La mucoviscidose (ou cystic fibrosis, CF) est une maladie caractérisée par une inflammation pulmonaire chronique qui contribue à la dégradation progressive de l’épithélium des voies aériennes des patients. Les glucocorticoïdes (GC) représentent un outil essentiel pour le traitement du patient mais leur efficacité et leur rapport bénéfice/risque restent cependant controversés. Les effets secondaires provoqués par l’administration de ces molécules pourraient être diminués par l’utilisation de leur protéine d’adressage, la corticosteroid-binding globulin (CBG). L’objectif de ce travail était d’étudier l’expression de la CBG chez les patients CF, afin d’optimiser leur traitement anti-inflammatoire par GC. Nous avons montré, dans un premier temps, que la synthèse hépatique de CBG était augmentée, tandis que son taux plasmatique était conservé chez les patients CF, comparé aux patients non-CF. Dans un second temps, nous nous sommes intéressés à l’expression de la CBG au niveau pulmonaire. L’inflammation chez les patients CF étant principalement pulmonaire, l’expression locale de CBG à ce niveau pourrait moduler l’efficacité du GC, en le recaptant. Nos données montrent que l’expression de cette CBG pulmonaire est diminuée chez les patients CF. Les études sur des modèles in vitro hépatiques et pulmonaires n’ont pas permis d’expliquer les résultats obtenus et ont souligné la limite des modèles et des outils à disposition. Le maintien de la concentration plasmatique de CBG et la diminution de la CBG pulmonaire chez les patients CF suggèrent ainsi que la CBG pourrait être utilisée comme outil thérapeutique dans le contexte de la mucoviscidose, afin d’optimiser le traitement par GC. / Cystic fibrosis (CF) is characterized by a chronic pulmonary inflammation, responsible of the progressive degradation of the airways epithelium. In CF, glucocorticoids (GC) are widely used but their efficiency and benefit/risk ratio are still discussed. The side effects, caused by the administration of these molecules, might be decreased by the use of their delivery protein, corticosteroid-binding globulin (CBG). The aim of the work was to study the expression of CBG in CF patients, in order to optimise their anti-inflammatory treatment by GC. First, we showed that the hepatic synthesis of CBG was increased while its plasmatic level was preserved in CF patients, compared to non-CF. Second, we were interested by the expression of CBG at the pulmonary level. The inflammation in CF patients being primarely pulmonary, the local expression of CBG in the lung could modulate the efficiency of GC through recapture. Our data showed that this expression of this pulmonary CBG was decreased in CF patients. The studies conducted in vitro on hepatic and pulmonary models did not explained our results and highlighted the limit of the models and tools at our disposal. The maintained plasmatic concentration of CBG and the decrease of pulmonary CBG in CF patients suggest that CBG might be useful as a therapeutic tool in the CF context, in order to optimise the GC treatment.

There is a need to understand how free-ranging animals respond and adapt to stress. However, little is currently known regarding the physiologic adaptations to stress in bears, and there are few tools available to wildlife managers to assess the health and stress status of free-ranging animals, including ursids. The hypothalamus-pituitary-adrenal (HPA) axis plays major roles in the physiological adaptation to stress, leading to the increased secretion of glucocorticoids (e.g. cortisol in most mammals) that mediate adaptive changes in physiology and behaviour. The vast majority of glucocorticoids are bound to its primary carrier protein, corticosteroid-binding globulin (CBG), in most animals, and only the unbound fraction is bioavailable. Thus, CBG plays a major role in modulating glucocorticoid dynamics, and this protein must be characterized to build a more complete understanding of the adaptive role that the HPA axis plays in mitigating stress in bears. The overall objective of this thesis was to characterize the HPA axis activity and CBG levels in bears, and develop tools targeted towards the monitoring of the health and stress status of American black bear (Ursus americanus), grizzly bear (U. arctos), and polar bear (U. maritimus). The binding characteristics of cortisol to CBG in bears were studied via saturation binding experiments, and this information was used to estimate free cortisol concentrations based on CBG concentrations. To quantify CBG concentrations in bears, an enzyme-linked immunosorbent assay (ELISA) was developed. Grizzly bear CBG cDNA was cloned and sequenced, and an antibody was developed against a peptide sequence of the deduced amino acid