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Thesis (Ph.D.) -- University of Adelaide, Dept. of Physiology, 2001. / Includes bibliographical references (leaves 228-257).

Thesis (M.Sc.)--York University, 2006. Graduate Programme in Kinesiology and Health Science. / Typescript. Includes bibliographical references (leaves 66-88). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR19754

Thesis (Ph. D.)--University of Missouri-Columbia, 1999. / Typescript. Vita. Includes bibliographical references (leaves 92-101). Also available on the Internet.

Thesis (Ph.D.) -- University of Adelaide, School of Medicine, Discipline of Medicine, 2007. / "April 2007" Bibliography: leaves 165-189. Also available in print form.

Thesis (Ph. D.)--University of Missouri-Columbia, 1999. / Typescript. Vita. Includes bibliographical references (leaves 92-101). Also available on the Internet.

Thesis (Ph.D.) - University of Queensland, 2003. / Includes bibliography.

There has been a global rise in obesity in the last three decades, and at present one in five women are obese at antenatal booking. Maternal obesity is associated with an increased risk of adverse pregnancy outcomes, including increased fetal size and prolonged pregnancy. In the longer-term, offspring of obese are at increased risk of premature death from a cardiovascular event in their adulthood. One mechanism that has been linked to these outcomes is fetal exposure to glucocorticoids in utero. During normal pregnancy, the maternal hypothalamic pituitary adrenal (HPA) axis undergoes major changes, resulting in exponentially increasing levels of the major circulating glucocorticoid cortisol, and other HPA axis hormones, such as corticotrophin releasing hormone (CRH). Cortisol and CRH are vital for normal fetal growth and length of gestation, but in excess they are associated with fetal growth restriction and preterm labour. In non-pregnant obesity, it is thought that the HPA axis is dysregulated, although evidence is inconclusive. Little is known about the effects of maternal obesity in pregnancy on the HPA axis. The work in this Thesis used clinical studies to test the hypothesis that the HPA axis is dysregulated in obese pregnant women with altered release, clearance and placental metabolism of cortisol. Associations with clinical outcomes related to fetal size and length of gestation were also studied. The HPA axis activity during pregnancy was investigated in a prospective case-control study cohort. Fasting serum cortisol levels were measured at 16, 28 and 36 weeks of gestation (obese n=276, lean n=135). In a subset (obese n=20, lean n=20), corticosteroid binding globulin (CBG), CRH, estrogens and progesterone were measured. Salivary cortisol was measured in samples collected at bedtime, waking and 30 minutes after waking at 16 weeks. Urinary glucocorticoid metabolites were measured at 19 weeks and 36 weeks (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects. All circulating hormone levels rose similarly in obese and lean during pregnancy, but were significantly lower in obese women. The diurnal rhythm of cortisol was maintained. Urinary glucocorticoids increased with gestation in lean, but not in obese, indicating a lesser activation of the HPA axis in obese compared with lean pregnancy. These findings associated with increased birthweight and longer gestation in obese pregnancy, suggesting that decreased HPA axis activity may underlie these obese related adverse pregnancy outcomes. Whether or not lower glucocorticoids in obese pregnancies are maintained at delivery was investigated by measuring active glucocorticoids (cortisol and corticosterone) and their inactive versions (cortisone and 11- dehydrocorticosterone, respectively) from matched maternal and cord plasma samples (n=259, BMI 18 – 55 kg/m2). Active glucocorticoids were significantly higher in maternal than cord blood, and inactive versions were significantly higher in cord than maternal blood. Increased maternal BMI associated with lower maternal cortisol, corticosterone and 11-dehydrocorticosterone. Despite significant correlations between maternal and cord blood glucocorticoid levels, increased maternal BMI did not associate with lower cord blood glucocorticoids. This suggests that conditions at delivery may overcome any potential negative effects of low maternal glucocorticoids on the fetus in the short-term. However, it may not preclude the longer-term effects of fetal exposure to lower glucocorticoid levels during obese pregnancy, and offspring follow-up studies are required. Potential mechanisms leading to altered HPA axis activity in obese pregnancy were explored by studying the pulsatile release and placental metabolism of glucocorticoid hormones. Glucocorticoid pulsatility is thought to be important for transcriptional regulation of glucocorticoid responsive genes, and disruptions to pulsatility have been reported in some disease processes. Glucocorticoids were measured in 10-minute serum sampling between 08.00h-11.00h and 16.00h- 19.00h. Peripheral tissue cortisol was measured from 20-minute sampling of interstitial fluid, over 24-hours, at 16-24 weeks and 30-36 weeks (obese n=7, lean n=8), and non-pregnant controls (obese n=4, lean n=3). Total circulating serum cortisol levels were higher in pregnancy than non-pregnancy in lean and obese, and increased significantly with advancing gestation in lean but not in obese. Pulsatility of cortisol was demonstrated in interstitial fluid in both non-pregnancy and pregnancy. In obese pregnancy, interstitial fluid pulse frequency was lower with advancing gestation. This may be a novel mechanism underlying the observed decreased HPA axis activity in obese pregnancy. Placental cortisol metabolism and transport was studied using an ex vivo placental perfusion model, perfused with a deuterium-labelled cortisol tracer combined with computational modeling. The findings challenge the concept that maternal cortisol diffuses freely across the placenta, but confirmed that 11β- HSD2 acts as major ‘barrier’ to cortisol transfer to the fetus, protecting the fetus from the high maternal circulating cortisol levels. In addition we showed preliminary evidence of local cortisol production within the placenta. The model is able to predict maternal-fetal cortisol transfer and can now be used in future experimental design. In conclusion, in obese pregnancy, lower maternal cortisol and urinary clearance suggested reduced HPA axis activity. Altered glucocorticoid pulsatility may underlie this change. Future studies of placental cortisol metabolism in maternal obesity could be conducted using an ex vivo perfusion model. The lower HPA axis activity in obese pregnancy represents a novel pathway underlying increased fetal growth.

