The endothelin 1 and endothelin receptor A gene polymorphisms increase the risk of developing papillary thyroid cancer.

The endothelin (EDN) axis (EDN1 and EDN1 receptor A, EDNRA) is involved in cellular growth, differentiation, invasiveness, and tumor progression in several cancers. We wanted to examine the possible impact of single nucleotide polymorphisms (SNPs) of EDN1 and EDNRA genes on papillary thyroid cancer (PTC) development and general characteristics of PTC. Study population consist of 113 PTC patients and 185 controls. EDN1 (G5665T, T-1370G) and EDNRA (C TT70G, G-231A) SNPs were investigated by real-time PCR. The GG genotype of EDNRA + 70 SNP was associated with threefold increased PTC risk (p = 0.01), and the combined CG + GG genotype was 2.48 fold higher among PTC patients compared to controls. The variant EDNRA - 231 allele was overrepresented in PTC patients according to controls (p = 0.05). The combined GT + TT genotype of EDN1 5665 SNP was related with late (age after 40 years) PTC onset (p = 0.04), and was more prominent among male patients with PTC according to females (p = 0.03). No significant associations between PTC and - 1370 SNP were found. There were no relationships between laboratory parameters and investigated polymorphisms. The EDNRA + 70 SNP was associated with PTC development. The EDN1 5665 SNP was linked with increased risk for late PTC onset and was more prominent among male patients with PTC.

Vascular endothelial growth factor G+405C polymorphism may contribute to the risk of developing papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Vascular endothelial growth factor (VEGF) is a mediator implicated with cell proliferation, differentiation and migration, and monocyte/macrophage chemotaxis. In present study, we aimed to investigate the relationship between VEGF gene polymorphisms (G+405C, T-460C, and A-2578C) and PTC susceptibility. METHODS: DNA was isolated from peripheral blood leukocytes of 127 patients with PTC and 203 healthy controls. Genotyping was performed by real-time PCR. Association of genotypes with susceptibility of PTC was analyzed with multivariate logistic regression adjusted for age, gender and smoking status. RESULTS AND CONCLUSION: In G+405C polymorphism, the frequencies of C allele (related with increased VEGF production) and combined CG+CC genotype were found to be higher (3.5 and 5-fold, respectively) among patients with PTC than controls (P<.001). However, VEGF T-460C and A-2578C polymorphisms are not associated with PTC risk. There was no relationship between VEGF polymorphisms and clinical/laboratory parameters of PTC. Haplotype analysis demonstrated that there was a strong linkage disequilibrium (LD) between -460/-2578 (D'=.89, r2 =.79), weak LD between +405/-460 (D'=.422, r2 =.035), and +405/-2578 (D'=.43, r2 =.038) locuses. Additionally, the +405/-460/-2578 GTA haplotype was found to be protective, whereas CTA haplotype to be related with increased PTC risk. As a conclusion, we suggest that VEGF G+405C polymorphism is associated with increased risk of PTC.

Interleukin-10-1082 gene polymorphism is associated with papillary thyroid cancer.

The etiopathogenesis of thyroid cancer has not been clearly elucidated although the role of chronical inflammation and the imbalance between pro- and anti-inflammatory cytokines may play a role in the etiology. The aim of the present study was to investigate whether cytokine gene polymorphisms are associated with papillary thyroid cancer (PTC), and to evaluate the relationship between genotypes and clinical/laboratory manifestation of PTC. Tumor necrosis factorα (TNFα) G-308A (rs 1800629), interleukin-6 (IL-6) G-174C (rs 1800795) and IL-10 A-1082G (rs 1800896) single nucleotide polymorphisms in DNA from peripheral blood leukocytes of 190 patients with thyroid cancer and 216 healthy controls were investigated by real-time PCR combined with melting curve analysis. There was no notable risk for PTC afflicted by TNFα-308 and IL-6-174 alone. However, IL-10-1082 G allele frequency were higher among PTC patients than healthy controls (p=0.009). The patients with IL-10-1082 GG geotype have twofold increased risk of developing thyroid cancer according to AA genotype (OR 2.07, 95% CI 1.21-3.55). In addition, the concomitant presence of IL-10-1082 G allele (GG+AG genotypes) together with IL-6 -174 GG genotype has a nearly twofold increased risk for thyroid cancer (OR 1.75 with 95% CI 1.00-3.05, p=0.049). We suggest that IL-10-1082 G allele is associated with an increased risk of PTC. The polymorphism of IL-10 gene can improve our knowledge about the pathogenesis of PTC, and could provide to estimate people at the increased risk for PTC.

