Systemic lupus erythematous (SLE) is a systemic autoimmune inflammatory disease with both genetic and epigenetic etiologies. Evidence suggests that deregulation of specific genes through epigenetic mechanisms may be a contributing factor to SLE pathology. There is increasing evidence that DNA methyltransferase activity may be involved. This study demonstrated modulation in expression of DNA methyltransferases (DNMTs) according to ethnicity in patients diagnosed with SLE. Furthermore, differential expression in one of the DNMTs was found in a subset of lupus patients on dehydroepiandrosterone (DHEA) therapy.
Real-time PCR analyses of DNMT1, DNMT3A and DNMT3B in peripheral blood mononuclear cells from a cohort of African American and European American lupus and non-lupus women were conducted. Also, global DNA methylation was assessed using the MethylFlashTM methylated quantification colorimetric assay.
Significant increase in DNMT3A (p < 0.001) was shown in lupus patients when compared to age-matched healthy controls. This increase was associated with a higher SLEDI index. More striking was that expression levels for African American (AA) women were higher than European American women in the lupus populations. A subset of AA women on DHEA therapy showed a significant decrease (p < 0.05) in DNMT3A expression in comparison to lupus patients not on the therapy. DHEA is an androgenic steroid found in low levels in the serum of lupus patients. Supplementation of this hormone has been shown to be beneficial to some lupus patients. DHEA was not shown to effect DNMT1 or DNMT3B expression. Increased expression was also noted in DNMT3B (p < 0.05) in lupus patients compared to age-matched healthy controls. However, no significant difference was noted in DNMT1 (p = 0.2148) expression between lupus patients and healthy controls. Although increases were detected in de novo methyltransferases, a global decrease (p < 0.001) in 5-methycytosine was observed in lupus patients when compared to age-matched healthy controls.
These findings suggest that epigenetic changes may play a critical role in the manifestations of the disease observed among ethnic groups, particularly African American women who often have a higher incidence of lupus. DHEA therapy effects on DNMT3A expression in AA women warrant further investigation in a larger population.
Lupus; DNA methyltransferases; DHEA; DNMT3A; DNMT3B; DNMT1
Dehydroepiandrosterone (DHEA) is an endogenous steroid that blocks carcinogenesis, retards aging, and exerts antiproliferative properties. In vitro, it is a potent inhibitor of glucose-6-phosphate dehydrogenase, the first committed step of the pentose phosphate pathway. In man, serum levels of DHEA and its sulfate peak in early adulthood and drop markedly with age. Epidemiologic evidence indicates that low levels of DHEA or its sulfate conjugate are linked to an increased risk of developing cancer or of death from cardiovascular disease. Like cancer, atherosclerosis is a proliferative process characterized by both initiation and promotion phases. This similarity provided a framework in which to study the antiatherogenic effects of DHEA. Rabbits were randomly assigned to four groups. Two groups of rabbits received aortic endothelial injury by balloon catheter and were fed a 2% cholesterol diet for 12 wk. DHEA, 0.5%, was incorporated into the diet of one group receiving the 2% cholesterol diet and endothelial injury and also into the diet of one of the control groups. Animals were killed after 12 wk and aortas, hearts, and livers were studied. Plasma samples were analyzed for total cholesterol, VLDL, LDL, HDL, triglycerides, DHEA, and DHEA-sulfate levels. The atherogenic insult resulted in severe atherosclerosis in animals not treated with DHEA. In those receiving DHEA there was an almost 50% reduction in plaque size (P = 0.006), inversely related to the serum level of DHEA attained. Fatty infiltration of the heart and liver were also markedly reduced. These beneficial actions were not attributable to differences in body weight gain, food intake, total plasma cholesterol or distribution of cholesterol among the VLDL, LDL, or HDL fractions. The results show that high levels of plasma DHEA inhibit the development of atherosclerosis and they provide an important experimental link to the epidemiologic studies correlating low DHEA-sulfate plasma levels with an enhanced risk of cardiovascular mortality.
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.
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.
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.
Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis. Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor α (PPARα)- and pregnane X receptor (PXR)-mediated induction of CYP4As and CYP3A23, and suppression of CYP2C11. DHEA treatment elevated the expression and activities of CYP3A4, CYP2C9, CYP2C19, and CYP2B6 in primary cultures of human hepatocytes. Induction of CYP3A4 in human hepatocytes was consistent with studies in rats, but induction of CYP2Cs was unexpected. The role of PXR in this response was studied in transient transfection assays. DHEA activated hPXR in a concentration-dependent manner. Because CYP2B6 induction by DHEA in human hepatocytes might involve either PXR or constitutive androstane receptor (CAR) activation, we performed experiments in primary hepatocytes from CAR knockout mice and observed that CAR was required for maximal induction of Cyp2b10 by DHEA. Furthermore, CAR-mediated Cyp2b10 induction by DHEA was inhibited by the inverse agonist of CAR, androstanol (5α-androstan-3α-ol). Further evidence for CAR activation was provided by cytoplasmic/nuclear transfer of CAR upon DHEA treatment. Elucidation of CAR activation and subsequent induction of CYP2B6 by DHEA presented an additional mechanism by which the sterol can modify the expression of P450s. The effect of DHEA on the activation of the xenosensors PPARα, PXR, and CAR, and the consequent potential for adverse drug/toxicant interactions should be considered in humans treated with this nutriceutical agent.
Objective: To study the effects of dehydroepiandrosterone (prasterone, DHEA) 200 mg/day on cytokine profiles in adult women with active systemic lupus erythematosus (SLE).
Methods: In a double blind, randomised, placebo controlled study conducted as part of a larger multicentre study, 30 adult women with active SLE received oral DHEA 200 mg/day or placebo for 24 weeks. Baseline prednisone (<10 mg/day) and other concomitant SLE medications were to remain constant. The levels of cytokines including interleukin (IL) 1, IL2, interferon γ, IL4, and IL10 were determined by ELISA. The mean change from baseline to 24 weeks of therapy was analysed.
Results: The two groups (DHEA n = 15; placebo n = 15) were well balanced for baseline characteristics. Only IL1ß and IL10 could be detected in the serum of lupus patients; however, there was no significant mean (SD) difference in serum IL1ß before and after treatment (9.94 (8.92) v 9.20 (6.49) pg/ml). IL10 demonstrated a greater and significant reduction from baseline (9.21 (9.66) to 1.89 (1.47) pg/ml in the DHEA treatment group).
Conclusions: In a 24 week study of adult Chinese women with mild to moderate SLE, treatment with DHEA 200 mg once daily resulted in significant reduction of serum levels of IL10. This finding may suggest why DHEA could significantly reduce lupus flares.
Background: In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), patients demonstrate low levels of adrenal hormones.
Objective: To investigate whether increased renal clearance and daily excretion contribute to this phenomenon.
Methods: Thirty patients with RA, 32 with SLE, and 54 healthy subjects (HS) participated. Serum and urinary levels of cortisol, cortisone, 17-hydroxyprogesterone (17OHP), androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulphate (DHEAS) were measured.
Results: Clearance of DHEAS and DHEA was lower in patients than in HS, and clearance of androstenedione was somewhat higher in patients than in HS, but daily excretion of this latter hormone was low. Clearance of cortisol, cortisone, and 17OHP was similar between the groups. The total molar amount per hour of excreted DHEA, DHEAS, and androstenedione was lower in patients than HS (but similar for cortisol). Serum DHEAS levels correlated with urinary DHEAS levels in HS and patients, whereby HS excreted 5–10 times more of this hormone than excreted by patients. Low serum levels of adrenal androgens and cortisol in patients as compared with HS were confirmed, and proteinuria was not associated with changes of measured renal parameters.
Conclusions: This study in patients with RA and SLE demonstrates that low serum levels of adrenal androgens and cortisol are not due to increased renal clearance and daily loss of these hormones. Decreased adrenal production or increased conversion or conjugation to downstream hormones are the most likely causes of inadequately low serum levels of adrenal hormones in RA and SLE.
