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1.  Dehydroepiandrosterone and age-related cognitive decline 
Age (Dordrecht, Netherlands)  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
2.  Dehydroepiandrosterone sulfate (DHEAS) levels reflect endogenous LH production and response to human chorionic gonadotropin (hCG) challenge in the older female macaque (Macaca fascicularis) 
Menopause (New York, N.Y.)  2013;20(3):329-335.
Hypothesis
We propose that the adrenal gland of an older higher primate female animal model will respond to a human chorionic gonadotropic (hCG) hormone challenge by secreting additional dehydroepiandrosterone sulfate (DHEAS). Such a response in surgically and chemically-castrated animals will provide proof-of-concept and a validated animal model for future studies to explore the rise of DHEAS during the menopausal transition of women.
Methods
Twenty four 18–26 y/o female cynomolgus monkeys were screened for ovarian function then either ovariectomized (n=4) or treated with a gonadotropic releasing hormone agonist (GnRHa) (n=20) to block ovarian steroid production. Following a recovery period from surgery or down-regulation, a single dose challenge (1,000 IU; IM) of human chorionic gonadotropin (hCG) was then administered in order to determine if LH/CG could accelerate circulating DHEAS production. Serum DHEAS, bioactive LH and urinary metabolites of ovarian sex steroids were monitored before, during and following these treatments.
Results
Circulating LH bioactivity and immunoreactive DHEAS concentrations were suppressed in all animals 14 days post administration of GnRHa. Urinary metabolites of estradiol and progesterone remained low following surgery or the flare reaction to GnRHa. Circulating DHEAS levels were increased following hCG administration and the increase in individual animals was proportional to the pre-treatment DHEAS baseline. Circulating DHEAS concentrations were positively correlated to endogenous LH bioactive concentrations prior to, and were increased by hCG challenge while no concomitant change was observed in ovarian steroid hormone excretion.
Conclusion
These data demonstrate a positive adrenal androgen response to LH/CG in older female higher primates and suggests a mechanism for the rise in adrenal androgen production during the menopausal transition in women. These results also illustrate that the nonhuman primate animal model can be effectively used to investigate this phenomenon.
doi:10.1097/GME.0b013e3182698f80
PMCID: PMC3546135  PMID: 23435031
DHEAS; menopause; adrenal androgens; LH/hCG
3.  Perimenopausal regulation of steroidogenesis in the nonhuman primate 
Neurobiology of Aging  2011;33(7):1487.e1-1487.e13.
Human aging is characterized by a marked decrease in circulating levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate (DHEAS), hormonal changes associated with cognitive decline. Despite beneficial effects of DHEA supplementation in rodents, studies in elderly humans have generally failed to show cognitive improvement after treatment. In the present study we evaluate the effects of age and estradiol supplementation on expression of genes involved in the de novo synthesis of DHEA and its conversion to estradiol in the rhesus macaque hippocampus. Using RT-PCR we demonstrate the expression of genes associated with this synthesis in several areas of the rhesus brain. Furthermore, real-time PCR reveals an age-related attenuation of hippocampal expression level of the genes CYP17A1, STS, and 3BHSD1/2. Additionally, short-term administration of estradiol is associated with decreased expression of CYP17A1, STS, SULT2B1, and AROMATASE, consistent with a downregulation not only of estrogen synthesis from circulating DHEA, but also of de novo DHEA synthesis within the hippocampus. These findings suggest a decline in neurosteroidogenesis may account for the inefficacy of DHEA supplementation in elderly humans, and that central steroidogenesis may be a function of circulating hormones and menopausal status.
doi:10.1016/j.neurobiolaging.2011.05.004
PMCID: PMC3196783  PMID: 21683476
Aging; Dehydroepiandrosterone; Hormone replacement; Menopause; Neurosteroidogenesis
4.  Causes and consequences of age-related steroid hormone changes: insights gained from nonhuman primates 
Journal of neuroendocrinology  2013;25(11):1062-1069.
