. After 24 h of adnexal detorsion, the rats in all groups were sacrificed and the adnexa were removed. The volume of ovarian stroma and edema were estimated using the Cavalieri Principle and were applied to serial paraffin sections. Ovary sections were also evaluated histopathologically.
Results
The volume of ovarian edema was 35.4% lower in the saline group compared to the control group (p> 0.05). The volume of ovarian edema increased by 73.4% in the DHEA group (p<0.05). In the experimental groups, stromal volume was 41.0% higher in the saline group and 52% higher in the DHEA group in comparison to the control group. Statistically significant differences were found when comparing the volume of both ovarian edema and stroma between experimental groups (Detorsion/Saline group – Detorsion/DHEA group; p< 0.01). Histopathologically, mononuclear cell infiltration and vascular dilatation, perivascular edema and common necrotic changes were obvious in the torsion-detorsion damaged ovary. These changes were partially ameliorated by DHEA treatment.
Conclusions
The present study shows that administration of DHEA has beneficial effects in the prevention of ischemia-reperfusion injuries of the ovaries.
PMCID: PMC4261661  PMID: 25610059
Ovarian torsion; DHEA; Stereology; Cavalieri Principle; Histopathology
16.  Adrenal Androgen Dehydroepiandrosterone Sulfate Inhibits Vascular Remodeling Following Arterial Injury 
Atherosclerosis  2009;206(1):77-85.
Recent epidemiologic studies have suggested that serum dehydroepiandrosterone sulfate (DHEAS) levels have a significant inverse correlation with the incidence of cardiovascular diseases. However, direct evidence for the association with DHEAS and vascular disorders has not yet been explored. DHEAS significantly reduced neointima formation 28 days after surgery without altering other serum metabolite levels in a rabbit carotid balloon injury model. Immunohistochemical analyses revealed the reduction of proliferating cell nuclear antigen (PCNA) index and increase of TdT-mediated dUTP-biotin Nick End Labeling (TUNEL) index, expressing differentiated vascular smooth muscle cell (VSMC) markers in the media 7 days after surgery. In vitro, DHEAS exhibited inhibitory effects on VSMC proliferation and migration activities, inducing G1 cell cycle arrest with upregulation of one of the cyclin dependent kinase (CDK) inhibitors p16INK4a and apoptosis with activating peroxisome proliferator-activated receptor (PPAR)-α in VSMCs. DHEAS inhibits vascular remodeling reducing neointima formation after vascular injury via its effects on VSMC phenotypic modulation, functions and apoptosis upregulating p16INK4a/activating PPARα. DHEAS may play a pathophysiological role for vascular remodeling in cardiovascular disease.
doi:10.1016/j.atherosclerosis.2009.02.021
PMCID: PMC2735614  PMID: 19298964
hormones; restenosis; vascular smooth muscle cell; apoptosis
17.  Does Hormone Replacement Normalize Bone Geometry in Adolescents with Anorexia Nervosa? 
Young women with anorexia nervosa (AN) have reduced secretion of dehydroepiandrosterone (DHEA) and estrogen contributing to skeletal deficits. In this randomized, placebo-controlled trial, we investigated the effects of oral DHEA+ combined oral contraceptive (COC) vs. placebo on changes in bone geometry in young women with AN. Eighty women with AN, aged 13-27 yr, received a random, double-blinded assignment to micronized DHEA (50 mg/d) + COC (20μg ethinyl estradiol/0.1mg levonorgestrel) or placebo for 18 mo. Measurements of aBMD at the total hip were obtained by dual-energy X-ray absorptiometry at 0, 6, 12, and 18 mo. We used the Hip Structural Analysis (HSA) Program to determine BMD, cross-sectional area (CSA), and section modulus at the femoral neck and shaft. Each measurement was expressed as a percentage of the age-, height-, and lean mass-specific mean from an independent sample of healthy adolescent females. Over the 18 months, DHEA+COC led to stabilization in femoral shaft BMD (0.0 ± 0.5 % of normal mean for age, height, and lean mass/year) compared with decreases in the placebo group (−1.1 ± 0.5% per year, p=0.03). Similarly, CSA, section modulus, and cortical thickness improved with treatment. In young women with AN, adrenal and gonadal hormone replacement improved bone health and increased cross sectional geometry. Our results indicate that this combination treatment has a beneficial impact on surrogate measures of bone strength, and not only bone density, in young women with AN.
