[Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S)].
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Sex differences due to dehydroepiandrosterone (DHEA) feeding affecting dehydroepiandrosterone sulfate secretion in golden Syrian hamsters.
The metabolism of orally administered dehydroepiandrosterone (DHEA) by male and female golden Syrian hamsters was examined by quantification of DHEA and dehydroepiandrosterone sulfate (DHEAS) in gallbladder bile, urine and feces using high-performance liquid chromatography (HPLC). Plasma levels of DHEA and DHEAS were also determined by radioimmunoassay (RIA). After 5 days of oral DHEA administration (100 mg/kg body weight twice a day), RIA showed that plasma levels of DHEA and DHEAS were increased approximately 3-6 and 4-5 times, respectively, compared to controls. More than 95 % of circulating DHEA (S) in the peripheral blood was DHEAS. There was no significant sex difference in DHEAS plasma levels between male and female animals in the DHEA-supplemented group. However, 0.2 - 0.3 % of ingested DHEA was conjugated to DHEAS and excreted in urine by females, whereas less than 0.002 % was excreted in urine by males (p < 0.005). DHEAS was excreted in bile by males after DHEA supplementation, and the sex differences in DHEAS levels observed in bile were statistically significant (male, 18.7 +/- 7.5 vs. female, 5.6 +/- 3.1 micromol/l) (p < 0.005). Small amounts of ingested DHEA were excreted in an unchanged state in feces, and no sex difference was observed. These results suggest that there is a considerable sex difference in the conjugation and excretion of orally administered DHEA in the hamster.
Administration, Oral↗
Activation of immune function by dehydroepiandrosterone (DHEA) in age-advanced men.
BACKGROUND: Substantial data from animal studies have demonstrated a stimulatory effect of dehydroepiandrosterone (DHEA) on immune function. However, little is known about the effects of DHEA on the human immune system. Since aging is associated with a decline in immune function and in DHEA production, we proposed that oral administration of DHEA to elderly men would result in activation of their immune system. METHODS: Nine healthy age-advanced men (mean age of 63 years) with low DHEA-sulfate levels participated in this study. They were treated nightly with an oral placebo for 2 weeks followed by DHEA (50 mg) for 20 weeks. Fasting (0800h-0900h) blood samples were obtained at 4- to 8-week intervals for immune function studies and hormone determinations. Freshly isolated peripheral lymphocytes were used for flow cytometric identification of lymphocyte subsets, cells expressing the IL-2 receptor (IL-2R), mitogen stimulation studies, and for determining natural killer (NK) cell number and cytotoxicity. Levels of interleukin-2 (IL-2) and IL-6 secreted from cultured lymphocytes were determined under basal and mitogen stimulated conditions. Sera were analyzed for soluble IL-2 Receptor (sIL-2R) levels, insulin-like growth factor-I (IGF-I) and IGF binding protein-I (IGFBP-I) concentrations. RESULTS: Baseline levels of serum DHEA sulfate (DHEAS), a stable marker of circulating DHEA levels, were 2 standard deviations below young adult values and increased 3-4 fold within 2 weeks. These levels were sustained throughout the duration of DHEA administration. When compared with placebo, DHEA administration resulted in a 20% increase (p < .01) in serum IGF-I, a decreasing trend in IGFBP-I, and a 32% increase in the ratio of IGF-I/IGFBP-I (p < .01). Activation of immune function occurred within 2-20 weeks of DHEA treatment. The number of monocytes increased significantly (p < .01) after 2 (45%) and 20 (35%) weeks of treatment. The population of B cells fluctuated with increases (p < .05) at 2 (35%) and 10 (29%) weeks of treatment. B cell mitogenic response increased 62% (p < .05) by 12 weeks unaccompanied by changes in serum IgG, IgA, and IgM levels. Total T cells and T cell subsets were unaltered. However, a 40% increase (p < .05) in T cell mitogenic response, 39% increase in cells expressing the IL-2R (CD25+) (p < .05), and 20% increase in serum sIL-2R levels (p < .01) were found at 12-20 weeks of DHEA treatment, suggesting a functional activation of T lymphocytes occurred. In vitro mitogen stimulated release of IL-2 and IL-6 was enhanced 50% (p < .05) and 30% (p < .01) respectively by 20 weeks of treatment without basal secretion being affected. NK cell number showed a 22-37% increase (p < .01) by 18-20 weeks of treatment with a concomitant 45% increase (p < .01) in cytotoxicity. There were no adverse effects noted with DHEA administration. CONCLUSION: Administration of oral DHEA at a daily dose of 50 mg to age-advanced men with low serum DHEAS levels significantly activated immune function. The mechanism(s) to account for the immunoenhancing properties of DHEA are unclear. Consideration is given to the potential role of an increase in bioavailable IGF-I, which by virtue of its mitogenic effects on immune cell function, may mediate the DHEA effects. While extended studies are required, our findings suggest potential therapeutic benefits of DHEA in immunodeficient states.