Like humans, rhesus macaques (Macaca mulatta) are large, long-lived diurnal primates, and show similar age-related changes in the secretion of many steroid hormones, including oestradiol, testosterone, cortisol, and dehydroepiandrosterone (DHEA). Consequently, they represent a pragmatic animal model in which to examine the mechanisms by which these steroidal changes contribute to perturbed sleep-wake cycles and cognitive decline in the elderly. Using remote serial blood sampling we have found the circulating levels of DHEA sulphate, as well as oestradiol and testosterone, decline markedly in old monkeys. Furthermore, using real-time PCR, we have shown that genes associated with the conversion of DHEA to oestradiol and testosterone (e.g., 3BHSD, 17BHSD, and aromatase) are highly expressed in brain areas associated with cognition and behavior, including the hippocampus, prefrontal cortex, and amygdala. Taken together, these findings suggest that administration of supplementary DHEA in the elderly may have therapeutic potential for cognitive and behavioral disorders, but with fewer negative side effects outside of the central nervous system. To test this we have developed a novel steroid supplementation paradigm for use in old animals; this involves oral administration of DHEA and testosterone at physiologically relevant times of the day to mimic the circadian hormone patterns observed in young adults. We are currently evaluating the efficacy of this steroid supplementation paradigm at reversing age-associated disorders, including perturbed sleep-wake cycles and cognitive decline as well as impaired immune response.
doi:10.1111/jne.12064
PMCID: PMC3883982  PMID: 23796387
dehydroepiandrosterone; oestradiol; testosterone; circadian rhythms
5.  Modulation of Higher Primate Adrenal Androgen Secretion with Estradiol or Estradiol and Progesterone Intervention 
Menopause (New York, N.Y.)  2013;20(3):10.1097/GME.0b013e318273a070.
Background
Circulating adrenal steroids rise during the menopausal transition (MT) in most mid-aged women and may contribute to differences in between-woman symptoms as well as ultimate health outcomes. However, the mechanism(s) for this shift in adrenal steroid production in mid-aged women is not known.
Objective
To determine if hormone replacement therapy (HT) for one year can modulate adrenal androgen production.
Method
Younger (9.8 +/− 0.4 y/o, n=20) and older (22.7+/−0.4 y/o, n=37) female laboratory macaques were ovariectomized (OVX), and then each group was treated with different regimens of HT for up to one year. Changes in adrenal histology and circulating adrenal androgens were monitored following estradiol treatment alone (E) or estrogen plus progesterone (E+P), and these changes were compare to the same measures in similar aged animals given vehicle (V).
Results
Zona reticularis (ZR) area and serum dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) were higher in younger compared to older V-treated animals (P< 0.02). Both E and E+P treatments decreased circulating DHEAS in the younger group (P<0.05). While E also decreased DHEAS in the older group, this was not statistically significant. In contrast, E+P treatment in the older group resulted in a rise in DHEAS over V, which was significantly higher than the results of E alone (p< 0.01). Circulating concentrations of DHEA exhibited similar trends but these changes did not reach statistical significance.
Conclusion
These data demonstrate that intervention with ovarian steroids can modulate adrenal androgen production in female higher primates and that both animal age and type of HT regimen determines the adrenal response.
doi:10.1097/GME.0b013e318273a070
PMCID: PMC3610787  PMID: 23435030
Adrenal; Steroids; Hormone Therapy; Replacement
6.  Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms 
PLoS Genetics  2011;7(4):e1002025.
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10−36), SULT2A1 (rs2637125; p = 2.61×10−19), ARPC1A (rs740160; p = 1.56×10−16), TRIM4 (rs17277546; p = 4.50×10−11), BMF (rs7181230; p = 5.44×10−11), HHEX (rs2497306; p = 4.64×10−9), BCL2L11 (rs6738028; p = 1.72×10−8), and CYP2C9 (rs2185570; p = 2.29×10−8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
Author Summary
Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It shows a significant physiological decline after the age of 25 and diminishes about 95% by the age of 85 years, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. Twin- and family-based studies have shown that there is a substantial genetic effect with heritability estimate of 60%, but no specific genes regulating serum DHEAS concentration have been identified to date. Here we take advantage of recent technical and methodological advances to examine the effects of common genetic variants on serum DHEAS concentrations. By examining 14,846 Caucasian individuals, we show that eight common genetic variants are associated with serum DHEAS concentrations. Genes at or near these genetic variants include BCL2L11, ARPC1A, ZKSCAN5, TRIM4, HHEX, CYP2C9, BMF, and SULT2A1. These genes have various associations with steroid hormone metabolism—co-morbidities of ageing including type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins—suggesting a wider functional role for DHEAS than previously thought.
