Correlation Between the Different Types of Antipsychotics and Serum Cortisol, Dehidroepiandrosterone Sulfat and their Ratio in Schizophrenia.

Background: Evidence for disturbances in HPA activation and abnormal HPA regulatory mechanisms in schizophrenia is accumulating. Aim: To compare serum levels of cortisol, DHEA-S and their ratio between patients with schizophrenia and healthy controls and among patients before and after treatment with different types of antipsychotics. Material and methods: In this clinical prospective study, 60 patients with schizophrenia and 40 healthy age and sex matched control subjects were included. All patients experienced an acute exacerbation of the illness (PANSS: P1 and P3 ≥ 4). Clinical evaluation of patients was performed using the Positive and Negative Symptom Scale. A questionnaire for socio-demographic and clinical data collection was used. Serum levels of cortisol, DHEA-S and their ratio were measured at baseline in all participants and after 3 and 6 weeks, respectively, of the antipsychotic treatment with different types of antipsychotics in patients with schizophrenia. Results: Patients with schizophrenia had significantly higher serum cortisol and DHEA-S levels in comparison to the control group. There was no significant difference in serum levels of cortisol, DHEA-S and their ratio between patients treated with different types of antipsychotics (typical/atypical). Serum levels of the analyzed hormones significantly reduce during the 6-week period of examination in both subgroups treated with different types of antipsychotics. Conclusion: Elevated serum cortisol and DHEA-S in schizophrenic patients might be associated with their role in the pathophysiology of the disorder. There is no significant difference in serum levels of cortisol, DHEA-S and their ratio among the patients treated with different types of antipsychotics.

Dehydroepiandrosterone sulfate improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome.

Stress-induced altered visceral sensation and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). These responses were demonstrated to be peripheral corticotropin-releasing factor (CRF) dependent and also mediated via proinflammatory cytokine in animal IBS model. Dehydroepiandrosterone sulfate (DHEA-S) is known to have anti-inflammatory properties by suppressing proinflammatory cytokine release. We hypothesized that DHEA-S improves stress-induced visceral changes and is beneficial for IBS treatment. We explored the effects of DHEA-S on lipopolysaccharide (LPS)- or repeated water avoidance stress (WAS)-induced visceral allodynia and increased colonic permeability (rat IBS models). The threshold of visceromotor response, i.e. abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue. DHEA-S abolished visceral allodynia and colonic hyperpermeability induced by LPS in a dose-dependent manner. It also blocked repeated WAS- or peripheral injection of CRF-induced visceral changes. These effects by DHEA-S in LPS model were reversed by bicuculline, a γ-aminobutyric acid (GABA)A receptor antagonist, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, naloxone, an opioid receptor antagonist, or sulpiride, a dopamine D2 receptor antagonist. However, domperidone, a peripheral dopamine D2 receptor antagonist did not modify the effects. Peripheral injection of astressin2-B, a selective CRF receptor subtype 2 (CRF2) antagonist also reversed these effects. In conclusion, DHEA-S blocked stress-induced visceral changes via GABAA, NO, opioid, central dopamine D2 and peripheral CRF2 signaling. DHEA-S may be useful for IBS treating.

Dehydroepiandrosterone (DHEA)-SO4 Depot and Castration-Resistant Prostate Cancer.

Dehydroepiandrosterone (DHEA)-SO4 of adrenal origin is the major C19 steroid in the serum. It is a precursor of intratumoral androgen biosynthesis in patients with advanced prostate cancer following chemical or surgical castration. DHEA is a product of the P450c17 (17α-hydroxylase-17,20-lyase) enzyme. Despite inhibition of P450c17 with new agents, e.g., Abiraterone acetate, Orterenol, and Galeterone, the level of enzyme inhibition rarely exceeds 90% leaving behind a significant depot for androgen biosynthesis within the tumor. For DHEA-SO4 to be utilized there is uptake by organic anion transporter polypeptides, deconjugation catalyzed by steroid sulfatase, and adaptive upregulation of prostate steroidogenic enzymes that will convert DHEA into either testosterone or dihydrotestosterone. The depot of DHEA-SO4 that remains after P450c17 inhibition and the adaptive responses that occur within the tumor to promote DHEA utilization contribute to mechanisms of drug resistance observed with P450c17 inhibitors. Knowledge of these mechanisms identify new targets for therapeutics that could be used to surmount drug resistance in prostate cancer.

