Development neurobiology of the stress response: multilevel regulation of corticotropin-releasing hormone function.

The ability to respond to adverse environmental cues is present in the neonatal and infant rat, although in an immature form: A number of laboratories have demonstrated stress-induced elevations of plasma glucocorticoids during the first two postnatal weeks. The limbic and hypothalamic mechanisms controlling the hormonal stress-response during this period are not fully understood and are, therefore, the focus of this report. Both hypothalamic corticotropin-releasing hormone (CRH) and vasopressin contribute to the release of ACTH from the pituitary in the adult. The relative roles of these two peptides during the neonatal (first week) and infant (second week) developmental period, are controversial. Evidence is presented that argues strongly for a major role for CRH. Up-regulation of hypothalamic CRH synthesis is a major component in the mature stress response. CRH-mRNA levels in the hypothalamic PVN are increased with cold stress by ninth postnatal day, but not during the first postnatal week. Further, down-regulation of CRH gene expression by glucocorticoids (GC) constitutes a critical "shut-down" mechanism for the hormonal stress response. In vivo and in vitro experiments supporting the "immaturity" of GC feedback on CRH synthesis during the first postnatal week are described. CRH-mediated neurotransmission, in both the endocrine and neuronal effector arms of the response to stress may be modulated via alteration of receptor number. The first member of the CRH receptor family, CRF1, probably mediates the neuroendocrine effects of CRH. The developmental profile of CRF1-mRNA reveals several distinctive spatial and temporal patterns. In the hippocampal CA1, CA2, and CA3a peak (300-600% adult values) CRF1-mRNA is found on postnatal day 6. In the amygdala, CRH receptor mRNA levels are maximal on the ninth postnatal day (at 180% of adult values). In cortex, a steady decline from high postnatal day 2 levels results in adult levels by 12. These findings demonstrate distinct, regional, age-specific control of the synthesis of CRF1. Receptor expression profile may provide important information regarding modulation of the age-specific roles of CRH in different regions. For example, a high ratio of hippocampus/amygdala receptors may preferentially activate negative hippocampal input to the hypothalamus during the neonatal period. Additionally, increased CRH receptor mRNA in the infant compared with the adult provides a mechanism for enhanced excitatory effect of the peptide at this age. In conclusion, increasing evidence exists for multiple control points of the early postnatal response and adaptation to stress. CRH synthesis in hypothalamus and amygdala, its sensitivity to GC feedback, and the abundance and distribution of at least two distinct CRH receptors in the limbic central nervous system and the pituitary are developmentally regulated. All serve as control points permitting an effective endocrine, autonomic, and behavioral response to stressful environmental cues

BVT.2733, a Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, Attenuates Obesity and Inflammation in Diet-Induced Obese Mice

BACKGROUND: Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is being pursued as a new therapeutic approach for the treatment of obesity and metabolic syndrome. Therefore, there is an urgent need to determine the effect of 11β-HSD1 inhibitor, which suppresses glucocorticoid action, on adipose tissue inflammation. The purpose of the present study was to examine the effect of BVT.2733, a selective 11β-HSD1 inhibitor, on expression of pro-inflammatory mediators and macrophage infiltration in adipose tissue in C57BL/6J mice. METHODOLOGY/PRINCIPAL FINDINGS: C57BL/6J mice were fed with a normal chow diet (NC) or high fat diet (HFD). HFD treated mice were then administrated with BVT.2733 (HFD+BVT) or vehicle (HFD) for four weeks. Mice receiving BVT.2733 treatment exhibited decreased body weight and enhanced glucose tolerance and insulin sensitivity compared to control mice. BVT.2733 also down-regulated the expression of inflammation-related genes including monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α) and the number of infiltrated macrophages within the adipose tissue in vivo. Pharmacological inhibition of 11β-HSD1 and RNA interference against 11β-HSD1 reduced the mRNA levels of MCP-1 and interleukin-6 (IL-6) in cultured J774A.1 macrophages and 3T3-L1 preadipocyte in vitro. CONCLUSIONS/SIGNIFICANCE: These results suggest that BVT.2733 treatment could not only decrease body weight and improve metabolic homeostasis, but also suppress the inflammation of adipose tissue in diet-induced obese mice. 11β-HSD1 may be a very promising therapeutic target for obesity and associated disease

Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity

Local glucocorticoid (GC) action depends on intracellular GC metabolism by 11β-hydroxysteroid dehydrogenases (11βHSDs). 11βHSD1 activates GCs, while 11βHSD2 inactivates GCs. Adipocyte-specific amplification of GCs through transgenic overexpression of 11βHSD1 produces visceral obesity and the metabolic syndrome in mice. To determine whether adipocyte-specific inactivation of GCs protects against this phenotype, we created a transgenic model in which human 11βHSD2 is expressed under the control of the murine adipocyte fatty acid binding protein (aP2) promoter (aP2-h11βHSD2). Transgenic mice have increased 11βHSD2 expression and activity exclusively in adipose tissue, with the highest levels in subcutaneous adipose tissue, while systemic indexes of GC exposure are unchanged. Transgenic mice resist weight gain on high-fat diet due to reduced fat mass accumulation. This improved energy balance is associated with decreased food intake, increased energy expenditure, and improved glucose tolerance and insulin sensitivity. Adipose tissue gene expression in transgenic mice is characterized by decreased expression of leptin and resistin and increased expression of adiponectin, peroxisome proliferator–activated receptor γ, and uncoupling protein 2. These data suggest that reduction of active GCs exclusively in adipose tissue is an important determinant of a favorable metabolic phenotype with respect to energy homeostasis and the metabolic syndrome

Insémination intra-utérine avec sperme de conjoint (facteurs pronostiques)

OBJECTIF: Identifier les facteurs pronostiques de grossesse après IIU-AC. DESIGN: Etude rétrospective. LIEU: CPMA, Centre Hospitalo-Universitaire de la Conception, Marseille. PATIENTS: 2019 cycles d'IIU-AC chez 851 couples. METHODES: Après stimulation ovarienne contrôlée, l'IIU-AC a été réalisée 36 heures après déclenchement de l'ovulation ou 24 heures après un pic spontanée de LH. PRINCIPAUX CRITERES D'EVALUATION: Taux de grossesse par cycle (TG) et taux d'accouchement par cycle (TA). RESULTATS: Le TG global était de 14,8% et le TA de 10,8%. Des TG et TA plus élevées ont été observées chez les patients présentant des troubles de l'ovulation, en particulier SOPK, ou en cas d'infertilité masculine. Les facteurs de bons pronostic mis en évidence sont l'infertilité secondaire de la patiente, le taux basal de FSH =2), l'épaisseur de l'endomètre (10-11 mm), et le nombre de spermatozoïdes mobiles progressifs inséminés (> 1 million). CONCLUSION: Les tentatives d'IIU-AC peuvent être proposées aux patientes dont l'âge est 7UI/L, nombre de spermatozoïdes progressifs mobiles inséminées < 1 million), la FIV devra être envisagée comme traitement de première intentionAIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

La congélation des embryons obtenus par fécondation in vitro (bilan de six années au CHU de Marseille)

Nous avons analysé rétrospectivement 6 années de congélation embryonnaire au CHU de Marseille afin de rechercher les facteurs prédictifs de l'obtention d'une grossesse clinique (GC) lors d'un transfert d'embryons congelés (TEC). 12,5% des tentatives de Fécondation In Vitro (n=403) aboutissent à une congélation. Le nombre moyen d'embryon congelé est de 2,9. 254 cycles de décongélation aboutissant à 223 TEC ont été étudiés. Le taux de GC/TEC est de 25,1% pour un nombre moyen d'embryons transférés de 1,8. Les facteurs prédictifs de l'obtention d'une GC sont : le jeune âge des patientes (<30 ans) lors de la congélation et de la décongélation, une infertilité d'origine masculine, des embryons congelés de type I ou II et une absence de perte de blastomère lors de la décongélation. Le taux de GC par ponction passe de 44,6% quand une congélation est effectuée à 61% grâce aux TEC.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF