Submitted by João Arthur Martins (joao.arthur@ufpe.br) on 2015-04-08T18:05:40Z No. of bitstreams: 2 TESE ANA CARLA MONTENEGRO.pdf: 533814 bytes, checksum: 925ac9e65f36a4cd19b6d292c56fd21a (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-04-08T18:05:40Z (GMT). No. of bitstreams: 2 TESE ANA CARLA MONTENEGRO.pdf: 533814 bytes, checksum: 925ac9e65f36a4cd19b6d292c56fd21a (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2012-02-15 / A associação de alterações do eixo neuroendócrino (hipotalâmico-pituitário-adrenal) com transtornos psiquiátricos é conhecida, entretanto há poucos relatos na literatura a respeito das mudanças no eixo HPA no período puerperal e depressão pós-parto. O puerpério é caracterizado pelo aumento na vulnerabilidade de transtornos psiquiátricos (depressão e transtornos de ansiedade), entretanto, não se sabe exatamente qual a participação das variações hormonais neuroendócrinas, e como se comportam estes hormônios na depressão pós-parto. Estima-se que a depressão pós-parto (DPP) afete entre 10-15% das mulheres no puerpério A DPP é muitas vezes associada com intenso sofrimento emocional e pode representar conseqüência negativa para mãe e recém nascido. Há inúmeros fatores de risco para DPP, entre eles, destacam-se história pessoal e familiar de transtornos psiquiátricos, fatores socioeconômicos, relação familiar conturbada e também fatores relacionados com o parto, puerpério precoce, fatores biológicos, genéticos e hormonais. A gestação humana influencia de forma importante o eixo hipotalâmico-pituitário-adrenal (HPA). O cortisol parece ser um bom marcador biológico da atividade do HPA. As mudanças que ocorrem na gestação e no puerpério alteram os parâmetros utilizados pelas técnicas laboratoriais que medem o cortisol. A persistência da globulina carreadora de cortisol (GCG) no pós-parto altera a medida do cortisol plasmático. A utilização do cortisol salivar para avaliação do eixo HPA tem sido muito estudada, com sensibilidade e especificidades semelhantes aos dos métodos usuais. O presente estudo teve por objetivo avaliar a relação do cortisol salivar com os transtornos psiquiátricos no puerpério. O estudo selecionou mulheres no pós-parto durante a consulta pós-natal de rotina do hospital Instituto de Medicina Integral Professor Fernando Figueira (IMIP), entre duas e 36 semanas de pós-parto. Foram aplicados dois questionários, um com as características sócio-demográficas e o SCID –I (Structered Clinical Interview for DSM-IV Axis Disorders). O estudo avaliou 66 mulheres, 33 apresentaram critérios para depressão pós-parto (DPP) e 33 não apresentaram sintomas de DPP. A média de idade da amostra foi de 26,24 anos ± 6,57 (range 17-41 anos), A média de pós-parto foi de 97,53 dias ± 50,11. Trinta e quatro mulheres (51,52%) tiveram parto cesariano, 23 (34,85%) apresentaram alguma complicação durante a gravidez (diabetes mellitus, hipertensão arterial, pré-eclâmpsia, ameaça de abortamento), 48 (72,73%) mulheres eram casadas ou moravam com o companheiro, 50 (75,76%) mulheres não trabalhavam. História pessoal de transtorno psiquiátrico estava presente em 11 (16,67%) mulheres. A média do cortisol salivar nas puérperas com DPP foi de 166,7±109,5 e das sem DPP foi de 199,6±141,3, p=0,22. O estudo conclui que não houve diferença entre os valores do cortisol entre mulheres que apresentaram DPP quando comparadas com as que não apresentaram. Transtorno psiquiátrico prévio a gestação esteve mais associado com DPP.