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.
dehydroepiandrosterone; human adipogenesis; 11β-hydroxysteroid dehydrogenase type 1; insulin sensitivity
To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age.
Longitudinal cohort study.
Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N =989, mean age 85.2, 63.5% women, 16.5% African American).
Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change.
Mean ± standard deviation DHEAS was 0.555 ± 0.414 μg/mL in 1996/97 and 0.482 ± 0.449 μg/mL in 2005/06 for women and 0.845 ± 0.520 μg/mL in 1996/97 and 0.658 ± 0.516 μg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (− 0.200 μg/mL) than in women (− 0.078 μg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 μg/mL (P =.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (β = − 0.04 μg/mL, P =.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio =1.46, 95% confidence interval =1.03–2.05).
DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.
dehydroepiandrosterone sulfate; cardiovascular disease; gender; aging
Background: Hypoandrogenicity is common in obesity and in chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Adrenal androgens such as androstenedione (ASD) and dehydroepiandrosterone (DHEA) sulphate are low, which partly depends on the influence of TNF in chronic inflammatory diseases. Leptin is stimulated by TNF and is associated with hypoandrogenicity in non-inflammatory conditions.
Objective: To study the interrelation between serum levels of leptin and adrenal steroids in SLE and RA.
Methods: In a retrospective study, serum levels of leptin, ASD, DHEA, and 17-hydroxyprogesterone (17OHP) were measured by ELISA, and serum levels of cortisol by radioimmunoassay in 30 patients with RA, 32 with SLE, and 54 healthy control subjects (HS).
Results: In SLE and RA but not HS, serum levels of ASD correlated negatively with serum levels of leptin (p<0.01) independently of prior prednisolone treatment in patients with SLE (p = 0.013) and tended to be independent of prednisolone in patients with RA (p = 0.067). In a partial correlation analysis, this interrelation remained significant after controlling for daily prednisolone dose in both patient groups. In both patient groups, serum leptin levels correlated negatively with the molar ratio of serum ASD/serum cortisol and serum ASD/serum 17OHP, and positively with the molar ratio of serum DHEA/serum ASD.
Conclusions: The negative correlation of serum leptin and ASD or, particularly, ASD/17OHP, together with its known anti-androgenic effects indicate that leptin is also involved in hypoandrogenicity in patients with SLE and RA. Leptin may be an important link between chronic inflammation and the hypoandrogenic state.
Objective: this analysis was to investigate the effects of dehydroepiandrosterone (DHEA) on cardiovascular risk factors in older women with frailty characteristics.
Design, setting and participants: the study was a double-blind, randomised, placebo-controlled trial of 99 women (mean 76.6 ± 6.0 year) with the low DHEA-S level and frailty.
Intervention: participants received 50 mg/day DHEA or placebo for 6 months; all received calcium (1,000–1,200 mg/day diet) and supplement (combined) and cholecalciferol (1,000 IU/day). Women participated in 90-min twice weekly exercise regimens, either chair aerobics or yoga.
Main outcome measures: assessment of outcome variables included hormone levels (DHEA-S, oestradiol, oestrone, testosterone and sex hormone-binding globulin (SHBG)), lipid profiles (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides), body composition measured by dual energy absorptiometry, glucose levels and blood pressure (BP).
Results: eighty-seven women (88%) completed 6 months of study; 88% were pre-frail demonstrating 1–2 frailty characteristics and 12% were frail with ≥3 characteristics. There were significant changes in all hormone levels including DHEA-S, oestradiol, oestrone and testosterone and a decline in SHBG levels in those taking DHEA supplements. In spite of changes in hormone levels, there were no significant changes in cardiovascular risk factors including lipid profiles, body or abdominal fat, fasting glucose or BP.