Is the measurement of inferior thyroid artery blood flow velocity by color-flow Doppler ultrasonography useful for differential diagnosis between gestational transient thyrotoxicosis and Graves' disease? A prospective study.

OBJECTIVE: To determine the role of peak systolic velocity, end-diastolic velocity and resistance indices of both the right and left inferior thyroid arteries measured by color-flow Doppler ultrasonography for a differential diagnosis between gestational transient thyrotoxicosis and Graves' disease during pregnancy. METHODS: The right and left inferior thyroid artery-peak systolic velocity, end-diastolic velocity and resistance indices of 96 patients with thyrotoxicosis (41 with gestational transient thyrotoxicosis, 31 age-matched pregnant patients with Graves' disease and 24 age- and sex-matched non-pregnant patients with Graves' disease) and 25 age and sex-matched healthy euthyroid subjects were assessed with color-flow Doppler ultrasonography. RESULTS: The right and left inferior thyroid artery-peak systolic and end-diastolic velocities in patients with gestational transient thyrotoxicosis were found to be significantly lower than those of pregnant patients with Graves' disease and higher than those of healthy euthyroid subjects. However, the right and left inferior thyroid artery peak systolic and end-diastolic velocities in pregnant patients with Graves' disease were significantly lower than those of non-pregnant patients with Graves' disease. The right and left inferior thyroid artery peak systolic and end-diastolic velocities were positively correlated with TSH-receptor antibody levels. We found an overlap between the inferior thyroid artery-blood flow velocities in a considerable number of patients with gestational transient thyrotoxicosis and pregnant patients with Graves' disease. CONCLUSIONS: This study suggests that the measurement of inferior thyroid artery-blood flow velocities with color-flow Doppler ultrasonography does not have sufficient sensitivity and specificity to be recommended as an initial diagnostic test for a differential diagnosis between gestational transient thyrotoxicosis and Graves' disease during pregnancy.

Polymorphisms of vascular cell adhesion molecule1 (VCAM1) in polycystic ovary syndrome determined by quantitative real-time polymerase chain reaction and melting curve analysis.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrinopathy associated with increased risk of obesity, insulin resistance (IR) and type 2 diabetes mellitus. Low-grade chronic inflammation and imbalance between pro- and anti-inflammatory cytokines has been proposed to play a role in the pathogenesis. Vascular cell adhesion molecule1 (VCAM1) is among the parameters reflecting low-grade chronic inflammation whose expression is increased by pro-inflammatory cytokines. This study examined the possible association of T-1591C and T-833C single nucleotide polymorphisms (SNPs) of VCAM1 gene with the occurrence and the clinical/biochemical characteristics of PCOS. STUDY DESIGN: We analyzed genotype and allele distributions of the above-mentioned SNPs in DNA from peripheral blood leukocytes of 169 patients with PCOS and 179 healthy women, by a real-time polymerase chain reaction (PCR) method combined with melting curve analysis using fluorescence-labeled hybridization probes. RESULTS: No significant associations between PCOS and the variant alleles of VCAM1-1591 (OR: 1.09, 95% CI=0.74-1.58) and -833 (OR: 1.42, 95% CI=0.59-3.43) were observed. None of the studied polymorphisms was found to affect IR indices and sVCAM levels significantly. However, PCOS women heterozygous for VCAM1-1591 polymorphism (CT) had significant increased triglyceride and decreased HDL-C in comparison with wild homozygous (TT) ones. CONCLUSIONS: Although there is no association between -1591 and -833 polymorphisms of VCAM1 gene and susceptibility to PCOS, higher triglyceride and lower HDL-C in VCAM1-1591 CT genotype suspect that heterozygous patients are prone to increased risk for atherosclerosis and cardiovascular disease. In addition, bearing in mind that PCOS is a consequence of interaction between various genetic and environmental factors, the association between heterozygocity of VCAM1-1591 polymorphism and some lipid parameters may depend on the impact of other known or unknown polymorphisms, being in linkage disequilibrium with this locus of VCAM1 gene.

