Simona Fica

FTO gene associates to metabolic syndrome in women with polycystic ovary syndrome

The FTO (Fat mass and obesity associated) locus has recently been associated with obesity and type 2 diabetes (T2D) in humans. To understand the role of the FTO gene in polycystic ovary syndrome (PCOS) we genotyped single nucleotide polymorphism (SNP) rs1421085 (C/T) in women with PCOS (n=207) and controls (n=100) from a Central European population. The homozygous C/C genotype showed increased prevalence in PCOS patients either obese or with metabolic syndrome (MetS) compared to lean PCOS patients or controls (27.6%, 38.9%, 22.3%, and 16.3%, respectively). In logistic regression, this genotype strongly associated with MetS (P<0.0001, OR 3.2, 95% CI 1.8-5.7) and impaired fasting glucose (IFG) with P<0.0007, OR 7.7, 95% CI 2.1-28.6, independently of BMI or age, and to AUC(gluc) during OGTT (P<0.0001, alpha=0.99), indicating an influential role of the FTO gene in the glucose intolerance component of MetS.

Sertoli-Leydig cell tumor - a rare androgen secreting ovarian tumor in postmenopausal women: case report and review of literature

Sertoli‐Leydig cell tumors (SLCT) constitute only 1‐0.5% of all primary ovarian neoplasms. We report a SLCT in a postmenopausal woman aged 69 years. The physical examination revealed severe hirsutism. Basal hormonal evaluation showed high plasma testosterone and estradiol values, with suppressed plasma gonadotropins. Computer tomograph scan revealed a right ovarian tumor mass of 4,3/3 cm, confirming an androgen secreting ovarian tumor. The histopathological and immunocytochemical examination established the diagnosis of well differentiated Sertoli‐Leydig cell tumor. The tumor was positive for cytokeratin KL 1 and S‐100 protein and, in isolated tumor cells, positive for alpha‐fetoprotein. Postsurgical evolution was favorable; controls after 6 months and 3,5 years showed marked reduction of hirsutism, normal plasma testosterone values and gonadotropins in normal postmenopausal range. We discuss the complex aspects of etiology and pathogenesis, the clinical and hormonal settings, the role of immunocytochemical markers in diagnosis, as well as the therapy and the prognostic features of this ovarian tumor.

Cancer Specific Mortality in Insulin-Treated Type 2 Diabetes Patients

Aims To test the hypothesis that cumulative exposure to insulin and long-acting insulin analogs might be associated with cancer mortality in diabetes patients. Methods All consecutive diabetes patients aged over 40 years, residing in a major urban area were screened at their first diabetes outpatient visit between 01/01/2001-12/31/2008 (n = 79869). Exclusion criteria were insulin treatment at screening, no insulin treatment until 12/31/2008, less than 6 months of glucose-lowering treatment alone before insulin initiation, insulin prescription before glargine became available, age <40/≥80 years at first insulin prescription, and <6 months of insulin exposure. A total 4990 subjects were followed-up for death based on death certificate, until 12/31/2011. Adjusted time-dependent competing risk regression analysis, with daily updates of treatment modalities was performed. Results are expressed for every 10,000 IU of cumulative dose or one year of cumulative time exposure to insulin. Results Mean baseline age was 62±9 years, and follow-up 4.7±1.9 years. Glargine cumulative dose was associated with lower cancer mortality risk (subhazard ratio, SHR: 0.94 (95%CI 0.89–0.99, p = 0.033)). Cumulative exposure limited to that attained one year prior to death revealed lower SHRs for cumulative time (0.94 (95%CI 0.89–0.99, p = 0.018)) and cumulative dose of glargine (0.92 (95%CI 0.86–0.98, p = 0.014)). Glargine cumulative time and cumulative dose were significant predictors for lower pancreatic and breast cancer mortality, but not for deaths from lung, colorectal, female genital, liver, and urinary tract cancer. No increased hazards were found for any other subtypes of insulins. Conclusions The cumulative dose exposure to insulin glargine was associated with a lower risk of cancer mortality in general, and of breast and pancreatic cancer in particular. This effect remained even after additional “fixed” cohort or propensity score analyses.

