A tripanossomíase ainda representa importante endemia nas Américas refletindo-se no sentido sócio-econômico onde é responsabilizada pelas taxas de aposentadoria precoce, como conseqüência direta da doença. As terapias até então utilizadas não promovem a cura total da doença além de provocarem efeitos colaterais danosos ao organismo do hospedeiro. É de conhecimento que os esteróides gonadais exercem profunda influência no curso das infecções, e no caso especifico da doença de Chagas, a orquiectomia leva a um estado de maior resistência do hospedeiro a \'Trypanosoma cruzi\'. O DHEA através de suas ações imuno-regulatórias promove o direcionamento da resposta celular do hospedeiro, que por sua vez é efetiva no controle da replicação de distintos patógenos como vírus, bactérias e protozoários. Portanto, a proposta do trabalho é inédita, pois avaliou o sinergismo entre a administração do DHEA e a orquiectomia no direcionamento da resposta imune do hospedeiro no decurso da infecção chagásica experimental em ratos Wistar machos infectados com a cepa y de \'T. cruzi\'. A parasitemia sofreu drástica redução para os grupos orquiectomizados e sujeitos a terapia com DHEA. Da mesma forma os parâmetros imunológicos analisados apresentaram aumento significante das concentrações de IFN-g, IL-12 e NO bem como do número de macrófagos. A histopatologia nos revelou que a orquiectomia e o tratamento com DHEA promoveram melhor reorganização do tecido cardíaco, bem como redução do número e tamanho dos ninhos de amastigotas existentes. Todos esses dados nos levam a crer que a ação sinérgica da terapia associada à orquiectomia promoveu direcionamento da resposta imune do tipo Th1 reduzindo os processos patológicos desencadeados pela infecção chagásica. / The ability of the gonadal hormones to influence and induce diverse immunological functions during the course of several parasitic infections has been extensively studied in the latest decades. Dehydroepiandrosterone and its sulphate are the most abundant steroid hormones secreted by the human adrenal cortex and are considered potent immune-activators. In this experiment, it was examined the effects of orchiectomy on the course of Trypanosoma cruzi infection in rats, treated and untreated with DHEA, by comparing blood and cardiac parasitism, macrophages number, Nitric Oxide and IFN-g levels. Orchiectomy led animals to enhanced resistance against infection by elevated number of macrophages, enhanced concentrations of NO and IFN-g and reduced amastigote burdens in heart when compared to control animals. DHEA replacement exerted a synergic effect, up-modulating the immune. Certainly male sex steroids play fundamental role in determining the fate of disease, through the regulation and modulation of the activity of the immune response.

A dehidroepiandrosterona (DHEA) tem sido considerada como o esteróide de múltiplas ações e vem interessando pesquisadores da área médica. Trabalhos demonstram a estimulação imunológica induzida pelo DHEA em animais de laboratório e humanos, como terapia alternativa e imunomoestimuladora nas infecções virais, bacterianas e parasitárias. O presente projeto avaliou os efeitos terapêuticos da administração de DHEA em ratos Wistar machos e fêmeas infectados com a cepa Y de Trypanosoma cruzi durante a fase aguda da infecção chagásica. Os parâmetros analizados foram o número de parasitas sangüíneos e teciduais, bem como produção de citocinas (TNF-, IFN-, IL-2, IL-12, IL-10, IL-4 e TGF-) e populações celulares (CD3+, CD4+ e CD8+), análise de glicose, colesterol e triglicérides, produção de anticorpos líticos, óxido nítrico, contagem global de leucócitos e macrófagos. Através dos resultados obtidos podemos concluir que o DHEA quando utilizado como tratamento na infecção chagásica experimental é parcilamente eficaz, pois reduz o número de parasitas sanguíneos e teciduais em ratos machos e fêmeas. Os diferentes parâmetros imunológicos analisados na vigência da terapia com DHEA revelou uma ação parcialmente efetiva sobre a resposta imunológica, o que favoreceu o controle da evolução da fase aguda da infecção experimental, deve ser levado em conta que a utilização deste hormônio não assume caráter curativo, apenas propicia melhores condições ao hospedeiro de direcionar sua resposta imunológica de forma a controlar a replicação parasitária, sem causar no hospedeiro os efeitos colaterais danosos ocasionados pelas drogas tripanossomicidas disponíveis atualmente no mercado. / Dehidroepiandrosterone (DHEA) has been considered for many researchers as the steroid of multiple functions. The immunologic stimulation triggered by DHEA has been demonstrated not only in animal models but also in humans. DHEA has been used as an alternative therapy to up-modulate immune response in host bearing viral, bacterial and parasitic infections. The present work evaluate the therapeutic effects of DHEA administration in male and female Wistar rats infected with the Y strain of T. cruzi during the acute phase of infection. The evaluated parameters were the blood and tecidual parasitic intensity, cytokines and cellular population, glucose analysis, cholesterol and triglycerides, percentage of lytic antibodies, nitric oxide, global counting of leukocytes and macrophages. DHEA, when used as a treatment of experimental T. cruzi infection is efficient; reducing the number of blood and tissue parasites of both genders. The therapy with DHEA demonstrated cellular and humoral immune stimulation for the control of the evolution of the acute phase. It has to be emphasized that DHEA therapy is not curative, but improves to the host immunological response to control the parasitic burden, without the harmful collateral effects caused by the available T. cruzi drugs in the market.