Aged↗
[A case report of mania precipitated by use of DHEA].
Dehydroepiandrosterone (DHEA) and its sulfate ester metabolite (DHEA-S) are precursors to testosterone and, to a lesser extent, to estrogen, and, for both sexes, they are produced in the adrenal cortex. They are among the most abundant steroids in the human body, yet their physiological roles remain unknown. DHEA and DHEA-S appear to have diverse biochemical activities, including actions within the central nervous system. So DHEA is produced in the central nervous system as well as the human adrenals and is present in the brain, concentrated in limbic regions, in levels much higher than other steroids. DHEA has been postulated to function as an excitory neuroregulator, antagonizing g-aminobutyric acid transmission. The main characteristic of DHEA is that its level of concentration in plasma varies throughout life, such level being low during the early childhood and after the age of 60 years. Adrenal production and serum concentrations of DHEA are then known to peak between ages 25 and 30 years and thereafter decrease with age, severe illness and chronic stress. The decrease of DHEA over time would appear to be responsible for morbidity related to aging process. Previous reports have found low levels of DHEA in association with physical and with frailty in the elderly (immunosenescence, increased incidence of osteoporosis, atherosclerosis and cancer, decreased cognitive functions and/or well-being). As it has been touted as a fountain of youth and a sexual tonic and promoted for a variety of illnesses associated with aging, DHEA is widely available over all the United States (since 1994) as a dietary supplement. In France, as a result of a massive advertising campaign, DHEA is already the subject of a widespread use and a growing demand although it has not yet been approved by the relevant authorities for sale as drug to the public. In practice, DHEA is prescribed and delivered under the sole responsibility of both doctor and chemist who ascertain the benefit-risk ratio and the quality of the product. DHEA may then be purchased on the internet or in the form of magistral preparations delivered on the basis of such prescription. Accordingly, there is little information or data on efficacy, drug interactions, results of long-term use, abrupt discontinuation or potential adverse effects related to the use of DHEA. We report a case of mania possibly precipitated by the use of high doses of DHEA (150-200 mg/day at the time of presentation) during several weeks in a 68 years old man who had already been hospitalized for an acute mania many years ago. Although, in this case, the patient suffered a bipolar diathesis in the past, oral DHEA may have played a role in the induction of his acute manic episode. Further research is required to assess the mood effects of DHEA, including its potential risk for patients with bipolar disorder.
Adult↗
Opposing effects of DHEA replacement in elderly subjects on declarative memory and attention after exposure to a laboratory stressor.
Aging is accompanied by a continuous decline of the adrenal steroid hormone DHEA and its ester DHEAS. Results from studies in rodents have demonstrated that DHEA(S) administration can enhance memory in several test paradigms. However studies from this laboratory did not find positive effects of DHEA treatment on cognitive performance in young and elderly humans. With respect to a possible mechanism of DHEA activity, effects on several neurotransmitter receptors as well as a possible antiglucocorticoid action are discussed. For high levels of glucocorticoids, a disruptive effect on hippocampal mediated memory is documented in rodents and humans. Therefore it was speculated that, if an antiglucocorticoid action of DHEA would underlie the observed beneficial effects of DHEA on memory, these effects might only be detectable if subjects are stressed (and therefore have high cortisol levels). To test this hypothesis 75 elderly women and men participated in a placebo controlled experiment. Subjects took DHEA (50 mg/day) or placebo for 2 weeks (double blind). Thereafter they participated in a standardized psychosocial laboratory stressor (Trier Social Stress Test; TSST). Before and after stress exposure subjects completed two declarative memory tests (visual-verbal and spatial) as well as one attention test. In addition recall of visual material learned before stress was assessed after stress. Baseline DHEAS levels were significantly lower compared with young adults. DHEA replacement increased DHEAS levels into ranges found in young subjects. DHEA-substituted subjects showed a trend towards a larger cortisol stress response. In the visual memory test subjects under DHEA recalled less items after stress which they had learned before stress. In the attention test however subjects under DHEA performed better than subjects from the placebo group after stress. No interaction between stress and DHEA was found for the spatial memory task. The effects of DHEA substitution on memory and attention after stress exposure seem to be heterogenous. While recall of previously learned material seems to be impaired, attention is enhanced. These results do not support the idea of a direct antiglucocorticoid or anti-stress effect of DHEA on hippocampal mediated memory functions.
Aged↗
Stereo- and regioselectivity account for the diversity of dehydroepiandrosterone (DHEA) metabolites produced by liver microsomal cytochromes P450.