doi:10.1371/journal.pgen.1002025
PMCID: PMC3077384  PMID: 21533175
7.  Dehydroepiandrosterone sulfate (DHEAS) as an endocrine marker of aging in calorie restriction studies 
Experimental gerontology  2013;48(10):1136-1139.
The adrenal steroid, dehydroepiandrosterone sulfate (DHEAS), is generally regarded as being a reliable endocrine marker of aging, because in humans and nonhuman primates its circulating concentrations are very high during young adulthood, and the concentrations then decline markedly during aging. Despite promising results from early studies, we were recently surprised to find that caloric restriction (CR) did little to prevent or delay the decline of DHEAS concentrations in old rhesus macaques. Here we summarize the use of circulating DHEAS concentrations as a biomarker of aging in CR studies and suggest reasons for its limited value. Although DHEAS can reliably predict aging in animals maintained on a standard diet, dietary manipulations may affect liver enzymes involved in the metabolism of steroid hormones. Consequently, in CR studies the reliability of using DHEAS as a biomarker of aging may be compromised.
doi:10.1016/j.exger.2013.01.001
PMCID: PMC3641169  PMID: 23318475
Adrenal gland; Biomarker; Cortisol; DHEAS; Rhesus macaque
8.  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
9.  Dehydroepiandrosterone Sulfate (DHEAS) Stimulates the First Step in the Biosynthesis of Steroid Hormones 
PLoS ONE  2014;9(2):e89727.
Dehydroepiandrosterone sulfate (DHEAS) is the most abundant circulating steroid in human, with the highest concentrations between age 20 and 30, but displaying a significant decrease with age. Many beneficial functions are ascribed to DHEAS. Nevertheless, long-term studies are very scarce concerning the intake of DHEAS over several years, and molecular investigations on DHEAS action are missing so far. In this study, the role of DHEAS on the first and rate-limiting step of steroid hormone biosynthesis was analyzed in a reconstituted in vitro system, consisting of purified CYP11A1, adrenodoxin and adrenodoxin reductase. DHEAS enhances the conversion of cholesterol by 26%. Detailed analyses of the mechanism of DHEAS action revealed increased binding affinity of cholesterol to CYP11A1 and enforced interaction with the electron transfer partner, adrenodoxin. Difference spectroscopy showed Kd-values of 40±2.7 µM and 24.8±0.5 µM for CYP11A1 and cholesterol without and with addition of DHEAS, respectively. To determine the Kd-value for CYP11A1 and adrenodoxin, surface plasmon resonance measurements were performed, demonstrating a Kd-value of 3.0±0.35 nM (with cholesterol) and of 2.4±0.05 nM when cholesterol and DHEAS were added. Kinetic experiments showed a lower Km and a higher kcat value for CYP11A1 in the presence of DHEAS leading to an increase of the catalytic efficiency by 75%. These findings indicate that DHEAS affects steroid hormone biosynthesis on a molecular level resulting in an increased formation of pregnenolone.
