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August 2001

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Dehydroepiandrosterone decreases mortality rate and improves cellular immune function during polymicrobial sepsis.

OBJECTIVE: Sepsis is associated with a marked depression of cellular immune function. The steroid hormone dehydroepiandrosterone (DHEA) is proposed to have immunoenhancing activities. We, therefore, investigated the effect of DHEA on the mortality rate and cellular immune functions in an experimental model of sepsis. DESIGN: Randomized animal study. SETTING: Level I trauma center, university research laboratory. SUBJECTS: Male NMRI mice. INTERVENTIONS: Mice were subjected to laparotomy (sham) or cecal ligation and puncture (CLP). Mice were treated with (sham/DHEA; CLP/DHEA) or without (sham; CLP) the steroid hormone DHEA (30 mg/kg sc). Animals were killed 48 hrs after the onset of sepsis. MEASUREMENTS AND MAIN RESULTS: The survival rate of septic mice was determined 24 and 48 hrs after onset of sepsis. Forty-eight hours after the septic challenge, a white blood cell count was performed and serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta concentrations were monitored using ELISA. Furthermore, the delayed type of hypersensitivity (DTH) reaction was evaluated on the basis of ear pinna swelling after dinitrofluorobenzene (DNFB) administration, and clinical variables (body weight, temperature, heart rate, fluid input/output, food intake) were monitored using metabolic cages. DHEA administration improved the survival rate (87% vs. 53% after 48 hrs; p <.001). This was accompanied by a restoration of the depressed DTH reaction and a reduction in TNF-alpha serum concentrations (20.7 +/- 1.4 pg/mL vs. 32.4 +/- 6.6 pg/mL). CONCLUSIONS: These results demonstrate that DHEA administration leads to an increased survival following a septic challenge. The immunoenhancing effect of DHEA is accompanied by a reduction of TNF-alpha release and an improved activity of T-cellular immunity. DHEA administration may, therefore, be beneficial in systemic inflammation.

Crit Care Med 2001 Feb;29(2):380-4

Dehydroepiandrosterone (DHEA) reduces neuronal injury in a rat model of global cerebral ischemia.

Introduction: Many studies report an inverse correlation between levels of DHEA and neurological diseases. Exogenous DHEA protects hippocampal neurons against excitatory amino acid induced neurotoxicity. The purpose of this experiment is to evaluate the effect of DHEA in an animal model of transient but severe forebrain ischemia. Methods: At thirteen days prior to induction of ischemia, male Wistar rats were implanted with various doses of DHEA-placebo, 25 mg, 50 mg or 100 mg. Forebrain ischemia was induced for 10 minutes using a modified four-vessel occlusion technique, with hippocampal neuronal injury assessed at 7 days post-ischemically and expressed as a percentage of total cells. Results: Both normal and necrotic hippocampal CA(1) cells were counted. Percentages of hippocampal injury observed were 88+/-13% in animals treated with placebo, 84+/-8% in the 25 mg DHEA group, and 60+/-7% in the 50 mg DHEA group. Animals treated with 100 mg DHEA displayed a significant (P<0.05) reduction of hippocampal CA(1) cell injury at 60+/-7% Conclusion: Treatment with a high dose, but not a low or moderate dose, of DHEA implantation reduces hippocampal CA(1) neuronal injury following severe but transient forebrain ischemia.

Brain Res 2001 Jan 12;888(2):263-266

Dehydroepiandrosterone in systemic lupus erythematosus.

DHEA has shown promise for the treatment of SLE in three controlled and several uncontrolled clinical trials, including one large multicenter study comprising nearly 200 patients. The main benefits of DHEA seem to be a decrease in corticosteroid requirements and improved overall symptomatology. Intriguing aspects of DHEA treatment in SLE that require further study are a possible bone protective effect and improvements in cognitive function. The most frequent side effect is mild acneiform dermatitis, and long-term concerns include lowered HDL cholesterol.

Rheum Dis Clin North Am 2000 May;26(2):349-62

Dehydroepiandrosterone prevents oxidative injury induced by transient ischemia/reperfusion in the brain of diabetic rats.

