Use of levothyroxine for euthyroid, thyroid antibody positive women with infertility: Analyses of aggregate data from a survey of European thyroid specialists (Treatment of Hypothyroidism in Europe by Specialists: An International Survey).

OBJECTIVES: The use of levothyroxine (LT4) treatment aiming to improve fertility in euthyroid women with positive thyroid peroxidase antibodies (TPOAb) is not supported by the available evidence. The aim of the study was to document the use of LT4 by European thyroid specialists in such patients. DESIGN: The data presented derive from Treatment of Hypothyroidism in Europe by Specialists, an International Survey (THESIS), a questionnaire conducted between 2019 and 2021 to document the management of hypothyroidism by European thyroid specialists. Here, we report the aggregate results on the use of LT4 in infertile, euthyroid women with positive TPOAb. RESULTS: A total of 2316/5406 (42.8%) respondents stated that LT4 may be indicated in TPOAb positive euthyroid women with infertility. The proportion of those replying positively to this question varied widely across different countries (median 39.4, range 22.9%-83.7%). In multivariate analyses males (OR: 0.8; CI: 0.7-0.9) and respondents >60 years (OR: 0.7; 0.6-0.8) were the least inclined to consider LT4 for this indication. Conversely, respondents managing many thyroid patients ("weekly" [OR: 1.4; CI: 1.0-1.9], "daily" [OR: 1.8; CI: 1.3-2.4]) and practicing in Eastern Europe (OR: 1.5; CI: 1.3-1.9) were most likely to consider LT4. CONCLUSIONS: A remarkably high number of respondents surveyed between 2019 and 2021, would consider LT4 treatment in TPOAb positive euthyroid women with infertility. This view varied widely across countries and correlated with sex, age and workload, potentially influencing patient management. These results raise concerns about potential risks of overtreatment.

Clinical characteristics and the treatment modalities of Graves' orbitopathy in a tertiary referral center in Turkey: changes over two decades.

PURPOSE: To evaluate the changes in demographics, clinical findings, and treatment modalities in Graves' orbitopathy (GO) patients at a tertiary referral center in Turkey over the last two decades. METHODS: The clinical data of 752 GO patients were evaluated retrospectively. Patients were divided into 2 groups according to the first ophthalmic examination date; Group 1(n:344) between January 1998 and December 2007 and Group 2(n:408) between January 2008 and December 2017. RESULTS: The number of nonsmokers was significantly higher in Group 2 (44.0 vs. 26.5%, p < 0.001). The time from the diagnosis of thyroid dysfunction and referral to our center was 32.4 months in Group 1 and 34.8 months in Group 2, (p = 0.166). The most common treatment of hyperthyroidism was antithyroid medications. Radioiodine ablation treatment rate was significantly lower in Group 2 (14.8 vs. 9.1%, p < 0.001). The time between the diagnosis of thyroid disease and orbital involvement was 22.0 vs. 26.6 months in Groups 1 and 2, respectively (p = 0.009). The time elapsed between the diagnosis of orbital disease and referral to our clinic was 21.0 months vs. 22.4 months in Group 1 and 2, respectively (p = 0.068). Orbital disease was most commonly mild, and inactive. Mild and moderate to severe GO and the mean Clinical Activity Score significantly increased, and the rate of sight-threatening disease and orbital decompression surgery significantly decreased in Group 2 (p = 0.042; p < 0.001, respectively). CONCLUSIONS: Mild and inactive orbital disease was the most common form of GO. The severity of GO is declining over the last two decades in Turkey.

Serum levels of fetuin A are increased in women with gestational diabetes mellitus.