Prevalence and treatment of central hypogonadism and hypoandrogenism in women with hypopituitarism.

PURPOSE: Women with hypopituitarism have increased morbidity and mortality, and hypogonadism has been suggested to be a contributing mechanism. The purpose of this study was to investigate the prevalence of central hypogonadism and hypoandrogenism in women with hypopituitarism at a single Swedish center. METHODS: All consecutive women (n = 184) who commenced growth hormone (GH) replacement therapy at Sahlgrenska University Hospital in Gothenburg between 1995 and 2015 were included. In accordance with the Endocrine Society Clinical Practice Guidelines, strict criteria, based on menstrual history combined with laboratory measurements, were used to define central hypogonadism. Hypoandrogenism was defined as subnormal levels of dehydroepiandrosterone sulfate and/or androstenedione. RESULTS: Central hypogonadism was present in 78% of the women, in 75% of those ≤ 52 years and in 82% of those > 52 years of age. Hypoandrogenism was found in 61% of all the women and in 92% of those with adrenocorticotropic hormone (ACTH) deficiency. The estrogen substitution rate in hypogonadal women ≤ 52 years was lower than the hormonal substitution rate in the other pituitary hormone axes (74% versus 100%, P < 0.001). The use of estrogen substitution tended to decrease between 2000 and 2016. Few women received androgen treatment. CONCLUSIONS: In this first study of hypogonadism in women with hypopituitarism, using stringent diagnostic criteria for hypogonadism, the prevalence of central hypogonadism and low androgen levels was high and estrogen substitution was insufficient. Further studies are needed to elucidate the importance of hypogonadism and insufficient sex steroid replacement for the increased morbidity in hypopituitary women.

Dehydroepiandrosterone sulfate and dehydroepiandrosterone sulfate/cortisol ratio in cirrhotic patients with septic shock: another sign of hepatoadrenal syndrome?

BACKGROUND: Cirrhotic patients are susceptible to sepsis and critical illness-related corticosteroid insufficiency (CIRCI). Dehydroepiandrosterone sulfate (DHEAS) is a corticotropin-dependent adrenal androgen, which has immunostimulating and antiglucocorticoid effects. Considering the synchronized synthesis of cortisol and DHEAS and their opposing effects to each other, investigators have proposed measuring these two hormones as a ratio. Severe sepsis has been associated with low DHEAS, especially relative to high cortisol. Despite growing interest in the role of adrenal androgen replacement in critical illness, there have been no data about DHEAS and the DHEAS/cortisol ratio in patients with liver cirrhosis. We studied whether low concentrations of DHEAS and decreased DHEAS/cortisol ratio are associated with poor outcome in patients with liver cirrhosis and septic shock. METHODS: We recruited 46 cirrhotic patients with septic shock, and 46 noncirrhotic counterparts matched by age and sex. We evaluated adrenal function using the short corticotropin stimulation test and analyzed the relation between DHEAS and cortisol. RESULTS: While the nonsurvivors in the cirrhotic group had significantly lower baseline DHEAS, lower baseline DHEAS/cortisol ratio, and reduced increments of both DHEAS and cortisol upon corticotropin stimulation, the survivors had lower baseline cortisol. Cirrhotic patients with lower DHEAS/cortisol ratio (<1.50) had higher levels of interleukin-6 and tumor necrosis factor alpha, higher Sequential Organ Failure Assessment scores, and higher rates of CIRCI and hospital mortality. Using the area under the receiver operating characteristic (AUROC) curve, both DHEAS and the DHEAS/cortisol ratio demonstrated a good discriminative power for predicting hospital survival (AUROC 0.807 and 0.925 respectively). The cirrhotic group had lower DHEAS and DHEAS/cortisol ratio but higher rates of CIRCI and hospital mortality, compared to the noncirrhotic group. CONCLUSIONS: There is dissociation between cortisol (increased) and DHEAS (decreased) in those cirrhotic patients who succumb to septic shock. Low DHEAS/cortisol ratios are associated with more severe diseases, inflammation, and CIRCI and can serve as a prognostic marker. More investigations are needed to evaluate the role of adrenal androgen in this clinical setting.