The purpose of this study was to quantify the oxidative metabolism of dehydroepiandrosterone (3beta-hydroxy-androst-5-ene-17-one; DHEA) by liver microsomal fractions from various species and identify the cytochrome P450 (P450) enzymes responsible for production of individual hydroxylated DHEA metabolites. A gas chromatography-mass spectrometry method was developed for identification and quantification of DHEA metabolites. 7alpha-Hydroxy-DHEA was the major oxidative metabolite formed by rat (4.6 nmol/min/mg), hamster (7.4 nmol/min/mg), and pig (0.70 nmol/min/mg) liver microsomal fractions. 16alpha-Hydroxy-DHEA was the next most prevalent metabolite formed by rat (2.6 nmol/min/mg), hamster (0.26 nmol/min/mg), and pig (0.16 nmol/min/mg). Several unidentified metabolites were formed by hamster liver microsomes, and androstenedione was produced only by pig microsomes. Liver microsomal fractions from one human demonstrated that DHEA was oxidatively metabolized at a total rate of 7.8 nmol/min/mg, forming 7alpha-hydroxy-DHEA, 16alpha-hydroxy-DHEA, and a previously unidentified hydroxylated metabolite, 7beta-hydroxy-DHEA. Other human microsomal fractions exhibited much lower rates of metabolism, but with similar metabolite profiles. Recombinant P450s were used to identify the cytochrome P450s responsible for DHEA metabolism in the rat and human. CYP3A4 and CYP3A5 were the cytochromes P450 responsible for production of 7alpha-hydroxy-DHEA, 7beta-hydroxy-DHEA, and 16alpha-hydroxy-DHEA in adult liver microsomes, whereas the fetal/neonatal form CYP3A7 produced 16alpha-hydroxy and 7beta-hydroxy-DHEA. CYP3A23 uniquely formed 7alpha-hydroxy-DHEA, whereas other P450s, CYP2B1, CYP2C11, and CYP2D1, were responsible for 16alpha-hydroxy-DHEA metabolite production in rat liver microsomal fractions. These results indicate that the stereo- and regioselectivity of hydroxylation by different P450s account for the diverse DHEA metabolites formed among various species.
Animals↗
Changes in serum sex hormone profiles after short-term low-dose administration of dehydroepiandrosterone (DHEA) to young and elderly persons.
In man, serum concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease with age after the twenties. For this reason, the decline in DHEA and DHEAS concentrations may be related to the development of some chronic diseases that are prevalent in the older age population. In this study, we evaluate the benefit and safety level of DHEA administration to men as a hormone replacement therapy. Twenty-two healthy Japanese males (age 26-63; mean +/- SD, 41.0 +/- 10.0 yrs.) received 25 mg DHEA once a day orally in the morning for two weeks. Serum concentrations of steroid hormones and cytokines were measured before and after the DHEA administration. Glucose tolerance and insulin resistance were also assessed before and after the DHEA administration using a 75 g oral glucose tolerance test and homeostasis model assessment (HOMA-R), respectively. Serum DHEA and DHEAS levels were significantly elevated after the DHEA administration for all ages of test subjects. In subjects who were older than 41 yrs. (older group) serum androstenedione and estradiol levels were elevated after the DHEA administration. Significant negative correlations were observed between the serum DHEA concentration and the serum concentration of fasting insulin, HOMA-R, leptin, and high-sensitivity C-reactive protein for all subjects. Daily administration of 25 mg DHEA increased the serum DHEA, DHEAS, androstenedione, and estradiol levels of the subjects of the older group to the same level as that of younger subjects.
Adult↗
Influence of oral dehydroepiandrosterone (DHEA) on urinary steroid metabolites in males and females.
Oral dehydroepiandrosterone (DHEA) replacement therapy may have a multitude of potential beneficial effects and exerts its action mainly via peripheral bioconversion to androgens (and estrogens). A daily dose of 50-mg DHEA has been shown by us and others to restore low endogenous serum DHEA concentrations to normal youthful levels followed by an increase in circulating androgens and estrogens. As the hepatic first-pass effect may lead to a non physiological metabolism of DHEA after oral ingestion we studied the influence of two single DHEA doses (50 and 100 mg) on the excretion of steroid metabolites in 14 elderly males [age 58.8+/-5.1 years (mean +/- SEM)] with endogenous DHEAS levels <1500 ng/ml and in 9 healthy females (age 23.3+/-4.1 years) with transient suppression of endogenous DHEA secretion induced by dexamethasone (dex) pretreatment (4x0.5 mg/day/4 days). Urinary steroid profiles in the elderly males were compared to the steroid patterns found in 15 healthy young men (age 28.9+/-5.1 years). In the females the results were compared to their individual baseline excretion without dex pretreatment. Urinary steroid determinations were carried out by semiautomatic capillary gas-liquid chromatography. In both genders DHEA administration induced significant increases in urinary DHEA (females: baseline vs. 50 mg vs. 100 mg: 361+/-131 vs. 510+/-264 vs. 1541+/-587 microg/day; males: placebo vs. 50 mg vs. 100 mg: 434+/-154 vs. 1174+/-309 vs. 4751+/-1059 microg/day) as well as in the major DHEA metabolites androsterone (A) and etiocholanolone (Et). Fifty mg DHEA led to an excretion of DHEA and its metabolites only slightly above baseline levels found in young females and in young men, respectively, whereas 100 mg induced clearly supraphysiological values. After 50 mg DHEA the ratios of urinary DHEA metabolites (A/DHEA, Et/DHEA) were not significantly different between elderly males vs. young male volunteers and young healthy females versus their individual baseline levels. In conclusion, an oral dose of 30 to 50 mg DHEA restores a physiological urinary steroid profile in subjects with DHEA deficiency without evidence for a relevant hepatic first-pass effect on urinary metabolites.