Both chronic hyperglycemia and ischemia/reperfusion (IR) cause an imbalance in the oxidative state of tissues. Normoglycemic and streptozotocin (STZ)-diabetic rats were subjected to bilateral carotid artery occlusion for 30 min followed by reperfusion for 60 minutes. Rats had either been treated with dehydroepiandrosterone (DHEA) for 7, 14 or 21 days (2 or 4 mg/day per rat) or left untreated. Oxidative state, antioxidant balance, and membrane integrity were evaluated in isolated synaptosomes. IR increased the levels of reactive species and worsened the synaptic function, affecting membrane Na/K-ATPase activity and lactate dehydrogenase release in all rats. The oxidative imbalance was much severer when transient IR was induced in STZ-diabetic rats. DHEA treatment restored H2O2, hydroxyl radical, and reactive oxygen species to close to control levels in normoglycemic rats and significantly reduced the level of all reactive species in STZ-diabetic rats. Moreover, DHEA treatment counteracted the detrimental effect of IR on membrane integrity and function: the increase of lactate dehydrogenase release and the drop in Na/K-ATPase activity were significantly prevented in both normoglycemic and STZ-diabetic rats. The results confirm that DHEA, an adrenal steroid that is synthesized de novo by brain neurons and astrocytes, possesses a multitargeted antioxidant effect. They also show that DHEA treatment is effective in preventing both derangement of the oxidative state and neuronal damage induced by IR in experimental diabetes.

Diabetes 2000 Nov;49(11):1924-31

Dehydroepiandrosterone replacement in women with adrenal insufficiency.

BACKGROUND: The physiologic role of dehydroepiandrosterone in humans is still unclear. Adrenal insufficiency leads to a deficiency of dehydroepiandrosterone; we therefore, investigated the effects of dehydroepiandrosterone replacement, in patients with adrenal insufficiency. METHODS: In a double-blind study, 24 women with adrenal insufficiency received in random order 50 mg of dehydroepiandrosterone orally each morning for four months and placebo daily for four months, with a one-month washout period. We measured serum steroid hormones, insulin-like growth factor I, lipids, and sex hormone-binding globulin, and we evaluated well-being and sexuality with the use of validated psychological questionnaires and visual-analogue scales, respectively. The women were assessed before treatment, after one and four months of treatment with dehydroepiandrosterone, after one and four months of placebo, and one month after the end of the second treatment period. RESULTS: Treatment with dehydroepiandrosterone raised the initially low serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone into the normal range; serum concentrations of sex hormone-binding globulin, total cholesterol, and high-density lipoprotein cholesterol decreased significantly. Dehydroepiandrosterone significantly improved overall well-being as well as scores for depression and anxiety. For the global severity index, the mean (+/-SD) change from base line was -0.18+/-0.29 after four months of dehydroepiandrosterone therapy, as compared with 0.03+/-0.29 after four months of placebo (P=0.02). As compared with placebo, dehydroepiandrosterone significantly increased the frequency of sexual thoughts (P=0.006), sexual interest (P=0.002), and satisfaction with both mental and physical aspects of sexuality (P=0.009 and P=0.02, respectively). CONCLUSIONS: Dehydroepiandrosterone improves well-being and sexuality in women with adrenal insufficiency.

N Engl J Med 1999 Sep 30;341(14):1013-20

Changes in cortisol/DHEA ratio in HIV-infected men are related to immunological and metabolic perturbations leading to malnutrition and lipodystrophy.

HIV-1 infection is associated with immune deficiency and metabolic perturbations leading to malnutrition and lipodystrophy. Because immune response and metabolic perturbations (protein and lipid metabolism) are partly regulated by glucocorticoids and DHEA, we determined serum cortisol and DHEA concentrations, and the cortisol/DHEA ratio in HIV-positive men, either untreated or receiving various antiretroviral treatments (ART), including highly active antiretroviral therapy (HAART). Cortisol levels were found increased in all patients, whatever the stage of the disease and independently of the ART treatment. In contrast, serum DHEA was elevated in the asymptomatic stage, and it was below normal values in AIDS patients, either untreated or mono-ART-treated. The DHEA level was low in HAART-treated patients with lipodystrophy (LD+) and highly increased in HAART-treated patients without lipodystrophy (LD-). Consequently, the cortisol/DHEA ratio was similar to controls in asymptomatic untreated or mono-ART-treated patients, but increased in AIDS patients. Interestingly, this ratio was increased in LD+ HAART-treated men, but normalized in LD- HAART-treated patients. Changes in the cortisol/DHEA ratio were negatively correlated with the in vivo CD4 T-cell counts, with the malnutrition markers, such as body-cell mass and fat mass, and with the increased circulating lipids (cholesterol, triglycerides, and apolipoprotein B) associated to the lipodystrophy syndrome. Our observations show that the cortisol/DHEA ratio is dramatically altered in HIV-infected men, particularly during the syndromes of malnutrition and lipodystrophy, and this ratio remains elevated whatever the antiretroviral treatment, including HAART. These findings have practical clinical implications, since manipulation of this ratio could prevent metabolic (protein and lipid) perturbations.