Sexualidad y climaterio: una mirada integral / Sexuality and climacteric: a comprehensive approach

Cuando hablamos de sexualidad humana debemos saber que estamos hablando de una compleja y cambiante interacción de factores biológicos y socioemocionales altamente influenciables por la familia, la religión y los patrones culturales. Esto se ve en los hombres y en las mujeres, especialmente en las mujeres. La sexualidad es un concepto intuitivo que cuesta definir. Según la Organización Mundial de la Salud, se define salud sexual como "un estado de bienestar físico, emocional, mental y social relacionado con la sexualidad, la cual no es solamente la ausencia de enfermedad, disfunción o incapacidad". Es una definición que tiene en cuenta varios conceptos, muy importantes todos ellos. La respuesta sexual consiste en una serie de cambios neurofisiológicos, hemodinámicos y hormonales que involucran al conjunto del organismo. Si bien es similar en ambos sexos, en las mujeres no siempre el inicio y la progresión se correlacionan en forma sistemática o lineal como en los hombres. Y de ese intrigante devenir de la respuesta sexual femenina surge la dificultad del diagnóstico de la "disfunción sexual femenina". Podríamos resumirla en "un conjunto de trastornos en los que los problemas fisiológicos o psicológicos dificultan la participación o la satisfacción en las actividades sexuales; lo cual se traduce en la incapacidad de una persona para participar en una relación sexual de la forma que le gustaría hacerlo"16. La menopausia es percibida por muchas mujeres como el fin de la sexualidad, y no solo como el fin de la vida reproductiva. Si bien es cierto que en esta etapa la actividad sexual suele declinar y puede verse afectada por una serie de factores hormonales, psicológicos y socioculturales, para la mayoría de las mujeres la sexualidad sigue siendo importante. Debemos comprender que la disfunción sexual femenina, en cualquier etapa de la vida, es multicausal y multidimensional. A la hora de realizar el abordaje de una paciente, debemos tener en cuenta todos los factores involucrados y saber con qué herramientas contamos. El abordaje terapéutico clásicamente incluye la terapia psicológica y la terapia hormonal. Sin embargo, recientemente se ha incorporado una nueva droga recientemente aprobada por la FDA de los Estados Unidos para el tratamiento del deseo sexual hipoactivo en la mujer: el flibanserín, un psicofármaco que actúa a nivel de mediadores del deseo sexual en el sistema nervioso central, favoreciéndolo. (AU)

When we talk about human sexuality, we know that we are talking about a complex and changing interaction between biological and socioemotional factors, which are highly influenced by society, family, religion and cultural norms. This can be seen in men and women especially in women. Sexuality is an intuitive concept difficult to define. According to the World Health Organization, it is defined as "A state of physical, emotional, mental and social well being related to sexuality, which is not merely the absence of disease, dysfunction or disabilityˮ. It is a definition that takes into account several concepts, all very important. Sexual response is a series of neurophysiological, hemodynamic and hormonal changes involving the whole body. While similar in both sexes, women are not always the onset and progression correlate systematically or linearly as in men. And that intriguing evolution of the female sexual response, the difficulty of diagnosis of "female sexual dysfunctionˮ. We could summarize it in "a group of disorders in which the physiological or psychological problems impede participation or satisfaction in sexual activities; which results in the inability of a person to participate in a sexual relationship the way she or he would like to do itˮ16. Menopause is perceived by many women as to the end of sexuality, not only as the end of reproductive life. Sexual activity declines with age, and may be affected by a number of hormonal, psychological and sociocultural factors, but, for most women it continues to be important. We must understand that female sexual dysfunction, at any stage of life is multicausal and multidimensional. When approaching a patient, it is important to know all the factors that are involved, and which tools we have for deal with it. Classically, the therapeutic approach has consisted of psychological therapy and hormone therapy. However, we have to consider a recently approved drug by the FDA for the treatment of hypoactive sexual desire in women: Flibanserin. It is a psychotropic substance that acts on the mediators of sexual desire on the central nervous system favoring it. (AU)

Dehydroepiandrosterone sulphate: diabolical hormone or epiphenomenon in aneurysmal subarachnoid hemorrhage?