sequence. The antibody showed good cross-reactivity against black, grizzly, and polar bear CBG, and the ELISA based on this antibody found differences in the mean CBG levels between species. Using this data, free cortisol levels were estimated, and mean levels were elevated in polar bears relative to black and grizzly bears. Having developed these tools, the roles that corticosteroid-binding globulin (CBG) and bioavailable cortisol played in the physiological adaptation to major life history traits and environmental challenges faced by ursids were investigated. Importantly, CBG was not modulated by the acute stress of capture and handling, despite the large differences in the magnitude of acute cortisol responses that are induced by these methods, suggesting that CBG levels may reflect the chronic health and stress status of bears. Altogether, there were few changes in CBG levels throughout much of the annual life cycle of bears, implying that CBG does not play a major adaptive role in the life history traits of bears and, instead, metabolic and environmental factors may be the key modulators of cortisol dynamics. However, CBG was not significantly associated with our measures of dietary patterns and nutrition, including body condition, seasonal dietary patterns, and fasting. The majority of the observed variation in the levels of this protein in bears remains unexplained. However, stress-induced free cortisol levels were negatively associated with urea to creatinine ratio (an indicator of dietary protein content and fasting status in grizzly and polar bears, respectively) and positively associated with lactation in hibernating black bears, suggesting that the variation in adrenal function may be playing an important role in the adaptation to adverse environmental conditions and/or metabolic stress in bears. In addition to serum cortisol dynamics, other proteins were also hypothesized to play adaptive roles in maintaining the hibernating phenotype in bears. Changes in the serum proteome during hibernation in black bears were assessed as a means to discover novel proteins that may be indicative of metabolic stress in bears. The serum proteomes of active and hibernating black bears were compared and analyzed for significant changes by two-dimensional electrophoresis and tandem mass spectrometry. Proteins involved with immune-related function were significantly altered during hibernation, leading to the proposal that the serum protein changes are essential for maintaining immune competence, wound healing, and bone structure. Altogether, this thesis developed a method to quantify CBG and estimated free cortisol concentrations in bears, and characterized their roles in the physiological adaptations associated with the major life history traits and environmental challenges faced by ursids. Also, novel serum proteins were identified as potential markers of immune function and health status in bears. These tools may be tremendously useful for wildlife managers and conservationists in determining how chronic stressors, including anthropogenic activities and climate change, may impact the stress and health performances of individual and populations of free-ranging bears.

There is a need to understand how free-ranging animals respond and adapt to stress. However, little is currently known regarding the physiologic adaptations to stress in bears, and there are few tools available to wildlife managers to assess the health and stress status of free-ranging animals, including ursids. The hypothalamus-pituitary-adrenal (HPA) axis plays major roles in the physiological adaptation to stress, leading to the increased secretion of glucocorticoids (e.g. cortisol in most mammals) that mediate adaptive changes in physiology and behaviour. The vast majority of glucocorticoids are bound to its primary carrier protein, corticosteroid-binding globulin (CBG), in most animals, and only the unbound fraction is bioavailable. Thus, CBG plays a major role in modulating glucocorticoid dynamics, and this protein must be characterized to build a more complete understanding of the adaptive role that the HPA axis plays in mitigating stress in bears. The overall objective of this thesis was to characterize the HPA axis activity and CBG levels in bears, and develop tools targeted towards the monitoring of the health and stress status of American black bear (Ursus americanus), grizzly bear (U. arctos), and polar bear (U. maritimus). The binding characteristics of cortisol to CBG in bears were studied via saturation binding experiments, and this information was used to estimate free cortisol concentrations based on CBG concentrations. To quantify CBG concentrations in bears, an enzyme-linked immunosorbent assay (ELISA) was