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Major Depressive Disorder (MDD) is the most common mental illness, with estimated lifetime prevalence of 25% (Kessler, Avenevoli, & Merikangas, 2001). Importantly, research suggests that the one-year prevalence rates of depression are relatively low in childhood, but dramatically increase, as much as six-fold, from early to late adolescence (Hankin et al., 1998; Kessler et al., 2003). These trends have led researchers to examine the developmental antecedents of depression in hopes of identifying risk factors associated with the first onset of disorder. This study examined the relationship between two empirically supported risk factors for depression: stress reactivity and cognitive vulnerabilities (CV). To varying degrees, these factors have been examined throughout development; yet, these bodies of literature have been surprisingly separate, which may contribute to the disappointing performance of selective intervention strategies to identify and treat youth at risk (Kovacs & Lopez-Duran, 2010). The current study examined the developmental antecedents and combined effects of two risk factors for depression. A sample of 127 adolescents and their mothers from the greater Philadelphia area completed questionnaires and interviews. In addition, adolescents participated in a social stress task to elicit a stress response. Measures of biological stress reactivity were measured through the endocrine system (e.g., cortisol) and the autonomic nervous system (e.g., heart rate). Findings suggest that a number of proximal stressors predict higher levels of both CV and stress reactivity components. We did not find evidence for more distal antecedents (e.g., early life stress, maternal depression, parenting styles) in the prediction of these risk factors, however. Importantly, this study highlights the combined risk factors of CVs and biological stress reactivity. Specifically, adolescents with higher levels of CV and a poorer ability to regulate after a stressor are at increased risk for depressive symptoms. Findings did not support the hypothesis that the mechanism through which CVs lead to depression is biological reactivity. The current study presents an important methodological and theoretical advancement in the body of literature examining risk factors for depression and stress reactivity. From the evidence obtained, it appears that in many cases these aspects of reactivity may operate synergistically in the development of depression and that the lack of physiological recovery may amplify the negative effects of different cognitive styles. The joint effects of cognitive and biological reactivity can enhance our understanding of reactions to stressful events and lead to more personalized treatment. Approaches that incorporate mindfulness and relaxation strategies may be particularly relevant to the regulation of physiological reactivity to stress that may reduce the prolonged feelings associated with stressful events. Overall, the results from the current study provide a more nuanced understanding of the relationship between stress responses and move beyond prior research on risk factors for depression. / Psychology

This study creates and analyzes a model of the Hypothalamus-Pituitary-Adrenal axis to better understand cortisol rhythmicity perpetuated by circadian inputs, system dynamics and feedback inherent within the system. Differential equations are created to model human physiology with cortisol and precursor hormone outputs fit to physiologic data. The model is created with an input of circadian cues from the hypothalamus which are designed to create a more realistic stimulation of the cortisol cascade over predecessors. The study also incorporates additional signaling pathways unique to this model. The project explores the properties of the model under mathematical analysis; then, the simulation of known medical pathologies is used to analyze the model's predictive ability. It is found that incorporating the additional signaling pathway of Arginine Vasopressin increases the model's predictive capability in certain pathological conditions over predecessor models. Additionally, the origination of ultradian rhythm is explored through simulation and two possible explanations are found. First, pulsatile release of Adrenocorticotropic Hormone combined with negative feedback into the system from glucocorticoid receptors elicits the observed ultradian oscillations in humans. Additionally, simulations of increased hypothalamic monitoring and control of cortisol concentrations create a natural oscillation within the desired period. Results from numerical perturbation simulations and dynamic sensitivity analysis are employed to offer justification for known pathological conditions developing from circadian dysregulation. / Master of Science / This study aims to better understand the body's natural cortisol rhythm by creating a mathematical model of the Hypothalamus-Pituitary-Adrenal axis. The model uses differential equations to simulate human physiology and includes circadian cues from the suprachiasmatic nucleus to create a more accurate representation of how cortisol is released in the body. The study also incorporates additional signaling pathways and interactions unique to this model. By analyzing the model and simulating known medical conditions, it was found found that incorporating these additional signaling pathways improved the model's predictive ability in certain situations. Then, numerical simulations were used to investigate how circadian dysregulation can lead to pathological conditions.The study also explored the origin of ultradian rhythm, or short-term fluctuations in cortisol levels, and found two possible explanations. One explanation is the pulsatile release of Adrenocorticotropic Hormone combined with negative feedback from glucocorticoid receptors. Another explanation is increased hypothalamic control of cortisol concentrations. Overall, this study provides insights into the complex dynamics of the Hypothalamus-Pituitary-Adrenal axis and the origination of pathology in the system.