Inflammation is purported to play an important role in the clinical course of subarachnoid hemorrhage. The current study by Höllig et al. entails using dehydroepiandrosterone sulfate, a hormone that inhibits key inflammatory pathways, as a predictor of functional outcome in these patients.

Dehydroepiandrosterone sulfate and cytochrome P450 inducers alleviate fatty liver in male rats fed an orotic acid-supplemented diet.

The effects of the peroxisome proliferator, dehydroepiandrosterone sulfate (DHEAS), and the typical cytochrome P450 (CYP) inducers phenobarbital (PB) and 3-methylcholanthrene (3-MC) on fatty liver were examined in rats. Treating rats with orotic acid caused marked accumulation of lipid droplets in the liver. This effect of orotic acid was almost eradicated by co-treatment with DHEAS and PB. While DHEAS or PB alone also alleviated fatty liver, treatment with 3-MC caused little effect on a reduction in lipid droplets. Histopathological examinations revealed numerous peroxisomes in the liver of rats treated with DHEAS. In addition, a significant increase in the expression on hepatic CYPs was observed in rats the fatty liver of which was attenuated. Regarding other enzymes associated with hepatic fatty acid oxidation, the expression levels of sirtuin 1, sirtuin 6, and carnitine palmitoyltransferase 1 were also upregulated most markedly by treatment with DHEAS alone. Thus, the attenuation in fatty liver observed in the present study is likely due to peroxisome proliferation and the induction of fatty acid-metabolizing enzymes by DHEAS and typical CYP inducers.

Dehydroepiandrostendione sulphate and prediction of live birth after IVF in young women with low anti-Müllerian hormone concentration.

Baseline dehydroepiandrostendione sulphate (DHEAS) has been demonstrated to discriminate between young, expected poor responders with favourable clinical pregnancy prospects after IVF treatment and their counterparts with significantly lower pregnancy chances. This study investigated DHEAS ability to predict live birth before starting the first gonadotrophin-releasing hormone (GnRH) antagonist ovarian stimulation for IVF/intracytoplasmic sperm injection in young women (⩽37years) with low serum AMH (<6.5pmol/l). Medical records of 90patients were analysed. DHEAS was predictive for live birth (AUC-ROC 0.69, 95% CI 0.59-0.79). Its predictive accuracy for live birth was similar to that of the number of oocytes retrieved. The cut-off value for DHEAS of 5.4µmol/l offered the best discriminative performance between patients who achieved live birth and those who did not. The live birth rate per initiated cycle in women with DHEAS concentration >5.4µmol/l was 5-fold higher compared with women with DHEAS ⩽5.4µmol/l (38.9% versus 7.4%, P<0.001) despite similar oocyte yield in both groups. In conclusion, the association between baseline DHEAS and probability of live birth after the GnRH antagonist IVF cycle in young women with low AMH was demonstrated. This association could not be explained by the effect of DHEAS on the oocyte yield. This study demonstrates an association of baseline dehydroepinadrostendione sulphate (DHEAS) concentration with implantation rate and live birth rate after the first gonadotrophin-releasing hormone antagonist IVF cycle in young women who are expected to respond poorly to ovarian stimulation. Compared with the number of oocytes retrieved, DHEAS showed a similar ability to distinguish women who will achieve a live birth from those who will not. However, as a parameter available to clinicians and patients before commencing an ovarian stimulation for IVF, DHEAS could be used in predicting probability of live birth at the initial consultation. Women whose DHEAS concentrations were above the derived cut-off value 5.4µmol/l had 5-fold more favourable prognosis for live birth than their counterparts with DHEAS concentrations below the cut-off value. The findings could not be explained by the difference in the oocyte yield and/or the number of embryos transferred but rather by the possible association between the endogenous DHEAS concentration and the oocyte competence to produce a viable embryo.