Adiponectin, body mass index and hepatic steatosis are independently associated with IGF-I status in obese non-diabetic women.

OBJECTIVE Low IGF-I levels have been associated with obesity, insulin resistance, hepatic steatosis, and were shown to predict cardiovascular mortality. Adiponectin, on the other hand, was proved to have an important protective role against metabolic and cardiovascular diseases. This study investigates the relation between hepatic steatosis, adiponectin and IGF-I levels in a group of non-diabetic obese Romanian women. DESIGN This cross-sectional study included 201 obese non-diabetic women, with mean age of 41.1±11.9 years and mean body mass index (BMI) of 44.1±8.3 kg/m(2), consecutively admitted to the Endocrinology Department of a University Hospital to be evaluated as candidates for bariatric surgery. Main measured parameters included total adiponectin (detected by ELISA method), insulin, C reactive protein (CRP), and IGF-I (all by chemiluminescence methods). Insulin sensitivity was assessed using the Quantitative Insulin Sensitivity Check Index (QUICKI). Patients were considered IGF-deficient if IGF-I z score was ≤2 standard deviations from mean for age. Hepatic ultrasound was used to determine the presence of significant steatosis (SS+). RESULTS Significant steatosis was observed in 60.7% of our patients and this feature was associated with reduced total adiponectin levels (p<0.001) and lower IGF-I z scores (p<0.001). IGF-I z score negatively correlated with BMI (r=-0.283, p<0.001), alanine aminotransferase (ALT) (r=-0.130, p=0.032), gamma glutamyltransferase (GGT) (r=-0.158, p=0.018) and logarithmic transformed (log) CRP (r=-0.232, p=0.001) and positively correlated with QUICKI (r=0.148, p=0.023) and log adiponectin (r=0.216, p=0.003). The relationship between IGF-I z score and log adiponectin remained significant after adjusting for age, BMI, ALT, QUICKI and log CRP (r=0.183, p=0.012). IGF-I deficiency was present in 33.3% of these obese women. In multivariate logistic analysis, BMI (p<0.001), ALT (p=0.003), log adiponectin (p<0.001) and SS (p=0.043) proved to be independently associated with IGF-I deficiency. CONCLUSIONS Adiponectin is significantly correlated with IGF-I z scores and, along with BMI, ALT and significant steatosis, is independently associated with IGF-I deficiency in obese non-diabetic women.

Association of insulin receptor genetic variants with polycystic ovary syndrome in a population of women from Central Europe

To assess the role of the insulin receptor gene in polycystic ovary syndrome (PCOS) we performed a case-control study in a female population (n=226) from Central Europe by examining the genetic associations of single nucleotide polymorphisms (rs8107575, rs2245648, rs2245649, rs2963, rs2245655, and rs2962) and inferred haplotypes around exon 9 of this gene. The ancestral T allele of single nucleotide polymorphism rs2963 or the corresponding haplotype (GGTC-C) showed association with PCOS with odds ratio 2.99, 95% confidence interval 1.4-6.3, independent of obesity but related to the presence of Acanthosis nigricans and insulin resistance, metabolic syndrome, or hyperandrogeny, thus providing a frame for future fine mapping of the susceptibility loci in PCOS.

IGF-1 and Insulin Resistance Are Major Determinants of Common Carotid Artery Thickness in Morbidly Obese Young Patients

We assessed the relationship between insulin resistance, serum insulin-like growth factor 1 (IGF-1) levels, and common carotid intima–media thickness (CC-IMT) in morbidly obese young patients. A total of 249 patients (aged 37.9 ± 9.8 years, body mass index [BMI] 45.6 ± 8.3 kg/m2) were evaluated (metabolic tests, serum IGF-1 measurements, homeostasis model assessment—insulin resistance [HOMA-IR], and ultrasonographically assessed CC-IMT) in a research program for bariatric surgery candidates. After adjusting for age, gender, BMI, systolic blood pressure, uric acid, antihypertensive and lipid-lowering treatment, metabolic syndrome, and metabolic class, both HOMA-IR and IGF-1 z-score were significantly associated with CC-IMT. These results were confirmed in logistic regression analysis, in which age (β = 1.11, P = .001), gender (β = 3.19, P = .001), HOMA-IR (β = 1.221, P = .005), and IGF-1 z-score (β = 1.734, P = .009) were the only independent determinants of abnormal CC-IMT, presumably modulating the effect of the other risk factors included in the regression. Area under the receiver–operating characteristic curve for the model was 0.841 (confidence interval: 0.776-0.907; P < .001). In conclusion, in morbidly obese young adults, insulin resistance and IGF-1 z-score are significantly associated with CC-IMT, independent of other major cardiovascular risk factors.