Administration, Oral↗
Studies of dehydroepiandrosterone (DHEA) with the human estrogen receptor in yeast.
Dehydroepiandrosterone (DHEA) is a C19 adrenal steroid synthesized in the human adrenal cortex and serving as a biosynthetic precursor to testosterone and 17beta-estradiol. Despite the fact that it is one of the most abundant steroid hormones in circulation, the physiological role of DHEA in humans remains unclear. The action of DHEA itself, such as its interactions with receptors and nuclear transcription factors, is not well understood, and a specific DHEA receptor has yet to be identified. Although the activity of DHEA can be due to its metabolism into androgens and estrogens, DHEA has been shown to interact with the androgen receptor and the estrogen receptor (ER) in vitro. We demonstrate in this study that DHEA (3beta-Hydroxy-5alpha-androstan-17-one) inhibits 17beta-estradiol (E2) binding to its receptor in vivo in yeast. DHEA stimulates human ER dimerization in yeast, as determined by ER fusion protein interactions, GAL4 reconstitution and subsequent measurement of increased beta-galactosidase activity. DHEA causes an increase in estrogen response element-dependent beta-galactosidase activity, demonstrating that the ER dimer induced by DHEA is transcriptionally active, but at a concentration of DHEA about 1000 times greater than E2. Inclusion of the nuclear receptor co-activator RIP140 in the yeast enhances ER transactivation by DHEA or E2 in a ligand-dependent manner; moreover, only in the presence of RIP140 is DHEA able to stimulate beta-galactosidase activity to levels similar to those achieved by E2. Ligand-receptor interaction for other C19-steroids was also examined. While 5-androstene-3beta, 17beta-diol (ADIOL) displayed estrogenic activity in this system, 4-androstene-17-dione (androstenedione) and 4-androstene-17beta-ol,3-one (testosterone) did not. We have investigated whether DHEA can interact with the human ER in vivo. Our findings demonstrate a mechanism by which DHEA interacts directly with estrogen signaling systems; however, because DHEA is several orders of magnitude less potent than E2 in this system, we conclude that it essentially is not an estrogen agonist.
Dehydroepiandrosterone↗
Steroid sulfatase gene variation and DHEA responsiveness to resistance exercise in MERET.
Genetic influences and endurance exercise have been shown to alter circulating concentrations of dehydroepiandrosterone (DHEA) and its sulfated conjugate, DHEAS. We hypothesized that acute resistance exercise (RE) and training (RET) would increase DHEA steroids, and the magnitude of the increase would be influenced by a steroid sulfatase (STS) gene variation. Fasting blood samples were collected before and after the first (S1) and last (S30) session of a 10-wk RET program in 62 men and 58 women [age: 21.0 yr (2.4)]. Acute RE increased both DHEA [+2.8 (0.4), S1; +1.6 ng/ml (0.4), S30; P < 0.001] and DHEAS [+154 (24), S1; +166 ng/ml (15), S30; P < 0.001] and decreased DHEAS:DHEA [-27 (8), S1; -15 (7), S30; P < 0.01]. RET reduced resting DHEAS (-122 ng/ml, P < 0.01) and decreased DHEA response to RE (-50%, P < 0.05). Subjects with an STS "G" allele (n = 36) had greater acute changes in DHEA [+4.4 (0.7) vs. +2.0 ng/ml (0.5), S1; +3.2 (0.6) vs. +1.0 ng/ml (0.4), S30; P < 0.01] and DHEAS:DHEA [-37 (11) vs. 5 (7), S30, P < 0.05] than those subjects with only an "A" allele (n = 84). The observed increase in DHEA and DHEAS and decrease in DHEAS:DHEA suggest RE-induced STS activation which is influenced by the STS polymorphism.