Human plasma contains cortisol (F) and corticosterone (B) at a ratio of ~10:1. B is well studied in mice and rats, which do not produce F due to absent adrenal Cyp17, but is largely neglected in humans. Differential transmembrane export of F > B by ABCB1 may account for accumulation of B in the CNS. Conversely, ABCC1, expressed in human adipose tissue, preferentially exports B>F. Here we tested the hypotheses that: (i) negative feedback suppression of the hypothalamic-pituitary-adrenal (HPA) axis is disproportionately sensitive to B; (ii) adipose tissue is disproportionately sensitive to F; and (iii) low plasma B contributes to impaired HPA axis negative feedback and increased F action in metabolic syndrome. We validated a stable isotope tracer for B in vitro and demonstrated distinct kinetics of B and F in vivo. In a randomised crossover study, we undertook ramped steady state infusion of B or F in 10 patients with Addison’s disease. Although levels of B were marginally lower than F, ACTH was similarly suppressed, and yet glucocorticoid-responsive transcripts in adipose tissue were much higher following F than B (PER1 2.2-fold and LPL 1.3-fold; p < 0.05). We assessed associations of ACTH-stimulated plasma B and F with features of metabolic syndrome in a cross-sectional study (n=279). Glucose tolerance was impaired with higher F (β=0.146, p=0.01) but lower B (β = -0.056, p = 0.05). These data support the concept of differential tissue sensitivity to B and F, whereby B suppresses the HPA axis more effectively than it induces adverse effects in adipose tissue. Enhanced CYP17 activity, causing ‘relative B deficiency’, may contribute to HPA axis activation and enhanced F action in adipose tissue in obesity. B therapy might allow control of HPA axis activation without inducing adverse metabolic effects. The ‘neglected second glucocorticoid’, corticosterone, may optimise glucocorticoid action in the human CNS, and simultaneously limit adverse metabolic effects driven by cortisol excess.

Objective: The current study used a high risk design to investigate whether the Cortisol Awakening Response (CAR) is a potential heritable trait marker of anxiety disorder risk. Method: The sample consisted of 274 healthy offspring (7-18 years old) including 101 offspring with a parental history of panic disorder (PD), generalized anxiety disorder (GAD), or social anxiety disorder (SAD) and 173 offspring with no parental psychopathology. Salivary cortisol was collected at wake-up, 30, and 60 minutes later, as well as at 4pm and 8pm on two consecutive days. The CAR was calculated using area under the curve with respect to ground (AUCg) and increase (AUCi). Correlation analyses of covariates were conducted. Results: No differences between high and low risk groups were detected when the combined sample of high risk offspring was examined. However, when anxiety disorder subtypes were considered, offspring with parental GAD or SAD had a significantly lower CAR and diurnal cortisol response than those with no parental psychopathology. No differences in the CAR or diurnal cortisol were found in offspring with parental PD. Age and puberty status correlated negatively with AUCg and awakening values and anxiety sensitivity correlated positively with AUCg and awakening values. Conclusions: A blunted CAR and diurnal cortisol response may represent a possible heritable risk marker that is specific to GAD or SAD. Further research is needed to confirm these findings. Study results may have important implications in identifying children at risk for anxiety disorders and creating early interventions intended to change the trajectory of risk.

Background: Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer. Methods: Lung cancer patients (. n=. 62, 34 female) were within 5. years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis. Results: The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively " flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=. .009). Cortisol slope also predicted survival time from initial diagnosis (. p=. .012). Flattened profiles were linked with male gender (. t=. 2.04, df=. 59, p=. .046) and low total and cytotoxic T cell lymphocyte counts (. r=. -.39 and -.30, p=. .004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival. Conclusions: Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

Background: Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer. Methods: Lung cancer patients (. n=. 62, 34 female) were within 5. years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis. Results: The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively " flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=. .009). Cortisol slope also predicted survival time from initial diagnosis (. p=. .012). Flattened profiles were linked with male gender (. t=. 2.04, df=. 59, p=. .046) and low total and cytotoxic T cell lymphocyte counts (. r=. -.39 and -.30, p=. .004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival. Conclusions: Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