Conclusion: research to date has not shown consistent effects of DHEA on cardiovascular risk, and this study adds to the literature that short-term therapy with DHEA is safe for older women in relation to cardiovascular risk factors. This study is novel in that we recruited women with evidence of physical frailty.
dehydroepiandrosterone; lipids; cardiovascular risk factors; elderly
Stress has well-known effects on adrenal glucocorticoid secretion, and chronic elevation of glucocorticoids can have detrimental effects on the brain. Dehydroepiandrosterone (DHEA), an androgen precursor synthesized in the adrenal glands or the brain itself, has anti-glucocorticoid properties, but little is known about the role of DHEA in the stress response, particularly in the brain. Here, we measured the effects of acute restraint on circulating corticosterone (CORT) and DHEA levels in wild song sparrows. Blood was collected from either the brachial or jugular vein. In songbirds, jugular plasma is enriched with neurally synthesized steroids, and therefore, jugular plasma is an indirect index of the neural steroidal milieu. Subjects were sampled during four times of year: breeding, molt, early nonbreeding, and mid-nonbreeding. Baseline CORT and DHEA levels showed similar seasonal changes; both steroids were elevated during the breeding season. Baseline CORT and DHEA levels were similar in jugular and brachial plasma. Acute stress had robust effects on CORT and DHEA that were season specific and vein specific. For CORT, during the molt, stress increased jugular CORT more than brachial CORT. For DHEA, during the breeding season, stress decreased jugular DHEA but not brachial DHEA. During the molt, stress increased jugular DHEA but not brachial DHEA. Acute stress did not affect brachial DHEA. These data suggest that acute stress specifically affects the balance between DHEA synthesis and metabolism in the brain. Furthermore, these results suggest that CORT and DHEA are locally synthesized in the brain during molt, when systemic levels of CORT and DHEA are low.
PMID: 18276756 CAMSID: cams343
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.
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.
It is known that long-term psychosocial stress may cause or contribute to different diseases and symptoms and accelerate aging. One of the consequences of prolonged psychosocial stress may be a negative effect on the levels of dehydroepiandrosterone (DHEA) and its sulphated metabolite dehydroepiandrosterone sulphate (DHEA-S). The aim of this study is to investigate whether levels of DHEA and DHEA-S differ in individuals who report perceived stress at work compared to individuals who report no perceived stress at work.
Morning fasting DHEA-S and DHEA levels were measured in serum in a non-stressed group (n = 40) and a stressed group (n = 41). DHEA and DHEA-S levels were compared between the groups using ANCOVA, controlling for age.
The mean DHEA-S levels were 23% lower in the subjects who reported stress at work compared to the non-stressed group. Statistical analysis (ANCOVA) showed a significant difference in DHEA-S levels between the groups (p = 0.010). There was no difference in DHEA level between the groups.
This study indicates that stressed individual have markedly lower levels of DHEA-S. Given the important and beneficial functions of DHEA and DHEA-S, lower levels of DHEA-S may constitute one link between psychosocial stress, ill health and accelerated ageing.
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.
a randomized, double-blinded, placebo-controlled trial. The intervention was oral DHEA 50 mg/d or placebo for 12 months.
58 women and 61 men, aged 60–88 yr, with low serum DHEA sulfate (DHEAS) levels at study entry.
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.
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.
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.
dehydroepiandrosterone; regional adiposity; insulin action
Hypothalamic–pituitary–adrenal underactivity has been reported in rheumatoid arthritis (RA). This phenomenon has implications with regard to the pathogenesis and treatment of the disease. The present study was designed to evaluate the secretion of the adrenal androgen dehydroepiandrosterone sulfate (DHEAS) and its relation to clinical variables in RA, spondyloarthropathy (Spa), and undifferentiated inflammatory arthritis (UIA). Eighty-seven patients (38 with RA, 29 with Spa, and 20 with UIA) were studied, of whom 54 were women. Only 12 patients (14%) had taken glucocorticoids previously. Age-matched, healthy women (134) and men (149) served as controls. Fasting blood samples were taken for determination of the erythrocyte sedimentation rate (ESR), serum DHEAS and insulin, and plasma glucose. Insulin resistance was estimated by the homeostasis-model assessment (HOMAIR). DHEAS concentrations were significantly decreased in both women and men with inflammatory arthritis (IA) (P < 0.001). In 24 patients (28%), DHEAS levels were below the lower extreme ranges found for controls. Multiple intergroup comparisons revealed similarly decreased concentrations in each disease subset in both women and men. After the ESR, previous glucocorticoid usage, current treatment with nonsteroidal anti-inflammatory drugs, duration of disease and HOMAIR were controlled for, the differences in DHEAS levels between patients and controls were markedly attenuated in women (P = 0.050) and were no longer present in men (P = 0.133). We concluded that low DHEAS concentrations are commonly encountered in IA and, in women, this may not be fully explainable by disease-related parameters. The role of hypoadrenalism in the pathophysiology of IA deserves further elucidation. DHEA replacement may be indicated in many patients with IA, even in those not taking glucocorticoids.