Adult↗
Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans.
The physiological importance and therapeutical interest of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are still controversial. Panhypopituitarism is characterized by the absence of secretion of adrenal and gonadal steroids and thus the production of their metabolites. The conversion of DHEA given orally into delta 5 derivatives, androgens, androgen metabolites, and estrogens was studied in ten patients with complete panhypopituitarism. Sex steroid therapy was withdrawn for at least 2 months. Each patient received, at 1-month intervals and in a random order, two single oral doses of DHEA (50 mg and 200 mg) and placebo. During each treatment, urine samples were collected for 24 h, and blood samples were drawn at hourly intervals for 8 h. In patients with pituitary deficiency, plasma DHEA and DHEAS were not detectable and increased, with the 50 mg dose, up to levels observed in young adults. The administration of 200 mg of DHEA induced an increase of both steroids to supraphysiological plasma levels. A small increase of delta 5-androstenediol was observed. In contrast, the increase of plasma delta 4-androstenedione was important and dose dependent. DHEA was also converted into the potent sex steroid testosterone (T). The administration of a 50 mg dose of DHEA restored plasma T to levels similar to those observed in young women. The 200 mg dose induced an important increase of plasma T, slightly below the levels observed in normal men. The increase of plasma dihydrotestosterone levels was small at both doses of DHEA, in contrast with the large conversion of DHEA into androsterone glucuronide and androstanediol glucuronide. Finally, DHEA administration induced a significant and dose dependent increase of plasma estrogens and particularly of estradiol. In conclusion, this short term study demonstrates that: 1) panhypopituitarism is a model of interest to study the metabolism of DHEA; 2) in the absence of pituitary hormones and of adrenal and gonadal steroids, DHEA given orally is mainly converted into delta 4 derivatives, which in turn are strongly metabolized into 5 alpha-3keto-reduced steroids; 3) a significant increase of sex active hormones was observed in plasma after 200 and even 50 mg of DHEA. Thus, biotransformation of DHEA into potent androgens and estrogens may explain several of the reported beneficial actions of this steroid in aging people.
Adult↗
Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people.
BACKGROUND: In view of the theoretical possibility of beneficial effects of DHEA or DHEAS in retarding age-associated deterioration in cognitive function, we have reviewed studies in this area. OBJECTIVES: To establish whether administration of DHEA, or its sulphate, DHEAS, improves cognitive function or reduces the rate of decline of cognitive function in normal older adults. SEARCH STRATEGY: Trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 10 October 2005 using the terms dhea*, prasterone, dehydroepiandrosterone*. In addition MEDLINE, EMBASE, PsycINFO and CINAHL were searched to find trials with volunteers who had no or minor memory complaints. Relevant journals, personal communications and conference abstracts were searched for randomized controlled trials investigating the effects of DHEA/S on cognition in older adults. SELECTION CRITERIA: All randomized placebo-controlled trials enrolling people aged over 50 without dementia and to whom DHEA/S in any dosage was administered for more than one day were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Data for the specified outcomes were independently extracted by two reviewers (JGE and RM) and cross-checked. Any discrepancies were discussed and resolved. No data pooling was undertaken owing to the lack of availability of the relevant statistics. MAIN RESULTS: Only three studies provided results from adequate parallel-group data. Barnhart 1999 enrolled perimenopausal women with complaints of decreased well-being and, using three cognitive measures, found no significant effect of DHEA compared with placebo at 3 months. Wolf 1998b enrolled 75 healthy volunteers (37 women and 38 men aged 59-81) in a study of the effect of DHEA supplements on cognitive impairment induced by stress; after two weeks of treatment, placebo group performance deteriorated significantly on a test of selective attention following a psychosocial stressor (p<0.05), while deterioration was not evident in the DHEA group (p=0.85). However, when compared with placebo, DHEA was associated with a significant impairment on a visual memory recall test (p<0.01) following the stressor. No significant effects were found on a third cognitive task. Effects were not found on tasks when administered in the absence of a stressor. van Niekerk 2001 found no effect on cognitive function in 46 men aged 62-76 from three months of DHEA supplementation. DHEA supplements were well tolerated and without significant adverse effects apart from the reduced performance in the visual memory recall test observed in one trial. AUTHORS' CONCLUSIONS: What little evidence there is from controlled trials does not support a beneficial effect of DHEA supplementation on cognitive function of non demented middle-aged or elderly people. There is no consistent evidence from the controlled trials that DHEA produces any adverse effects. In view of growing public enthusiasm for DHEA supplementation, particularly in the USA, and the theoretical possibility of long-term neuroprotective effects of DHEA/S, there is a need for further high quality trials in which the duration of DHEA treatment is longer than one year, and the number of participants is large enough to provide adequate statistical power.