Effects of dehydroepiandrosterone sulphate (DHEAS) replacement on insulin action and quality of life in hypopituitary females: a double-blind, placebo-controlled study.

OBJECTIVE: Addition of dehydroepiandrosterone sulphate (DHEAS) to standard pituitary replacement may improve quality of life and glucose metabolism. Conflicting results from the previous work probably relate to differences in populations studied and assessment techniques used. We examined the effects of DHEAS on insulin action and the quality of life in female patients with hypopituitary hypoadrenalism. DESIGN: Randomized, double-blind, placebo-controlled, crossover design was used. Patients received either DHEAS 50 mg daily or placebo for 12 weeks. PATIENTS: Fourteen hypopituitary females on stable standard replacement therapy and with low DHEAS were enrolled. MEASUREMENTS: Insulin action by euglycaemic hyperinsulinaemic clamp and extensive quality of life parameters were assessed after each treatment. RESULTS: Serum DHEAS (DHEAS 5·4 ± 0·8 vs placebo <0·8 ± 0·0 µm; P < 0·001) and androstenedione (DHEAS 4·1 ± 0·8 vs placebo 1·3 ± 0·2 nm; P < 0·05) rose to within the normal range after DHEAS 50 mg daily. There were no differences between treatments in testosterone, sex hormone-binding globulin (SHBG) or IGF-1. Quality of life measures were unchanged after DHEAS. There were no differences between treatments in fasting glucose, serum insulin, HbA1c or in insulin action (glucose infusion rates required to maintain euglycaemia; DHEAS 21·9 ± 2·5 vs placebo 24·5 ± 2·1 µmol/kg/min; P = 0·4). Triglyceride concentrations were lower following DHEAS (DHEAS 1·24 ± 0·18 vs placebo 1·41 ± 0·19 mm; P < 0·05) but other lipid parameters remained unchanged. CONCLUSION: There were no differences compared with placebo in quality of life or insulin action after DHEAS replacement therapy for 12 weeks. These results do not provide evidence for the addition of DHEAS to standard hypopituitary replacement therapy.

DHEA: el andrógeno más producido pero el menos entendido / DHEA: the androgen produced but least understood

Dehidroepiandrosterona (DHEA) y su derivada sulfatada (DHEAS) son los esteroides más abundantes en el cuerpo humano, pero aún se deconoce su mecanismo de acción y sus implicancias fisiológicas. Se le ha atribuido múltiples efectos antienvejecimiento, antiinflamatorio y antiarteriosclerótico entre otros y en EEUU se vende al público como complemento energético y para aumento del libido, sin restricción de la FDA...

Differential effect of oral dehydroepiandrosterone-sulphate on metabolic syndrome features in pre- and postmenopausal obese women.

OBJECTIVE: To analyze the effect in obese pre- and postmenopausal women of a daily dose of 100 mg dehydroepiandrosterone-sulphate (DHEA-S) provided over a period of 3 months as replacement therapy against metabolic syndrome. CONTEXT: Although DHEA-S appears to be effective against certain features of metabolic syndrome, its usefulness against this syndrome as a whole has not been evaluated to date. DESIGN/PATIENTS: A randomized, double-blind placebo-controlled trial was conducted involving 61 postmenopausal women, who received DHEA-S (n = 41) or placebo (n = 20) for 3 months. The effect of DHEA-S treatment on the same postmenopausal women was compared with the effects observed in a group of premenopausal women (n = 20). MEASUREMENTS: Anthropometric measurements were taken at the beginning and at the end of the treatment. Similarly, different parameters that define metabolic syndrome and other cardiometabolic variables were determined. RESULTS: Dehydroepiandrosterone-sulphate replacement produced weight loss in the obese women studied. Moreover, waist circumference, glucose and systolic and diastolic blood pressure, among other metabolic syndrome parameters, improved in the postmenopausal group, who showed a significant reduction in the total metabolic syndrome score (P < 0·05). In contrast, in premenopausal women, the effect of DHEA-S was limited to obesity parameters, and no effect was observed on metabolic syndrome components. No significant changes were evident in the placebo group. CONCLUSIONS: An oral dose of DHEA-S is useful for weight loss. In obese postmenopausal women, the hormone significantly improves plasma biochemical levels and anthropometric characteristics, leading to a better metabolic profile, which highlights the usefulness of this therapy against metabolic syndrome in this group of women.