Dehydroepiandrosterone, a C-19 steroid, is found endogenously with the highest circulating serum levels. It is converted to important steroids such as the sex hormones oestrogen and testosterone. DHEA has come under the spotlight as a purported “fountain of youth” due to its well-characterised age-related decline. The supplementation of DHEA in both the elderly and those with a pathophysiological deficiency has been shown to be of benefit, particularly with regard to wellbeing and depression. The role of DHEA in the periphery has not been elucidated beyond its role as a precursor hormone in sex steroid biosynthesis, though it has been established as a neuroactive neurosteroid, capable of exerting neuroprotective effects in the brain. Since the importance of free radicals in aging and neurodegeneration is well established, investigations were conducted on the ability of DHEA to inhibit free radical generation or scavenge existing free radicals. DHEA was able to significantly inhibit quinolinic acid-induced lipid peroxidation, a measure of membrane damage, over a range of concentrations, although the reduction did not appear to be dose-dependent. This was observed in both in vitro and in vivo studies. Thus, the ability of a compound to reduce the degree of lipid peroxidation may indicate its value as a neuroprotectant. However, DHEA did not significantly reduce cyanide induced generation of the superoxide free radical, suggesting that DHEA is not an effective free radical scavenger of the superoxide anion and that the reduction in lipid peroxidation does not occur through a scavenging mechanism. Apoptosis is a physiological process which is necessary for development and homeostasis. However, this form of programmed cell death can be initiated through various mechanisms and too much apoptotic cell death results in deleterious effects in the body. DHEA was shown not to induce apoptosis. Even the lowest concentration of DHEA investigated in this thesis shows a remarkable decrease in the degree of apoptosis caused by intrahippocampal chemical insult by the neurotoxin quinolinic acid. Cresyl violet was used to visualise tissue for histological examination which revealed that DHEA is able to preserve the normal healthy morphology of hippocampal cells which have been exposed to quinolinic acid. Cells maintained their integrity and showed little evidence of swelling associated with necrosis. Organ culture studies were performed by assessing the impact of DHEA on several pineal metabolites. The study revealed that DHEA exerted an effect on the metabolism of indoleamines in the pineal gland. Melatonin, the chief pineal hormone, did not appear to be affected while the concentrations of N-acetylserotonin, serotonin and methoxytryptamine showed significant alterations. Thus, the neuroprotective mechanism of DHEA does not appear to be mediated by an increase in the presence of melatonin. The biological importance of metal ions in neurodegeneration is also well established and thus the potential interaction between DHEA and metal ions was considered as a mechanism of action. Spectroscopic and electrochemical analyses were performed to determine whether DHEA is able to interact with metal ions as a ligand. These reveal that DHEA does not form a strong bond with the metals investigated, namely copper (II) and iron (III), but that a weak interaction is evident. These investigations were conducted in a rodent model, which has neither large amounts of endogenous DHEA, nor the enzymatic infrastructure present in humans. Thus, the theory that DHEA exerts its effects through downstream metabolic products is unlikely. However, these investigations reveal that there is merit in the statement that DHEA itself is a neuroprotective molecule, and confirm that the further investigation of DHEA is an advisable strategy in the war against neurodegeneration and aging.

