Events around conception such as maternal undernutrition and twinning may have effects on offspring physiology and disease risk in adulthood. Periconceptional undernutrition alters offspring physiology and adult pathology without affecting birth size, while twinning affects birth size and physiology but with inconsistent effects on adult pathology. We investigated the effects of these two periconceptional events and their interaction on maternal cardiovascular adaptation to pregnancy and fetal growth, physiology and endocrinology in late gestation in sheep. Pre and/or postconception undernutrition resulted in increased uterine blood flow in late gestation, but no change in maternal blood volume. Preconception undernutrition alone resulted in a relatively large placenta with a small, slow-growing fetus in late gestation. In contrast, postconception undernutrition alone resulted in a fetus with rapid late-gestation growth that was maintained through a maternal fast. Fetuses of ewes undernourished throughout both periods were similar in growth rate and size to controls. Maternal fasting also demonstrated that plasma levels of C-type natriuretic peptide are acutely and independently regulated by nutrient supply in mother and fetus. Fetuses of ewes undernourished both pre- and postconception had increased glucose disposal following a glucose challenge. Hypothalamic-pituitary-adrenal axis tests in these fetuses showed decreased pituitary adrenocorticotropin hormone response to direct stimulation but increased adrenal response to decreased cortisol negative feedback. Twin fetuses grew more slowly in late gestation than singletons. Twins also had a smaller insulin response to arginine and a greater insulin response to glucose, but periconceptional undernutrition abolished this difference. Twins had suppressed baseline hypothalamic-pituitary-adrenal axis function and decreased adrenal sensitivity compared to singletons, but increased fetal pituitary adrenocorticotropin hormone response to direct stimulation and decreased cortisol negative feedback. These studies suggest that firstly, fetal size is a poor reflection of fetal growth trajectory, physiology and endocrinology. Secondly, pre- and postconception undernutrition affect late-gestation fetal growth in different ways, while undernutrition in both periods alters fetal endocrine status in late gestation. Thirdly, the biology of twin fetal development is fundamentally different from that of singletons, which may explain the inconsistency of the relationship between birth weight and adult disease risk in twins. / Auckland Medical Research Foundation, Health Research Council of New Zealand

Events around conception such as maternal undernutrition and twinning may have effects on offspring physiology and disease risk in adulthood. Periconceptional undernutrition alters offspring physiology and adult pathology without affecting birth size, while twinning affects birth size and physiology but with inconsistent effects on adult pathology. We investigated the effects of these two periconceptional events and their interaction on maternal cardiovascular adaptation to pregnancy and fetal growth, physiology and endocrinology in late gestation in sheep. Pre and/or postconception undernutrition resulted in increased uterine blood flow in late gestation, but no change in maternal blood volume. Preconception undernutrition alone resulted in a relatively large placenta with a small, slow-growing fetus in late gestation. In contrast, postconception undernutrition alone resulted in a fetus with rapid late-gestation growth that was maintained through a maternal fast. Fetuses of ewes undernourished throughout both periods were similar in growth