Chronic psychological and physiological stress is linked to a high prevalence of cardiovascular disease (CVD). Potentially dangerous cardiovascular responses (e.g., exacerbated cortisol production) can occur with high levels of stress and chronic hypercortisolemia is associated with CVD. The ingestion of carbohydrate (CHO) prior to physical stress may attenuate cortisol responses to stress. The purpose of this project was to investigate the potential effect of CHO ingestion on cortisol production and responses to concurrent stress challenges. Sixteen apparently healthy non-smoking men 21-30 years old participated in a randomized, cross-over, double blind, placebo controlled trial. Participants were tested on four separate sessions. In session 1, general procedures were explained, and participants provided written informed consent as well as a health history questionnaire. Anthropometric data were obtained and participants performed a VO2 peak test during session 2, as well as a 90 sec familiarization session with the mental stress challenges. During the third and fourth sessions, either a 6.6% CHO solution or non-CHO control beverage (water containing non-caloric ingredients tasting like the CHO beverage) was randomly assigned and orally ingested at 0.6g/kg body weight 15 min prior to performing a dual-concurrent-stress (DCS) challenge. The DCS procedure consisted of physical stress (i.e., exercise) combined with computerized mental stress tests of color word associations and arithmetic. Ten mL of blood were obtained at each blood draw: 70, 40, and 15 min prior to the start of exercise, immediately at onset of exercise, 10, 20, 30, and 35 min during exercise, and 15, 30, 45, and 60 min during a post exercise recovery period. There was a significant main effect for treatment regarding mean cortisol production, and the DCS challenge was effective at increasing anxiety and acting as an effective stressor. Mean cortisol production was consistently lower during and after DSC. This is a potential beneficial implication for individuals that work in high-stress conditions. These findings support a prevention based approach to address the high prevalence of CVD among individuals and others working in high-stress occupations such as firefighters.

Dying produces human remains and is a unique period of human lives that remains poorly understood. The aims of this research were to validate the use of hair cortisol concentration (HCC) analysis in the study of stress at the end of life and to explore the effects of biocultural factors on stress experience in the last months of life. This study examined the dead from the 1st century CE Egypt, 19th-20th century Missouri, and 21st century Florida. A framework of embodiment and the good death was employed to interpret lived experience from HCC and examine the relationships between HCC, death, cause of death, duration of disease, and medical care and treatment. HCC in the dead is higher than in the living, varies considerably between individuals, and can fluctuate across the last months of life. High HCC at the end of life cannot be easily accounted for by medications, serious disease, or decomposition; are within possible biological ranges; and are dynamic. However, leaching of cortisol from the archaeological samples is likely. Duration of disease or presence of multiple medical conditions does not influence HCC. While modern medical advancements do not improve stress levels in the dead, a reduction in stress is observed following hospital entry in the past. HCC is a valid measure of stress at the end of life. The last months of life are periods of significant stress but dying is an inherently personal and dynamic experience that varies between individuals and over many months leading up to death due to the interaction of multiple biocultural factors. These findings contribute to the understanding of a unique period of individual lives, suggest that studies of HCC in bioarchaeology must focus on the dying period and be wary of leaching, and highlight the potential of HCC in palliative care research. / Dissertation / Doctor of Philosophy (PhD) / Today, death is often regarded with uncertainty and even fear, yet little is known about the experience of dying, especially in the past. Dying is difficult to study in modern people because of communication challenges and the number of complex factors at play while studies of the past are limited because human remains do not reveal how individuals felt. A better understanding of the dying experience can help bioarchaeologists clarify the relationship between dying, death, and skeletal remains and could help improve the care of dying people today. This research evaluated a new method of stress assessment to study experiences in the last months of life in archaeological, historic, and modern samples. Hair cortisol concentration (HCC) analysis measures stress hormones in human hair to reconstruct stress experience at the time the hair was growing. High levels of HCC in dead individuals from 1st century AD Egypt, 19th-20th century Missouri, and 21st century Florida indicate that dying is stressful across time and place. HCC values from the Egyptian sample were higher than most living people but were lower than other archaeological samples which may be a result of cortisol leaching out of the hair shaft after death. Although higher than living people, HCC levels still differed between individuals and across individual hair shafts, indicating that stress experience can be different between individuals and change over an individual’s final months. These differences are not a result of biological factors such as duration of disease or the presence of certain preexisting conditions suggesting that stress at the end of life is complex. Despite advancements in medicine, the modern sample displayed similar HCC levels to those from earlier historic periods and for a number of individuals from the historic sample, hospital entry led to a temporary reduction in HCC levels. Together, these findings suggest that, while modern medical advancements have not improved stress levels at the end of life, some aspects of care could reduce stress. The results of this study indicate that dying is a stressful, complex, and dynamic phenomenon that modern medical treatment alone may not be able to improve. Furthermore, studies of HCC in archaeology must focus on the effects of dying and be wary of leaching. Ultimately, HCC analysis could contribute to a greater knowledge of the dying experience, the understanding of past peoples, and improvement of the experience of dying.