The clinical and therapeutic potentials of dehydroepiandrosterone and pregnenolone in schizophrenia.

Neurosteroids such as dehydroepiandrosterone (DHEA), pregnenolone (PREG), and their sulfates (DHEAS and PREGS) display multiple effects on the central nervous system. Specifically, neurosteroids have various functions associated with neuroprotection, response to stress, mood regulation, and cognitive performance. In addition, neurosteroid levels are altered in stress-related neuropsychiatric disorders. This review focuses on the alterations of these neurosteroids in schizophrenia and on their association with clinical and neurocognitive manifestations. As described henceforth, findings from clinical studies have revealed that PREG, DHEA, and their sulfates might be involved in the pathophysiology of schizophrenia, and in some of its manifestations. Clinical trials for the evaluation of these neurosteroids face challenges in terms of experimental design, dosing strategy, data analysis, and interpretation. The review concludes with a list of suggested topics for future research. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Involvement of nitric oxide in the protective effects of dehydroepiandrosterone sulphate on stress induced neurobehavioral suppression and brain oxidative injury in rats.

The involvement of nitric oxide (NO) in the effects of dehydroepiandrosterone sulphate (DHEAS) on restraint stress induced neurobehavioral and brain oxidative/nitrosative stress markers was investigated in rats. Exposure of rats to restraint stress suppressed behavioral activity in the elevated plus maze and this was associated with increases in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) and brain NO metabolite (NOx) levels in brain homogenates. Pretreatment with DHEAS (5-40mg/s.c.) reversed the stress induced changes in behavioral and oxidative stress markers and also brain NOx levels. The beneficial effect of DHEAS (40mg/kgs.c.) was blocked by pretreatment with nitric oxide synthase inhibitor, L-NAME (50mg/kgi.p.) while pretreatment of rats with NO-precursor l-Arginine (100mg/kg i.p.) produced potentiation of action of sub effective dose of DHEAS (5mg/kgs.c.). The DHEAS effects were stress specific as these behavioral and biochemical parameters were not much influenced in non-stressed rats. These observations suggest that pretreatment with DHEAS has a protective effect on restraint stress induced alteration of neurobehavioral changes and brain oxidative injury in rats and NO-dependent mechanisms may be involved in this effect.

Effects of dehydroepiandrosterone-sulfate (DHEA-S) and benznidazole treatments during acute infection of two different Trypanosoma cruzi strains.

A significant role for hormones in regulating the balance of Th1- and Th2-associated cytokines with a role in modulating diseases has been accumulating. Previously, we reported that dehydroepiandrosterone (DHEA), the most abundant steroid hormone synthesized by the adrenal cortex, markedly reduced the blood and tissue parasites in experimentally Trypanosoma cruzi-infected rats. Based on these findings, the main purpose of this study was to investigate the effect of dehydroepiandrosterone-sulfate ester (DHEA-S) therapy alone or in combination with benznidazole (BNZ) (recommended in Brazil for the treatment of T. cruzi infection) will be effective during the acute phase of two different lineages of T. cruzi strains: type I (Y strain) and type II (Bolivia strain) of T. cruzi. Administration of either DHEA-S or BNZ alone or in combination significantly reduced the Y strain parasite load as compared with untreated. Furthermore treatment with DHEA-S resulted in Bolivia strain clearance. This protective effect of DHEA-S was associated with the host's immune response, as evidence by enhanced levels of interferon-gamma and interleukin-2. DHEA-S treatment also increased peritoneal macrophages levels and nitrite production. DHEA-S treatment was effective in reducing the mortality rate as compared to BNZ alone or to combiner DHEA-S+BNZ treatment of T. cruzi Bolivia strain infected animals. These findings suggest that hormonal therapy may have a protective effect in the treatment of T. cruzi infection.