developed. Grizzly bear CBG cDNA was cloned and sequenced, and an antibody was developed against a peptide sequence of the deduced amino acid sequence. The antibody showed good cross-reactivity against black, grizzly, and polar bear CBG, and the ELISA based on this antibody found differences in the mean CBG levels between species. Using this data, free cortisol levels were estimated, and mean levels were elevated in polar bears relative to black and grizzly bears. Having developed these tools, the roles that corticosteroid-binding globulin (CBG) and bioavailable cortisol played in the physiological adaptation to major life history traits and environmental challenges faced by ursids were investigated. Importantly, CBG was not modulated by the acute stress of capture and handling, despite the large differences in the magnitude of acute cortisol responses that are induced by these methods, suggesting that CBG levels may reflect the chronic health and stress status of bears. Altogether, there were few changes in CBG levels throughout much of the annual life cycle of bears, implying that CBG does not play a major adaptive role in the life history traits of bears and, instead, metabolic and environmental factors may be the key modulators of cortisol dynamics. However, CBG was not significantly associated with our measures of dietary patterns and nutrition, including body condition, seasonal dietary patterns, and fasting. The majority of the observed variation in the levels of this protein in bears remains unexplained. However, stress-induced free cortisol levels were negatively associated with urea to creatinine ratio (an indicator of dietary protein content and fasting status in grizzly and polar bears, respectively) and positively associated with lactation in hibernating black bears, suggesting that the variation in adrenal function may be playing an important role in the adaptation to adverse environmental conditions and/or metabolic stress in bears. In addition to serum cortisol dynamics, other proteins were also hypothesized to play adaptive roles in maintaining the hibernating phenotype in bears. Changes in the serum proteome during hibernation in black bears were assessed as a means to discover novel proteins that may be indicative of metabolic stress in bears. The serum proteomes of active and hibernating black bears were compared and analyzed for significant changes by two-dimensional electrophoresis and tandem mass spectrometry. Proteins involved with immune-related function were significantly altered during hibernation, leading to the proposal that the serum protein changes are essential for maintaining immune competence, wound healing, and bone structure. Altogether, this thesis developed a method to quantify CBG and estimated free cortisol concentrations in bears, and characterized their roles in the physiological adaptations associated with the major life history traits and environmental challenges faced by ursids. Also, novel serum proteins were identified as potential markers of immune function and health status in bears. These tools may be tremendously useful for wildlife managers and conservationists in determining how chronic stressors, including anthropogenic activities and climate change, may impact the stress and health performances of individual and populations of free-ranging bears.

Binding parameters of soluble Type I and Type II receptors were assessed in hippocampus of adult, adrenalectomized, male and female rats. No sex differences in the number of either Type I or Type II receptors could be demonstrated between gonadally intact animals. When females treated with 17β-estradiol benzoate (10 μg/day) were compared with males, a statistically significant reduction in Type II receptors was observed in the females; progesterone produced no further decrease in receptor numbers. The amount of tissue-associated corticosteroid-binding globulin in gonadally intact animals (perfused with dextran-saline) was twice as great in females as males. Sex-dependent differences in these gonadally intact rats were found in the affinity, measured as the dissociation constant (Kd), of both the Type I and Type II receptors. For both receptors, affinity in cytosols from females was reduced. The difference for the Type II receptor was slight, but the Kd value of the type I receptor was several-fold higher in females. The difference in affinity was evident with both natural and synthetic steroid ligands. There appears to be little, if any, difference in affinity between the hippocampal Type I and the Type II receptors in females. This suggests that the occupancy of Type I receptors in females is substantially less than that of males at low circulating concentrations of corticosteroids.