<P> The general purpose of this dissertation was to use a psychobiological approach to examine the psychosocial, biological and behavioural factors associated with social physique anxiety (SPA) in women. With this perspective in mind, the broad objectives of the present dissertation were as follows: (1) to examine the relationship between social physique anxiety and cortisol, (2) to implement an exercise intervention to change social physique anxiety and cortisol, and (3) to understand the mechanisms responsible for exercise-induced changes in social physique anxiety. </p> <P> Specifically, in Study 1, the purpose was to experimentally manipulate physique evaluative threat in a controlled laboratory setting to determine if physique evaluative threat (i.e., social physique anxiety; SPA) produces concomitant changes in cortisol secretion. Additionally, this study examined if perceptions of physique evaluative threat were related to cortisol responses. Participants were 50 women who were randomly assigned to an experimental, or a control condition. Results indicated that post-manipulation, the experimental condition had higher cortisol levels than the control condition. Furthermore, regression analyses indicated that a post-manipulation measure of physique evaluative threat explained 7.2% of the variance in post-manipulation cortisol levels. Taken together, these findings suggest that acute changes in physique evaluative threat cause changes in cortisol levels and provide an empirical basis for studying cortisol's role in body image disturbance and related pathologies (e.g., eating disorders). </P> <P> In Study 2, a controlled experimental design was used to compare the effects of an 8- week exercise (aerobic versus resistance) training intervention on changes in SPA and changes in cortisol. In addition, this study examined the physical and psychosocial mechanisms underlying the effects of exercise training on SPA and explored the possible protective effects of exercise training on state SPA and cortisol responses to an acute physique evaluative threat situation. Forty six women were randomly assigned to one of two exercise conditions: aerobic or resistance training. Analyses indicated that the aerobic condition experienced greater improvements in trait SPA than the resistance training condition and both groups exhibited significant decreases in cortisol levels (compared to baseline). In addition, changes in aerobic self-efficacy and perceived physical endurance partially mediated the effect of the exercise intervention on trait SPA. Finally, the results demonstrated that 8-weeks of exercise training (regardless of mode) may buffer the state SPA response to a physique evaluative threat manipulation. </p> <P> In summary, these studies provide a broader understanding of the factors associated with SPA. The results demonstrated that for women, situations that elicit physique evaluative threat elicit concomitant changes in cortisol. Exercise training is an effective strategy for improving SPA, reducing cortisol responses, and possibly providing a protective effect against the state SPA response among young women. Aerobic exercise training is more effective for improving SPA than resistance training and this is due in part to increases in aerobic self-efficacy and perceived physical endurance. The dissertation studies provide momentum for extending the scope of research on SPA and for determining the best approach for improving SPA among women. </p> / Thesis / Doctor of Philosophy (PhD)