PURPOSE: Fetuin A is associated with insulin resistance and type 2 diabetes mellitus (DM). We aimed to investigate circulating fetuin A concentrations in gestational diabetes mellitus (GDM). METHODS: Serum fetuin A levels were studied in 26 pregnant women with GDM and 24 healthy pregnant women between 24th and 28th gestational weeks. Fetuin A levels were also evaluated in 18 of women with GDM at postpartum. RESULTS: Fetuin A concentrations were significantly increased in women with GDM compared to healthy pregnant women (35.0 ± 3.2 vs. 32.0 ± 4.4 ng/ml; p = 0.01). Also, fetuin A levels in women with GDM significantly decreased at postpartum period (35.0 ± 3.2 vs. 31.7 ± 3.9 ng/ml; p = 0.001). In whole pregnant women, there were positive correlations between fetuin A and HbA1c (r = 0.418, p = 0.002), total cholesterol (r = 0.332, p = 0.018) and triglycerides (r = 0.306, p = 0.031). Multivariate regression analysis demonstrated that HbA1c was the important predictor of circulating fetuin A level (beta = 0.375, p = 0.01). CONCLUSION: In conclusion, our results indicate that serum fetuin A concentrations are increased in women with GDM and decreased after delivery. Therefore, fetuin A might have a role in the development of insulin resistance and the metabolic changes in GDM.

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Patients' Persistent Symptoms, Clinician Demographics, and Geo-Economic Factors Are Associated with Choice of Therapy for Hypothyroidism by European Thyroid Specialists: The "THESIS" Collaboration.

Background: Hypothyroidism is common, however, aspects of its treatment remain controversial. Our survey aimed at documenting treatment choices of European thyroid specialists and exploring how patients' persistent symptoms, clinician demographics, and geo-economic factors relate to treatment choices. Methods: Seventeen thousand two hundred forty-seven thyroid specialists from 28 countries were invited to participate in an online questionnaire survey. The survey included respondent demographic data and treatment choices for hypothyroid patients with persistent symptoms. Geo-economic data for each country were included in the analyses. Results: The response rate was 32.9% (6058 respondents out of 17,247 invitees). Levothyroxine (LT4) was the initial treatment preferred by the majority (98.3%). Persistent symptoms despite normal serum thyrotropin (TSH) while receiving LT4 treatment were reported to affect up to 10.0% of patients by 75.4% of respondents, while 28.4% reported an increasing such trend in the past 5 years. The principal explanations offered for patients' persistent symptoms were psychosocial factors (77.1%), comorbidities (69.2%), and unrealistic patient expectations (61.0%). Combination treatment with LT4+liothyronine (LT3) was chosen by 40.0% of respondents for patients who complained of persistent symptoms despite a normal TSH. This option was selected more frequently by female thyroid specialists, with high-volume practice, working in countries with high gross national income per capita. Conclusions: The perception of patients' dissatisfaction reported by physicians seems lower than that described by hypothyroid patients in previous surveys. LT4+LT3 treatment is used frequently by thyroid specialists in Europe for persistent hypothyroid-like symptoms even if they generally attribute such symptoms to nonendocrine causes and despite the evidence of nonsuperiority of the combined over the LT4 therapy. Pressure by dissatisfied patients on their physicians for LT3-containing treatments is a likely explanation. The association of the therapeutic choices with the clinician demographic characteristics and geo-economic factors in Europe is a novel information and requires further investigation.

Characteristics of specialists treating hypothyroid patients: the "THESIS" collaborative.

Introduction: Thyroid specialists influence how hypothyroid patients are treated, including patients managed in primary care. Given that physician characteristics influence patient care, this study aimed to explore thyroid specialist profiles and associations with geo-economic factors. Methods: Thyroid specialists from 28 countries were invited to respond to a questionnaire, Treatment of Hypothyroidism in Europe by Specialists: an International Survey (THESIS). Geographic regions were defined according to the United Nations Statistics Division. The national economic status was estimated using World Bank data on the gross national income per capita (GNI per capita). Results: 5,695 valid responses were received (response rate 33·0%). The mean age was 49 years, and 65·0% were female. The proportion of female respondents was lowest in Northern (45·6%) and highest in Eastern Europe (77·2%) (p <0·001). Respondent work volume, university affiliation and private practice differed significantly between countries (p<0·001). Age and GNI per capita were correlated inversely with the proportion of female respondents (p<0·01). GNI per capita was inversely related to the proportion of respondents working exclusively in private practice (p<0·011) and the proportion of respondents who treated >100 patients annually (p<0·01). Discussion: THESIS has demonstrated differences in characteristics of thyroid specialists at national and regional levels, strongly associated with GNI per capita. Hypothyroid patients in middle-income countries are more likely to encounter female thyroid specialists working in private practice, with a high workload, compared to high-income countries. Whether these differences influence the quality of care and patient satisfaction is unknown, but merits further study.