Le narval (Monodon monoceros) est une espèce emblématique de l'Arctique. Les narvals sont de plus en plus exposés à des perturbations anthropiques, pouvant augmenter leur niveau de stress et, par conséquent, avoir des impacts inconnus sur la dynamique de la population. La validation et l’étude de biomarqueurs de stress chronique pourraient donc améliorer les efforts de conservation chez cette espèce. La déhydroépiandrostérone (DHEA) et son métabolite sulfaté, la DHEA-S, sont collectivement appelés DHEA(S). Lorsque combinés sous forme de ratios avec le cortisol (cortisol/DHEA(S)), ils se sont révélés prometteurs dans l'évaluation du stress chronique chez les humains et certaines espèces animales domestiques ou sauvages. Au cours de projets de pose d’émetteurs en 2017 et 2018 dans la baie de Baffin, Nunavut, Canada, des narvals (n = 14) ont été échantillonnés au début et à la fin des manipulations. La DHEA(S) sérique a ensuite été mesurée à l’aide de deux techniques immuno-enzymatiques (ELISAs) développées pour les humains et disponibles commercialement. Une validation partielle des deux ELISAs a pu être réalisée par détermination du coefficient de variation intra-essai, confirmation de la linéarité de dilution de la DHEA(S) et calcul du pourcentage de récupération. La DHEA était également bien conservée dans le sérum de narvals suite à un stockage prolongé de 12 et 24 mois à -80°C, soulignant le potentiel d'analyse d'échantillons archivés. Les valeurs sériques moyennes (ng/ml ± SEM) de cortisol, de DHEA(S) et des ratios cortisol/DHEA(S) au début et à la fin des manipulations respectivement étaient les suivantes : cortisol = 30,74 ± 4,87 et 41,83 ± 4,83; DHEA = 1,01 ± 0,52 et 0,99 ± 0,50; DHEA-S = 8,72 ± 1,68 et 7,70 ± 1,02; cortisol/DHEA = 75,43 ± 24,35 et 84,41 ± 11,76; cortisol/DHEA-S = 4,16 ± 1,07 et 6,14 ± 1,00). Le cortisol sérique et le ratio cortisol/DHEA-S étaient statistiquement plus élevés à la fin des manipulations (P = 0,024 et P = 0,035 respectivement). De plus, le cortisol sérique à la fin des manipulations était positivement corrélé à la longueur totale du corps de l’animal (P = 0,042) et avait tendance à être plus élevé chez les mâles (P = 0,086). Cette étude confirme que ces ELISAs sont une méthode d’analyse facile à réaliser, rapide et appropriée pour mesurer la DHEA(S) sérique chez le narval. La DHEA(S) sérique et les ratios cortisol/DHEA(S) représentent des biomarqueurs potentiels pour évaluer le stress chronique chez les narvals et possiblement chez d'autres espèces de cétacés. / Narwhals (Monodon monoceros) are an iconic Arctic species and are increasingly being exposed to anthropogenic disturbances that may increase their stress levels with unknown consequences for the overall population dynamics. The validation and measurement of chronic stress biomarkers could contribute towards an improved understanding and conservation efforts for this species. Dehydroepiandrosterone (DHEA), and its sulfated metabolite DHEA-S, are collectively referred to as DHEA(S). When serum DHEA(S) concentrations are combined in a ratio with cortisol (cortisol/DHEA(S)), it has shown promise for evaluating chronic stress in humans, domestic animals, and wildlife. During field tagging in 2017 and 2018 on Baffin Bay, Nunavut, Canada, wild narwhals (n = 14) were sampled at the beginning and end of capture-tagging procedures (acute stressor). Serum DHEA(S) were measured with commercially available competitive enzyme-linked immunosorbent assays (ELISA) developed for humans. A partial validation of the assays was performed by determination of the intra-assay coefficient of variation, confirmation of the DHEA(S) dilutional linearity, and the calculation of the percentage of recovery. In addition, DHEA was conserved following extended storage at -80°C, highlighting the potential to analyze archival samples. Mean values (ng/mL ± SEM) of narwhal serum cortisol, DHEA(S), and cortisol/DHEA(S) ratios at the beginning and at the end of handling respectively are reported (cortisol = 30.74 ± 4.87, 41.83 ± 4.83; DHEA = 1.01 ± 0.52, 0.99 ± 0.50; DHEA-S = 8.72 ± 1.68, 7.70 ± 1.02; cortisol/DHEA = 75.43 ± 24.35, 84.41 ± 11.76, and cortisol/DHEA-S = 4.16 ± 1.07, 6.14 ± 1.00). Serum cortisol and cortisol/DHEA-S were statistically higher at the end of the capture (P = 0.024 and P = 0.035 respectively). Moreover, serum cortisol at the end of handling and prior to release was positively correlated to total body length (P = 0.042) and tended to be higher in males (P = 0.086). This study showed that these assays are easy to perform, rapid, and suitable for measuring serum DHEA(S) of narwhals and that serum DHEA(S) and calculated cortisol/DHEA(S) are potential biomarkers for chronic stress in narwhals and possibly other species of cetaceans, but this requires additional study.