Is the measurement of inferior thyroid artery blood flow velocity by color-flow Doppler ultrasonography useful for differential diagnosis between gestational transient thyrotoxicosis and Graves' disease? A prospective study

OBJECTIVE: To determine the role of peak systolic velocity, end-diastolic velocity and resistance indices of both the right and left inferior thyroid arteries measured by color-flow Doppler ultrasonography for a differential diagnosis between gestational transient thyrotoxicosis and Graves' disease during pregnancy. METHODS: The right and left inferior thyroid artery-peak systolic velocity, end-diastolic velocity and resistance indices of 96 patients with thyrotoxicosis (41 with gestational transient thyrotoxicosis, 31 age-matched pregnant patients with Graves' disease and 24 age- and sex-matched non-pregnant patients with Graves' disease) and 25 ageand sex-matched healthy euthyroid subjects were assessed with color-flow Doppler ultrasonography. RESULTS: The right and left inferior thyroid artery-peak systolic and end-diastolic velocities in patients with gestational transient thyrotoxicosis were found to be significantly lower than those of pregnant patients with Graves' disease and higher than those of healthy euthyroid subjects. However, the right and left inferior thyroid artery peak systolic and end-diastolic velocities in pregnant patients with Graves' disease were significantly lower than those of non-pregnant patients with Graves' disease. The right and left inferior thyroid artery peak systolic and end-diastolic velocities were positively correlated with TSH-receptor antibody levels. We found an overlap between the inferior thyroid artery-blood flow velocities in a considerable number of patients with gestational transient thyrotoxicosis and pregnant patients with Graves' disease. CONCLUSIONS: This study suggests that the measurement of inferior thyroid artery-blood flow velocities with colorflow Doppler ultrasonography does not have sufficient sensitivity and specificity to be recommended as an initial diagnostic test for a differential diagnosis between gestational transient thyrotoxicosis and Graves' disease during pregnancy.

Lack of association between intercellular adhesion molecule-1 (ICAM-1) polymorphisms and polycystic ovary syndrome.

PURPOSE: This study examined the possible association of G241R and K469E single nucleotide polymorphisms (SNPs) of ICAM-1 gene with the occurrence and clinical/biochemical characteristics of polycystic ovary syndrome (PCOS). METHODS: G241R and K469E SNPs in DNA from peripheral blood leukocytes of 169 PCOS and 259 healthy control women were investigated by real-time PCR combined with melting curve analysis using fluorescence-labeled hybridization probes. RESULTS: We did not find significant differences in the distributions of G241R and K469E polymorphisms, nor in the haplotype frequencies between PCOS and control women. None of the studied polymorphisms were found to affect insulin resistance indices significantly. CONCLUSIONS: These preliminary results suggest that the 241 and 469 SNPs of ICAM-1 gene may not be risk factors for PCOS. Further studies with a larger cohort, analyzing other ICAM-1 polymorphisms are necessary to support our observations before any statement can be made about the relationship between PCOS and ICAM-1 polymorphisms.

MGMT immunoexpression in growth hormone-secreting pituitary adenomas and its correlation with Ki-67 labeling index and cytokeratin distribution pattern.

Recent publications suggest the utility of temozolomide (TMZ) in the management of aggressive pituitary adenomas and carcinomas, resistant to conventional treatments. The response to TMZ is inversely correlated with tumoral expression of O-6 methylguanine DNA methyl transferase (MGMT). Therefore, we aimed to assess MGMT immunoexpression in pure GH-secreting pituitary adenomas, in an effort to predict the likelihood of response to TMZ, and to correlate MGMT immunoexpression with Ki-67 LI and cytokeratin (CK) distribution pattern. Our material consisted of 36 GH-secreting pituitary adenomas (21 female,15 male, mean age 42.5±10.5), operated at our center between 2003 and 2010. Immunostaining for MGMT, Ki-67, and CK was performed using avidin-biotin-peroxidase complex method. Immunoreactivity for MGMT and Ki-67 was evaluated microscopically and recorded as percentages of positive nuclear immunostaining. CK distribution pattern was also evaluated microscopically and assoreted into dot-like and nondot-like pattern subtypes. MGMT immunoexpression scored as 0=none, 1=<10%, 2=<25%, 3=<50%, and 4=>50%. Staining for MGMT was <10% (score 1) in 30 (83.3%), 10-25% (score 2) in 3 (8.3%), 25-50% (score 3) in 2 (5.6%) and >50% (score 4) in 1 (2.8%) of the tumors, respectively. There was no correlation between Ki-67 LI and CK distribution pattern with MGMT immunoreactivity (P>0.05). Data from the current study suggest a large proportion of GH-secreting adenomas, including those with dot-like CK distribution pattern and high Ki-67 LI, demonstrate negative/low MGMT immunoreactivity and could be treated with TMZ, if conventional treatment fails.

