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

Prenatal ethanol (E) exposure has marked effects on development of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. E rats show HPA hyperresponsiveness to stressors and altered reproductive function in adulthood. Importantly, prenatal ethanol differentially alters stress responsiveness in adult males and females, raising the possibility that gonadal hormones play a role in mediating ethanol effects on HPA function. To address this possibility, two studies were conducted to test the hypothesis that the differential alterations in HPA activity observed in E compared to control males are mediated, at least in part, by ethanol-induced changes in HPG effects on HPA regulation. The first study compared the effects of gonadectomy (GDX) on HPA and HPG activity in adult male offspring from prenatal E, pair-fed (PF) and ad libitum-fed control (C) dams. There were no differences among groups in basal testosterone levels under intact conditions. However, E males showed increased adrenocorticotropin but blunted testosterone and luteinizing hormone (LH) responses to restraint stress compared to PF and/or C rats, and no stress-induced elevation in arginine vasopressin (AVP) mRNA levels. GDX eliminated these differences among groups. The second study explored dose-related effects of testosterone on HPA regulation. Testosterone had less of an inhibitory effect on stress-induced CORT and LH increases in E than in PF and C males. Furthermore, testosterone had a reduced effect on central corticotropin-releasing hormone pathways, but an increased effect on central AVP pathways in E compared to PF and/or C males. Importantly, reduced androgen receptor (AR) mRNA levels, possibly reflecting downregulation of AR in key brain areas, may counteract the increased inhibitory AVP signals upstream from the paraventricular nucleus, and thus contribute to the HPA hyperresponsiveness seen in E males. Together these findings suggest that central regulation of both the HPA and HPG axes are altered by prenatal ethanol exposure. The capacity of testosterone to regulate HPA activity is altered in E males, with some effects mediated by the nutritional effects of ethanol. These changes would impair the ability to maintain homeostasis in E animals and have implications for the development of secondary disabilities in children with Fetal Alcohol Spectrum Disorder. / Medicine, Faculty of / Graduate

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.

A 69-year-old man was referred for elevated thyroid hormone levels. He had no symptoms apart from mild hyperhidrosis and heat intolerance with occasional headaches. Past medical history included a right hemithyroidectomy for a multinodular goiter and Hashimoto's disease. At presentation the patient had a firm, slightly enlarged left thyroid lobe. There were no visual abnormalities, and the rest of the physical findings were unremarkable. Laboratory findings included elevated values of free T4, free T3, total T 3, thyrotropin-secreting hormone (TSH), antithyroglobulin, and antimicrosomal antibodies. Normal values were found for cortisol, prolactin, testosterone, follicle-stimulating hormone, luteinizing hormone, a-subunit, and thyroid-stimulating immunoglobulin. Thyroid 123I scan showed an increased 5-hour uptake of 23% and a 24-hour uptake of 53% with a diffuse uniform enlargement of the left side. TSH level did not increase after a thyrotropin-releasing hormone stimulation test. Serum sex hormone binding globulin was elevated. Magnetic resonance imaging of the pituitary revealed a pituitary macroadenoma with suprasellar extension to the optic chiasm. Histologic examination of the adenoma after transsphenoidal hypophysectomy showed cells that stained positive for TSH. TSH-secreting pituitary adenomas account for 1% of functioning pituitary tumors and are an exceedingly rare cause of hyperthyroidism. To our knowledge, this is the first report of pituitary tumor inducing hyperthyroidism in the setting of Hashimoto's disease. There is a possibility that TSH elevation related to Hashimoto's disease might have contributed to the development of a TSH-secreting pituitary adenoma.

Indiana University-Purdue University Indianapolis (IUPUI) / LHX3 is a LIM-homeodomain transcription factor that has essential roles in pituitary and nervous system development in mammals. Children who are homozygous for recessive mutations in the LHX3 gene present with combined pituitary hormone deficiency disease (CPHD) characterized by deficits of multiple anterior pituitary hormones. Most LHX3 patients also present with additional defects associated with the nervous system including a characteristic limited head rotation and sometimes deafness. However, of the 10 types of LHX3 mutation described to date, one mutation type (W224ter) does not result in the limited head rotation, defining a new form of the disease. W224ter patients have CPHD but do not have nervous system symptoms. Whereas other mutations in LHX3 cause loss of the entire protein or its activity, the W224ter mutation causes specific loss of the carboxyl terminal of the LHX3 protein—a region that we have shown to contain critical regulatory domains for pituitary gene activation. To better understand the molecular and cellular etiology of CPHD associated with LHX3 gene mutations, I have generated knock-in mice that model the human LHX3 W224ter disease. The resulting mice display marked dwarfism, thyroid disease, female infertility, and reduced male fertility. Immunohistochemistry, real-time quantitative polymerase chain reaction (PCR), and enzyme-linked immunosorbant assays (ELISA) were used to measure hormones and regulatory factor protein and RNA levels, an approach which is not feasible with human patients. We have generated a novel mouse model of human pediatric CPHD. Our findings are consistent with the hypothesis that the actions of the LHX3 factor are molecularly separable in the nervous system and pituitary gland.

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Die Entwicklung der Hypophyse ist ein komplexer Prozess, an dem viele Transkriptionsfaktoren beteiligt sind. Bedeutende Funktionen haben die Bone Morphogenetic Proteins 2, 4 und 7. Ziel der Arbeit war es, an Patienten mit angeborener kombinierter Hypophyseninsuffizienz diese 3 Gene auf Mutationen zu untersuchen. Dabei wurden die Exons, Exon-Intron-Übergänge sowie die 3`- und 5`-untranslatierten Regionen sequenziert. Neu identifizierte Varianten wurden anschließend in einer gesunden Kontrollkohorte untersucht, um pathogenetisch nicht relevante Genvarianten auszuschließen. Um die funktionelle Relevanz der Varianten beurteilen zu können, wurden phylogenetische Analysen und Untersuchungen mittels Programmen zum Einfluss auf die Proteinstruktur und -funktion durchgeführt. Neben bekannten Varianten, konnten wir neue Varianten mit und ohne Aminosäureaustausch identifizieren. Eine neue Mutation im kodierenden Bereich von BMP4 erschien dabei besonders relevant. Wir konnten sie nur bei einem Patienten nachweisen, der zusätzlich zur kombinierten Hypophyseninsuffizienz Skelettveränderungen aufwies. Die hohe Konservierung und diese spezifische Klinik legen eine funktionelle Relevanz nahe.

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