The comorbidity between female sexual dysfunction (FSD) and major depressive disorder (MDD) is well documented; however, the mechanism(s) underlying the relationship between these disorders has not been defined. The literature has associated the adrenal hormones cortisol and dehydroepiandrosterone (DHEA) with FSD and MDD, suggesting a biological mechanism that may elucidate the comorbidity between these disorders. Based on evidence pointing to a high cortisol/DHEA ratio (C/D Ratio) in MDD and low DHEA in FSD, this study investigated if the potential association between a high C/D Ratio and FSD would be greater for women with a history of MDD when compared to women without a history of MDD. Two groups of women (MDD history group; control group), each with a range of sexual function, collected saliva samples, completed questionnaires, and participated in a clinical interview and a psychophysiological assessment. Results did not support the hypothesis that the relationship between the C/D Ratio and sexual function would be greater for women with a history of MDD. Relevant to the effects of hormones on sexual function, a higher C/D Ratio was associated with lower frequency of sexual activity and lower sexual assertiveness. Results also showed DHEA positively associated with overall frequency of sexual activity, while cortisol was associated with lower subjective assessment of sexual desire/arousal prior to erotic stimuli. Lastly, secondary analyses revealed a positive association between DHEA and frequency of sexual activity, which was mediated by women's sexual desire. These results suggest that the effects of the C/D Ratio on FSD are not associated with a history of MDD. Results also point to contrasting roles for C/D Ratio and DHEA in FSD. In particular, a high C/D Ratio may have inhibitory effects on frequency of sexual activity and sexual assertiveness, while high DHEA may have facilitatory effects on sexual activity frequency through heightened sexual desire. Lastly, high cortisol may predispose women to have a negative assessment of sexual stimuli. These findings contribute to a further understanding of the roles of the C/D Ratio, DHEA, and cortisol in female sexuality and offer support for future studies investigating the role of these hormones in FSD.

The comorbidity between female sexual dysfunction (FSD) and major depressive disorder (MDD) is well documented; however, the mechanism(s) underlying the relationship between these disorders has not been defined. The literature has associated the adrenal hormones cortisol and dehydroepiandrosterone (DHEA) with FSD and MDD, suggesting a biological mechanism that may elucidate the comorbidity between these disorders. Based on evidence pointing to a high cortisol/DHEA ratio (C/D Ratio) in MDD and low DHEA in FSD, this study investigated if the potential association between a high C/D Ratio and FSD would be greater for women with a history of MDD when compared to women without a history of MDD. Two groups of women (MDD history group; control group), each with a range of sexual function, collected saliva samples, completed questionnaires, and participated in a clinical interview and a psychophysiological assessment. Results did not support the hypothesis that the relationship between the C/D Ratio and sexual function would be greater for women with a history of MDD. Relevant to the effects of hormones on sexual function, a higher C/D Ratio was associated with lower frequency of sexual activity and lower sexual assertiveness. Results also showed DHEA positively associated with overall frequency of sexual activity, while cortisol was associated with lower subjective assessment of sexual desire/arousal prior to erotic stimuli. Lastly, secondary analyses revealed a positive association between DHEA and frequency of sexual activity, which was mediated by women's sexual desire. These results suggest that the effects of the C/D Ratio on FSD are not associated with a history of MDD. Results also point to contrasting roles for C/D Ratio and DHEA in FSD. In particular, a high C/D Ratio may have inhibitory effects on frequency of sexual activity and sexual assertiveness, while high DHEA may have facilitatory effects on sexual activity frequency through heightened sexual desire. Lastly, high cortisol may predispose women to have a negative assessment of sexual stimuli. These findings contribute to a further understanding of the roles of the C/D Ratio, DHEA, and cortisol in female sexuality and offer support for future studies investigating the role of these hormones in FSD.