Ann N Y Acad Sci 2000;917:962-70

Inhibition of human immunodeficiency virus type-1 (HIV-1) replication by immunor (IM28), a new analog of dehydroepiandrosterone.

The inhibition of HIV-1 replication in vitro by Immunor 28 (IM28), an analog of dehydroepiandrosterone (DHEA), was monitored using the HIV-1 laboratory wild-type strain IIIB. Evaluation of the 50% inhibitory dose (IC50) revealed a decrease in HIV-1 replication giving an IC50 value around 22 microM. The toxicity of the drug has been determined also, in MT2 cells and PBMCs. 60 microM of IM28 provoked a 50% decrease in cell viability while DHEA caused the same decrease at 75 microM in MT2 cells. These values are 125 microM for IM28 in PBMCs and 135 microM for DHEA. Thus, DHEA is less toxic than IM28, but IM28 has a higher antiviral activity.

Nucleosides Nucleotides Nucleic Acids 2000 Oct-Dec;19(10-12):2019-24

Serum levels of interleukin-6 and dehydroepiandrosterone sulphate in response to either fasting or a ketogenic diet in rheumatoid arthritis patients.

OBJECTIVE: To investigate the effects of either a 7-day fast or a 7-day ketogenic diet upon serum interleukin-6 (IL-6) and dehydroepiandrosterone sulphate (DHEAS) in RA patients. METHODS: We measured serum concentrations of DHEAS and IL-6 in 23 RA patients with active disease, 10 of whom followed a 7-day sub-total fast and 13 of whom consumed a ketogenic diet (isoenergetic, carbohydrate < 40 g/day) for 7 days. Clinical and laboratory variables were measured at baseline, on day 7 and after re-feeding on day 21. Correlation analyses were used to assess the associations between serum IL-6, DHEAS and disease activity variables at each timepoint. RESULTS: Fasting, but not the ketogenic diet, decreased serum IL-6 concentrations by 37% (p < 0.03) and improved disease activity at day 7. Both fasting and the ketogenic diet increased serum DHEAS levels by 34% as compared with baseline (both p < 0.006). Levels of IL-6, but not DHEAS, correlated with several disease activity variables. CONCLUSION: Both fasting and a ketogenic diet significantly increased serum DHEAS concentrations in RA patients. Only fasting significantly decreased serum IL-6 levels and improved disease activity. As the increases in serum DHEAS were similar in response to both fasting and a ketogenic diet, it is unlikely that the fall in serum IL-6 or clinical improvements after fasting were directly related to increases in serum DHEAS. The fasting-induced fall in serum IL-6 may underlie the fall in CRP and ESR observed in RA patients in response to a 7-day fast.

Clin Exp Rheumatol 2000 May-Jun;18(3):357-62

Dehydroepiandrosterone, pregnenolone and sex steroids down-regulate reactive astroglia in the male rat brain after a penetrating brain injury.

Astrocytes are a target for steroid hormones and for steroids produced by the nervous system (neurosteroids). The effect of gonadal hormones and several neurosteroids in the formation of gliotic tissue has been assessed in adult male rats after a penetrating wound of the cerebral cortex and the hippocampal formation. The hormones testosterone, 17beta-estradiol and progesterone and the neurosteroids dehydroepiandrosterone, pregnenolone and pregnenolone sulfate resulted in a significant decrease in the accumulation of astrocytes in the proximity of the wound and in a decreased bromodeoxyuridine incorporation in reactive astrocytes. Of all steroids tested, dehydroepiandrosterone was the most potent inhibitor of gliotic tissue formation. These findings suggest that neurosteroids and sex steroids may affect brain repair by down-regulating gliotic tissue.

Int J Dev Neurosci 1999 Apr;17(2):145-51

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