Frequency of adiponectin gene polymorphisms in polycystic ovary syndrome and the association with serum adiponectin, androgen levels, insulin resistance and clinical parameters.

AIM: Although the association between adiponectin gene polymorphisms and insulin resistance has been investigated in many studies, there are only a few studies, which have investigated adiponectin gene polymorphisms in patients with polycystic ovary syndrome (PCOS). The objectives of this study were to determine the frequency of T45G polymorphisms localised in exon 2 of the adiponectin gene in a Turkish population with PCOS and to determine the association of T45G polymorphisms with insulin resistance and serum adiponectin levels in PCOS. MATERIALS AND METHODS: Ninety-six patients with PCOS and 93 healthy control subjects were included in the study. Insulin resistance was estimated via HOMA-IR. Serum adiponectin levels were measured by ELISA. For determination of adiponectin gene polymorphisms, PCR was performed with appropriate primers after genomic DNA was obtained from the peripheral blood of the patients and control subjects. RESULTS: Adiponectin levels were low in patients with PCOS than control subjects. There was no significant statistical difference between the PCOS and control groups with respect to the frequency of polymorphisms and the genotype distribution. Adiponectin gene polymorphisms were not associated with the anthropometric parameters, hyperandrogenism and adiponectin levels in PCOS. However, the fasting insulin level and insulin resistance were significantly higher and more frequent, respectively, in the polymorphic group compared to the other genotypes among patients with PCOS. CONCLUSION: The risk of PCOS, hyperandrogenism in patients with PCOS and low serum adiponectin levels cannot be directly attributed to T45G adiponectin gene polymorphisms in exon 2, rather these polymorphisms may be associated with insulin resistance and hyperinsulinemia in PCOS.

Serum resistin and adiponectin levels in women with polycystic ovary syndrome.

AIM: This study was performed to compare the serum levels of resistin and adiponectin in women with polycystic ovary syndrome (PCOS) and normal controls. MATERIALS AND METHODS: Seventy-six patients (36 obese, 40 non-obese) with PCOS and 42 healthy subjects were included in the study. Serum levels of resistin, adiponectin, follicle-stimulating hormone, luteinising hormone, dehydroepiandrosterone sulfate (DHEA-S), 17-hydroxy progesterone, free testosterone, androstenedione, glucose, insulin and lipid parameters were measured. Insulin resistance and carbohydrate metabolism were evaluated by using the homeostasis model (HOMA) and the area under the insulin curve (AUCI). RESULTS: Plasma resistin levels, HOMA-IR and AUCI were significantly higher and adiponectin level was lower in women with PCOS than those in healthy women. Plasma resistin levels were similar among obese and non-obese women with PCOS. No correlation was observed between resistin, body mass index (BMI), HOMA-IR, AUCI, insulin, lipid parameters and serum androgen levels. In obese PCOS patients, adiponectin levels were lower than in the lean PCOS patients. A negative correlation was observed among adiponectin, HOMA-IR, AUCI, BMI, testosterone, DHEAS, total-cholesterol, LDL-cholesterol and lipoprotein (a) levels. CONCLUSION: These results suggest that the serum adiponectin level may be involved in the pathogenesis of PCOS. But resistin levels were independently associated with insulin resistance and BMI in PCOS patients. Nevertheless, wider-scale trials are required to be performed on this subject.