Background: Studies with experimental administration of alcohol offer inconsistent approaches and interpretations in which ways an acute alcohol exposure affects the HPA-system and the cortisol secretion. So far published alcohol experiments differ in alcohol application, the possibility of alcohol self-administration at the subjects own discretion as well as the age of the participants. Question: Is cortisol secretion modified by gender during alcohol infusion? Do men and women show different cortisol levels under alcohol exposure when compared to the baseline? Is there a dose-response relationship between cortisol secretion and acute alcohol exposure? Have family history, smoking habits and alcohol induced side effects like nausea an influence on the cortisol secretion under alcohol exposure? Materials and methods: 48 18 year old subjects participated in two identical sessions in which they were able to regulate their maximum blood alcohol concentration up to a safety limit of 1.2 ‰ (i.e., 0.12%). The experiment was conducted by using a special software for self-infusion of ethanol (CASE) which guided the participants through a two and a half hours long experiment. CASE is founded on a validated physiologically-based pharmacokinetic model and involves calculating the infusion volume needed to increase the blood alcohol concentration in a linear manner. The BAC increases after each alcohol request by 0,075 ‰ (i.e., 0.0075%) within in two and a half minutes. If the subject infuses no alcohol the blood alcohol concentration will decrease by 0.01 ‰ (i.e., 0.001%) per minute. Through the precise calculation of the infusion rate, individual differences can be eliminated. Cortisol levels were measured at five time points: an initial baseline measurement and four measurements at fixed time points during the alcohol self-administration of subjects with two completed alcohol experiments. As an appropriate measure to examine the effect of alcohol self-administration on cortisol secretion, the maximum blood alcohol concentration was determined. In addition the day of experiment, gender and family history were observed as well as exploratory maximum nausea and smoking habits. Results: In conclusion, the results confirmed that women have higher cortisol levels than men at baseline and under alcohol influence. Blood alcohol concentration as examined influencing variable was shown to have different effects on the HPA system on day one and two. On the first day of experimentation there was no effect of blood alcohol concentration on the HPA system. On the second day a dose-response relationship could be identified between cortisol secretion and acute alcohol exposure. Individually higher blood alcohol concentrations attenuated cortisol stronger in comparison to subjects with lower blood alcohol concentrations. Family history, smoking habits and unpleasant side effects (nausea) did not affect the cortisol secretion under alcohol exposure in this series of experiments. Conclusions: Current data suggests that alcohol experiments affect the cortisol secretion in young social drinkers. These findings could be detected for the first time. Up to this point there has not been an experimental study that investigated and evaluated the dose-effect relationship between cortisol secretion and alcohol in a study design which uses intravenous alcohol self-administration. It can be theorized that the first day of experimentation is suitable as a settling-in phase due to unspecific confounding factors, whereas the second day can be considered, in an identical setting, apt for hypothesis testing. The increased cortisol level in women when compared to men is consistent with previous studies and there was no indication that family history, smoking habits and alcohol induced unpleasant side effects have an influence on cortisol secretion.

Plusieurs études antérieures ont proposé que la ménarche pouvait représenter une vulnérabilité accrue au développement de la dépression en augmentant la réactivité au stress chez les filles ayant atteint leur cycle menstruel. Dans la présente étude, les symptômes dépressifs et les niveaux de cortisol salivaire ont été mesurés chez 198 garçons et 142 filles (11 - 13 ans), et ce, à quatre reprises au cours de leur première année de transition vers l’école secondaire, une période de stress chez les adolescents. Les résultats ont montré que les filles qui avaient atteint la ménarche au moment de la transition vers le secondaire avait des niveaux significativement plus élevés de symptômes dépressifs et de cortisol salivaire entre l’automne et le printemps, comparativement aux filles qui n'avaient pas encore atteint la ménarche. Ces dernières présentaient des niveaux plus élevés de symptômes dépressifs que les filles sans et les garçons. Les filles sans ménarche présentaient d’avantages des niveaux de symptômes dépressives plus élevés que les garçons. En utilisant l’âge de ménarche comme variable catégorique, les résultats démontrent que les filles ayant eu leur ménarche plus jeunes présentent des symptômes dépressifs plus élevés tout au long de l'année scolaire, alors que les filles qui ont commencé leur cycle menstruel à l’âge dit ‘normal’ présentent des symptômes dépressifs transitoires. Globalement, ces résultats suggèrent que la ménarche est un indice significatif d’une vulnérabilité accrue pour les symptômes dépressifs et les niveaux de cortisol plus élevés chez les adolescentes qui font leur entrée au secondaire. Également, ces résultats suggèrent qu’un âge précoce de ménarche peut exposer à long-terme le cerveau en développement à des niveaux élévés de cortisol, rendant ainsi ce groupe d’adolescentes plus vulnérables à la dépression. / It has been proposed that the onset and/or earlier age at menarche confer greater vulnerability to depressive symptoms by increasing the reactivity of menarcheal girls to stressors associated with adolescence. In the present study, we measured depressive symptoms and salivary cortisol levels in 198 boys and 142 girls (11 -13 years) tested four times during their first year of transition into high school, a period known to be associated with stress among adolescents. Results showed that girls who had reached menarche before the transition to high school transit presented significantly higher depressive symptoms and salivary cortisol levels across the school year, when compared to girls who had not reached menarche and boys. Girls who had reached menarche presented significantly higher depressive scores than girls who had not reached menarche and boys. Girls who did had not reached menarche also scored significantly higher on depressive symptoms when compared to boys. When we divided the menarcheal girls as a function of age of onset, we found that girls with early age at menarche presented consistently higher scores for depressive symptoms from the start of the school year to early spring. Girls with on-time menarche scored higher for symptoms of depression, but these were more transitory. Altogether, these results show that onset of menarche is associated with greater depressive symptoms and higher cortisol levels in adolescent girls going through the stress of high school transition. These findings also suggest that early menarche may confer greater vulnerability to depression due to long-term exposure of the developing brain to high cortisol levels.