Dehydroepiandrosterone sulfate; inflammatory arthritis
Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances in women with diminished ovarian reserve (DOR), and to reduce miscarriage rates by 50-80%. Such an effect is mathematically inconceivable without beneficial effects on embryo ploidy. This study, therefore, assesses effects of DHEA on embryo aneuploidy.
In a 1:2, matched case control study 22 consecutive women with DOR, supplemented with DHEA, underwent preimplantation genetic screening (PGS) of embryos during in vitro fertilization (IVF) cycles. Each was matched by patient age and time period of IVF with two control IVF cycles without DHEA supplementation (n = 44). PGS was performed for chromosomes X, Y, 13, 16, 18, 21 and 22, and involved determination of numbers and percentages of aneuploid embryos.
DHEA supplementation to a significant degree reduced number (P = 0.029) and percentages (P < 0.001) of aneuploid embryos, adjusted for relevant covariates. Short term supplementation (4-12 weeks) resulted in greatest reduction in aneuploidy (21.6%, 95% CI -2.871-46.031).
Beneficial DHEA effects on DOR patients, at least partially, are the likely consequence of lower embryo aneuploidy. DHEA supplementation also deserves investigation in older fertile women, attempting to conceive, where a similar effect, potentially, could positively affect public health.
To investigate whether androgen conversion rates after supplementation with dehydroepiandrosterone (DHEA) differ, and whether differences between patients with diminished ovarian reserve (DOR) are predictive of pregnancy chances in association with in vitro fertilization (IVF).
In a prospective cohort study we investigated 213 women with DOR, stratified for age (≤38 or >38 years) and ovarian FMR1 genotypes/sub-genotypes. All women were for at least 6 weeks supplemented with 75 mg of DHEA daily prior to IVF, between initial presentation and start of 1st IVF cycles. Levels of DHEA, DHEA-sulfate (DHEAS), total T (TT) and free T (FT) at baseline (BL) and IVF cycle start (CS) were then compared between conception and non-conception cycles.
Mean age for the study population was 41.5 ± 4.4 years. Forty-seven IVF cycles (22.1 %) resulted in clinical pregnancy. Benefits of DHEA on pregnancy rates were statistically associated with efficiency of androgen conversion from DHEA to T and amplitude of T gain. Younger women converted significantly more efficiently than older females, and selected FMR1 genotypes/sub-genotypes converted better than others. FSH/androgen and AMH/androgen ratios represent promising new predictors of IVF pregnancy chances in women with DOR.
DOR at all ages appears to represent an androgen-deficient state, benefitting from androgen supplementation. Efficacy of androgen supplementation with DHEA, however, varies depending on female age and FMR1 genotype/sub-genotype. Further clarification of FMR1 effects should lead to better individualization of androgen supplementation, whether via DHEA or other androgenic compounds.