Hyperthyroidism: a risk factor for female sexual dysfunction.

INTRODUCTION: Hyperthyroidism is a common hormonal disorder in women that may cause female sexual dysfunction (FSD). AIM: To assess sexual function in women with hyperthyroidism. METHODS: A total of 40 women with clinical hyperthyroidism and 40 age-matched voluntary healthy women controls were included in the study. All the subjects were evaluated with a detailed medical and sexual history, including a Female Sexual Function Index (FSFI) questionnaire for sexual status and the Beck Depression Inventory (BDI) for psychiatric assessment. MAIN OUTCOMES MEASURES: The levels of serum thyroid-stimulating hormone (TSH), thyroid hormones, sex hormone binding globulin (SHBG), total testosterone (tT), free testosterone (fT), prolactin, estradiol, follicle-stimulating hormone, and luteinizing hormone were measured. RESULTS: The mean total FSFI scores were 24.2 ± 9.96 in the hyperthyroidic group and 29 ± 10.4 in the control group (P < 0.0001). Desire (P < 0.040), arousal (P < 0.0001), lubrication (P < 0.0001), orgasm (P < 0.0001), satisfaction (P < 0.0001), and pain (P < 0.007) domain scores were also significantly lower in women with hyperthyroidism. The mean BDI score for hyperthyroidic patients was significantly greater than the score for the control group (P < 0.0001). The mean SHBG level in the hyperthyroidic group was found to be significantly higher than the level in the controls (P < 0.0001), whereas the mean fT level in the hyperthyroidic group was lower than in the control group (P < 0.0001). The FSFI score showed a significant negative correlation with the serum SHBG (r = -0.309, P = 0.005), free triiodothyronine (r = -0.353, P = 0.006) and free tetraiodothyronine (r = -0.305, P = 0.018) levels, BDI scores (r = -0.802, P = 0.0001) and positive correlation with tT (r = 0.284, P = 0.011), fT (r = 0.407, P = 0.001), and TSH (r = 0.615, P = 0.0001) levels. CONCLUSIONS: A significant percentage of women with clinical hyperthyroidism had sexual dysfunction. Increased depressive symptoms, increased SHBG level, and decreased fT levels were all found to be associated with FSD in clinical hyperthyroidism.

Vascular endothelial growth factor -2578 A/C, -460 T/C and +405 G/C polymorphisms in polycystic ovary syndrome.

OBJECTIVE: Vascular endothelial growth factor (VEGF) may be involved in the physiological regulation of ovarian angiogenesis and pathogenesis of polycystic ovary syndrome (PCOS). VEGF -2578 A/C, -460 T/C and +405 G/C single nucleotide polymorphisms (SNPs) are known to be related to VEGF production. STUDY DESIGN: In order to investigate the possible association between VEGF gene and PCOS susceptibility, we analyzed genotype and allele distributions of above mentioned SNPs in 137 patients with PCOS and 155 healthy women. Differences in genotype distributions and allele frequencies in the cases and controls were compared for statistical significance using the chi(2)-test. Haplotype frequencies were estimated using a contingency chi(2)-test. Mann-Whitney U test was used for the statistics of the clinical and biochemical parameters. RESULTS: No significant association between PCOS and the variant alleles of VEGF -2578 (OR: 0.91, 95% CI=0.65-1.26), -460 (OR: 0.78, 95% CI=0.56-1.08), and +405 (OR: 1.25, 95% CI=0.81-1.93) was observed. However, haplotype analysis demonstrated that the frequency of CTG haplotype, was higher among PCOS compared with controls (p=0.019) and that there is a strong linkage disequilibrium (D'=0.873, r(2)=0.752) between -2578 and -460 polymorphisms. CONCLUSIONS: These preliminary results suggest that the -2578, -460 and +405 SNPs of VEGF gene are not significant risk factors for PCOS development alone. However, because of the high VEGF producer CTG haplotype was more frequent among the PCOS, we suppose that investigated polymorphisms--interacting with other genetic and environmental factors--could play a role in the development of PCOS.