rate and size to controls. Maternal fasting also demonstrated that plasma levels of C-type natriuretic peptide are acutely and independently regulated by nutrient supply in mother and fetus. Fetuses of ewes undernourished both pre- and postconception had increased glucose disposal following a glucose challenge. Hypothalamic-pituitary-adrenal axis tests in these fetuses showed decreased pituitary adrenocorticotropin hormone response to direct stimulation but increased adrenal response to decreased cortisol negative feedback. Twin fetuses grew more slowly in late gestation than singletons. Twins also had a smaller insulin response to arginine and a greater insulin response to glucose, but periconceptional undernutrition abolished this difference. Twins had suppressed baseline hypothalamic-pituitary-adrenal axis function and decreased adrenal sensitivity compared to singletons, but increased fetal pituitary adrenocorticotropin hormone response to direct stimulation and decreased cortisol negative feedback. These studies suggest that firstly, fetal size is a poor reflection of fetal growth trajectory, physiology and endocrinology. Secondly, pre- and postconception undernutrition affect late-gestation fetal growth in different ways, while undernutrition in both periods alters fetal endocrine status in late gestation. Thirdly, the biology of twin fetal development is fundamentally different from that of singletons, which may explain the inconsistency of the relationship between birth weight and adult disease risk in twins. / Auckland Medical Research Foundation, Health Research Council of New Zealand

Ο άξονας Υποθάλαμος – Υπόφυση – Επινεφρίδια και το συμπαθητικό νευρικό σύστημα είναι τα περιφερικά σκέλη του συστήματος απάντησης στο στρες, με στόχο τη διατήρηση της ομοιόστασης του οργανισμού. Ανεπάρκεια ανταπόκρισης των επινεφριδίων στη σοβαρή νόσο μπορεί να παρουσιαστεί χωρίς προφανή βλάβη στον άξονα ΥΥΕ. Σε πολλούς ασθενείς με σοβαρή νόσο, τα επίπεδα κορτιζόλης παρά το ότι είναι αυξημένα, δεν είναι αρκετά ώστε να εκδηλώσουν επαρκή επινεφριδιακή απάντηση σε σχέση με τη σοβαρότητα της νόσου. Η βέλτιστη απάντηση του άξονα ΥΥΕ σε καταστάσεις νόσου παραμένει υπό αμφισβήτηση. Η διάγνωση της πιθανής σχετικής με τη νόσο παροδικής επινεφριδιακής ανεπάρκειας και η ανάγκη για χορήγηση κορτικοστεροειδών είναι ακόμη υπό συζήτηση. Σκοπός της μελέτης αυτής είναι η εκτίμηση της επινεφριδιακής απάντησης ανάλογα με τη σοβαρότητα της νόσου στην οξεία φάση της νόσου και η μελέτη του άξονα ΥΥΕ τόσο στην οξεία φάση, όσο και στην ανάρρωση. Για το σκοπό αυτό μελετήθηκαν 56 νοσηλευόμενοι ασθενείς με διαφορετικής βαρύτητας νόσημα (ΑΕΕ, ήπια νόσο, σήψη και σοβαρή σήψη), καθώς και 15 υγιή άτομα – μάρτυρες. Σε όλους τους συμμετέχοντες, κατά την εισαγωγή τους (1η ημέρα), μετρήθηκε η κορτιζόλη και η ACTH. Κατόπιν εφαρμόστηκε η δοκιμασία με χαμηλή δόση (1μg) κορτικοτροπίνης και δύο ώρες αργότερα η δοκιμασία με τη συνήθη δόση (250μg) κορτικοτροπίνης. Τη δεύτερη ημέρα νοσηλείας στους ασθενείς μετρήθηκε η ημερήσια διακύμανση της κορτιζόλης. Κατά την 5η -6η ημέρα νοσηλείας (φάση ανάρρωσης) έγινε επανάληψη των δοκιμασιών σε 15 ασθενείς (7 με σήψη και 8 με σοβαρή σήψη). Από την επεξεργασία των αποτελεσμάτων, στην ομάδα των ΑΕΕ και της σοβαρής σήψης παρατηρούνται οι υψηλότερες τιμές κορτιζόλης, καθώς επίσης και εξάλειψη της ημερήσιας διακύμανσης της κορτιζόλης. Παράλληλα, σε όλους τους ασθενείς παρατηρείται διαχωρισμός των επιπέδων κορτιζόλης και ACTH. Η αύξηση της κορτιζόλης (Δmax κορτιζόλης) μετά από διέγερση με 1 μg κορτικοτροπίνης δεν διέφερε μεταξύ των ομάδων νόσου, ενώ η Δmax κορτιζόλης μετά από διέγερση με 250μg κορτικοτροπίνης παρουσίασε οριακά σημαντική διαφορά με μια τάση να είναι υψηλότερη στην ομάδα