Treatment of Obesity with Thyroid hormones in Europe. Data from the THESIS* Collaboration.

PURPOSE: The use of thyroid hormones (TH) to treat obesity is unsupported by evidence as reflected in international guidelines. We explored views about this practice, and associations with respondent characteristics among European thyroid specialists. METHODS: Specialists from 28 countries were invited to a survey via professional organisations. The relevant question was whether "Thyroid hormones may be indicated in biochemically euthyroid patients with obesity resistant to lifestyle interventions". RESULTS: Of 17,232 invitations 5695 responses were received (33% valid response rate; 65% women; 90% endocrinologists). Of these, 290 (5.1%) stated that TH may be indicated as treatment for obesity in euthyroid patients. This view was commoner among non-endocrinologists (8.7% vs. 4.7%, p < 0.01), private practice (6.5% vs. 4.5%, p < 0.01), and varied geographically (Eastern Europe, 7.3%; Southern Europe, 4.8%; Western Europe, 2.7%; and Northern Europe, 2.5%). Respondents from Northern and Western Europe were less likely to use TH than those from Eastern Europe (p < 0.01). Gross national income (GNI) correlated inversely with this view (OR 0.97, CI: 0.96-0.97; p < 0.001). Having national guidelines on hypothyroidism correlated negatively with treating obesity with TH (OR 0.71, CI: 0.55-0.91). CONCLUSIONS: Despite the lack of evidence, and contrary to guidelines' recommendations, about 5% of respondents stated that TH may be indicated as a treatment for obesity in euthyroid patients resistant to life-style interventions. This opinion was associated with (i) respondent characteristics: being non-endocrinologist, working in private practice, treating a small number of hypothyroid patients annually and (ii) national characteristics: prevalence of obesity, Eastern Europe, low GNI and lack of national hypothyroidism guidelines.

Antithyroid drugs in Graves' hyperthyroidism: differences between "block and replace" and "titration" regimes in frequency of euthyroidism and Graves' orbitopathy during treatment.

PURPOSE: Whereas antithyroid drugs (ATD) are the preferred treatment modality for Graves' hyperthyroidism (GH), there is still controversy about the optimal regimen for delivering ATD. To evaluate whether 'Block and Replace' (B + R) and 'Titration' (T) regimes are equivalent in terms of frequency of euthyroidism and Graves' Orbitopathy (GO) during ATD therapy. METHODS: A prospective multicentre observational cohort study of 344 patients with GH but no GO at baseline. Patients were treated with ATD for 18 months according to B + R or T regimen in line with their institution's policy. RESULTS: Baseline characteristics were similar in both groups. In the treatment period between 6 and 18 months thyrotropin (TSH) slightly increased in both groups, but TSH was on average 0.59 mU/L (95% CI 0.27-0.85) lower in the B + R group at all time points (p = 0.026). Serum free thyroxine (FT4) remained stable during the same interval, with a tendency to higher values in the B + R group. The point-prevalence of euthyroidism (TSH and FT4 within their reference ranges) increased with longer duration of ATD in both groups; it was always higher in the T group than in the B + R group: 48 and 24%, respectively, at 6 months, 81 and 58% at 12 months, and 87 and 63% at 18 months (p < 0.002). There were no significant differences between the B + R and T regimens with respect to the fall in thyrotropin binding inhibiting immunoglobulins (TBII) or thyroid peroxidase antibodies (TPO-Ab). GO developed in 15.9% of all patients: 9.1 and 17.8% in B + R group and T group, respectively, (p = 0.096). GO was mild in 13% and moderate-to-severe in 2%. CONCLUSION: The prevalence of biochemical euthyroidism during treatment with antithyroid drugs is higher during T compared to B + R regimen. De novo development of GO did not differ significantly between the two regimens, although it tended to be higher in the T group. Whether one regimen is clinically more advantageous than the other remains unclear.

Asymmetry indicates more severe and active disease in Graves' orbitopathy: results from a prospective cross-sectional multicentre study.