The postnatal period is a critical time for development where external influences can help shape the long-term structure and function of the brain. Adverse experiences or stressors during the postnatal period, such as abuse or neglect, can have huge consequences on the long term function, health and susceptibility to disease. One environmental factor, whose importance is becoming increasingly more recognised for normal development, is light. Abnormal light during the first three weeks of life has been shown to have long term effects on the circadian system of rodents. On the other hand, the effects of abnormal light during the postnatal period on the stress system have yet been relatively unexplored. Therefore the aim of this thesis was to assess if altered postnatal light environment, such as that a preterm baby might be exposed to, has any long-term effects on the stress system. Mice were raised under constant light (LL), constant darkness (DD) or a normal 12:12hr light:dark cycle (LD) for the first three weeks of life from postnatal day (P)1 up until P21. From P21, all mice were then housed in LD conditions and the stress system was assessed by looking at several different levels of the HPA axis including neuropeptide expression in the brain, body and adrenal weight, and plasma corticosterone levels under both basal and stressed conditions. Learning and memory, anxiety-like behaviour and circadian output rhythms were also evaluated. Finally, mother-pup behaviour and maternal HPA axis were assessed to see if maternal care was changed by altered postnatal light. Both LL and DD rearing caused changes in the HPA axis of offspring with LL raised mice showing alterations in neuropeptide and glucocorticoid receptor expression in the brain. Postnatal DD resulted in a blunted corticosterone response to a stressor in females but had no effect in males. In terms of behaviour, LL raised mice had increased depressive-like behaviour. In contrast, postnatal light appears to have no effect on learning and memory or anxiety behaviour. When we looked at circadian output rhythms, we found that LL rearing appears to confer resilience to the rhythm disrupting effects of LL later on in life as seen by the maintenance of locomotor activity, body temperature and plasma corticosterone rhythms in LL. Maternal care and maternal stress systems appeared unaltered under the different postnatal light environments suggesting that the changes we see in the offspring are attributed to mechanisms other than alterations in maternal care.

Les glucocorticoïdes sont des substances très utilisées en thérapeutique, mais parfois détournées de leur utilisation première par les sportifs. Si l’effet ergogénique d’une prise de courte durée de glucocorticoïdes chez l’homme a été démontré, les répercussions de cette prise chez la femme et les mécanismes impliqués restent mal connus. Dans une première étude, nous nous sommes intéressés aux effets d’une prise de courte durée de prednisone (50 mg/j/7j) lors de la réalisation d’un exercice submaximal jusqu’à épuisement chez des volontaires sains de sexe féminin pratiquant une activité physique régulière. Nous avons mis en évidence une performance significativement améliorée sous glucocorticoïdes, avec des altérations métaboliques et hormonales vs. placebo comparables à celles mises en évidence chez le sujet de sexe masculin. Il apparaît donc qu’il n’existe pas d’effet « genre », à l’exception toutefois d’une absence d’insulino-résistance sous corticoïdes chez la femme. Dans une deuxième étude effectuée lors d’un exercice de plus longue durée, la prise de prednisone vs. placebo induit en fin d’exercice une augmentation des concentrations d’acides aminés branchés et de la glycémie, pouvant être interprétée comme une augmentation de la néoglycogénèse. Dans une troisième étude, nous avons mis en évidence qu’un traitement d’une semaine de prednisone per os ne semblait altérer l’axe hypothalamo-hypophysosurrénalien que de manière très transitoire, avec un retour à des concentrations basales de cortisol et de DHEA seulement 3 jours après la fin du traitement. Enfin, dans une étude préliminaire effectuée sur modèle animal, grâce au concours du Laboratoire de Neurobiologie, la prednisone semble augmenter la sérotonine et son métabolite chez les souris sédentaires au repos. / Glucocorticoids are widely used as therapeutic substances, but sometimes diverted from their primary use by athletes. The ergogenic effect of short-term glucocorticoid administration was previously demonstrated in men subjects but its effect in women as well as the mechanisms involved remain unknown. In a first study, we investigated the effects of short-term prednisone intake (50 mg/j/7j) during a submaximal exercise until exhaustion in healthy recreationally-trained women. Under glucocorticoid, performance was significantly improved, with comparable hormonal and metabolic alterations vs placebo as in male subjects. It appears therefore that there is no "gender" effect, except an absence of glucocorticoid- induced insulin resistance in women. In a second study realized during a more prolonged exercise, prednisone intake induced vs. placebo, an increase in branched amino acids and in blood glucose concentrations at the end of exercise, which can be interpreted as an increase in gluconeogenesis. In a third study, we have highlighted that 1-week per os prednisone treatment only suppressed hypothalamic-pituitary-adrenal axis in very transient manner, with a return of cortisol and DHEA concentrations to basal values 3 days after the end of treatment. Finally, in a preliminary study on animal model, thanks to the Neurobiology Laboratory, prednisone seemed to increase serotonin and its metabolite in resting sedentary mices.