ACTA ENDOCRINOLOGICA (BUC)

Aim: We aimed to assess the final outcome of combined therapeutic approaches in patients with macroprolactinomas that were resistant to dopamine agonists (DA).\r\nPatients: Records of patients with macroprolactinoma hospitalized in the Institute of Endocrinology, Bucharest, between 1978-2005, were reviewed. There were 29 eligible patients resistant to DA therapy (8 men and 21 women), out of 119 patients with macroprolactinomas (24.4%); age at diagnosis of the resistant patients ranged between 16-59 years (31.9 ? 2.4 years), with mean prolactin (PRL) levels 2,110.2 ? 656.6 ng/mL (range 42-16,000 ng/mL). The mean maximal tumor diameter was 2.7 ? 0.2 cm (range 1-6.8 cm).\r\nMethods: Rapid fluoroimmunoassay using Europium was used for hormonal levels; computed tomography imaging and/or MRI were used to assess tumor size. Study design: The resistance to DA drugs was evaluated using initial criteria: the lack of prolactinoma response to current daily dose of Bromocriptine (BRC) 7.5 mg/day or to Cabergoline (CAB) up to 2 mg/week for at least 6 months (step 1) or final criteria: the lack of response to high BRC doses (30 mg/day) or CAB doses between 2.5-4 mg/week for at least 6 months (step 2). The lack of response was considered if PRL levels remained above the upper normal limit (20 ng/mL) and the tumor mass size decreased by less than 50%. All resistant cases at step 1 received thereafter maximal medical therapy with DA drugs, according to step 2. Thereafter, resistant macroprolactinomas after step 2 were submitted to step 3 - high voltage radiotherapy ? surgery. Serum PRL levels and tumor size were finally evaluated 110 ? 26.5 months later (range: 6-381).\r\nResults: Outcome of medical therapy with DA (n=29): Overall, 7 out of 29 resistant macroprolactinomas (24.1%) were successfully treated by increasing BRC dose (n=5) or changing BRC to CAB (n=2). But 22/119 (18.5%) patients remained resistant to DA drugs independent of dose, duration or type of drug used. 14 patients failed to normalize PRL levels despite CAB treatment in doses up to 7 mg/week. Outcome of radiotherapy alone or combined with surgery (n=15): PRL normalization was achieved in 4 patients out of the only 7 assessed at least at 18 months after radiotherapy. Withdrawal of DA therapy revealed 2 cured cases, both after radiotherapy and surgery. Outcome of surgery: Only one patient normalized PRL levels after surgery, but she soon relapsed. Apparently, only one case of acquired resistance to DA drugs was revealed. We found that 15.1% (18/119) of the patients with macroprolactinoma did not finally normalize their serum PRL even after combined therapy approaches (DA + radiotherapy ? surgery), after 79 ? 17.4 months (range 6 to 206 months) treatment total duration and 45.4 ? 19 months (range 3 to 206 months) after radical therapies, respectively.\r\nConclusion: In summary, the resistance was successfully treated in 38% cases (11 out of 29).

Objective. Although bariatric surgery including gastrectomy has recently emerged as a useful treatment for type 2 DM with obesity, it is not clear whether gastrectomy itself can have beneficial effects on glucose metabolism. Therefore, in this study, we investigated changes in blood glucose in patients with and without diabetes who underwent gastrectomy. Methods. From Jan 2010 to May 2014, 77 patients with diabetes and 77 patients without diabetes who underwent gastrectomy at Chonbuk National University Hospital, South Korea, were included. We compared fasting plasma glucose levels and HbA1c value before and after gastric surgery. Results. After gastrectomy, 59 patients (38.3%) showed reduced fasting plasma glucose levels at the 1 year point, and 80 patients (51.9%) exhibited reduced fasting plasma glucose at 3 years, irrespective of their diabetes status. Among 77 patients with diabetes, decreased fasting plasma glucose was observed in 22 (28.6%) and 46 patients (59.7%) 1 and 3 years after gastrectomy, respectively. In patients who exhibited reduced fasting plasma glucose after gastrectomy, the degree of reduced glucose was as follows: 56.4±48.5 vs 23.2±16.1 mg/dL after 1 year, 58.3±52.3 vs 18.4±13.7 mg/dL after 3 years, in DM and non-DM patient respectively. Conclusions. Although there was a significant drop in mean fasting glucose after gastrectomy, not all patients experienced a drop in fasting glucose. Gastrectomy did not show a consistent association with glucose reduction in patients with and without diabetes, and in about half of the patients, fasting plasma glucose levels increased after gastrectomy. Therefore, bariatric surgery including gastrectomy needs to be performed with care in diabetes, and glucose monitoring including oral glucose tolerance tests should be done for assessing or prediction of the glucose state after gastric surgery in non-DM patients.

Context. Regulatory T cells (Tregs) have critical roles in preventing autoimmune diseases such as Hashimoto’s thyroiditis (HT). Forkhead box P3 (Foxp3), the master transcription factor of Tregs, plays a pivotal role in Treg function. Objective. Herein, we investigated the association of two single nucleotide polymorphisms (SNPs) of the Foxp3 gene with HT development. Methods and study design. A total of 129 HT patients and 127 healthy subjects were genotyped for rs3761548 (-3279 A/C) and rs3761549 (-2383 C/T) in the Foxp3 gene, using polymerase chain reaction-restriction fragment length polymorphism. Results. Genotypic and allelic distribution of rs3761548 SNP showed a significant association with HT. The CC genotype was observed in 37.2% of patients versus 22.1% of the controls [P<0.008, odds ratio (OR): 2.1; 95% confidence interval (CI): 1.2-3.6] and the AC genotype in 41.1% of patients compared to 54.3% of the controls (P<0.025, OR: 2.1; CI: 1.2-3.6). In addition, higher frequency of C allele in patients compared to controls (P=0.05, OR: 1.4; 95% CI: 0.9-2) suggested that patients with the CC genotype and C allele had increased susceptibility to HT. There were significantly higher serum levels of anti-thyroid peroxidase (ATPO) antibody in patients with the rs3761548 CC genotype (1156±163 IU/mL) compared to the other genotypes (≈582-656 IU/mL; P<0.004). We observed a greater frequency of the AC genotype in patients who had decreased ATPO antibody levels (P=0.02). Conclusions. The association of the rs3761548 SNP with risk of HT and its influence on ATPO antibody levels suggested an important role for Foxp3 in the biology and pathogenesis of HT.

The aim of this study is to analyze and identify the main predictors that may indicate multifocal growth of PTC. Materials and methods. The main and control groups included patients with the category of malignant multifocal process T1-3mN0Mx (n=109) and unifocal T1- T3N0Mx (n=50) respectively, who underwent thyroidectomy with lymphadenectomy. Ultrasound characteristics of the nodes, tissue changes of the thyroid gland were taken into account. Results. Fibrous changes can be considered as one of the risk factors of the presence of additional PTC lesion. Discussion. There is no unambiguity in the definition of predictors of multifocal PTC growth. Conclusions. No clear predictors of multifocal PTC have been identified. It is advisable to improve the quality of ultrasound, to focus on single-focus PTC in patients with fibrinous changes in the thyroid gland at normal levels of TSH.

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.

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.

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.

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

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