doi:10.1002/jbmr.2005
PMCID: PMC3812374  PMID: 23744513
DHEAS; anorexia nervosa; adolescents; bone geometry; estrogen replacement therapy
18.  DHEA metabolism in prostate: For better or worse? 
Dehydroepiandrosterone (DHEA) is commonly used in the USA as a nutritional supplement for antiaging, metabolic support or other uses. Investigations into understanding the effects of DHEA on human prostate cancer progression have posed more questions than answers and highlight the importance of communications between stromal and epithelial elements within the prostate that contribute to the regulation of DHEA metabolism. Intracrine metabolism of DHEA to androgens (A) and/or estrogens (E) may occur in one cell compartment (stromal) which may release paracrine hormones or growth/inhibitory factors to the epithelial cells. Alternatively no metabolism of DHEA may occur, resulting in no harmful consequences of high levels of DHEA in prostate tissues. We herein review the tissue components involved and interactions with the prohormone, DHEA and/or resulting metabolites, including dihydrotestosterone (DHT) or 17β-Estradiol (E2) in an in-vitro model of endocrine-immune-paracrine interactions within the prostate. This work raises questions and hypotheses concerning the role of DHEA in prostate in normal tissues, vs. preneoplastic tissues.
doi:10.1016/j.mce.2008.10.019
PMCID: PMC2667103  PMID: 19013497
DHEA; TGF β1; Androgen Receptor; Estrogen Receptor; stromal; epithelial prostate; PSA; testosterone; coculture; red clover isoflavones
19.  DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet☆ 
FEBS Open Bio  2014;4:141-146.
Dehydroepiandrosterone (DHEA) and the dehydroepiandrosterone sulfate (DHEA-S) are steroids produced mainly by the adrenal cortex. There is evidence from both human and animal models suggesting beneficial effects of these steroids for obesity, diabetes mellitus, hypertension, and osteoporosis, conditions associated with the post-menopausal period. Accordingly, we hypothesized that DHEA supplementation in ovariectomized (OVX) female rats fed a high-fat diet would maintain glucose-induced insulin secretion (GSIS) and pancreatic islet function. OVX resulted in a 30% enlargement of the pancreatic islets area compared to the control rats, which was accompanied by a 50% reduction in the phosphorylation of AKT protein in the pancreatic islets. However, a short-term high-fat diet induced insulin resistance, accompanied by impaired GSIS in isolated pancreatic islets. These effects were reversed by DHEA treatment, with improved insulin sensitivity to levels similar to the control group, and with increased serine phosphorylation of the AKT protein. These data confirm the protective effect of DHEA on the endocrine pancreas in a situation of diet-induced overweight and low estrogen concentrations, a phenotype similar to that of the post-menopausal period.
Highlights
•Dehydroepiandrosterone (DHEA) is a physiological precursor of androgens and estrogens.•Ovariectomized rats fed a high-fat diet showed insulin resistance and impaired glucose-induced insulin secretion.•These effects were reversed by DHEA treatment, with improved insulin secretion and sensitivity.