των υγιών μαρτύρων. Η συχνότητα της απάντησης ή μη στη συνήθη δοκιμασία με βάση το κριτήριο Δmax κορτιζόλης <9 δεν διέφερε μεταξύ των υγιών και των ομάδων ασθενών, ενώ όλοι οι ασθενείς επιβίωσαν χωρίς τη χορήγηση κορτικοειδών, ανεξάρτητα από την απάντηση ή μη στις δοκιμασίες με ACTH. Στους ασθενείς με σήψη, η Δmax κορτιζόλης μετά από διέγερση με 250 μg κορτικοτροπίνης ήταν υψηλότερη στη φάση ανάρρωσης σε σχέση με την οξεία φάση, ενώ στους ασθενείς με σοβαρή σήψη η αντίστοιχη διαφορά δεν ανεδείχθη σε σημαντικό βαθμό. Η βασική κορτιζόλη ήταν υψηλότερη στην οξεία φάση σε σχέση με τη φάση ανάρρωσης και στις δύο ομάδες νόσου. Συμπερασματικά, διαπιστώνονται ήπιες αλλαγές στον άξονα ΥΥΕ, ανάλογα με τη σοβαρότητα του νοσήματος. Παρόλα αυτά, δεν επιβεβαιώνεται η ύπαρξη σχετικής επινεφριδιακής ανεπάρκειας σε μη βαριά νοσούντες ασθενείς. / Relative corticosteroid insufficiency maybe is common in critically ill patients, associated with poor outcome; however it is not known the response of the hypothalamic-pituitary-adrenal (HPA) axis in nursed patients. Our aim was to evaluate the response of HPA axis in non-critically ill nursed (NCIN) patients. Fifty -six nursed patients, divided into four groups (stroke, mild disease, sepsis and severe sepsis) as well as a control group (n=15) were studied. At admission (day 1), cortisol and ACTH measured and a low - dose (1mug ) corticotropin test was performed, followed two hours later by a standard-dose (250 mug). Diurnal variation of cortisol was obtained on day 2. A second identical set of low and standard set of corticotropin tests were performed on day 5 or 6 (recovery phase). In patients with stroke and severe sepsis cortisol had the highest values and its diurnal variation was abolished. Dissociation of ACTH and cortisol was found in all patients. The Deltamax of cortisol after the 1 mug corticotropin test did not differ among the groups while after the 250 mug corticotropin test was borderline higher in controls. The ratio of responders (Deltamax of cortisol >/= 9 mug/dL) to non-responders after 1 mug or 250 mug corticotrophin tests did not differ among patients and controls. All patients had a good outcome without glucocorticoid treatment. In conclusion, mild alterations of the HPA axis, depending on the severity of illness occurred. However, relative corticosteroid insufficiency in non-critically ill nursed patients did not confirm.

Endocrine and Metabolic Aspects of Various Sleep Disorders MUDr. Zuzana Vimmerová Lattová Abstract: Recent epidemiological and experimental data suggest a negative influence of shortened or disturbed night sleep on glucose tolerance. However, no comparative studies of glucose metabolism have been conducted in clinical sleep disorders. Dysfunction of the HPA axis may play a causative role in some sleep disorders and in other sleep disorders it may be secondary to the sleep disorder. Moreover, dysfunction of the HPA axis is regarded as a possible causative factor for the impaired glucose sensitivity associated with disturbed sleep. However, data on HPA system activity in sleep disorders are sparse and conflicting. We studied 25 obstructive sleep apnea (OSA) patients, 18 restless legs syndrome (RLS) patients, 21 patients with primary insomnia and compared them to 33 healthy controls. We performed oral glucose tolerance test and assessed additional parameters of glucose metabolism. The dynamic response of the HPA system was assessed by the DEX-CRH-test which combines suppression (dexamethasone) and stimulation (CRH) of the stress hormone system. Compared to controls, increased rates of impaired glucose tolerance were found in OSA (OR: 4.9) and RLS (OR: 4.7), but not in primary insomnia. In addition, HbA1c...