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.

O sucesso da adaptação imediata para a vida extrauterina depende da apropriada função pulmonar. Em neonatologia humana, é estabelecido que a cesariana eletiva aumenta o risco de angústia respiratória, como resultado da reduzida remoção do fluido pulmonar. Neste contexto, este estudo objetivou avaliar a influência da condição obstétrica no desempenho respiratório dos recém-nascidos caninos no período de transição, em especial os fatores que determinam a remoção do fluido pulmonar. Para tal, foram selecionadas 20 fêmeas caninas e 37 neonatos, os quais constituíram dois grupos, de acordo com a condição obstétrica: Eutocia Vaginal (n=10 parturientes; n= 17 neonatos) e Cesariana Eletiva (n= 10 parturientes; n= 20 neonatos). A avaliação materna consistiu na dosagem sérica de cortisol e catecolaminas (adrenalina e noradrenalina) em momentos pontuais no pré, intra e pós-parto. Os neonatos foram avaliados por meio do escore de vitalidade neonatal, bem como avaliação das frequências cardíaca e respiratória, aferição da temperatura corpórea e peso corporal, avaliação hemogasométrica venosa, dosagem sérica de cortisol e catecolaminas, lactatemia, glicemia, oximetria de pulso e avaliação radiográfica pulmonar em momentos pontuais no decorrer das primeiras 24 horas de vida. Adicionalmente, foi avaliado a composição eletrolítica e a concentração de cortisol no líquido amniótico de cada filhote. O parto vaginal determinou menor estresse materno, porém, maior concentração de cortisol no líquido amniótico e soro sanguíneo dos filhotes, contribuindo para melhor adaptação cardiorrespiratória e metabólica. Por outro lado, a cesariana eletiva resultou em maior estresse materno, contrariamente ao perfil hormonal dos filhotes e retardou a remoção do fluido pulmonar, resultando em hipoxemia mais severa, além de dificultar a resposta compensatória ao desequilíbrio ácido-básico sanguíneo e termorregulação. Em conclusão, a condição obstétrica impõe diferenças na adaptação pulmonar, interferindo no desempenho respiratório de cães no período de transição feto-neonatal. / The success of immediate adaptation to extrauterine life depends on appropriate lung function. In human neonatology, it is established that elective cesarean section increases the risk of respiratory distress as a result of reduced pulmonary fluid reabsortion. In this context, this study aimed to evaluate the influence of the obstetric condition on the respiratory performance of canine neonates in the transition period, specially the factors that determine the removal of the pulmonary fluid. For this purpose, 20 canine females and 37 neonates were selected, according to the obstetric condition: Vaginal Eutocia (n = 10 bitches, n = 17 neonates) and Elective Cesarian Section (n = 10 bitches, n = 20 neonates). Maternal evaluations were performed to evaluate serum cortisol and catecholamines (adrenaline and noradrenaline) levels at punctual moments in pre, intra and postpartum. Neonates were evaluated for the neonatal vitality score, as well as evaluation of heart and respiratory rates, body temperature and body weight, venous hemogasometric evaluation, serum cortisol and catecholamines, blood lactate, blood glucose, pulse oximetry and radiographic evaluation during the first 24 hours of life. Additionally, the electrolyte composition and cortisol concentration in the amniotic fluid of each puppy was evaluated. The vaginal delivery determined lower maternal stress, however, a higher cortisol concentration in the amniotic fluid and neonatal blood serum, contributing to a better cardiorespiratory and metabolic adaptation. On the other hand, elective cesarean section resulted in higher maternal stress contrary to the neonatal hormonal profile and delayed the removal of the pulmonary fluid, resulting in more severe hypoxemia, besides a less efficient compensatory response to acid-base imbalance and thermoregulation. In conclusion, the obstetric condition imposes differences in pulmonary adaptation, interfering in the respiratory performance of dogs in the transition from fetal to neonatal life.