Cortisol, the principal glucocorticoid secreted from the adrenal glands, is essential for life. Healthy cortisol levels are maintained through negative feedback on the central nervous system (CNS) – pituitary stimulatory apparatus which regulates production of adrenocorticotropin (ACTH) and contains a light–entrained intrinsic CNS driven diurnal rhythm. Cortisol participates in a regulatory mechanism where inflammatory cytokines stimulate cortisol release and cortisol in turn suppresses cytokine release. The effects of cortisol in inflammatory states include elevating blood pressure and metabolic regulation. This thesis contains three exploratory studies examining circulating cortisolaemia using the best available methodologies (total and free cortisol and corticosteroid-binding globulin (CBG)) in clinical states characterized by immune activation/ inflammation and altered blood pressure. These clinical states include: (1) septic shock, (2) hypertensive disorders of pregnancy and (3) obesity-induced hypertension. Prior to the studies described here, little was know about cortisolaemia in these common pathological states. Septic shock is a life threatening condition that complicates severe infection and is characterized by systemic inflammation and refractory hypotension. High plasma total cortisol levels and attenuated responses to synthetic ACTH stimulation are associated with increased mortality. The use of corticosteroids in septic shock has been highly controversial for decades, however recent trials have reported haemodynamic and survival benefits associated with the use of physiologic steroid replacement in patients with relative adrenal insufficiency (RAI) – currently defined as a total cortisol increment of 248 nmol/L or less following ACTH (250 μg) stimulation. However, CBG and albumin levels fall by around 50% with an increase in plasma free cortisol in critical illness. Hence, total cortisol may not reflect the biologically active free (unbound) cortisol, suggesting that standard assays for plasma cortisol (which measure total plasma cortisol) underestimate HPA axis activity. In this study, we have showed that plasma free cortisol is a better guide to circulating glucocorticoid activity in systemic infection than total cortisol. We have also validated the use of Coolens’ method in estimating free cortisol in systemic infection, using plasma total cortisol and CBG measurements as plasma free cortisol is not performed in clinical laboratories. Free cortisol measurement allows better categorization of RAI and non-RAI groups with a free cortisol increment of 110 nmol/L as cut-off. Moreover, we have shown that survivors of RAI have normal adrenocortical function on follow-up testing suggesting a lack of functional adrenal reserve rather than adrenal damage during critical illness. Larger randomized controlled trials will be required to redefine RAI using free cortisol measurements and relate that to clinical outcomes and responses to corticosteroid therapy. Nitric oxide (NO) is normally produced in the endothelium by the constitutive form of the NO synthase and this physiologic production is important for blood pressure regulation and blood flow distribution. Studies have shown that an overproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock. Clinical studies of non-selective inhibitors of the L-arginine nitric oxide pathway showed increased mortality from cardiovascular complications. However, glucocorticoids, which improve vasopressor sensitivity, may act by partially suppressing NO synthesis through selective direct inhibition of iNOS, and suppression of inflammatory cytokine synthesis. Hence, plasma nitrate/ nitrite (NOx) levels may provide a titratable end point to individualize glucocorticoid therapy in sepsis. The NOx study in this thesis showed that cortisol (total and free), CBG and NOx correlated to illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx levels, predicted septic shock. NOx levels were characteristically stable within individuals but inter-individual differences were only partly accounted for by illness severity or renal dysfunction. NOx levels correlated weakly with cortisol, did not relate to the need for vasopressors and were not suppressed by hydrocortisone treatment. Thus, NOx is not a suitable target for glucocorticoid therapy in septic shock. Pregnancy is the only sustained physiologic state of hypercortisolism in humans. A large body of data suggests that excessive foetal and prenatal glucocorticoid exposure leads to reduced birth weight and adverse health in offspring such as elevated blood pressure and insulin resistance. Pre-eclampsia and gamete donor pregnancies are associated with immune activation, elevated inflammatory cytokines as well as elevated blood pressure. Prior to the study described in this thesis however, there was no prospective data on maternal cortisolaemia in these complicated pregnancies. My study has demonstrated for the first time that there was a substantial fall in plasma CBG levels in the last few weeks of gestation with a corresponding rise in free cortisol in normal pregnancy, a finding obscured for methodological reasons in past studies. This free cortisol elevation in late pregnancy may facilitate organ maturation in the foetus and perhaps prepare the mother for the metabolic demands of labour. In pre-eclampsia and gestational hypertension, plasma CBG, total and free cortisol levels were lower in late third trimester; and in IUGR, plasma CBG levels were suppressed from 28 weeks gestation until delivery but with no significant difference in plasma total and free