Aged↗
DHEA-S levels in hypopituitaric patients with severe GH deficiency are strongly reduced across lifespan. Comparison with IGF-I levels before and during rhGH replacement.
Both IGF-I and DHEA-S undergo an age-related decrease and their decrease could be involved in age-related changes in body composition, structure functions and metabolism. On the other hand, it is well known that mean IGF-I levels are clearly reduced in hypopituitaric patients with GH deficiency (GHD) while data about dehydroepiandrosterone sulfate (DHEA-S) levels in hypopituitarism are scanty. We evaluated DHEA-S and IGF-I levels and their relationship in 90 patients with panhypopituitarism (HYPOPIT) with severe GHD [49 women and 41 men; age, mean+/-SE: 47.9+/-1.49 yr, range: 20-80 yr, BMI: 26.4+/-0.6 kg/m2; 21 with childhood-onset (CO) and 69 with adult-onset (AO) HYPOPIT]. DHEA-S and IGF-I levels were also evaluated in 24 HYPOPIT with GHD after 3-month recombinant human GH (rhGH) replacement. Data in HYPOPIT were compared with those in a large group of healthy controls (NS, 233 women and 103 men, aged 20-80 yr; all subjects were within +/-15% of their ideal body weight). In NS both DHEA-S levels and IGF-I were gender-independent while showed a strong, inverse correlation with age (r=-0.6; p<0.001 and r=-0.56; p<0.0001, respectively). Nevertheless, no relationship was found between DHEA-S and IGF-I levels in NS. In HYPOPIT, age-adjusted mean DHEA-S and IGF-I levels were clearly lower than those in NS (2.3+/-0.4 vs 16.0+/-0.7 microg/l, p<0.005; 71.1 +/- 4.5 vs 170+/-4.7 microg/l, p<0.005). IGF-I levels in CO-HYPOPIT were lower (p<0.01) than those in AO-HYPOPIT (49.6+/-4.8 vs 77.0+/-5.4 microg/l), while DHEA-S levels were similar in both subgroups (2.6+/-0.7 vs 2.3+/-0.4 microg/l). In HYPOPIT both DHEA-S and IGF-I were independent of age and gender while there was a trend toward a positive association between each other (r=0.45; p<0.003). Analyzing individual levels in HYPOPIT with respect to age-adjusted normal ranges, IGF-I levels were below normal in 84, 62 and 0% between 20-40, 40-60 and 60-80 yr, respectively. On the other hand, DHEA-S levels were below normal in 84, 86 and 67% between 20-40, 40-60 and 60-80, respectively. In HYPOPIT rhGH treatment strikingly increased IGF-I levels (150+/-3.2 vs 85.3+/-4.1 microg/l, p<0.005) while did not modify DHEA-S levels (1.7+/-0.2 vs 1.6+/-0.2 microg/l). In conclusion, our results demonstrate that DHEA-S and IGF-I are negatively and independently associated to age in physiological conditions but not in hypopituitaric patients in whom both are strikingly reduced. Both DHEA-S and IGF-I levels in HYPOPIT show some overlap with those in normal subjects; thus the assay of these parameters is not diagnostic for hypopituitarism. DHEA-S reduction in HYPOPIT does not depend on IGF-I as indicated also by evidence that GH replacement restores IGF-I but does not modify DHEA-S levels.
Adult↗
DHEA inhibits cell growth and induces apoptosis in BV-2 cells and the effects are inversely associated with glucose concentration in the medium.
Dehydroepiandrosterone (DHEA), a major steroid secreted by the adrenal gland which decreases with age after adolescence, is available as a nutritional supplement. DHEA is known to have antiproliferative effects but the mechanism is unclear. In this study using BV-2 cells, a murine microglial cell line, we investigated the effect of DHEA on cell viability and the interaction between DHEA and glucose concentrations in the medium. We showed that DHEA inhibited cell viability and G6PD activity in a dose-dependent manner and that the effect of DHEA on cell viability was inversely associated with glucose concentrations in the medium, i.e. lowered glucose strongly enhanced the inhibition of cell viability by DHEA. DHEA inhibited cell growth by causing cell cycle arrest primarily in the G0--G1 phase, and the effect was more pronounced at zero glucose (no glucose added, G0) than high glucose (4.5 mg/ml of the medium, G4.5). Glucose deprivation also enhanced apoptosis induced by DHEA. At G4.5, DHEA did not induce formation of DNA ladder until it reached 200 microM. However, at G0, 100 microM DHEA was able to induce apoptosis, as evidenced by the formation of DNA ladder, elevation of histone-associated DNA fragmentation and increase in cells positively stained with annexin V-FITC and annexin V-FITC/propidium iodide. The interactions between DHEA and glucose support the contention that DHEA exerts its antiproliferative effects through alteration of glucose metabolism, possibly by inhibition of G6PD activity leading to decreased supply of ribose-5-phosphate for synthesis of DNA and RNA. Although DHEA is only antiproliferative at pharmacological levels, our results indicate that its antiproliferative effect can be enhanced by limiting the supply of glucose such as by energy restriction. In addition, the present study shows that glucose concentration is an important factor to consider when studying the antiproliferative and toxicological effects of DHEA.
