ACTA ENDOCRINOLOGICA (BUC)

Context. Epidemiological data have shown that obesity increases the risk of developing colorectal cancer and also an increased body mass index (BMI) is associated with a worse prognosis. Bevacizumab based systemic therapy, an antiVEGF targeted therapy, is an important treatment option for metastatic colorectal cancer (mCRC) patients. Obesity is associated with high level of vascular endothelial growth factor (VEGF), that might provoke resistance to antiVEGF monoclonal antibody. Objective. To evaluate the efficacy in terms of progression free survival (PFS) and overall survival (OS) of bevacizumab systemic therapy in patients with mCRC. Design. Retrospective cohort, single center study. Subjects and Methods. Between January 2007 and December 2012, 112 patients with mCRC, who followed bevacizumab based systemic therapy in the “Ion Chiricuta” Oncology Institute in Cluj-Napoca, were included in our analysis. Results. Values of BMI ≥ or <27 kg/sqm was found that PFS is statistically significant superior in patients with BMI<27 kg/sqm (n=77) than in those with BMI ≥ 27 kg/sqm (n=35), 24 months versus 17.9 months (p = 0.04). Five years OS was not influenced by the BMI, 35% vs 30% (p=0.29). In patients with liver metastases with values of BMI ≥ 27 kg/ sqm have PFS lower than patients with a BMI <27 kg/sqm, 17.5 months versus 24.5 months (p = 0.02). Five years OS was not influenced by the BMI, 39% (BMI <27 kg/sqm) vs. 22% (BMI ≥ 27 kg/sqm) (p = 0.09). Conclusions. This study demonstrated the negative influence of BMI on both PFS on the entire sample of patients and in patients with liver metastases only, BMI cutoff value proved to be 27 kg/square meter and shows that the BMI may be an important prognostic factor with a high clinical relevance in patients with mCRC.

Introduction. Bone formation takes place through a continuous remodeling process, which involves the resorption of old bone by osteoclasts and the formation of new bone tissue by osteoblasts, melatonin contributing to the hormonal modulation of the action of osteoblasts and osteoclasts. Aim. The aim of this study is to evidence the influence of melatonin administered in combination with estrogen on bone turnover markers in female Wistar rats with bilateral surgical ovariectomy. Material and method. The study was performed on 40 female Wistar rats with a weight of 160-200 g, which underwent bilateral surgical ovariectomy. At 14 days postovariectomy, hormone replacement therapy (estradiol benzoate – E2b – 10 μg/day) and combined estrogen (estradiol benzoate – E2b – 10 μg/day) and melatonin (added to the drinking water in a concentration of 25 μg/mL or 50 μg/mL – ethanol concentration 0.01%) – treatment were initiated over a period of 12 consecutive weeks. Subsequently, venous blood was collected for the determination of serum osteocalcin and C-terminal telopeptide of collagen type I levels. Results. Melatonin administered in combination with estrogen to ovariectomized female rats induces an increase in serum osteoalcin levels (statistically significant differences between all four groups p=0.001) and a decrease in serum C-terminal telopeptide of collagen type I levels (statistically significant differences between group I and the other three groups p=0.005; p=0.001; p=0.001 and between group II and group IV p=0.007). The influence on bone formation and resorption markers depends on the administered melatonin dose and on the post-ovariectomy estradiol level. Conclusions. Melatonin potentiates the effects of estradiol on bone in ovariectomized rats.

Background. Diabetes mellitus and new left bundle branch block (LBBB) increase the risk of adverse cardiac outcomes and are considered a coronary artery disease equivalent. Objective. The aim of our study was to determine whether the presence of new or presumably new left bundle branch block could be the first manifestation of coronary artery disease in diabetic patients. Design. We performed a crosssectional analysis which included 273 patients with new LBBB admitted between January 2011 and June 2013 in the Cardiovascular Diseases Institute Iasi. The median follow-up was 7 days (hospitalization period). Patients were divided into two groups according to their glycemic status: diabetic and non-diabetic patients. Results. Our study demonstrates that the presence of new LBBB in diabetic patients is unequivocally associated and could be the first manifestation of an extensive coronary artery disease. Diabetic patients had either one, two or three coronary artery diseases (48.09%) and were more likely to have a decreased ejection fraction (EF) < 50% (p <0.001), almost half of them having an EF <30 %. Conclusions. The association of diabetes mellitus with new LBBB is a high probability criterion for the diagnosis of coronary artery disease, even in asymptomatic patients.