PURPOSE: Patients with Graves' orbitopathy can present with asymmetric disease. The aim of this study was to identify clinical characteristics that distinguish asymmetric from unilateral and symmetric Graves' orbitopathy. METHODS: This was a multi-centre study of new referrals to 13 European Group on Graves' Orbitopathy (EUGOGO) tertiary centres. New patients presenting over a 4 month period with a diagnosis of Graves' orbitopathy were included. Patient demographics were collected and a clinical examination was performed based on a previously published protocol. Patients were categorized as having asymmetric, symmetric, and unilateral Graves' orbitopathy. The distribution of clinical characteristics among the three groups was documented. RESULTS: The asymmetric group (n = 83), was older than the symmetric (n = 157) group [mean age 50.9 years (SD 13.9) vs 45.8 (SD 13.5), p = 0.019], had a lower female to male ratio than the symmetric and unilateral (n = 29) groups (1.6 vs 5.0 vs 8.7, p < 0.001), had more active disease than the symmetric and unilateral groups [mean linical Activity Score 3.0 (SD 1.6) vs 1.7 (SD 1.7), p < 0.001 vs 1.3 (SD 1.4), p < 0.001] and significantly more severe disease than the symmetric and unilateral groups, as measured by the Total Eye Score [mean 8.8 (SD 6.6) vs 5.3 (SD 4.4), p < 0.001, vs 2.7 (SD 2.1), p < 0.001]. CONCLUSION: Older age, lower female to male ratio, more severe, and more active disease cluster around asymmetric Graves' orbitopathy. Asymmetry appears to be a marker of more severe and more active disease than other presentations. This simple clinical parameter present at first presentation to tertiary centres may be valuable to clinicians who manage such patients.

Graves' orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune condition, which is associated with poor clinical outcomes including impaired quality of life and socio-economic status. Current evidence suggests that the incidence of GO in Europe may be declining, however data on the prevalence of this disease are sparse. Several clinical variants of GO exist, including euthyroid GO, recently listed as a rare disease in Europe (ORPHA466682). The objective was to estimate the prevalence of GO and its clinical variants in Europe, based on available literature, and to consider whether they may potentially qualify as rare. Recent published data on the incidence of GO and Graves' hyperthyroidism in Europe were used to estimate the prevalence of GO. The position statement was developed by a series of reviews of drafts and electronic discussions by members of the European Group on Graves' Orbitopathy. The prevalence of GO in Europe is about 10/10,000 persons. The prevalence of other clinical variants is also low: hypothyroid GO 0.02-1.10/10,000; GO associated with dermopathy 0.15/10,000; GO associated with acropachy 0.03/10,000; asymmetrical GO 1.00-5.00/10,000; unilateral GO 0.50-1.50/10,000. CONCLUSION: GO has a prevalence that is clearly above the threshold for rarity in Europe. However, each of its clinical variants have a low prevalence and could potentially qualify for being considered as a rare condition, providing that future research establishes that they have a distinct pathophysiology. EUGOGO considers this area of academic activity a priority.

Calpain 10 gene single-nucleotide 44 polymorphism may have an influence on clinical and metabolic features in patients with polycystic ovary syndrome.