46 XX male syndrome with hypogonadotropic hypogonadism: A case report.

We report a 46 XX male syndrome diagnosed after failure of gonadotropin therapy taken for hypogonadotropic hypogonadism due to a pituitary macroadenoma. A 39-year-old man with a non-functioning pituitary macroadenoma was admitted to our clinic due to vision loss and infertility. After pituitary surgery, vision loss improved while infertility still existed. Low testosterone levels without elevated gonadotropins were established suggesting hypogonadotropic hypogonadism due to pituitary adenoma. Gonadotropin treatment was initiated. There was no response to treatment after 12 months. A karyotype analysis was ordered to investigate other causes of infertility. Karyotype analysis showed a 46 XX male syndrome that can explain the failure of gonadotropin therapy. Testosterone therapy was started instead of gonadotropin therapy. 46 XX male syndrome usually presents with hypergonadotropic hypogonadism. However, in our case, it presented with hypogonadotropic hypogonadism due to pituitary mass not responding to gonadotropin therapy. It is important to keep in mind to obtain a genetic analysis of patients whose gonadotropin therapy failed, even if their gonadotropin levels are not elevated.

Risk factors for cardiovascular disease in patients with subclinical hypothyroidism.

INTRODUCTION: The relationship between subclinical hypothyroidism (SCH) and cardiovascular disease is not fully understood. We investigated risk factors for cardiovascular disease (lipid profile, lipoproteins, insulin resistance, C-reactive protein [CRP] homocysteine [Hcy] and fibrinogen levels) and their relationships with thyroid hormones in SCH patients and controls. METHODS: Thirty-eight SCH patients and 44 controls were enrolled in this study. No patients had any substantial confounding medical conditions (including diabetes mellitus or coronary heart disease) or were taking thyroid-related medication. RESULTS: Serum total cholesterol (P<0.05), low-density lipoprotein cholesterol (P<0.05) and triglycerides (P<0.001) were higher in patients with SCH than in controls. Serum lipoprotein(a) (Lp[a]) levels were higher in SCH subjects but this difference did not reach statistical significance (P=0.07). No significant differences were noted in CRP, Hcy, fibrinogen, high-density lipoprotein cholesterol, apolipoprotein A-1, apolipoprotein B (Apo B) or insulin resistance between patients with SCH and controls (in all cases, P>0.05). Free triiodothyronine (FT3) negatively correlated with Apo B (r=.0.46, P=0.005) and Lp(a) (r=.0.31, P=0.03) in patients with SCH and negatively correlated with Lp(a) (r=.0.30, P=0.04) in controls. All of these parameters were comparable between patients with thyroid-stimulating hormone (TSH) >10 microIU/ml and TSH <10 microIU/ml (in SCH patients, P>0.05). CONCLUSION: Our results suggest that SCH is associated with some lipid and lipoprotein abnormalities. Our results also suggest that this association does not depend on the subject's TSH level.

Predictive score for the development or progression of Graves' orbitopathy in patients with newly diagnosed Graves' hyperthyroidism.

OBJECTIVE: To construct a predictive score for the development or progression of Graves' orbitopathy (GO) in Graves' hyperthyroidism (GH). DESIGN: Prospective observational study in patients with newly diagnosed GH, treated with antithyroid drugs (ATD) for 18 months at ten participating centers from EUGOGO in 8 European countries. METHODS: 348 patients were included with untreated GH but without obvious GO. Mixed effects logistic regression was used to determine the best predictors. A predictive score (called PREDIGO) was constructed. RESULTS: GO occurred in 15% (mild in 13% and moderate to severe in 2%), predominantly at 6-12 months after start of ATD. Independent baseline determinants for the development of GO were clinical activity score (assigned 5 points if score > 0), TSH-binding inhibitory immunoglobulins (2 points if TBII 2-10 U/L, 5 points if TBII > 10 U/L), duration of hyperthyroid symptoms (1 point if 1-4 months, 3 points if >4 months) and smoking (2 points if current smoker). Based on the odds ratio of each of these four determinants, a quantitative predictive score (called PREDIGO) was constructed ranging from 0 to 15 with higher scores denoting higher risk; positive and negative predictive values were 0.28 (95% CI 0.20-0.37) and 0.91 (95% CI 0.87-0.94) respectively. CONCLUSIONS: In patients without GO at diagnosis, 15% will develop GO (13% mild, 2% moderate to severe) during subsequent treatment with ATD for 18 months. A predictive score called PREDIGO composed of four baseline determinants was better in predicting those patients who will not develop obvious GO than who will.

Serum Ghrelin Levels in patients with Hashimoto's thyroiditis.