doi:10.1016/j.fob.2014.01.005
PMCID: PMC3907747  PMID: 24490138
High fat diet; Menopause; Pancreatic islets; Insulin sensitivity; Insulin secretion; p-Akt/Akt; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; HFD, high-fat diet; SHAM, sham-operated rats; SHL, sham rats fed a HFD; OVX, ovariectomized rats; OHL, ovariectomized rats fed HFD; OHLD, ovariectomized rats fed a HFD and treated with DHEA; Kitt, glucose disappearance rate; GTT, glucose tolerance test; GSIS, glucose-induced insulin secretion; SDS–PAGE, sodium dodecyl sulfate poly-acrylamide electrophoresis; PI, propidium iodide; PI3K, phosphatidylinositol-3-kinase; PI3K-PDK1-Akt, PI3K-3-phosphoinositide dependent kinase-Akt
20.  Oxidative Stress-Mediated Brain Dehydroepiandrosterone (DHEA) Formation in Alzheimer’s Disease Diagnosis 
Neurosteroids are steroids made by brain cells independently of peripheral steroidogenic sources. The biosynthesis of most neurosteroids is mediated by proteins and enzymes similar to those identified in the steroidogenic pathway of adrenal and gonadal cells. Dehydroepiandrosterone (DHEA) is a major neurosteroid identified in the brain. Over the years we have reported that, unlike other neurosteroids, DHEA biosynthesis in rat, bovine, and human brain is mediated by an oxidative stress-mediated mechanism, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and β-amyloid peptide. Neurosteroids are involved in many aspects of brain function, and as such, are involved in various neuropathologies, including Alzheimer’s disease (AD). AD is a progressive, yet irreversible neurodegenerative disease for which there are limited means for ante-mortem diagnosis. Using brain tissue specimens from control and AD patients, we provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting levels of the precursor in the blood stream. We tested for the presence of this DHEA precursor in human serum using a Fe2+-based reaction and determined the amounts of DHEA formed. Fe2+ treatment of the serum resulted in a dramatic increase in DHEA levels in control patients, whereas only a moderate or no increase was observed in AD patients. The DHEA variation after oxidation correlated with the patients’ cognitive and mental status. In this review, we present the cumulative evidence for oxidative stress as a natural regulator of DHEA formation and the use of this concept to develop a blood-based diagnostic tool for neurodegenerative diseases linked to oxidative stress, such as AD.
doi:10.3389/fendo.2011.00069
PMCID: PMC3356139  PMID: 22654823
Alzheimer’s disease; dehydroepiandrosterone; diagnostic tool; neurosteroids
21.  Oriental Medicine Kyung-Ok-Ko Prevents and Alleviates Dehydroepiandrosterone-Induced Polycystic Ovarian Syndrome in Rats 
PLoS ONE  2014;9(2):e87623.
Kyung-Ok-Ko (KOK), a traditional herbal prescription composed of Rehmannia glutinosa Liboschitz var. purpurae, Lycium chinense, Aquillaria agallocha, Poria cocos, Panax ginseng, and honey, has been widely used in traditional Oriental medicine as a vitalizing medicine or as the prescription for patients with age-associated disorders such as amnesia and stroke. However, the potential protective value of KOK for the treatment of polycystic ovarian syndrome (PCOS) is largely unknown. We investigated whether pre-administration (daily from 2 hours before PCOS induction) and post-administration (daily after induction of PCOS) of KOK (0.5, 1.0, and 2.0 g/kg/day, p.o.) could have a protective effect in a dehydroepiandrosterone (DHEA, s.c.)-induced PCOS rat model. Pre-administration of KOK significantly decreased the elevated body weight and ovary weight, elevated size and number of follicular cysts, elevated level of serum glucose, and estradiol after DHEA injection. KOK reduced the elevated percentage of CD8 (+) T lymphocytes in lymph nodes, the elevated mRNA expression of CD11b and CD3 in ovaries, and infiltration of macrophages in ovarian tissue with PCOS. KOK diminished the increased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), chemokines (IL-8, MCP-1), and iNOS in the ovaries, and increased the reduced mRNA expression of growth factors (EGF, TGF-β) by DHEA injection. Post-administration of KOK also improved the DHEA-induced PCOS-like symptoms, generally similar to those evident from pre-administration of KOK. KOK may effectively prevent and improve DHEA-induced PCOS via anti-inflammatory action, indicating its preventive and therapeutic potential for suppressing PCOS.