Risk Factors Associated with Hypogonadism in β–Thalassemia Major Patients: Predictors for a Frequent Complication of a Rare Disease

Abstract Background: β-Thalassemia major (BTM) is a rare disease that challenges clinicians because of the high prevalence of complications despite progress in the development of new therapeutic methods. The aim of this study was to identify clinical and hematological parameters associated with hypogonadism, the most frequent iron overload-related complication found in Romanian patients. Methods: Patients with BTM were evaluated in the Endocrinology Department of Elias Hospital between February 2004 and December 2013. Only patients who provided written informed consent were included in the study. A complete physical and hormonal evaluation was performed on all patients, and data regarding treatment of the hematological disease were collected. Results: Of the evaluable patients, 85 were included in the study (median age, 21[10] years; range, 13–36 years). We found that 30.6% of the study participants (26 of 85) had normal gonadal status, 54.1% (46 of 85) had early forms of hypogonadism (delayed or arrested puberty), and 15.3% (n = 13) developed hypogonadism after complete sexual maturation. Patients with any form of hypogonadism were older (median age 22 vs 16.5 years, P = 0.047), had significantly lower average hemoglobin levels (P = 0.003), and had higher levels of serum ferritin (P = 0.006) versus patients without hypogonadism. Patients with delayed puberty were associated with increased average serum ferritin levels (P = 0.007), decreased hemoglobin levels (P = 0.001), and increased age at initiation of iron chelation therapy (P < 0.01). We found no significant differences between patients with early forms of hypogonadism and those with hypogonadism after complete sexual maturation, with respect to the analyzed parameters. Patients with adult hypogonadism were significantly older (median age 26 vs 16.5 years, P = 0.007) and tended to have higher serum ferritin levels (P = 0.056) compared with patients without hypogonadism. Conclusion: Our data show that hypogonadism is highly prevalent among Romanian patients with BTM, its presence being associated with higher iron overload and lower hemoglobin values. The late start of iron chelation therapy was particularly associated with pubertal abnormalities.

Overweight and Underweight Prevalence Trends in Children from Romania - Pooled Analysis of Cross-Sectional Studies between 2006 and 2015.

Aim: High-quality national representative data on obesity in Romanian children are needed to shape public health policies. To provide a unified data landscape on national prevalence, trends and other factors associated with underweight, overweight, and obesity in Romanian children aged 6-19 years, across the last decade (2006-2015). Methods: Using a common protocol, we selected published and unpublished studies that measured Romanian children in schools between 2006 and 2015. Childrens BMI was classified using the current WHO, IOTF, and CDC references. Results: 25,060 children from 8 Romanian counties were included in the analysis. The prevalence of underweight children was 5%/4.5%/8.5% (WHO/IOTF/CDC), while the prevalence of overweight (including obese) children was 28.3%/23%/23.2% (WHO/IOTF/CDC). The prevalence of overweight children did not change significantly over the last decade (chi-square test p = 0.6). Male gender (odds ratio (OR) 1.37; 95% CI 1.29-1.45, compared to female); prepubertal age (OR = 3.86; 95% CI 3.41-4.36,compared to postpubertal age), and urban environment (OR 1.12; 95% CI 1.01-1.26, compared to rural environment) had higher risk for overweight. Conclusion: While the prevalence of underweight children was low, almost one in four children in Romania was overweight or obese (according to WHO criteria) between 2006 and 2015. This prevalence remained relatively stable over the last decade. Male gender, prepubertal age, and urban environment, were the most relevant risk factors associated with overweight status in Romanian children.