Diminished ovarian reserve; Androgens; Androgen deficiency; Androgen supplementation; Dehydroepiandrosterone (DHEA); Testosterone; FMR1 gene; Premature ovarian aging; Follicle stimulating hormone (FSH); Anti-Müllerian hormone (AMH); Pregnancy rates; In vitro fertilization (IVF); Adrenal insufficiency
AIM--Since most forms of Kaposi sarcoma are much more common in men than in women, the aim of this study was to examine serum concentrations of sex steroids in HIV positive men with and without Kaposi sarcoma. METHODS--Blood samples from 34 HIV positive men without Kaposi sarcoma (KS-) and 28 with Kaposi sarcoma (KS+) and from 35 HIV negative men (controls) were analysed for adrenal and gonadal steroids. Further analysis was done in subgroups classified by CD4 lymphocyte counts. RESULTS--KS+ patients had significantly higher serum dehydroepiandrosterone (DHEA) and testosterone concentrations than the KS- patients, and their DHEA, DHEA sulphate, testosterone, and androstenedione values were higher than in the controls. The KS+ patients with more than 500 CD4 lymphocytes per mm3 had significantly higher serum DHEA, DHEA sulphate, and testosterone than the KS- patients with the same CD4 counts; those with 500-200 CD4 cells/mm3 had higher serum DHEA and testosterone than the equivalent KS- men; and those with < 200 CD4 cells/mm3 had raised DHEA only compared with KS- men. Both KS+ and KS- men had higher serum progesterone and oestradiol than the controls. Glucocorticoids were not significantly altered. CONCLUSIONS--The high androgen levels in KS+ patients, particularly in the early stages of the disease (> 500 CD4 cells/mm3), may affect the immune system by inducing an abnormal cytokine profile, or by increasing T8 proliferation and activation, or both. This raises the question of the relationship between androgens and Kaposi sarcoma.
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.
Dehydroepiandrosterone; DHEA; DHEAS; neuroprotection; neurogenesis; apoptosis; depression; schizophrenia; dementia; cortisol
Prolonged increases in plasma glucocorticoids can exacerbate neurodegeneration. In rats, these neurodegenerative effects can be reduced by dehydroepiandrosterone (DHEA), an androgen precursor with anti-glucocorticoid actions. In song sparrows, season and acute restraint stress affect circulating levels of corticosterone and DHEA, and the effects of stress differ in plasma collected from the brachial and jugular veins. Jugular plasma is an indirect index of the neural steroidal milieu. Here, we directly measured corticosterone and DHEA in several brain regions and jugular plasma, and examined the effects of season and acute restraint stress (30 min) (n = 571 samples). Corticosterone levels were up to 10× lower in brain than in jugular plasma. In contrast, DHEA levels were up to 5× higher in brain than in jugular plasma and were highest in the hippocampus. Corticosterone and DHEA concentrations were strongly seasonally regulated in plasma but, surprisingly, not seasonally regulated in brain. Acute stress increased corticosterone levels in plasma and brain, except during the molt, when stress unexpectedly decreased corticosterone levels in the hippocampus. Acute stress increased DHEA levels in plasma during the molt but had no effects on DHEA levels in brain. This is the first study to measure (i) corticosterone or DHEA levels in the brain of adult songbirds and (ii) seasonal changes in corticosterone or DHEA levels in the brain of any species. These results highlight several critical differences between systemic and local steroid concentrations and the difficulty of using circulating steroid levels to infer local steroid levels within the brain.
PMID: 19473242 CAMSID: cams333
DHEA; glucocorticoid; hippocampus; molt; neurosteroid; song sparrow
Rapid and accurate risk stratification in patients with community-acquired pneumonia (CAP) is an unmet clinical need. Cortisol to dehydroepiandrosterone (DHEA) ratio was put forward as a prognostic marker in sepsis. We herein validated the prognostic value of the adrenal hormones DHEA, DHEA-Sulfate (DHEAS), cortisol/DHEA-, cortisol/DHEAS- and DHEA/DHEAS – ratios in patients with CAP.
We assessed severity of illness using the pneumonia severity index (PSI) and measured adrenal hormone concentrations in 179 serum samples of prospectively recruited patients hospitalized with CAP. We calculated spearman rank correlation, logistic regression analysis and Kaplan Meier curves to study associations of adrenal hormones and outcomes.