doi:10.1371/journal.pone.0087623
PMCID: PMC3919730  PMID: 24520334
22.  Dehydroepiandrosterone supplement increases malate dehydrogenase activity and decreases NADPH-dependent antioxidant enzyme activity in rat hepatocellular carcinogenesis 
Beneficial effects of dehydroepiandrosterone (DHEA) supplement on age-associated chronic diseases such as cancer, cardiovascular disease, insulin resistance and diabetes, have been reported. However, its mechanism of action in hepatocellular carcinoma in vivo has not been investigated in detail. We have previously shown that during hepatocellular carcinogenesis, DHEA treatment decreases formation of preneoplastic glutathione S-transferase placental form-positive foci in the liver and has antioxidant effects. Here we aimed to determine the mechanism of actions of DHEA, in comparison to vitamin E, in a chemically-induced hepatocellular carcinoma model in rats. Sprague-Dawley rats were administered with control diet without a carcinogen, diets with 1.5% vitamin E, 0.5% DHEA and both of the compounds with a carcinogen for 6 weeks. The doses were previously reported to have anti-cancer effects in animals without known toxicities. With DHEA treatment, cytosolic malate dehydrogenase activities were significantly increased by ~5 fold and glucose 6-phosphate dehydrogenase activities were decreased by ~25% compared to carcinogen treated group. Activities of Se-glutathione peroxidase in the cytotol was decreased significantly with DHEA treatment, confirming its antioxidative effect. However, liver microsomal cytochrome P-450 content and NADPH-dependent cytochrome P-450 reductase activities were not altered with DHEA treatment. Vitamin E treatment decreased cytosolic Se-glutathione peroxidase activities in accordance with our previous reports. However, vitamin E did not alter glucose 6-phosphate dehydrogenase or malate dehydrogenase activities. Our results suggest that DHEA may have decreased tumor nodule formation and reduced lipid peroxidation as previously reported, possibly by increasing the production of NADPH, a reducing equivalent for NADPH-dependent antioxidant enzymes. DHEA treatment tended to reduce glucose 6-phosphate dehydrogenase activities, which may have resulted in limited supply for de novo synthesis of DNA via inhibiting the hexose monophophaste pathway. Although both DHEA and vitamin E effectively reduced preneoplastic foci in this model, they seemed to function in different mechanisms. In conclusion, DHEA may be used to reduce hepatocellular carcinoma growth by targeting NADPH synthesis, cell proliferation and anti-oxidant enzyme activities during tumor growth.
doi:10.4162/nrp.2008.2.2.80
PMCID: PMC2815321  PMID: 20126370
Hepatocellular carcinoma; DHEA; malate dehydrogenase; NADPH and glucose 6-phosphate dehydrogenase
23.  Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults 
Summary
We present results of a randomized, placebo-controlled trial to examine the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism and body composition in 225 healthy adults aged 55 to 85 years.
Introduction
Dehydroepiandrosterone (DHEA) levels decline dramatically with age, concurrent with the onset of osteoporosis, suggesting a role for DHEA supplementation in preventing age-related bone loss.
Methods
We conducted a randomized, placebo-controlled trial to examine the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism and body composition in 225 healthy adults aged 55 to 85 years.
Results
DHEA treatment increased serum DHEA and DHEA sulfate levels to concentrations seen in young adults. Testosterone, estradiol and insulin-like growth factor (IGF-1) levels increased in women (all p<0.001), but not men, receiving DHEA. Serum C-terminal telopeptide of type-1 collagen levels decreased in women (p=0.03), but not men, whereas bone-specific alkaline phosphatase levels were not significantly altered in either sex. After 12 months, there was a positive effect of DHEA on lumbar spine BMD in women (p=0.03), but no effect was observed for hip, femoral neck or total body BMD, and no significant changes were observed at any site among men. Body composition was not affected by DHEA treatment in either sex.