Animals↗
The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women.
OBJECTIVE: The biological role of the adrenal sex steroid precursors--DHEA and DHEA sulphate (DS) and their decline with ageing remains undefined. We observed previously that administration of a 50 daily dose of DHEA for 3 months to age-advanced men and women resulted in an elevation (10%) of serum levels of insulin-like growth factor-I (IGF-I) accompanied by improvement of self-reported physical and psychological well-being. These findings led us to assess the effect of a larger dose (100 mg) of DHEA for a longer duration (6 months) on circulating sex steroids, body composition (DEXA) and muscle strength (MedX). SUBJECTS AND DESIGN: Healthy non-obese age-advanced (50-65 yrs of age) men (n = 9) and women (n = 10) were randomized into a double-blind placebo-controlled cross-over trial. Sixteen subjects completed the one-year study of six months of placebo and six months of 100 mg oral DHEA daily. MEASUREMENTS: Fasting early morning blood samples were obtained. Serum DHEA, DS, sex steroids, IGF-I, IGFBP-1, IGFBP-3, growth hormone binding protein (GHBP) levels and lipid profiles as well as body composition (by DEXA) and muscle strength (by MedX testing) were measured at baseline and after each treatment. RESULTS: Basal serum levels of DHEA, DS, androsternedione (A), testosterone (T) and dihydrotestosterone (DHT) were at or below the lower range of young adult levels. In both sexes, a 100 mg daily dose of DHEA restored serum DHEA levels to those of young adults and serum DS to levels at or slightly above the young adult range. Serum cortisol levels were unaltered, consequently the DS/cortisol ratio was increased to pubertal (10:1) levels. In women, but not in men, serum A, T and DHT were increased to levels above gender-specific young adult ranges. Basal SHBG levels were in the normal range for men and elevated in women, of whom 7 of 8 were on oestrogen replacement therapy. While on DHEA, serum SHBG levels declined with a greater (P < 0.02) response in women (-40 +/- 8%; P = 0.002) than in men (-5 +/- 4%; P = 0.02). Relative to baseline, DHEA administration resulted in an elevation of serum IGF-I levels in men (16 +/- 6%, P = 0.04) and in women (31 +/- 12%, P = 0.02). Serum levels of IGFBP-1 and IGFBP-3 were unaltered but GHBP levels declined in women (28 +/- 6%; P = 0.02) not in men. In men, but not in women, fat body mass decreased 1.0 +/- 0.4 kg (6.1 +/- 2.6%, P = 0.02) and knee muscle strength 15.0 +/- 3.3% (P = 0.02) as well as lumbar back strength 13.9 +/- 5.4% (P = 0.01) increased. In women, but not in men, an increase in total body mass of 1.4 +/- 0.4 kg (2.1 +/- 0.7%; P = 0.02) was noted. Neither gender had changes in basal metabolic rate, bone mineral density, urinary pyridinoline cross-links, fasting insulin, glucose, cortisol levels or lipid profiles. No significant adverse effects were observed. CONCLUSIONS: A daily oral 100 mg dose of DHEA for 6 months resulted in elevation of circulating DHEA and DS concentrations and the DS/cortisol ratio. Biotransformation to potent androgens near and slightly above the range of their younger counterparts occurred in women with no detectable change in men. Given this hormonal milieu, an increase in serum IGF-I levels was observed in both genders but dimorphic responses were evident in fat body mass and muscle strength in favour of men. These differences in response to DHEA administration may reflect a gender specific response to DHEA and/or the presence of confounding factor(s) in women such as oestrogen replacement therapy.
Aged↗
DHEA therapy for women: effect on sexual function and wellbeing.