AIM: This study was designed in order to examine the relationship between Calpain 10 [single-nucleotide polymorphism (SNP) 19,43,44,63] gene polymorphisms and clinical and hormonal characteristics in women with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: One hundred and seven patients with PCOS and 114 healthy subjects were included in this study. Serum levels of sex steroids were measured for each individual. Insulin resistance (IR) was evaluated by the homeostasis model assessment (HOMA) and quantitative insulin-sensitivity check index (QUICKI) methods. Insulin and glucose responses to the oral glucose tolerance test (OGTT) were analyzed by calculating the areas under the curve for insulin (AUCI) and glucose by the trapezoidal methods.We used PCR and restriction fragment length polymorphism technique to examine Calpain 10 SNP 19, 43, 44, and 63 polymorphisms. RESULTS: Allele distribution of Calpain 10 SNP 44 gene polymorphism was observed as significantly different between the groups. Calpain 10 SNP 44 TC genotype was found to be increased in PCOS subjects (69.15%) compared to the control subjects (50%). However, when compared to control subjects, patients with PCOS had similar Calpain 10 SNP 19, Calpain 10 SNP 43, and SNP 63 gene polymorphisms. When compared with normal Calpain 10 gene SNP 44 allele in PCOS subjects, subjects with PCOS having Calpain 10 gene SNP 44 allele polymorphism had higher free testosterone, androstenedione, DHEA-S, and fasting insulin levels. Also, PCOS women with Calpain 10 gene SNP 44 allele polymorphism had high Ferriman-Gallwey (F-G) score, acne, prevalence of menstrual disturbances, waist-hip ratio, HOMA-IR, AUCI levels and low QUICKI levels. CONCLUSION: The findings show that Calpain 10 gene SNP 44 allele polymorphism may have a role in PCOS pathogenesis. However, larger-scale studies are needed in this field.

Atherogenic lipoprotein phenotype and LDL size and subclasses in women with gestational diabetes.

AIMS: Women with gestational diabetes are more likely to develop Type 2 diabetes and cardiovascular disease after pregnancy; however, the exact nature of the lipid alterations present is not clear. In Mediterranean women with gestational diabetes, we measured low-density lipoprotein (LDL) size and all seven subclasses, as well as the 'atherogenic-lipoprotein phenotype'[ALP, e.g. concomitant presence of elevated triglycerides, reduced high-density lipoprotein (HDL)-cholesterol and increased small, dense LDL]. METHODS: In 27 women with gestational diabetes and 23 healthy pregnant women matched for age, weeks of gestation and body mass index, we measured plasma lipids and LDL size and subclasses by gradient gel electrophoresis between 24 and 28 weeks of gestation. RESULTS: Although no significant differences were found in the concentrations of any of the plasma lipids, compared with control subjects women with gestational diabetes had lower LDL size (P = 0.0007) due to reduced LDL-I (P = 0.0074) and increased LDL-IVA (P = 0.0146) and -IVB (P < 0.0001) subclasses. Correlation analysis revealed that fasting glucose, homeostasis model assessment and glycated haemoglobin were inversely correlated with LDL-I and positively with LDL-IVA and -IVB (all P < 0.05). ALP due to high HDL-cholesterol levels was not seen in either group, whereas elevated small, dense LDL were more common in women with gestational diabetes than control subjects (33% vs. 4%, P = 0.0107). CONCLUSIONS: Increased levels of small, dense LDL are common in Mediterranean women with gestational diabetes. Whether these findings affect the atherogenic process and clinical end-points in these women remains to be determined by future prospective studies.

The association of neurofibromatosis, bilateral pheochromocytoma and primary hyperparathyroidism.

Neurofibromatosis (NF) is a hereditary disease and carries increased risk of both benign and malignant tumor development. Pheochromocytoma or hyperparathyroidism have been reported to be associated with NF type 1 (NF1). However, the coexistance of pheochromocytoma and parathyroid adenoma in a patient with NF1 is very rare. We report a case of a 37-year-old male with NF1, bilateral pheochromocytoma and parathyroid adenoma. This association sould be kept in mind in patients with NF1 in initial evaluation as well as during follow-up.

The effects of rosiglitazone and metformin on insulin resistance and serum androgen levels in obese and lean patients with polycystic ovary syndrome.