Conclusion
Among older healthy adults, daily administration of 50 mg of DHEA has a modest and selective beneficial effect on BMD and bone resorption in women, but provides no bone benefit for men.
doi:10.1007/s00198-007-0520-z
PMCID: PMC2435090  PMID: 18084691
Body composition; Bone metabolism; Bone mineral density (BMD); Dehydroepiandrosterone (DHEA) levels; Placebo-controlled trial; Testosterone
24.  DHEA replacement in hypoadrenal women - investigation on protein anabolism and skeletal muscle function 
Mayo Clinic proceedings. Mayo Clinic  2008;83(11):1218-1225.
Objective
To determine whether dehydroepiandrosterone replacement in hypoadrenal women improves performance, muscle protein accretion and mitochondrial functions.
Participants and methods
Thirty-three hypoadrenal women were enrolled between 1st May 2002 and 31st May 2003. 28 completed a 12 week prospective randomized, placebo-controlled, crossover study with either daily placebo or 50 mg DHEA with a 2-week of washout, and then crossed over to the other treatment. Body composition, physical performance, whole body and muscle protein metabolism and mitochondrial functions were determined.
Results
DHEA administration significantly increased plasma levels of DHEA-S, testosterone and androstenedione but did not change body composition, muscle strength, peak aerobic capacity, and whole body protein turnover or synthesis rates of mitochondrial, sarcoplasmic or mixed muscle proteins. Muscle mitochondrial oxidative enzymes and mRNA levels of genes encoding mitochondrial proteins and nuclear transcription factors did not change following DHEA administration. However, mRNA levels of muscle myosin heavy chain isoform 1 (MHC I) (P<0.005) which determines muscle fiber type as well as those of IGF Binding Proteins 4 and 5 significantly decreased (P<0.04 respectively).
Conclusion
Three months of DHEA increased DHEA-S and androgen levels but had no impact on physical performance, body composition, protein metabolism or on muscle mitochondrial biogenesis in hypoadrenal women. However, lowering of mRNA levels of binding proteins of IGF 1 and MHC I suggest potential effects of DHEA on muscle fibre type on long term treatment.
PMCID: PMC2753533  PMID: 18990320
Dehydroepiandrosterone; hypoadrenal; muscle strength
25.  SYNERGISTIC EFFECTS OF DEHYDROEPIANDROSTERONE AND FLUOXETINE ON PROLIFERATION OF PROGENITOR CELLS IN THE DENTATE GYRUS OF THE ADULT MALE RAT 
Neuroscience  2008;158(4):1644-1651.
The 5-HT re-uptake inhibitor (SSRI) fluoxetine and the adrenal hormone dehydroepiandrosterone (DHEA) both increase the proliferation of progenitor cells in the adult hippocampus and also have antidepressant activity. This paper explores the combined ability of fluoxetine and DHEA to affect this process in the dentate gyrus of adult rats. We show that DHEA can render an otherwise ineffective dose of fluoxetine (2.5 mg/kg) able to increase progenitor cell proliferation to the same extent as doses four times higher (10 mg/kg). This synergistic action does not appear to be mediated by alterations in brain-derived neurotrophic factor (BDNF) gene expression; or by TrkB, mineralocorticoid, glucocorticoid, or 5-HT (5HT1A) receptor expression in the dentate gyrus; or by altered levels of plasma corticosterone. In a second experiment, the synergism between DHEA and fluoxetine was replicated. Furthermore, flattening the diurnal rhythm of plasma corticosterone by implanting additional corticosterone pellets s.c. prevented the effect of fluoxetine on progenitor cell division. This was not overcome by simultaneous treatment with DHEA, despite the latter’s reported anti-glucocorticoid actions. The cellular mechanism for the potentiating action of DHEA on the pro- proliferative effects of fluoxetine in the adult hippocampus remains to be revealed. Since altered neurogenesis has been linked to the onset or recovery from depression, one consequence of these results is to suggest DHEA as a useful adjunct therapy for depression.
doi:10.1016/j.neuroscience.2008.10.035
PMCID: PMC2653077  PMID: 19068226
neurogenesis; fluoxetine; dehydroepiandrosterone; corticosterone; synergism; dentate gyrus

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