La schizophrénie est un trouble psychiatrique répandu qui affecte grandement la vie de l’individu touché. Même si certains facteurs ont été identifiés comme causes de cette maladie, notamment des facteurs génétiques, ceux-ci n’expliquent pas entièrement les bases biologiques qui la sous- tendent. Certaines causes infectieuses ont été soulevées, dont la « toxoplasmose ». Celle-ci réfère à une infection par un parasite, Toxoplasma gondii (TG), qui touche environ le tiers de la population humaine mondiale. Des études animales ont montré que ce parasite peut manipuler le comportement de son hôte en menant à une diminution de la peur et à une augmentation de la prise de risque. Les résultats d’autres études portent à croire que ces types de comportements pourraient également être affectés par ce parasite chez l’humain, et ce, peut-être de manière plus importante chez les personnes souffrant de schizophrénie. La peur et la prise de risque étant toutes deux fortement associées aux réponses de stress, nous avons émis l’hypothèse que TG pourrait être relié à des différences au niveau de la réponse de stress chez l’humain, particulièrement chez la personne souffrant de schizophrénie. Nous avons testé si les biomarqueurs de stress (cortisol salivaire et des cheveux) diffèrent chez des personnes avec un diagnostic de schizophrénie et des contrôles en fonction de l’infection par TG. Nous avons aussi vérifié si TG était relié à des symptômes psychotiques spécifiques et/ou à de l’impulsivité (comme marqueur proxy des comportements de prise de risque). Dans cette étude, nous avons utilisé des échantillons de sang, de salive et de cheveux pour mesurer les anticorps TG, les niveaux de cortisol circulant et la sécrétion de cortisol à long terme, respectivement. Les résultats montrent que les personnes avec une schizophrénie infectées par TG présentent des concentrations de cortisol des cheveux significativement plus élevées que les personnes avec une schizophrénie non infectées, un effet qui n'a pas été trouvé chez les participants contrôles. Aucune différence de cortisol salivaire n'a été observée entre les participants infectés par TG et non infectés, autant dans le groupe schizophrène que contrôle. De plus, il n'y a aucune association entre TG et les symptômes psychotiques positifs ou entre TG et l'impulsivité. Ces résultats suggèrent que l’infection par TG est associée à des différences dans la production de cortisol à long terme chez les personnes avec une schizophrénie, mais pas dans la sécrétion de cortisol à court terme. / Schizophrenia is an important psychiatric disorder that greatly affects the life of the affected individual. Although some factors have been identified as causes of this disease, including genetic factors, these do not fully explain the biological basis behind it. Some infectious causes have been raised, including the “toxoplasmosis”. It refers to an infection by a parasite, Toxoplasma gondii (TG), which affects approximately one third of the world's human population. Animal studies have shown that this parasite can manipulate its host's behavior leading to decreased fear and increased risk taking. The results of other studies suggest that these types of behaviors could also be affected by this parasite in humans, and perhaps to a greater extent in people with schizophrenia. Since fear and risk-taking are both strongly associated with stress responses, we hypothesized that TG might be related to differences in the stress response in humans, particularly in people suffering from schizophrenia. We tested whether stress biomarkers (salivary and hair cortisol) differ in people with schizophrenia and controls depending on TG infection. We also checked whether TG was related to specific psychotic symptoms and/or impulsivity (as a proxy marker of risk-taking behaviors). In this study, we used blood, saliva, and hair samples to measure TG antibodies, circulating cortisol levels, and long-term cortisol secretion, respectively. Results show that TG-infected people with schizophrenia had significantly higher hair cortisol concentrations than uninfected people with schizophrenia, an effect that was not found in control participants. No difference in salivary cortisol was observed between TG- infected and uninfected participants, neither in the schizophrenic group nor in the control group. Moreover, there was no association between TG and positive psychotic symptoms or between TG and impulsivity. These results suggests that TG infection is linked to differences in long-term cortisol secretion in people with schizophrenia, but not in short-term cortisol secretion.

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