Background. Prior studies examining cyclic mastalgia and sex hormones have failed to\r\nreveal any specific endocrine cause and their results of them are inconsistent.\r\nAim. To evaluate luteal hormonal levels in women with marked premenstrual mastalgia\r\nin response to toremifene.\r\nMethods. In a double-blind crossover randomization procedure after one baseline cycle,\r\n32 women were randomized to receive 20 mg toremifene, and 30 women placebo from cycle\r\nday 15 until the next menstruation for three menstrual cycles. After a wash-out cycle the women\r\nwere crossed over to receive placebo and toremifene, respectively. The luteal hormonal levels\r\nwere measured at baseline, and during the third cycle of toremifene and placebo. The study was\r\nsetup in a general practice population from two Finnish hospital districts. Serum FSH, estradiol,\r\nprogesterone, prolactin, androstenedione, total and free testosterone were measured.\r\nResults. When all the toremifene-treated cycles were compared with all the placebo\r\ncycles and with the baseline, the median estradiol levels were 0.36, 0.27 and 0.31 nmol/L,\r\nrespectively (baseline versus toremifene, P=0.005; baseline versus placebo P=0.095; and\r\ntoremifene versus placebo P<0.001). The median progesterone levels were at baseline 32.5\r\nnmol/L, during placebo 34.5 nmol/L and during toremifene 42.5 nmol/L (baseline versus\r\ntoremifene P=0.002; baseline versus placebo P=0.802; and toremifene versus placebo\r\nP=0.002). The median prolactin level was significantly higher during the toremifene cycles\r\n(268 mU/L) as compared to the baseline (222 mU/L, P=0.046). There were no significant\r\nchanges in other hormone concentrations evaluated.\r\nConclusion. Toremifene seems to have a luteotropic effect in women suffering from\r\npremenstrual mastalgia.

The stress response is mediated by the hypothalamo-pituitary-adrenal (HPA) system.\r\nActivity of the hypothalamic paraventricular nucleus (PVN) forms the basis of the HPAaxis.\r\nBehavioral and endocrine responsivity to threat and their ontogenetic changes may be\r\nmediated by PVN.\r\nMethods. 6-hydroxydopamine (6-OHDA) remains the most widely used substance in\r\nanimal models for inducing highly reproducible brain lesions. In our study, parvocellular neurons\r\nfrom the PVN of male Wistar rats were chemical lesioned by right-unilateral stereotaxic injection\r\nof two different doses of 6-OHDA (8&#956;g/3&#956;l and 16&#956;g/3&#956;l) and were subjected to a battery of\r\nbehavioral tests designed to assess spatial memory formation (radial arm-maze task) and anxiety\r\n(elevated plus maze). Further, we were interested in knowing whether a 6-OHDA lesion of the\r\nPVN would result in an imbalance in neuronal oxidative stress levels.\r\nResults. 6-OHDA-induced PVN lesions significantly increased the number of\r\nworking memory errors, suggesting effects on short-term memory, without affecting longterm\r\nmemory, explored by number of reference memory errors in radial arm-maze task. In\r\nelevated plus maze measuring anxiety, 6-OHDA significantly diminished anxiety-like\r\nbehavior in a dose-dependent manner. In addition, the neurotoxin induced a reduction in\r\nsuperoxide dismutase (SOD) and glutathione peroxidase (GPX) specific activities, while\r\nmalondialdehyde (MDA) level was found increased in the temporal lobe of rat brain, the\r\nmost vulnerable cortical area to oxidative stress effects.\r\nConclusion. Results suggest that 6-OHDA lesion of the PVN affects behavioral\r\nperformance via interactions with systems governing arousal level and possibly by\r\nincreasing neuronal oxidative stress.

Context. Polycystic ovary syndrome (PCOS) is associated with increased prevalence of preeclampsia (PE); microRNAs (miRs) could play an important role in the pathogenesis of PE and PCOS. Objective. To investigate the expression levels of miRs 155-5p and 518b in blood leukocytes of patients with PE and PCOS. Design. Using real-time quantitative PCR method, miR-155-5p and miR-518b were examined from PE, PCOS, PE+PCOS, and controls. Subjects and Methods. The relative expression of the target miRs in patient samples was compared to control samples. The results were calculated as relative quantification values. Results. Confounding variables were controlled using analyses for covariance. Significant differences were observed in miR-155-5p (p=0.008) and miRNA-518 (p=0.016) expression levels among the groups. miR-155- 5p (p=0.014) and miR-518b (p=0.036) were upregulated in PCOS patients and miR-518b (p=0.028) were increased in cases with PCOS+PE. Near significant difference was found (p=0.06) in miR-518b expression levels in cases with PE, compared to controls. miR-518b was observed to be positively correlated with alanine transaminase in cases with PE (r=0.80; P=0.017) and PE+PCOS (r=0.80, p=0.017). Conclusions. Our preliminary findings suggested that expression profiling of miR-155-5p and miR-518b in blood leukocytes were upregulated in pregnant women with PCOS. Moreover, miR-518b was found to be related to PE in cases with PCOS