AIM: The aim of this study was to assess the effects of metformin and rosiglitazone on insulin resistance and serum androgen levels in both obese and lean patients with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Forty lean [body mass index (BMI) < 25 kg/m2] and 40 overweight and obese (BMI > 25 kg/m2) patients were included in the study. Waist and hip measurements, serum sex steroid levels, insulin response to 75-g oral glucose tolerance test, fasting insulin, fasting C-peptide levels and homeostasis model assessment of insulin resistance (HOMA-IR) were determined in all patients. The degree of hirsutism was determined by the Ferriman-Gallwey scoring system. Patients were divided into two groups, with 40 (20 overweight and obese; 20 non-obese) patients each. One group was treated with metformin (MET group) 850 mg bid while the other received rosiglitazone (ROSI group) 4 mg/day for 12 weeks. All measurements were repeated at the end of this period. RESULTS: After the 12-week treatment period, HOMA-IR, area under the curve of insulin, fasting insulin and C-peptide levels were observed to have be decreased significantly in all groups. The decrease in the parameters mentioned above was similar in the four groups. The serum levels of free testosterone, androstenedione and DHEA-S decreased in all groups, but the decrease was statistically significant only in the ROSI groups. Within the lean MET group one patient became pregnant and was hence excluded from the final data analysis. Menstruations became regular after metformin therapy in 41.6% of lean and 35.7% of obese patients who had menstrual disturbance prior to the study. Rosiglitazone therapy improved menstrual disturbance in 61.5 % of lean and 53.8% of obese patients. CONCLUSIONS: Our data showed that both metformin and rosiglitazone increased insulin sensitivity in obese patients with PCOS as expected, and in lean patients as well. Rosiglitazone seemed to be more effective in decreasing the androgen levels and in achieving slightly greater improvement in menstrual disturbance than metformin.

Effects of PPARgamma and PPARalpha agonists on serum leptin levels in diet-induced obese rats.

Leptin and peroxisome proliferator-activated receptors are two important adipose tissue factors involved in energy metabolism regulation. It has been shown that PPARgamma agonists decrease leptin levels. However, the effects of PPARalpha agonists on leptin have not been investigated much. The aim of this study was to compare the effects of a PPARgamma agonist rosiglitazone (RSG) and PPARalpha agonist gemfibrozil (G) on body weight and serum insulin and leptin levels in diet-induced obese rats. Male Wistar rats were divided into six groups according to diet and drug therapy. After four weeks, serum glucose, triglyceride, insulin and leptin levels were significantly decreased in the high-fat-fed and RSG-treated groups compared to the group fed a high-fat diet only (162 +/- 19 vs. 207 +/- 34 mg/dl, 58 +/- 20 vs. 112 +/- 23 mg/dl, 3.1 +/- 1.0 vs. 15.2 +/- 4.0 ng/ml, 1.6 +/- 0.5 vs. 3.6 +/- 1.6 ng/ml, respectively). However, these parameters were not statistically different in RSG animals treated with a standard diet compared to the standard diet group. The high fat+RSG group gained much more weight compared to high-fat and high-fat+G groups (p > 0.05). Additionally, serum glucose, insulin and leptin levels were significantly decreased in the high-fat-fed and G-treated group compared to high-fat group (149 +/- 19 vs. 207 +/- 34 mg/dl, 57 +/- 16 vs. 112 +/- 23 mg/dl, 4.3 +/- 2.1 vs. 15.2 +/- 4.0 ng/ml, 1.6 +/- 0.4 vs. 3.6 +/- 1.6 ng/ml, respectively). These results suggest that PPARalpha agonists may decrease serum glucose, insulin and leptin levels as PPARgamma agonists do in diet-induced obese rats.

Insulin secretion and insulin sensitivity in normal pregnancy and gestational diabetes mellitus.

The purpose of this study was to evaluate insulin sensitivity, beta-cell function and islet-cell-directed autoimmunity in pregnant women with normal glucose tolerance and gestational diabetes mellitus (GDM). A total of 21 women with normal glucose tolerance and 21 women with GDM were evaluated at 24-36 weeks' gestation. Insulin resistance and beta-cell function were evaluated using the continuous infusion of glucose with model assessment (CIGMA) method, which aims to give a near-physiological stimulus and to evaluate the endogenous insulin and glucose response. Islet-cell autoantibody was positive in one woman with GDM, and glutamic acid decarboxylase autoantibodies were negative in both groups. The calculated CIGMA insulin resistance (CIGMA IR) was 2.04 +/- 1.74 and 1.08 +/- 1.22 in patients with GDM and in control subjects, respectively (p < 0.05). CIGMA percentage beta-cell values were 64.04 +/- 44.55% and 87.07 +/- 52.77% in patients with GDM and control subjects, respectively (p > 0.05). Decreased insulin sensitivity in late pregnancy was more evident in lean GDM subjects with mild hyperglycemia who did not require insulin therapy, and beta-cell function was partially preserved in this group of patients.