doi:10.1371/journal.pone.0089727
PMCID: PMC3931814  PMID: 24586990
10.  Testosterone Increases Circulating Dehydroepiandrosterone Sulfate Levels in the Male Rhesus Macaque 
The adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are two of the most abundant hormones in the human circulation. Furthermore, they are released in a circadian pattern and show a marked age-associated decline. Adult levels of DHEA and DHEAS are significantly higher in males than in females, but the reason for this sexual dimorphism is unclear. In the present study, we administered supplementary androgens [DHEA, testosterone and 5α-dihydrotestosterone (DHT)] to aged male rhesus macaques (Macaca mulatta). While this paradigm increased circulating DHEAS immediately after DHEA administration, an increase was also observed following either testosterone or DHT administration, resulting in hormonal profiles resembling levels observed in young males in terms of both amplitude and circadian pattern. This stimulatory effect was limited to DHEAS, as an increase in circulating cortisol was not observed. Taken together, these data demonstrate an influence of the hypothalamo-pituitary–testicular axis on adrenal function in males, possibly by sensitizing the zona reticularis to the stimulating action of adrenocorticopic hormone. This represents a plausible mechanism to explain sex differences in circulating DHEA and DHEAS levels, and may have important implications in the development of hormone therapies designed for elderly men and women.
doi:10.3389/fendo.2014.00101
PMCID: PMC4070064  PMID: 25009533
adrenal gland; aging; androgen; dehydroepiandrosterone; non-human primate; testosterone
11.  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
12.  A Review of Age-Related Dehydroepiandrosterone Decline and Its Association with Well-Known Geriatric Syndromes: Is Treatment Beneficial? 
Rejuvenation Research  2013;16(4):285-294.
Abstract
Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant steroids in humans. DHEA levels fall with age in men and women, reaching values sometimes as low as 10%–20% of those encountered in young individuals. This age-related decrease suggests an “adrenopause” phenomenon. Studies point toward several potential roles of DHEA, mainly through its hormonal end products, making this decline clinically relevant. Unfortunately, even if positive effects of DHEA on muscle, bone, cardiovascular disease, and sexual function seem rather robust, extremely few studies are large enough and/or long enough for conclusions regarding its effects on aging. Moreover, because it has been publically presented as a “fountain of youth” equivalent, over-the-counter preparations lacking pharmacokinetic and pharmacodynamic data are widely used worldwide. Conceptually, supplementing a pre-hormone is extremely interesting, because it would permit the human organism to adequately use it throughout long periods, increasing or decreasing end products according to his needs. Nevertheless, data on the safety profile of long-term DHEA supplementation are still lacking. In this article, we examine the potential relation between low DHEA levels and well-known age-related diseases, such as sarcopenia, osteoporosis, dementia, sexual disorders, and cardiovascular disease. We also review risks and benefits of existing protocols of DHEA supplementation.
doi:10.1089/rej.2013.1425
PMCID: PMC3746247  PMID: 23647054
13.  Enhancement of Cognitive and Electrophysiological Measures of Hippocampal Functioning in Rats by a Low, But Not High, Dose of Dehydroepiandrosterone Sulfate (DHEAS) 
Dehydroepiandrosterone sulfate (DHEAS) is a steroid hornone that is synthesized, de novo, in the brain. Endogenous DHEAS levels correlate with the quality of mental and physical health, where the highest levels of DHEAS occur in healthy young adults and reduced levels of DHEAS are found with advanced age, disease, or extreme stress. DHEAS supplementation, therefore, may serve as a therapeutic agent against a broad range of maladies. This paper summarizes laboratory findings on dose-response relationships between DHEAS and cognitive and electrophysiological measures of hippocampal functioning. It was found that a low, but not a high, dose of DHEAS enhanced hippocampal primed burst potentiation (a physiological model of memory) as well as spatial (hippocampal-dependent) memory in rats. This complex dose-response function of DHEAS effects on the brain and memory may contribute toward the inconsistent findings that have been obtained by other investigators in studies on DHEAS administration in people.
doi:10.1080/15401420490900290
PMCID: PMC2657507  PMID: 19330152
neurosteroid; dehydroepiandrosterone; DHEA; hippocampus; long-term potentiation; memory
14.  Dynamics of Adrenal Steroids Are Related to Variations in Th1 and Treg Populations during Mycobacterium tuberculosis Infection in HIV Positive Persons 
PLoS ONE  2012;7(3):e33061.
Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.
doi:10.1371/journal.pone.0033061
PMCID: PMC3303789  PMID: 22431997
15.  Androstenediol Complements Estrogenic Bioactivity during the Menopausal Transition 
Menopause (New York, N.y.)  2012;19(6):650-657.