Thyroid autoimmunity in 72 children with type 1 diabetes mellitus: relationship with pancreatic autoimmunity and child growth.

Abstract The aim of this study was to assess the association between pancreatic and thyroid autoimmunity (TA) and determine impact of thyroid antibodies on statural growth. Seventy-two children with type 1 diabetes mellitus (T1DM) and no clinical evidence of thyroid disorders were evaluated: glycated haemoglobin (A1c), thyroid peroxidase antibodies (TPOAb), glutamic acid decarboxylase antibody (GADA), tyrosine phosphatase antibodies (IA2A), and thyroid-stimulating hormone (TSH). The score of standard deviation for height (SDS) was calculated. There were 72 patients, 38 (52.7%) boys and 34 (47.2%) girls, with a mean age of 10.89±4.26 years and a mean duration of T1DM of 3.41±2.56 years. TPOAb were present in 23.6% of patients; 12.5% of subjects were positive for GADA and 41.6% for IA2A. Patients with TA had more prevalent GADA and IA2A (23.5% vs. 9%, p<0.001, and 58.8% vs. 36.3%, p<0.001, respectively). A1c was higher in patients with TA (9.7%±2.05% vs. 8.6%±2.11%, p=0.05). TA was associated with lower SDS (0.26 vs. 0.98, p=0.043). TSH was higher in patients with TA (3.39 vs. 2.15 μU/mL, p<0.05). Logistic regression analysis revealed that a negative SDS for height was independently associated with duration of diabetes (p=0.049) and TSH (p=0.027) but not with birth weight, A1c, and TPOAb. In conclusion, TA was found in 23.6% T1DM children. Patients with TA had significantly higher prevalence of GADA and IA2A and significantly higher A1c vs. patients without TA. Our data suggest significant association between TA and height in children with T1DM. SDS was independently associated with diabetes duration and TSH.

Serum immunoglobulin G4 levels and Graves’ disease phenotype

PurposeWe investigated, at diagnosis, the relationship between serum immunoglobulin G4 levels and the main characteristics of Graves’ disease: hyperthyroidism severity, goiter size, presence of active Graves’ ophthalmopathy, antithyroid antibodies status, and titer.MethodsThis prospective study included 80 newly diagnosed Graves’ disease patients. The main parameters measured at diagnosis: thyroid-stimulating hormone, free thyroxine, free triiodothyronine, total triiodothyronine, thyroglobulin, antithyroid peroxidase antibodies, anti-thyroglobulin antibodies, thyroid-stimulating hormone receptor antibodies, immunoglobulin G4.ResultsIn Graves’ disease patients, serum immunoglobulin G4 levels were higher than in general population (p = 0.028) and higher in men compared to women (p = 0.002). Only one female patient with intense hypoechoic goiter, high anti-thyroglobulin antibody, and antithyroid peroxidase antibody titers had an elevated serum immunoglobulin G4 level at diagnosis. Patients with immunoglobulin G4 levels above the 75th percentile (>237.52 mg/dl, N = 20) were younger at Graves’ ophthalmopathy onset (p < 0.001), had higher antithyroid peroxidase antibody (p = 0.01), and anti-thyroglobulin antibody levels (p = 0.006) and required shorter duration of the first methimazole treatment cycle (p = 0.041) than patients with immunoglobulin G4 below the 75th percentile. At diagnosis, patients with immunoglobulin G4 levels above the 90th percentile (>286.28 mg/dl, N = 8) had lower total triiodothyronine values (p = 0.001) than patients with IgG below the 90th percentile. No significant correlations were found between smoking status (p = 0.58), goiter size (p = 0.50), the presence of ophthalmopathy (p = 0.42) or thyroid-stimulating hormone receptor antibody titers (p = 0.45) and the mean value of immunoglobulin G4 levels at diagnosis.ConclusionsOur data suggest that Graves’ disease patients with elevated immunoglobulin G4 levels at diagnosis have a phenotype characterized by higher anti-thyroglobulin antibody and antithyroid peroxidase antibody titers, less severe T3 hyperthyroidism, younger age at ophthalmopathy onset and require a shorter duration of the first methimazole treatment cycle.