cortisol. Women with assisted reproduction using donor gametes/ embryos had significantly lower plasma CBG, total and free cortisol levels even in those with normal pregnancy outcomes. Low CBG may be due to reduced synthesis or enhanced inflammation-driven degradation. Low maternal cortisol may be due to a lack of placental corticotropin-releasing hormone, or reduced maternal ACTH, driving cortisol production. This unanticipated maternal hypocortisolism in complicated pregnancies may trigger precocious activation of the foetal HPA axis and could have implications for postnatal and adult health. Speculatively, since excess prenatal GCs increase HPA axis activity, we proposed that maternal hypocortisolism may predispose to the hypocortisolaemic state characterized by fatigue, pain and stress sensitivity, in offspring. The third state of immune/ inflammatory activation associated with blood pressure dysregulation studied in this thesis is obesity. The epidemiologic relationship between obesity and hypertension is widely recognised. Central obesity in particular has been associated with exaggerated HPA responses to stimuli. Studies of severe dieting and starvation resulted in hypercortisolism and a significant decrease in CBG. The HPA axis and the renin-angiotensin-aldosterone system (RAAS) have been implicated in the pathophysiology of obesity-induced hypertension. However, there is little data on the effect of moderate weight loss (30% caloric restriction) on adrenocortical function, and the relation of adrenal hormones to altered blood pressure with weight loss. In this study, measures of HPA axis and RAAS and blood pressure monitoring were performed in twenty-five obese subjects before and after a 12-week diet program (6000kJ/day). Short-term, moderate weight loss (mean 8.5 kg) was associated with a small reduction in blood pressure (mean arterial pressure 6 mmHg) and significantly reduced levels of aldosterone and renin but not cortisol levels. These findings suggest that aldosterone may have an important role in the blood pressure reduction with weight loss via a renin mediated mechanism, perhaps involving renal sympathetic tone. In contrast to severe caloric restriction, HPA axis activation does not occur with moderate weight loss. This suggests a threshold effect of weight loss on the HPA axis where greater caloric restriction is required for HPA stimulation, or a counterbalancing of central and direct adrenal effects on HPA axis function. Overall, these three exploratory studies have provided novel data on HPA axis function in systemic infection, pregnancy and in diet-induced weight loss. Each study offers a basis for further studies of HPA axis function in these disorders. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1289330 / Thesis(Ph.D.)-- School of Medicine, 2007.

Cortisol, the principal glucocorticoid secreted from the adrenal glands, is essential for life. Healthy cortisol levels are maintained through negative feedback on the central nervous system (CNS) – pituitary stimulatory apparatus which regulates production of adrenocorticotropin (ACTH) and contains a light–entrained intrinsic CNS driven diurnal rhythm. Cortisol participates in a regulatory mechanism where inflammatory cytokines stimulate cortisol release and cortisol in turn suppresses cytokine release. The effects of cortisol in inflammatory states include elevating blood pressure and metabolic regulation. This thesis contains three exploratory studies examining circulating cortisolaemia using the best available methodologies (total and free cortisol and corticosteroid-binding globulin (CBG)) in clinical states characterized by immune activation/ inflammation and altered blood pressure. These clinical states include: (1) septic shock, (2) hypertensive disorders of pregnancy and (3) obesity-induced hypertension. Prior to the studies described here, little was know about cortisolaemia in these common pathological states. Septic shock is a life threatening condition that complicates severe infection and is characterized by systemic inflammation and refractory hypotension. High plasma total cortisol levels and attenuated responses to synthetic ACTH stimulation are associated with increased mortality. The use of corticosteroids in septic shock has been highly controversial for decades, however recent trials have reported haemodynamic and survival benefits associated with the use of physiologic steroid replacement in patients with relative adrenal insufficiency (RAI) – currently defined as a total cortisol increment of 248 nmol/L or less following ACTH (250 μg) stimulation. However, CBG and albumin levels fall by around 50% with an increase in plasma free cortisol in critical illness. Hence, total cortisol may not reflect the biologically active free (unbound) cortisol, suggesting that standard assays for plasma cortisol (which measure total plasma cortisol) underestimate HPA axis activity. In this study, we have showed that plasma free cortisol is a better guide to circulating glucocorticoid activity in systemic infection than total cortisol. We have also validated the use of Coolens’ method in estimating free cortisol in systemic infection, using plasma total cortisol and CBG measurements as plasma free cortisol is not performed in clinical laboratories. Free cortisol measurement allows better categorization of RAI and non-RAI groups with a free cortisol increment of 110 nmol/L as cut-off. Moreover, we have shown that survivors of RAI have normal adrenocortical function on follow-up testing suggesting a lack of functional adrenal reserve rather than adrenal damage during critical