Serotonin gilt als Hauptangriffsstelle gängiger Antidepressiva bei schweren Depressionen, wie bspw. selektive Serotonin-Wiederaufnahmehemmer (SSRI), und -Enhancer (SSRE). Es bleibt offen, ob SSRI / E ausschließlich über die Manipulation des Serotoninspiegels wirken, oder ob alternative Signalwege daran beteiligt sind. Ansatzpunkte hierfür sind beispielsweise die neurotrophen Signalwege (spez. Brain derived neurotophic factor, BDNF) oder die Hypothalamus-Hypophysen-Nebennieren- (HPA) – Signalwege des Stressachsensystems. Ebenfalls wurde in Nagetiermodellen beobachtet, dass mit der Dysregulation des zentralen Serotoninsystems bei schweren Depressionen, ein Rückgang der Neurogenese im Gyrus dentatus des Hippocampus einhergeht. Ziel dieser Arbeit war, das Zusammenspiel von Serotonin, BDNF, adulter Neurogenese und der Stressachse zu untersuchen. Zentrum der Studien ist ein Mausmodell, mit einer genetischen Depletion des zentralen Serotonin-synthetisierenden Enzyms Tryptophanhydroxylase 2 (sog. Tph2-/- Mäuse). Es wurden die physiologische Reaktionen auf die Behandlung mit gängigen Antidepressiva abhängig von der Abwesenheit von Serotonin untersucht, um mögliche alternative Signalwege aufzeigen zu können. Die bekannte Zunahme der Neurogenese nach SSRI/SSRE-Behandlung wurde in Wildtyptieren beobachtet, während die Therapie in Tph2-/- Mäusen keine direkte kausale Wirkung zeigte. Im Gegensatz dazu waren die BDNF-Spiegel in depressionsrelevanten Hirnregionen in Tph2-/- Mäusen nach SSRI, signifikant verringert. Auch zeigen die Studien eine neurobiologische Relevanz von Serotonin im ZNS, bei den antidepressiven Mechanismen einer Elektrokonvulsiven Krampftherapie. Ebenfalls deuten erhöhte Neurogeneseraten bei lebenslanger Abwesenheit von Serotonin im ZNS, Therapiemethoden-unabhängig, möglicherweise auf eine modulierte Stressreaktion hin. Untersuchungen der Parameter des HPA-Stressachsensystems, wiesen auf einen grundlegend veränderten Stresshormonspiegel in Tph2-/- Mäusen hin. / Serotonin, the "molecule of happiness" is an important target for antidepressants. The mainly prescribed drugs in major depression are selective serotonin re-uptake inhibitors (SSRI); but recently, SSR-enhancer (SSRE) have also attracted clinical attention. However, only a quarter of patients responds to treatment. It needs to be determined, whether SSRI/E act solely via manipulating serotonin levels or whether other pathways are involved, e.g. neurotrophic signaling (brain-derived neurotrophic factor, BDNF) or the hypothalamus-pituitary-adrenal (HPA)-axis. Furthermore, in major depression, dysregulation of central serotonin signaling is accompanied with a decline in hippocampal neurogenesis, as has been observed in rodent models. At the center of this thesis is a mouse model deficient in the central serotonin-synthesizing enzyme, tryptophan hydroxylase 2 (Tph2-/- mice). I have investigated physiological responses to antidepressant treatment in the absence of brain serotonin, and the possible role of alternative pathways. I observed the typical increase in neurogenesis upon SSRI treatment in WT mice, while it had no effect in Tph2-/- mice. In contrast, BDNF levels were significantly decreased in Tph2-/- mice after treatment with no effect in WT control mice. Furthermore, my results show a critical role of brain serotonin in the neurobiological effects of electroconvulsive seizure. Surprisingly, in animals lacking central serotonin, increased neurogenesis was observed independently of the treatment. The gathered data indicated an altered stress response; therefore, parameters of the HPA-axis have been studied, indicating a downregulated HPA system in Tph2-/-animals in baseline state, but showed no difference in treatment or feedback control. This thesis gives insight into the mechanisms of antidepressant action and reveals ideas for novel pathways involved in the process that could be used as targets in therapeutic approaches and further research in major depression.

Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF-/- littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF-/- mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women.