OBJECTIVE: Hypothyroidism is associated with changes in appetite and body weight. Ghrelin is an orexigenic peptide, and it stimulates appetite and increases food intake. However, the potential relationship between circulating ghrelin levels, hypothyroidism, and thyroid antibodies has not been adequately studied. DESIGN: Forty-seven patients with hypothyroidism due to Hashimoto's thyroiditis and 48 euthyroid subjects were enrolled in the study. Thyroid hormones and antibodies, insulin, glucose, ghrelin levels, and lipid parameters were measured in all the subjects. MAIN OUTCOME: Hypothyroid group showed significantly decreased serum levels of ghrelin and ghrelin=body mass index (BMI) compared to euthyroid group (31.9 +/- 21.5 pg/mL vs. 50.5 +/- 34.8 pg/mL, p < 0.001; and 1.24 +/- 0.93 vs. 2.12 +/- 1.53, p < 0.0001). In hypothyroid group, 6 months after treatment, ghrelin levels and ghrelin/BMI remained lower than euthyroid group (33.2 +/- 21.1 pg/mL vs. 50.5 +/- 34.8 pg/mL, p < 0.001; and 1.27 +/- 0.86 vs. 2.12 +/- 1.53, p < 0.0001). Ghrelin levels were decreased in hypothyroid patients with high thyroid peroxidase antibody (TPOAb) titre compared to hypothyroid patients with low TPOAb titre (19.1 +/- 23.1 pg/ mL vs. 35.3 +/- 17.4 pg/mL, p < 0.01). Ghrelin levels correlated positively with free triiodothyronine (FT3) and free thyroxine (FT4), and negatively with age, thyroglobulin antibody (TAb), TPOAb, total cholesterol (T-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and triglycerides (TG) in hypothyroid group. In euthyroid group, circulating ghrelin levels correlated negatively with age, FT3, FT4, TG, and VLDL-C levels. No significant correlation was observed between ghrelin and homeostasis model assessment for insulin resistance (HOMA-IR) and between ghrelin and quantitative insulin sensitivity check index (QUICKI) in both groups. Regression analysis revealed that FT3 level is the most important predictor of ghrelin levels. CONCLUSION: Thyroid hormones and antibodies seem to have a potential effect on serum ghrelin levels in patients with hypothyroidism.

Orbital gallium-67 scintigraphy in Graves' ophthalmopathy: a disease activity parameter that predicts the therapeutic response to immunosuppressive treatment.

In this study, orbital gallium-67 citrate ((67)Ga) scintigraphy was evaluated as a disease activity parameter that can predict the therapeutic response to immunosuppressive treatment in Graves' ophthalmopathy. Orbital scintigraphic analysis was performed on 32 patients demonstrating moderate to severe Graves' ophthalmopathy. Single-photon emission computed tomography (SPECT) images were obtained 48 hours after intravenous injection of 148 MBq of radioactive (67)Ga complex, and orbit/occipital (O/Occ) ratios were calculated to correct the background activity. Intravenous methylprednisolone was given as immunosuppressive treatment to 24 patients (group 1) and 8 patients were followed up without any treatment and evaluated as controls (group 2). Orbital (67)Ga scintigraphy was repeated in all patients after 6 months to analyze the changes in clinical findings and orbital (67)Ga accumulation. In Group 1, the mean +/- standard deviation (SD) (67)Ga O/Occ ratio of responders (2.23 +/- 0.2, 16 cases) was statistically different from nonresponders (1.49 +/- 0.1, 8 cases, p < 0.001). Additionally, the corticosteroid treatment provided a significant decrease in orbital (67)Ga accumulation in responders (p < 0.001), however, it did not change statistically in nonresponders (p:0.13). In group 2, the patients did not demonstrate clinical improvement and orbital (67)Ga uptake did not change after the follow-up period (p:0.81). The receiver-operator-characteristic curve showed that the best threshold for discriminating responder and nonresponder groups was 1.70 (sensitivity, 94%; specificity, 88%). This study demonstrated that orbital (67)Ga scintigraphy may be a useful imaging technique in predicting the therapeutic response to immunosuppressive treatment in Graves' ophthalmopathy.