DHEA is increasingly available commercially as a supplement aimed at improving libido and wellbeing in postmenopausal women. However there is scant evidence to support the use of DHEA for this purpose, and safety data for DHEA therapy are lacking. Dehydroepiandrosterone (DHEA) and its sulphate DHEAS are the most abundant circulating sex steroid hormones in women, providing a large precursor reservoir for the intracellular production of androgens and oestrogens in non-reproductive tissues. Levels of DHEA and DHEAS decline with age. It has been proposed that restoring the circulating levels of these steroids to those found in young people may have anti-ageing effects and improve wellbeing and sexual function. However this is not supported by the published literature. We have reviewed the physiology of DHEA and DHEAS in women and the published literature pertaining to the use of DHEA therapy for libido and wellbeing in postmenopausal women. The literature was searched using Medline (Ovid) and Pub-Med for original studies. Overall, the interpretation of data from randomised controlled trials conducted in well women is limited by inadequate sample size and short treatment durations with inconsistent results for the outcomes of libido and wellbeing. Studies of DHEA in women with adrenal insufficiency, although indicating potential improvements in mood and libido, are also limited by their short treatment phase durations. In addition safety data for DHEA therapy are lacking. The potential value of DHEA therapy for women still requires exploration in adequately powered well-designed randomised placebo-controlled trials. The studies of DHEA therapy in women with adrenal insufficiency suggest that this group is the most likely to derive health benefits from DHEA supplementation.
Adjuvants, Immunologic↗
Dehydroepiandrosterone sulphate (DHEAS) in the oldest old, aged 85 and over.
Dehydroepiandrosterone (DHEA) and its sulphonated metabolite DHEAS are the major secretory products of the human adrenal gland. Despite the abundancy of these steroids in the circulation the precise function is uncertain. It has been postulated that they may be involved in the maturing and aging processes in man. An intriguing inverse relation has been described between DHEAS and cardiovascular mortality in men. In women from the same population this was not the case and in fact mortality due to cardiovascular disease was highest in women with the highest levels of DHEAS. Another interesting association is reported between DHEA and DHEAS and the enhancement of memory retention in mice. Reduced plasma concentration of DHEAS have been described in patients with Alzheimer's disease compared with age-matched controls. In the framework of a gerontologic study concerning all 1259 inhabitants aged 85 years and over of the Dutch community of Leiden (population +/- 105,000), DHEAS levels were determined in 138 subjects of this cohort. Of these, 53 were healthy subjects, selected from the population according to the health criteria of the SENIEUR protocol, which is based on clinical, pharmacological and laboratory data. This enabled us to assess reference values for this age group. Additionally DHEAS levels were measured in 64 young controls, 20-40 years of age, who also fulfilled these criteria. Reference values for the oldest old, derived from the healthy group, are 1.7 +/- 1.4 mumol/l for women and 2.2 +/- 1.1 mumol/l for men. DHEAS levels decreased fourfold between the young adults and those aged 85 and over. In men this decrease continued after the age of 85. DHEAS values tended to be higher in men than in women, both in the elderly, in all subgroups of elderly subjects, and in the young control group, but this sex-difference did not reach statistical significance. No difference was found between the DHEAS levels in subgroups according to the health status, the survival rate or the diagnosis of probable Alzheimer's disease. Many uncertainties concerning the role of DHEAS in the neuro-immuno-endocrinological network have yet to be unravelled and the question remains whether the age-related decrease of DHEAS is related to organ-specific failure on the level of the adrenals or the gonads, or whether it is a result of changes in feedback or regulatory mechanisms. DHEAS is one of the few compounds that shows a gradual decrease with advancing age, reaching an asymptotic low at the age of the maximum recorded life span.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
DHEA replacement in women with adrenal insufficiency--pharmacokinetics, bioconversion and clinical effects on well-being, sexuality and cognition.
Standard replacement for adrenal insufficiency (AI) consists of glucocorticoids and mineralocorticoids while DHEA deficiency is routinely ignored. Thus, AI represents the ideal pathophysiological model of isolated DHEA deficiency. We investigated the effects of DHEA replacement in 24 women with primary and secondary AI employing a double blind, placebo-controlled, randomized crossover design. A DHEA dose of 50 mg/d was chosen based on preceding single-dose pharmacokinetics and bioconversion studies. Each patient received four months of treatment with DHEA and four months placebo, with a one-month washout period. Measurements included serum steroid hormones, somatotropic parameters and psychometric assessment of well-being, mood, cognition and sexuality. Treatment with DHEA raised the initially low serum concentrations of DHEA, DHEAS, androstenedione, and testosterone into the normal range. DHEA induced a slight increase in serum IGF-I, but only in patients with primary AI, suggesting a growth hormone-mediated effect. DHEA treatment significantly improved overall wellbeing as well as scores for depression, anxiety, and their physical correlates. Furthermore, DHEA significantly increased both sexual interest and the level of satisfaction with sex. DHEA replacement had no influence on the cognitive performance, which was already on a high level at baseline. In conclusion, DHEA replacement improves well-being and sexuality in women with adrenal insufficiency. If this is due to a direct effect of DHEA on the brain, an indirect effect via increased androgen synthesis, or both, remains to be elucidated. Long-term studies in patients of both sexes are needed to further define the role of DHEA in standard replacement for adrenal insufficiency.
Adrenal Insufficiency↗