DHEA has been determined to have medically significant activity and is the parent compound to the more active metabolites; 17α-AED, 17β-AED and 17β-AET, which exhibit strong biological activity that has been attributed to androgenic, estrogenic or anti-glucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED and 17β-AET for their ability to activate the human AR, ER and GR receptors and determine the relative androgenicity, estrogenicity and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERβ may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR receptor; only in the presence of high dexamethasone concentrations. These results underscore the major difference between androstene hormone interactions with these nuclear receptors. 17β-AED and 17α-AED, androstene epimers that produce either survival or death, were utilized to treat T98G Glioblastoma cells. We identified 26 genes oppositely regulated by 17β-AED and 17α-AED to directly affect the cellular life or death decision. Network analysis demonstrated that these 26 genes are essential to regulating three critical Glioblastoma pathways. This report, for the first time, demonstrates that naturally occurring, chemically identical adrenal hormones (17β-AED or 17α-AED) direct a cellular life or death decision through contrasting modulation of identical signaling pathways and core regulators. Chronic pressure ulcers represent a significant health problem and are characterized by hypoxia, bacterial infection, repetitive ischemia/reperfusion and altered cellular and systemic stress responses. Whole genome microarray analysis was utilized in conjunction with IPA® premiere networking software to analyze chronic wound edge tissue. IPA® network analysis identified Ubiquitin C (UBC) as the most significant network. Sixteen (16) ubiquitin C associated genes were identified to be different in the chronic pressure ulcer and normal skin control. Targeted network analysis associated core regulators to 8 UBC associated genes that are unique to chronic pressure ulcers. The identification of these genes will allow the establishment of more effective treatments for Spinal Cord Injury (SCI) patients with chronic pressure ulcers.

A redução dos hormônios gonadais seja pelo processo natural de falência folicular denominado nas humanas de menopausa, seja pela ooforectomia, está associado com aumento da incidência de doença cardiovascular em mulheres no período pós menopausa. O objetivo desse estudo é avaliar o efeito da ooforectomia e a suplementação com DHEA sobre a morfologia dos cardiomiócitos, a expressão de proteínas celulares envolvidas com crescimento e apoptose celular e a função cardíaca. A ooforectomia induz maior ganho de massa corporal e do coração, no entanto, a avaliação morfológica do VE mostrou que há uma redução da espessura dos cardiomiócitos e do número de núcleos. Ademais, o immunoblotting demonstrou uma diminuição na expressão das proteínas IR, IRS1 e AKT nos corações das ratas ooforectomizadas e os parâmetros hemodinâmicos foram semelhantes entre os grupos. O tratamento com DHEA reverteu a redução do número de núcleos sem interferir nos demais parâmetros avaliados. Os dados obtidos nos permite concluir que a ausência dos esteroides gonadais por si só resulta em modificações morfológicas dos cardiomiócitos que podem estar relacionados ao processo de apoptose sem afetar a função de bomba do coração e o uso do DHEA é capaz de reverter a redução numérica dos núcleos. / The reduction of gonadal hormones by menopause, the natural process of failure in the human follicle, or by surgical removal, is associated with increased incidence of cardiovascular disease in postmenopause women. The aim of this study is to evaluate the effect of oophorectomy and the DHEA supplementation on the morphology of cardiomyocytes, on the expression of proteins involved in cell growth, on apoptosis (IGF-1R, IR, IRS-1, PI3K, AKT, MAPKp42/44, JAK2) and on the cardiac function. Oophorectomy enhances both the body mass e heart weight, however the left ventricle showed a reduction in cardiomyocyte thickness by 15% and in the number of nuclei by 20%. Moreover the immunoblotting showed a decrease from 25 to 50% in the expression of IR, IRS-1 and AKT proteins in the hearts of oophorectomized rats. The hemodynamic parameters were similar between groups. Treatment with DHEA reversed the reduction in the number of nuclei with no change in the other parameters evaluated. Our data allow us to conclude that the absence of gonadal steroids per se induces morphological changes in the cardiomyocytes that may be related to apoptosis with no change on the heart pump function. The DHEA supplementation is able to reverse the reduced number of nuclei.