Context. The grey mullet, Mugil cephalus, is an edible fish of high economic importance. Breeding biology with reference to hormonal/growth factor regulation of oocyte maturation needs to be known for its commercial production. Objective. The present study was conducted to examine the potency of maturation inducing hormones, chorionic gonadotropin (hCG), bovine-insulin, and insulin like growth factor1 (h-IGF-1) I on ovarian steroidogenesis and oocyte maturation. Design. The role of hormones and growth factors on steroidogenesis and oocyte maturation was investigated using specific inhibitors, Wortmannin for phosphatidylinositol-3 (PI3) kinase, trilostane for 3β-hydroxysteroid dehydrogenase, 1-octanol and 1-heptanol for gap junctions, actinomycin D for transcription and cycloheximide for translation of signal molecules. Methods. Actions of hormonal and growth factors were examined for steroidogenesis, by radioimmunoassay and oocyte maturation by germinal vesicle breakdown (GVBD). Specific inhibitors were used to determine the cell signaling pathways, PI3 kinase. Results. All the inhibitors attenuated the hCGinduced oocyte maturation (GVBD%), steroidogenesis including transcription, translation, gap junctions and PI3 kinase signaling. These inhibitors failed to inhibit h-IGF-I and b-insulin-induced oocyte maturation, steroidogenesis, translation and PI3 kinase signaling. Conclusion. hCG induces oocyte maturation via steroid dependent pathway involving gap junctions, transcription, translation and PI3 kinase signaling, unlike h-IGF-I and b-insulin in the mullet.

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Context. Obesity is a complex and heterogeneous disorder with multiple phenotypes described. Although metabolomic biomarkers of obesity have been extensively studied, biomarkers of obesity phenotypes and differences between these phenotypes and normal-weight (NW) persons have been less investigated. Objective. The objective of this cross-sectional analysis was to investigate serum amino acids (AA) as markers of metabolic alterations in obesity phenotypes and NW. Design. Cross-sectional Subjects and Methods. By targeted metabolomics we analyzed serum samples of 70 women using ultrahighperformance liquid chromatography/mass spectrometry. Participants were divided into 3 groups: NW, metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO). Results. Five AAs were significantly different between study groups: cysteine, methionine, asparagine, glutamine, and lysine (p-value <0.05 and variable importance in the projection >1). Cysteine increased linearly with metabolic unwellness from NW to MUHO. Lysine and glutamine were significantly higher, and asparagine was significantly lower in NW and MHO than in MUHO. Conclusions. By trend and group analysis we identified specific changes in serum AAs along with the progression of metabolically unwellness.

Introduction. Life threatening heart disorders secondary to paediatric and adolescent hyperthyroidism are exceptional.\r\nAim. We aimed to study cardiothyreosis frequency and outcome in children and adolescents with hyperthyroidism diagnosed between 1980 and 2010.\r\nMaterial and methods. In this retrospective study we observed 160 clinical and biological hyperthyroidisms in children (&#8804; 16 years) and adolescents (16-20 years).\r\nResults. Among them four girls aged 3, 16, 17 and 18, without previous familial history of heart diseases, had congestive heart failure (2.5%) without rhythmic troubles. Symptoms of cardiac insufficiency were resistant to digitalis and diuretics, but after anti thyroid drugs, there was an integral restitution of heart function in three\r\ncases and a persistent mitral, aortic and tricuspid regurgitation in one case arguing for heart rheumatic disease prior to hyperthyroidism.\r\nConclusion. Heart failure secondary to thyroid hormones excess is extremely rare before age of 20. Among 160 paediatric and adolescent hyperthyroidisms seen in 30\r\nyears, four girls had life threatening congestive cardiac insufficiency (2.5%), but after euthyroidism, heart insufficiency disappeared totally in all cases which\r\npleaded for a direct action of thyroid hormones excess on heart function.