Real-life safety and efficacy of vildagliptin as add-on to metformin in patients with type 2 diabetes in Turkey--GALATA study.

OBJECTIVE: To evaluate tolerability/safety and the efficacy of the combination of vildagliptin plus metformin in a real-life population of patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This multicenter, single-arm, 6 month, observational, prospective cohort study was conducted at 39 centers across Turkey. T2DM patients on vildagliptin and metformin for ≤4 weeks were enrolled regardless of their previous antidiabetic therapy. MAIN OUTCOME MEASURES: Efficacy was evaluated by measuring hemoglobin A1c (HbA1c) levels. Tolerability/safety parameters evaluated included hypoglycemic events, gastrointestinal events, peripheral edema and weight gain. RESULTS: This study enrolled 665 patients with a mean ± standard deviation (SD) age of 55.1 ± 10.2 years and female predominance (n = 394, 59.2%). Safety was assessed in all enrolled patients. Hypoglycemia was reported in 10 (1.5%) patients (95% confidence interval = 0.8-2.7%). Efficacy was assessed in 289 (43.5%) patients treated for 6 ± 1 months; these patients showed a mean decrease in HbA1c of 0.8% from baseline value of 7.8% (p < 0.001). The percentages of patients who achieved HbA1c targets of ≤6.5% and ≤7.0% were significantly increased, from 10.7% to 33.6% and from 22.1% to 52.6%, respectively (p < 0.001 each). The decrease in HbA1c was independent of baseline HbA1c (≤8% vs. 8-10% vs. ≥10%), age (≤65 vs. >65 years) and body mass index (<30 vs. ≥30 kg/m(2)) (p < 0.001 each). In total, 136 adverse events (AEs) were observed in 71 (10.7%) patients; 10 (1.5%) patients experienced hypoglycemia and gastrointestinal AEs were most commonly reported (n = 29, 4.4%). CONCLUSIONS: In a 'real-life' setting, the vildagliptin and metformin combination was associated with significant improvements in reaching target HbA1c levels, even in elderly and obese patients with T2DM. Moreover, vildagliptin and metformin demonstrated a good overall tolerability/safety profile.

The effect of thyroid autoimmunity on T-cell responses in early pregnancy.

Thyroid autoimmunity (TAI) is common in women of reproductive age. There is a relationship between TAI and recurrent pregnancy loss and infertility. In pregnant patients with thyroid autoimmunity, the T helper-1 (Th1)/T helper-2 (Th2) ratio may shift to a Th1-type response and these activated T lymphocytes may lead to implantation failure. The aims of this study were to investigate the serum levels of Th1-, Th2-, and T-helper-17-(Th17)-associated cytokines in pregnant patients with TAI, and to evaluate how these cytokines change with l-thyroxin treatment during pregnancy. Twenty pregnant women with TAI diagnosed in the first trimester of pregnancy who were not on l-thyroxine treatment, 14 pregnant women with known TAI before pregnancy already been on l-thyroxine treatment, and 19 pregnant patients without TAI were included in this study. Thyroid function tests, thyroid autoantibodies, and cytokine levels were measured at the first and the second trimesters. In pregnant patients who were diagnosed with TAI in the first trimester, both serum IL-2 levels and IL-17 levels were significantly higher than those of the control group. There were no significant differences between groups for serum IL-4, IL-6, IL-23, IL-10, and IFNγ levels. In the second trimester, no significant differences were found between groups for all the cytokines measured. There are significant differences in Th1- and Th17-associated cytokine levels between patients with TAI and the control group in the first trimester. In the second trimester cytokine levels were similar among all groups. This pattern may be associated with the clinical benefits of l-thyroxine treatment.

PREGO (presentation of Graves' orbitopathy) study: changes in referral patterns to European Group On Graves' Orbitopathy (EUGOGO) centres over the period from 2000 to 2012.