Growth factors decrease in subjects with mild to moderate Alzheimer's disease (AD): potential correction with dehydroepiandrosterone-sulphate (DHEAS).

The integrity of neuroprotection is an important component against the development of cognitive disorders and AD. Within this context, DHEAS would seem to have some positive metabolic and endocrine effects to delay brain aging by recovering the impairment of neuroprotective growth factors. In the present study we measured by ELISA the secretion of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and transforming growth factor-beta1 (TGFbeta1) in the supernatants of cultured circulating peripheral blood mononuclear cells (PBMC) from which natural killer cells (NK) were separated (PBMC-NK) (pg/ml/7.75x10(6) cells) in healthy subjects and in age-matched patients with mild to moderate AD. The growth factors were measured in spontaneous conditions and after stimulation with growth hormone (GH) 1 microg/ml (IGF-1), lipopolysaccharide (LPS) 1 microg/ml (VEGF) and glucose 10 microM (TGF(beta1). AD group demonstrated at baseline a severe reduction of IGF-1 (3.7+1.2 pg/ml after GH), VEGF (63+/-18 pg/ml spontaneous and 210+/-65 pg/ml after LPS) and TGF(beta1 (33+/-10 pg/ml spontaneous and 75+/-12 pg/ml after glucose) secretions compared to healthy elderly subjects (IGF-1, 9.5+/-2.8 pg/ml after GH, p<0.001; VEGF, 117+/-38 pg/ml spontaneous, p<0.001 and 690+/-120 pg/ml after LPS, p<0.001; and TGF(beta1, 73+/-21 pg/ml spontaneous, p<0.001 and 169+/-53 pg/ml after glucose, p<0.001). Significant positive correlations between IGF-1 and VEGF concentrations were found both in healthy subjects (r=0.87, p<0.001) and in AD subjects (r=0.87, p<0.001). The co-incubation of NK cells with DHEAS (10(6) M/ml/cells) significantly increase IGF-1, VEGF and TGF (beta1 production, reaching in AD group the normal concentrations found in healthy subjects (IGF-1, 7.9 + 2.4 pg/ml after GH; VEGF, 105+/-31 pg/ml spontaneous and 670+/-112 pg/ml after LPS; and TGFfbeta1, 68+/-18 pg/ml spontaneous and 155+/-48 pg/ml after glucose). These data suggested that DHEAS is able to increase the immunoendocrine production of neuroprotective growth factors, which is reduced in AD subjects, so suggesting a new approach in the treatment of dementia.

Dehydroepiandrosterone sulphate improves cholestasis-associated fatigue in bile duct ligated rats.

Fatigue is a common debilitating symptom in patients with primary biliary cirrhosis (PBC). The mechanism of fatigue is still poorly understood. However, it has been reported that levels of the steroid dehydroepiandrosterone sulphate (DHEAS) are reduced in plasma of patients with PBC, and substitutive therapy has been suggested to improve fatigue symptoms experienced during the course of this disease. In this study, we tested the effect of DHEAS on whole body fatigue in rats following bile duct ligation (BDL). Fatigue was estimated by the time spent on an electrified grid as a result of falling off a treadmill and by performance of rats on an infrared beam monitor which allows the assessment of travelled distance and stereotypic movement activities. On day 5 after BDL surgery, cholestatic rats exhibited increased whole body fatigue as reflected by significantly increased time spent on the electrified grid, reduced travelled distance and reduced stereotypic movements. Administration of 5 mg kg(-1) of DHEAS to BDL rats for three consecutive days significantly normalized their behaviour. Fatigue scores were also found to be reduced in cirrhotic rats 4 weeks after BDL surgery, and DHEAS treatment for 3 days reduced fatigue scores at this stage. Dehydroepiandrosterone sulphate treatment was sufficient to increase brain levels of DHEAS in the BDL rats in a manner that is significantly and highly correlated with those of plasma DHEAS and brain dehydroepiandrosterone (DHEA). Substitutive therapies with DHEAS or DHEA could represent novel approaches in the management of fatigue due to cholestasis-induced liver failure.