A modulação das respostas imunológicas frente à administração de substâncias farmacologicamente ativas em modelos experimentais infectados por Trypanossoma cruzi tem contribuído de maneira importante nas investigações de novas terapias para a doença de Chagas. O presente estudo teve como objetivo avaliar um possível efeito sinérgico imunoestimulatório subseqüente à administração de sulfato de zinco e DHEA durante o curso da infecção. O DHEA tem sido amplamente estudado e possui ação comprovada no direcionamento da resposta imune Th1, sendo muito efetivo para diferentes patógenos tais como vírus, bactérias e protozoários. O zinco é considerado um oligoelemento de extrema importância para a manutenção das funções imunes. Age como um inibidor da apoptose celular além de coordenar a seleção fisiológica de células intra-tímicas. Durante a fase aguda da infecção, zinco e DHEA apresentaram atividade estimulatória sobre a imunidade do hospedeiro, potencializando a resposta imune gerada contra o parasita. Comprovamos também a ação sinérgica de DHEA e zinco, através dos parâmetros analisados tais como parasitemia sangüínea e tecidual, além de fatores imunológicos como aumento nas concentrações de NO, IFN-?, IL-12, e número de macrófagos. Este efeito imuno-modulador durante a fase aguda da infecção chagásica pode contribuir para a prevenção dos danos teciduais observados na fase crônica da doença. / The modulation of the immune responses as well as the administration of pharmacologically active substances in infected T. cruzi experimental models has contributed to important investigations of new therapies in the treatment of Chagas\' disease. However, the use of antiparasitary drugs in the chronic indeterminate or in the cardiac chronic phases of Chagas disease is still a controversial issue. This study has as objectives to evaluate a possible synergic immunostimulatory effect after the administration of zinc and DHEA during the course of the infection. A bulk of evidences has been presented confirming the effectiveness action of DHEA on the Th1 immune response against a wide range of pathogens such like viruses, bacteria and protozoans. Zinc is considered an oligoelement of essential importance in the maintenance of the immune functions, as well as inhibiting cell apoptosis besides the function of coordinate the physiological selection of thymic T cells. During the acute phase of infection, zinc and DHEA displayed enhanced stimulatory activity on host\'s immune response. A synergistic action of zinc and DHEA was also observed through the evaluations of distinct parameters such as blood and tissue parasitism, number of macrophages and NO levels as well as elevated concentrations of some immunological interleukins such as IFN-? and IL-12. This work also demonstrates that the enhanced immunostimulatory effect observed during the acute phase certainly contributes in the prevention of tissue damage that normally occurs during the late chronic phase.

A privação dos hormônios sexuais em fêmeas contribui para o aparecimento de distúrbios metabólicos e endócrinos devido à ausência de estrógenos. Nesse estudo foi avaliado o efeito da castração e da suplementação com DHEA sobre aspectos metabólicos em ratas. A ovariectomia aumentou a adiposidade e o consumo de ração, diminuiu o consumo hídrico, além de promover resistência à insulina e intolerância à glicose, e o uso do DHEA reduziu a sensibilidade à insulina. Ainda, a castração levou a redução nos níveis plasmáticos de DHEA, estradiol, VLDL-c e triacilglicerol, albumina, uréia e creatinina, e o tratamento com DHEA restaurou parcialmente a concentração de estradiol no grupo OVX+DHEA. E por fim, a ooforectomia reduziu a expressão proteica do IRb, IRS1, PI3K e AKT no fígado, músculo gastrocnêmio ou coração, além diminuir o grau de fosforilação em tirosina da pp185 (IRS1/2). Deste modo, concluímos que a castração promoveu resistência à insulina e intolerância à glicose associada à obesidade, e neste modelo, o uso do DHEA piorou a sensibilidade à insulina nos animais. / Deprivation of sex hormones in females contributes to the onset of metabolic and endocrine disorders due loss of estrogen. In this study the effect of castration and supplementation with DHEA on metabolic aspects in rats was evaluated. Ovariectomy increased adiposity and food consumption, decreased water consumption, besides promoting insulin resistance and glucose intolerance, and the use of DHEA reduced insulin sensitivity. Furthermore, castration led to decreasing of DHEA plasma levels, estradiol, VLDL-c and triacylglycerol, albumin, urea and creatinine, and DHEA treatment partially restored the concentration of estradiol in OVX+DHEA group. Finally, ovariectomy reduced the protein expression IRb, IRS1, PI3K and AKT in the liver, gastrocnemius muscle or heart. Indeed, decrease tyrosine phosphorylation status of pp185 (IRS1/2) was observed. Thus, we conclude that castration promoted insulin resistance and glucose intolerance associated with obesity, and in this model, the use of DHEA impairs insulin sensitivity in animals.