There was a significant correlation between PSI score and total cortisol (r = 0.24, p = 0.001), DHEAS (r = −0.23, p = 0.002), cortisol/DHEA (r = 0.23, p = 0.003), cortisol/DHEAS (r = 0.32, p = <0.0001) and DHEA/DHEAS (r = 0.20, p = 0.009). In age and gender adjusted logistic regression analysis, cortisol (OR: 2.8, 95% CI: 1.48–5.28) and DHEA (OR: 2.62, 95% CI: 1.28–5.34), but not DHEAS and the different ratios were associated with all-cause mortality. The discriminatory accuracy of cortisol and DHEA in ROC analysis (area under the curve) was 0.74 and 0.61. In Kaplan Meier analysis, patients in the highest deciles of cortisol and DHEA (p = 0.005 and p = 0.015), and to a lesser extent of cortisol/DHEAS ratio (p = 0.081) had a higher risk of death.
Cortisol, DHEAS and their ratios correlate with CAP severity, and cortisol and DHEA predict mortality. Adrenal function in severe pneumonia may be an important factor for CAP outcomes.
Posttraumatic stress disorder (PTSD) is associated with increased smoking initiation, maintenance and relapse. Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are neurosteroids that have been associated with mood measures as well as smoking status, and nicotine is associated with increased DHEA and DHEAS levels. Given the difficulties with mood experienced by smokers with PTSD, the purpose of the current study was to evaluate the association between negative affect and anxiety sensitivity with DHEA and DHEAS levels. Ninety-six smokers with and without PTSD provided blood samples for neurosteroid analyses, and completed self-report measures of anxiety sensitivity and electronic diary ratings of negative affect. As expected, PTSD smokers reported higher levels of anxiety sensitivity (F[1,94]=20.67, partial η2= 0.18, p<.0001) and negative affect (F[1,91]=7.98, partial η2= .08, p=.006). After accounting for age and gender, DHEAS was significantly inversely associated with both anxiety sensitivity (F[3,92]=6.97, partial η2= 0.07, p=.01) and negative affect (F[3,87]=10.52, partial η2= 0.11, p=.002) across groups. Effect sizes indicated that these effects are moderate to high. No significant interactions of diagnosis and DHEA(S) levels with mood measures were detected. Given that nicotine is known to elevate DHEA(S) levels, these results suggest that DHEAS may serve as a biomarker of the association between mood and nicotine among smokers. Implications for the results include 1) the use of DHEAS measurement across time and across quit attempts; and 2) the potential for careful use of DHEA supplementation to facilitate abstinence during smoking cessation.
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.
Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual’s ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging.
Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged ≥65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points.
Overall, there was a slight decline in DHEAS levels over time (−0.013 μg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32–2.33) and extreme variability (HR 1.89, CI 1.47–2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88–1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001).
Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.
DHEA; DHEAS; Mortality; Aging; Elderly
The decline in immunologic function with age is associated with an increase in susceptibility to infections and the occurrence of autoimmune diseases and cancers. Hence, the restoration of immunologic function is expected to have a beneficial effect in reducing pathology and maintaining a healthy condition in advanced age. A number of therapeutic strategies have been employed to intervene in the aging immune system. This article reviews the effect of dietary restriction (DR), dehydroepiandrosterone (DHEA) treatment, melatonin (MLT) therapy, and exercise on modulating the immune responses and retarding/reducing immunosenescence. DR has been subject to intensive research and is known to be the most efficacious means of increasing longevity, reducing pathology and enhancing immune function.
The circulatory levels of the androgenic hormone DHEA and the pineal hormone MLT decrease with increasing age, and this decrease has been correlated with the age-related decline in the immune system. Therefore, the observation that immunosenescence is associated with low levels of DHEA and MLT has provided a rationale for therapeutic intervention. DHEA treatment and MLT therapy both exhibit immunostimulatory actions and preliminary reports indicate that hormonal (DHEA or MLT) substitution therapy reverses immunosenescence in mice. Similarly, exercise in some studies has been shown to enhance the immune response. However, these findings have not been confirmed by other laboratories. Thus, at the present time, it is difficult to draw any definitive conclusions on the efficacy of DHEA, MLT, and exercise on reversing or restoring the aging immune system.