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.

The ongoing challenge of discrepant growth hormone and insulin-like growth factor I results in the evaluation of treated acromegalic patients: a systematic review and meta-analysis.

OBJECTIVE: Growth hormone (GH) and insulin-like growth factor I (IGF-I) are the principal biomarkers used to assess disease activity in acromegaly, and any discrepancy between them renders interpretation of results inconclusive. Purpose of this study was to assess the frequency of this discrepancy and identify parameters that might affect its occurrence. DESIGN: A systematic review of MEDLINE and Scopus was performed (1987-2013) followed by a meta-analysis to address the frequency of discrepant results between GH and IGF-I levels. Meta-regression and subgroup analyses were performed assessing the effects of the year of publication, the different types of GH testing and GH assays used, as well as the impact of treatment with somatostatin analogues (SSAs) on the occurrence of this discrepancy. RESULTS: The analysis retrieved 39 eligible studies totalling 7071 patients. The pooled discordance rate between GH and IGF-I was 25·7% (95% CI: 22·3-29·4), and the predominant format was that of elevated IGF-I with normal GH levels (15·3%, 95% CI: 12·5-18·7). No significant correlation between the discordance rate and the year of publication was shown; whereas, the use of ultrasensitive GH assays resulted in higher discordance rates (30·7%, 95% CI: 25·9-35·9 vs 19·8%, 95% CI: 14·1-27·2, P = 0·04) as did treatment with SSAs (32·5%, 95% CI: 27·8-37·4) vs (21·6%, 95% CI: 17·8-25·6, P = 0·001). CONCLUSIONS: Discrepancy between GH and IGF-I results is encountered in a quarter of treated patients with acromegaly, especially when using ultrasensitive GH assays or in patients receiving SSAs, a fact that the clinician should take into consideration when making clinical decisions.

Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis.

OBJECTIVE: Somatic mutations in the GNAS1 gene, which encodes the alpha-subunit of G stimulatory proteins (gsp), are frequently detected in somatotroph pituitary tumors and have been associated to specific clinical and histopathological characteristics. However, the question whether the presence of a somatic gsp mutation affects the response to somatostatin analog treatment remains unresolved. DESIGN: Following a literature search, we performed a meta-analysis, including 8 eligible studies, in order to estimate the effect of gsp mutation on the percent reduction of growth hormone (GH) levels during an acute octreotide suppression test (OST). A total of 310 patients with acromegaly [126 gsp (+) and 184 gsp (-)] were included in the analysis. RESULTS: The presence of the gsp mutation was related with a greater reduction in GH levels on OST [Weighted Mean Difference (WMD): 9.08 % (95 % CI, 2.73, 15.42); p = 0.005; random effects model]. There was significant heterogeneity for this effect estimate (I(2) = 58 %, p value for heterogeneity = 0.02). A sensitivity analysis after exclusion of a study with different methodology of OST provided similar estimates [WMD: 6.93 % (95 % CI, 1.40, 12.46); p = 0.01], albeit with no significant heterogeneity (I(2) = 35 %, p value for heterogeneity = 0.16). CONCLUSIONS: The present meta-analysis suggests a role for gsp mutation as a prognostic factor of treatment response to somatostatin analogs.

Hormonal parameters and sex hormone receptor gene polymorphisms in men with autoimmune diseases.

Autoimmune diseases (ADs) are more common in women than in men. Sex hormones may play a role. Sex hormone receptors (SHR) are expressed in cells of the immune system. We investigated the possible role of hormonal parameters and of common polymorphisms of the estrogen receptor alpha (ESR1), beta (ESR2), and androgen receptor (AR) genes in the appearance of AD in men. 277 men were studied; 125 with ≥1 AD: Hashimoto's autoimmune thyroiditis (n = 65), Graves' disease (n = 12), SLE (n = 10), and RA (n = 38). 152 were controls. Hormonal and biochemical parameters were measured after discontinuation for ≥1 month of any corticosteroid therapy. ESR1 PvuII, ESR2 AluI, and the AR (CAG)n repeats polymorphisms were analyzed. AD patients had higher estradiol levels (31.32 ± 12.10, controls 20.37 ± 7.91 pg/ml, p < 0.001). In multivariate analysis, significant predictors for AD were estrogen and BMI. The allele frequency of ESR1 PvuII and ESR2 AluI did not differ between patients and controls (AD: 47.8 %, 37.6 %; controls 49.8 %, 39.9 %). The distribution of (CAG)n did not differ between groups. In AD group, shorter (CAG)n alleles were associated with younger age of AD onset (short: 38.52 ± 14.8, long: 47.14 ± 17.34 years, p = 0.048). Carriers of ESR1 PvuII presented less frequently ≥2 AD (carriers 6.5 %, non-carriers 25.1 %, p = 0.019); carriers of AluI had lower SHBG levels and higher ΒΜΙ compared to non-carriers (p < 0.04). Higher estradiol may play a role in AD in men. Distribution of SHR gene polymorphisms is similar between patients and controls. Shorter AR (CAG)n repeats may predispose for younger AD onset. Coexistence of ≥2 AD is less frequent in carriers of ESR1 PvuII. ESR2 AluI may adversely affect obesity parameters.