Acute and chronic effects of different concentrations of free fatty acids on the insulin secreting function of islets.

INTRODUCTION: Lipotoxic effects of free fatty acids (FFAs) on insulin secreting function of islet beta-cells have been demonstrated in recent studies. This toxic effect is especially prominent on postprandial hypertriglyceridemic period. Hypertriglyceridemia and high FFAs levels are the most common metabolic disturbances seen in diabetes mellitus (DM), in particular in uncontrolled cases. AIM OF STUDY: To investigate acute and chronic effects of different concentrations of FFAs on insulin secreting function of pancreas islet beta-cells. MATERIAL AND METHOD: We determined the acute and chronic effects of FFAs on insulin secretion dynamics of isolated rat islets. The insulinotropic effects of four D-glucose concentrations (Nil, 5.6, 8.3 and 27.7 mM) were studied in freshly isolated and perifused islets in the presence of two different concentrations (250 micromol/l and 1,250 micromol/l) of three FFAs (palmitate, stearate and oleate) to determine the acute effects. Chronic effects were investigated similarly on islet cells incubated for 72 hours in the presence of nil, 250 micromol/l and 1,250 micromol/l concentrations of FFAs. RESULTS: There was only a slight increase in insulin secretion at both concentrations of FFAs in freshly isolated islets, and the recovery was complete with a slight decrease in pathologic FFA channel. However, after 72 hour incubation at physiological or higher concentrations of FFAs, insulin secretion was significantly lower, even in the presence of high levels of D-glucose when compared to either nil channel results, or results of the fresh samples. Insulin levels of recovery phase were slightly but significantly lower in physiological and pathologically high FFA conditions when compared to nil condition. In addition, first phase insulin release response was lost in these islets. CONCLUSION: FFAs slightly increased the insulin output of normal fresh pancreas beta-cells. However, chronic exposure to FFAs resulted in loss of first phase insulin release and blunted insulin secretion response to various levels of D-glucose stimulation.

Effects of extracellular pH upon the insulinotropic action of alpha-D-glucose pentaacetate.

The pentaacetate ester of alpha-D-glucose was recently introduced as a new insulin secretagogue. Its insulinotropic action appears mainly attributable to the catabolism of its hexose moiety in islet cells, but a direct effect of the ester itself upon a receptor apparently displaying analogy with that involved in the recognition of bitter agents by taste buds may also be operative. In the present study, the secretory response of rat isolated pancreatic islets to alpha-D-glucose pentaacetate (1.7 mM) was found to be preserved, except in the absence of any other exogenous nutrient, when the extracellular pH was raised from about 7.4 to 8.0. Inversely, however, when the extracellular pH was lowered to about 7.0, alpha-D-glucose pentaacetate inhibited both basal and D-glucose- or L-leucine-stimulated insulin output. These findings are interpreted to support a dual mode of action of alpha-D-glucose pentaacetate upon insulin secretion, a lowering of extracellular pH revealing a negative component of the islet B-cells functional response to such a monosaccharide ester.

A case of Costello syndrome with endocrine features.

The case of a 21-year-old woman with findings consistent with Costello syndrome (CS) is reported. Most previously reported cases of CS were in young children. In addition to the classic features, the patient had endocrine disturbances including secondary amenorrhea, goiter, and adrenal insufficiency. This last abnormality may be the cause of the hypoglycemic episodes seen in CS. Osteoporosis and anemia were additional features. This case provides new information on the endocrine features and prognosis of CS.