Objective
The perimenopausal increase in circulating dehydroepiandrosterone sulfate (DHEAS) levels during the menopausal transition (MT) is accompanied by other adrenal steroids that have the potential to alter the estrogen/androgen balance and explain the wide inter-woman range of estrogen-related symptoms experienced during the MT.
Methods
Annual serum samples from the Study of Women’s Health Across the Nation (SWAN), which had previously been analyzed for immunoreactive estradiol (E2), testosterone (T), DHEAS and sex hormone binding globulin (SHBG), were selected based on DHEAS concentration and analyzed for immunoreactive and bioactive estrogens and androgens, including immunoreactive androstenedione (Adione), dehydroepiandrosterone (DHEA) and 5-androstene-3β,17β-diol (androstenediol, Adiol).
Results
A two-fold increase in circulating Adione and T was found to rise in parallel with the rise in circulating DHEAS, while DHEA and Adiol concentrations rose seven to eightfold. Circulating Adiol, which has both androgenic and estrogenic biological activity, was significantly associated (p<0.02) with circulating estrogen bioactivity only when E2 concentrations were low and Adiol levels were high.
Conclusions
The wide range of circulating levels of Adiol and its contribution to total circulating estrogenicity during the MT is consistent with the observed inter-woman difference in symptoms at this time. Therefore, we conclude that Adiol contributes to circulating estrogenicity when E2 production falls at menopause and may contribute significantly to the endocrine changes experienced by midlife women.
doi:10.1097/gme.0b013e31823df577
PMCID: PMC3366061  PMID: 22415563
Androstenediol; estrogenicity; menopause; adrenal
16.  Administration of Dehydroepiandrosterone (DHEA) Enhances Visual-Spatial Performance in Post-Menopausal Women 
Behavioral neuroscience  2011;125(5):742-752.
The current paper examines the effect of administering Dehydroepiandrosterone (DHEA) on visual-spatial performance in post-menopausal women (N=24, ages 55-80). The concurrent reduction of serum DHEA levels and visual-spatial performance in this population, coupled with the documented effects of DHEA’s androgenic metabolites on visual-spatial performance, suggest that DHEA administration may enhance visual-spatial performance. The current experiment used a double-blind placebo-controlled crossover design in which 50 mg of oral DHEA was administered daily in the drug condition to explore this hypothesis. Performance on the Mental Rotation, Subject-Ordered Pointing, Fragmented Picture Identification, Perceptual Identification, Same-Different Judgment, and Visual Search tasks and serum levels of DHEA, DHEAS, testosterone, estrone and cortisol were measured in the DHEA and placebo conditions. In contrast to prior experiments using the current methodology that did not demonstrate effects of DHEA administration on episodic and short-term memory tasks, the current experiment demonstrated large beneficial effects of DHEA administration on Mental Rotation, Subject-Ordered Pointing, Fragmented Picture Identification, Perceptual Identification and Same-Different Judgment. Moreover, DHEA administration enhanced serum levels of DHEA, DHEAS, testosterone and estrone, and regression analyses demonstrated that levels of DHEA and its metabolites were positively related to cognitive performance on the visual-spatial tasks in the DHEA condition
doi:10.1037/a0025151
PMCID: PMC3715689  PMID: 21942436
Dehydroepiadrosterone (DHEA); post-menopausal women; cognition; visual-spatial tasks; androgens
17.  Sex differences in the relationship between DHEAS and health 
Experimental gerontology  2007;42(10):979-987.
Dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS) have been the focus of considerable publicity because of their demonstrated associations with a broad range of health outcomes. Yet, knowledge about the effects of endogenous DHEA(S) on health in humans is limited and often inconclusive, largely because few of the studies have been based on prospective surveys of population-representative samples. This analysis uses a national longitudinal survey in Taiwan to investigate whether DHEAS is associated with subsequent changes (2000–2003) in functional limitations, cognitive impairment, depressive symptoms, and global self-rated health. Multivariate regression models based on this older Taiwanese sample show that among men, lower levels of DHEAS are related to declines in mobility and self-assessed health status and increases in depressive symptoms, while both low and very high levels of DHEAS are associated with poor cognitive function. There are no significant associations among women. These findings differ from those in a previous cross-sectional analysis based on the Taiwan study and underscore the importance of using prospective data to examine the effects of DHEAS on health. The evidence based on this and other longitudinal studies suggests that endogenous DHEAS is related to health outcomes for men, but not women, in both Western and non-Western populations.
doi:10.1016/j.exger.2007.05.005
PMCID: PMC2968710  PMID: 17604586
Dehydroepiandrosterone; Dehydroepiandrosterone sulfate; Health; Mental Health; Longitudinal Survey; Aged; Taiwan
18.  3β-HSD ACTIVATES DHEA IN THE SONGBIRD BRAIN 
Neurochemistry international  2007;52(4-5):611-620.
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 3β-hydroxysteroid dehydrogenase/isomerase (3β-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 3β-HSD in the adult and developing songbird brain. Studies examining neural 3β-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 3β-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 neurohormone in songbirds, and 3β-HSD is a key enzyme in the songbird brain.
doi:10.1016/j.neuint.2007.05.003
PMCID: PMC2441539  PMID: 17643555
3beta-HSD; adrenal; aggression; aromatase; brain; DHEA; estrogen; neurosteroid; season; song; sparrow; stress; testosterone; zebra finch
19.  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
20.  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
21.  DHEA administration and exercise training improves insulin resistance in obese rats 
Background
Dehydroepiandrosterone (DHEA) is precursor of sex steroid hormone. We demonstrated that acute DHEA injection to type 1 diabetes model rats induced improvement of hyperglycemia. However, the effect of the combination of DHEA administration and exercise training on insulin resistance is still unclear. This study was undertaken to determine whether 6-weeks of DHEA administration and/or exercise training improve insulin resistance in obese male rats.
Methods
After 14 weeks of a high-sucrose diet, obese male Wistar rats were assigned randomly to one of four groups: control, DHEA administration, exercise training, and a combination of DHEA administration and exercise training (n = 10 each group).
Results
After 6-weeks of DHEA administration and/or exercise training, rats in the combination group weighed significantly less and had lower serum insulin levels than rats in the other groups. Moreover, the rats treated with DHEA alone or DHEA and exercise had significantly lower fasting glucose levels (combination, 84 ± 6.5 mg/dL; DHEA, 102 ± 9.5 mg/dL; control, 148 ± 10.5 mg/dL). In addition, insulin sensitivity check index showed significant improvements in the combination group (combination, 0.347 ± 0.11; exercise, 0.337 ± 0.16%; DHEA, 0.331 ± 0.14; control, 0.308 ± 0.12). Muscular DHEA and 5α-dihydrotestosterone (DHT) concentrations were significantly higher in the combination group, and closely correlated with the quantitative insulin-sensitivity check index (DHEA: r = 0.71, p < 0.01; DHT: r = 0.69, p < 0.01).
Conclusion
These results showed that a combination of DHEA administration and exercise training effectively improved fasting blood glucose and insulin levels, and insulin sensitivity, which may reflect increased muscular DHEA and DHT concentrations.
doi:10.1186/1743-7075-9-47
PMCID: PMC3433349  PMID: 22647230
Exercise training; Insulin sensitivity; Sex steroid hormone; Obesity
22.  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
23.  Administration of Dehydroepiandrosterone (DHEA) Increases Serum Levels of Androgens and Estrogens But Does Not Enhance Short-term Memory in Post-Menopausal Women 
Brain research  2012;1483:54-62.