illness. Larger randomized controlled trials will be required to redefine RAI using free cortisol measurements and relate that to clinical outcomes and responses to corticosteroid therapy. Nitric oxide (NO) is normally produced in the endothelium by the constitutive form of the NO synthase and this physiologic production is important for blood pressure regulation and blood flow distribution. Studies have shown that an overproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock. Clinical studies of non-selective inhibitors of the L-arginine nitric oxide pathway showed increased mortality from cardiovascular complications. However, glucocorticoids, which improve vasopressor sensitivity, may act by partially suppressing NO synthesis through selective direct inhibition of iNOS, and suppression of inflammatory cytokine synthesis. Hence, plasma nitrate/ nitrite (NOx) levels may provide a titratable end point to individualize glucocorticoid therapy in sepsis. The NOx study in this thesis showed that cortisol (total and free), CBG and NOx correlated to illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx levels, predicted septic shock. NOx levels were characteristically stable within individuals but inter-individual differences were only partly accounted for by illness severity or renal dysfunction. NOx levels correlated weakly with cortisol, did not relate to the need for vasopressors and were not suppressed by hydrocortisone treatment. Thus, NOx is not a suitable target for glucocorticoid therapy in septic shock. Pregnancy is the only sustained physiologic state of hypercortisolism in humans. A large body of data suggests that excessive foetal and prenatal glucocorticoid exposure leads to reduced birth weight and adverse health in offspring such as elevated blood pressure and insulin resistance. Pre-eclampsia and gamete donor pregnancies are associated with immune activation, elevated inflammatory cytokines as well as elevated blood pressure. Prior to the study described in this thesis however, there was no prospective data on maternal cortisolaemia in these complicated pregnancies. My study has demonstrated for the first time that there was a substantial fall in plasma CBG levels in the last few weeks of gestation with a corresponding rise in free cortisol in normal pregnancy, a finding obscured for methodological reasons in past studies. This free cortisol elevation in late pregnancy may facilitate organ maturation in the foetus and perhaps prepare the mother for the metabolic demands of labour. In pre-eclampsia and gestational hypertension, plasma CBG, total and free cortisol levels were lower in late third trimester; and in IUGR, plasma CBG levels were suppressed from 28 weeks gestation until delivery but with no significant difference in plasma total and free cortisol. Women with assisted reproduction using donor gametes/ embryos had significantly lower plasma CBG, total and free cortisol levels even in those with normal pregnancy outcomes. Low CBG may be due to reduced synthesis or enhanced inflammation-driven degradation. Low maternal cortisol may be due to a lack of placental corticotropin-releasing hormone, or reduced maternal ACTH, driving cortisol production. This unanticipated maternal hypocortisolism in complicated pregnancies may trigger precocious activation of the foetal HPA axis and could have implications for postnatal and adult health. Speculatively, since excess prenatal GCs increase HPA axis activity, we proposed that maternal hypocortisolism may predispose to the hypocortisolaemic state characterized by fatigue, pain and stress sensitivity, in offspring. The third state of immune/ inflammatory activation associated with blood pressure dysregulation studied in this thesis is obesity. The epidemiologic relationship between obesity and hypertension is widely recognised. Central obesity in particular has been associated with exaggerated HPA responses to stimuli. Studies of severe dieting and starvation resulted in hypercortisolism and a significant decrease in CBG. The HPA axis and the renin-angiotensin-aldosterone system (RAAS) have been implicated in the pathophysiology of obesity-induced hypertension. However, there is little data on the effect of moderate weight loss (30% caloric restriction) on adrenocortical function, and the relation of adrenal hormones to altered blood pressure with weight loss. In this study, measures of HPA axis and RAAS and blood pressure monitoring were performed in twenty-five obese subjects before and after a 12-week diet program (6000kJ/day). Short-term, moderate weight loss (mean 8.5 kg) was associated with a small reduction in blood pressure (mean arterial pressure 6 mmHg) and significantly reduced levels of aldosterone and renin but not cortisol levels. These findings suggest that aldosterone may have an important role in the blood pressure reduction with weight loss via a renin mediated mechanism, perhaps involving renal sympathetic tone. In contrast to severe caloric restriction, HPA axis activation does not occur with moderate weight loss. This suggests a threshold effect of weight loss on the HPA axis where greater caloric restriction is required for HPA stimulation, or a counterbalancing of central and direct adrenal effects on HPA axis function. Overall, these three exploratory studies have provided novel data on HPA axis function in systemic infection, pregnancy and in diet-induced weight loss. Each study offers a basis for further studies of HPA axis function in these disorders. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1289330 / Thesis(Ph.D.)-- School of Medicine, 2007.