BACKGROUND/AIMS: The epidemiology of Graves' orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time. METHODS: Prospective observational study of European Group On Graves' Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000. RESULTS: The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, including smoking rates (40.0% vs 40.2%). Mild (60.5% vs 41.2%, p<0.01) and inactive GO (63.2% vs 39.9%, p<0.01) were more prevalent in 2012. The times from diagnosis of thyroid disease to being seen in EUGOGO centres (6 vs 16 months) and from first symptoms of GO (9 vs 16 months) or from diagnosis of GO (6 vs 12 months) to first consultation in EUGOGO centres were shorter in 2012 (p<0.01). The initial management plans for GO were no different except surgical treatments for patients with mild inactive disease were more frequently offered in the 2012 cohort than in 2000 (27.3% vs 17%, p<0.05), and selenium supplements were offered only in the 2012 cohort (21.2% vs 0%, p<0.01). CONCLUSIONS: These findings suggest that the clinical manifestations of patients with GO may be changing over time in Europe.

Orbital gallium-67 scintigraphy in Graves' ophthalmopathy.

Assessment of orbital disease activity in patients with Graves' ophthalmopathy is important in planning the therapeutic approach. In this study, orbital uptake of gallium-67 citrate ((67)Ga) was evaluated in 46 consecutive patients demonstrating active or inactive Graves' ophthalmopathy. The disease activity with Graves' ophthalmopathy was evaluated by using clinical activity score (CAS). Orbital (67)Ga scintigraphies of 8 patients without any history of ophthalmic, thyroid, or autoimmune disease were studied as controls. (67)Ga scintigraphy was performed 48 hours after intravenous injection of 4 mCi (128 MBq) of radioactive complex. Single-photon emission computed tomography (SPECT) images were obtained with a gamma camera. Intravenous corticosteroid treatment was given to 8 selected patients demonstrating bilateral active orbital disease and (67)Ga scintigraphy was repeated 6 months after the treatment. Quantitative analysis of mean orbital (67)Ga uptake demonstrated significant difference between active, inactive, and control groups (p = 0.0001). The orbital uptake of (67)Ga was significantly elevated in the active group compared to the inactive and control groups. A threshold orbital (67)Ga uptake value was calculated to differentiate active and inactive groups based on receiver operating characteristic (ROC) analysis. A significant correlation was found between the CAS and the (67)Ga orbital uptake (r = 0.73, p = 0.0001). Clinical improvement and significant decrease in orbital (67)Ga uptake were achieved after immunosuppressive treatment (p = 0.0004). These preliminary results suggest that orbital (67)Ga scintigraphy may provide objective assessment of the disease activity in Graves' ophthalmopathy.

Effects of rosiglitazone treatment on the pentose phosphate pathway and glutathione-dependent enzymes in liver and kidney of rats fed a high-fat diet.

BACKGROUND: Animals fed high-fat diets have been shown to develop hyperglycemia, insulin resistance, hyperlipidemia, and moderate obesity, which resemble the human metabolic syndrome. Obesity, the metabolic syndrome, and some thiazolidinediones, which act as insulin sensitizers, may increase oxidative stress, and/or influence the levels of cellular reducing equivalents and homeostasis. OBJECTIVE: This study investigated the effects of a high-fat diet, rosiglitazone, or a high-fat diet plus rosiglitazone on metabolic syndrome parameters and crucial liver and kidney enzyme activities in rats. METHODS: Male Wistar rats were assigned to 4 groups (n = 6 per group): (1) the fat (F) group was fed a rodent diet comprising 45 kcal% fat, (2) the rosiglitazone (R) group was fed a standard rat chow comprising 4.97 kcal% fat plus rosiglitazone (3 mg/kg.d), (3) the fat + rosiglitazone (FR) group was fed a rodent diet comprising 45 kcal% fat (as lard, product D12451) plus rosiglitazone (3 mg/kg.d), and (4) the control (C) group was fed a standard rat chow comprising 4.97 kcal% fat. Animals were housed for 4 weeks, at which time the liver and kidney were isolated for spectrophotometric determination of enzyme activities. Body weight was measured before treatment (baseline) and then weekly throughout the study. Adiposity was measured at the end of the 4 weeks. RESULTS: The activities of glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR), and glutathione-S-transferase (GST) were significantly reduced in the livers of groups F, R, and FR compared with group C (all P < 0.05). Kidney G6PD, 6-PGD, and GR were found to be significantly lower in group R compared with the other groups (all P < 0.05). Kidney GST was similar in all groups. Plasma glucose, triglyceride, and insulin concentrations were significantly higher than in group F versus the other groups (all P < 0.05). Adiposity was increased in groups F and FR compared with groups C and R (all P < 0.05). Serum cholesterol concentrations were similar in all groups. CONCLUSIONS: In this study, high-fat diet in rats decreased the enzyme activities responsible for pentose phosphate pathway and glutathione-dependent metabolism in liver but not in kidney. Similarly, these enzyme activities were inhibited with rosiglitazone treatment alone in both organs.

The effect of calpain-10 gene polymorphism on the development of type 2 diabetes mellitus in a Turkish population.

INTRODUCTION: The variations in the Calpain-10 gene have been suggested to be related to susceptibility to type 2 diabetes mellitus (T2DM) in different populations. In this study, we investigated the relationship between single nucleotide polymorphism (SNP)-19, -44 and -63 in the Calpain-10 gene and the development of T2DM in a Turkish population. MATERIAL AND METHODS: A total of 211 subjects were recruited: 118 patients with a diagnosis of T2DM and 93 unrelated healthy subjects. RESULTS: There were no significant differences in the genotype and allele distribution of SNPs studied between the patients with T2DM and controls (p > 0.05), whereas the frequencies of 121 haplotype and 122/121 haplotype combination were found to be higher in patients with T2DM than in controls (p < 0.05). No association was observed between the variations in the Calpain-10 gene and glycaemic control and lipid parameters (p > 0.05). The SNP-19 insertion/insertion was significantly related to increased body mass index (BMI) in male diabetic patients (p < 0.05). CONCLUSIONS: The present study indicates that 121 haplotype and 122/121 haplotype combination of SNP-19, -44 and -63 in the Calpain-10 gene are associated with the development of T2DM in Turkish patients.

Cost Effectiveness of Insulin Glargine versus Neutral Protamin Hagedorn Insulin in the Treatment of Type 2 Diabetes Patients in Turkey.

Background: Type 2 diabetes mellitus (T2DM) poses a significant burden on population well being and healthcare expenditure in Turkey, with disease prevalence continuing to increase. Insulin treatment is necessary for patients failing to achieve glycaemic control with lifestyle modification or oral antidiabetic drugs. While neutral protamin Hagedorn (NPH) insulin has been traditionally prescribed for insulin introduction, insulin glargine has been shown to reduce glycated hemoglobin (HbA1c) with a more favourable hypoglycaemic profile. Objective: To evaluate the cost-effectiveness of insulin glargine compared to NPH insulin in patients with T2DM in Turkey, from a Social Security Institution perspective. Methods: A previously published discrete event simulation model of T2DM progression was utilised to characterise the cost-effectiveness of insulin glargine in a Turkish population given the benefits observed in clinical practice. Improvements in glycaemic control have been incorporated using data from The Health Improvement Network (THIN) database in the United Kingdom, combined with meta-regression results describing the relationship between hypoglycaemia and glycaemic control. Outcomes were evaluated over a 40-year horizon, and costs and benefits discounted at an annual rate of 3.5%. Results are reported in Turksih lira (TL), 2012. Results: Over a lifetime, the Incremental Cost-effectiveness Ratio (ICER) of insulin glargine compared to NPH was 40,101 TL per Quality-adjusted Life Year (QALY). Almost 52 hypoglycaemic events per patient were avoided with the use of insulin glargine compared to NPH, at an incremental lifetime cost of 7,140 TL per patient. The cost-effectiveness of insulin glargine is reduced when modelling only those benefits considered in the trial setting, while the cost-effectiveness profile can be expected to further improve in patients with higher HbA1c levels at baseline. Conclusion: It is difficult to interpret the results of modelling as there is no official cost-effectiveness threshold in Turkey. However, the results may be evaluated using thresholds derived according to methodology proposed by the World Health Organisation (WHO). Insulin glargine is expected to be costeffective compared to NPH insulin, with an ICER below three times the estimated gross domestic product (GDP) per capita; 56,850 TL.