The current study examines the effect of administering dehydroepiandrosterone (DHEA) on short-term memory. This experiment used a double-blind placebo-controlled cross-over design to explore the effects of a four week regimen of 50 mg oral DHEA on performance on the digit span, verbal span, and Modified Sternberg (Oberauer) tasks. The results demonstrate that the current regimen of drug administration significantly increases serum levels of DHEA, DHEAS, testosterone and estrone and substantially alters the patterns of correlations among the serum levels of these hormones. Despite this substantial change in the hormonal milieu, DHEA administration produced no beneficial effects on cognitive performance in the digit span, verbal span, or modified Sternberg paradigm tasks. Ancillary analyses of the relation between hormone levels and cognitive performance demonstrated a strong positive correlation between DHEA levels and performance on digit span forward/backward and verbal span forward in the placebo drug condition, but not in the DHEA condition. We interpret the juxtaposition of the null results of DHEA administration and the correlation of DHEA levels and performance in the placebo condition to indicate that the referenced correlations arise because a third variable (i.e., age) is associated with both performance and DHEA levels. Additional analyses supported this hypothesis.
doi:10.1016/j.brainres.2012.09.015
PMCID: PMC3488281  PMID: 22985672
Hormone Replacement Therapy; Aging; Short-term Memory; Cognition
24.  Circulating Dehydroepiandrosterone Sulfate Levels in Women with Bilateral Salpingo-Oophorectomy during the Menopausal Transition 
Menopause (New York, N.Y.)  2011;18(5):494-498.
Background
A rise in circulating dehydroepiandrosterone sulfate (DHEAS) concentration occurs during the menopausal transition (MT) that is ovarian-stage but not age-related. The objective of this study was to determine the source of the rise in circulating DHEAS.
Methods
Circulating DS concentrations in women that had undergone bilateral salpingo-oophorectomy (BSO) were compared to the pattern of circulating DHEAS in women that progressed through the MT naturally. Annual serum samples from the Study of Women's Health Across the Nation (SWAN) over a ten year study period were used. From1272 women in the SWAN cohort that were eligible for longitudinal evaluation of DHEAS annual samples, eighty one underwent BSO during the pre- or early-perimenopause stage of the menopausal transition and were potentially available for study. Of these eighty one BSO participants, twenty had sufficient annual samples for evaluation of the post-BSO trajectory of circulating DHEAS. SWAN women not having previous hormone replacement therapy those with intact ovaries were compared to women that underwent a BSO immediately after a pre- or early perimenopausal annual visit. There were no intervention and circulating concentrations of DHEAS was the main outcome.
Results
A detectable rise in DHEAS was observed in fourteen (70%) of the twenty BSO women which is similar to the proportion (85%) of women with intact ovaries that had a detectable DHEAS rise. The mean rise in DHEAS (5-8%) was similar in both BSO and non-BSO women.
Conclusion
The MT rise in DHEAS (5-8%) occurring in the absence of ovaries is largely of adrenal origin.
doi:10.1097/gme.0b013e3181fb53fc
PMCID: PMC3123411  PMID: 21178790
Dehydroepiandrosterone sulfate; menopause; adrenal; ovary
25.  Neurobiological and Neuropsychiatric Effects of Dehydroepiandrosterone (DHEA) and DHEA Sulfate (DHEAS) 
DHEA and DHEAS are steroids synthesized in human adrenals, but their function is unclear. In addition to adrenal synthesis, evidence also indicates that DHEA and DHEAS are synthesized in the brain, further suggesting a role of these hormones in brain function and development. Despite intensifying research into the biology of DHEA and DHEAS, many questions concerning their mechanisms of action and their potential involvement in neuropsychiatric illnesses remain unanswered. We review and distill the preclinical and clinical data on DHEA and DHEAS, focusing on (i) biological actions and putative mechanisms of action, (ii) differences in endogenous circulating concentrations in normal subjects and patients with neuropsychiatric diseases, and (iii) the therapeutic potential of DHEA in treating these conditions. Biological actions of DHEA and DHEAS include neuroprotection, neurite growth, and antagonistic effects on oxidants and glucocorticoids. Accumulating data suggest abnormal DHEA and/or DHEAS concentrations in several neuropsychiatric conditions. The evidence that DHEA and DHEAS may be fruitful targets for pharmacotherapy in some conditions is reviewed.
doi:10.1016/j.yfrne.2008.11.002
PMCID: PMC2725024  PMID: 19063914
Dehydroepiandrosterone; DHEA; DHEAS; neuroprotection; neurogenesis; apoptosis; depression; schizophrenia; dementia; cortisol

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