High prevalence of exon 8 G533C mutation in apparently sporadic medullary thyroid carcinoma in Greece.

OBJECTIVE: Genetic screening for ret mutation has become routine practice in the evaluation of medullary thyroid carcinoma (MTC). Approximately 25% of these tumours are familial, and they occur as components of the multiple endocrine neoplasia type 2 syndromes (MEN 2A and 2B) or familial MTC. In familial cases, the majority of mutations are found in exons 10, 11, 13, 14 or 15 of the ret gene. A rare mutation involving exon 8 (G533C) has recently been reported in familial cases of MTC in Brazil and Greece; some of these cases were originally thought to be sporadic. The aim of this study was to re-evaluate a series of sporadic cases of MTC, with negative family history, and screen them for germline mutations in exon 8. DESIGN AND PATIENTS: Genomic DNA was extracted from peripheral lymphocytes in 129 unrelated individuals who had previously been characterized as 'sporadic' based on the negative family history and negative screening for ret gene mutations. Samples were analysed in Applied Biosystems 7500 real-time PCR and confirmed by sequencing. MEASUREMENTS AND RESULTS: The G533C exon 8 mutation was identified in 10 of 129 patients with sporadic MTC. Asymptomatic gene carriers were subsequently identified in other family members. CONCLUSION: In our study, we found that 7·75% patients with apparently sporadic MTC do carry G533C mutation involving exon 8 of ret. We feel that there is now a need to include exon 8 mutation screening in all patients diagnosed as sporadic MTC, in Greece.

Estradiol levels predict short-term adverse health outcomes in postmenopausal acute stroke women.

BACKGROUND: Data on the role of endogenous sex steroids in cerebrovascular disease are sparse. Estradiol is a hormone with diverse actions on the central nervous system. Our aim was to investigate the role of circulating estradiol levels in a postmenopausal acute stroke population. METHODS: During a time-period of 2 years, we prospectively studied 302 postmenopausal female patients hospitalized for an acute stroke in two tertiary hospitals. We addressed the question whether endogenous estradiol is associated with stroke severity on admission and functional outcome 1 month after stroke, as assessed by the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS), respectively. RESULTS: Estradiol levels were significantly related to stroke severity on admission, as expressed by NIHSS, even after correcting for confounding factors in the multivariate analysis (beta 0.353, P < 0.001). Estradiol was an independent determinant of 1-month mortality and adverse functional outcome (mRS ≥ 4), [odds ratio (OR) with 95% confidence intervals (CI): 3.341 (1.617-6.902), P = 0.001 and 2.277 (1.273-4.074), P = 0.006, respectively]. CONCLUSIONS: We identified an independent association of endogenous estradiol levels with stroke severity and short-term mortality and outcome. These findings suggest challenging the role of estradiol as a neuroprotective agent.

Clinical and biochemical impact of BCL1 polymorphic genotype of the glucocorticoid receptor gene in patients with adrenal incidentalomas.

BACKGROUND: Adrenal incidentaloma (AI) is a common clinical problem. Subtle hormonal abnormalities are present in a substantial proportion of patients. BCL1 gene polymorphism of the glucocorticoid receptor (GR) is associated with increased sensitivity to glucocorticoid action. The genotype- phenotype associations of this polymomorphism in patients presenting with AI has not been extensively investigated. AIM: A cross-sectional study in secondary/tertiary care centers. SUBJECTS/METHODS: Ninety-five subjects with AI were genotyped for the BCL1 GR gene polymorphism. Patients underwent an oral glucose tolerance test and a dexamethasone suppression test (DST). The presence of subclinical hypercortisolism, features of metabolic syndrome, and osteoporosis/ osteopenia were also assessed. RESULTS: No significant differences in markers of adrenal function between BCL1 carriers and non-carriers were revealed. Also, no difference was found in the features of metabolic syndrome, as well as in bone metabolism and density between these 2 groups. However, DST suppressor patients belonged more frequently to the BCL1 carriers group (41 out of 69 patients, 59.4% vs 9 out of 26 patients, 34.6%, p=0.0039), had smaller total adenoma size (2.4±0.2 cm vs 3.5±0.4 cm, p=0.04), and lower incidence of bilateral adrenal masses (18.8% vs 46.2%, p=0.01). CONCLUSIONS: AI patients who also carry the polymorphic BCL1 variant exhibit smaller size adrenal nodules. Those AI patients with complete DST suppression had a higher incidence of the polymorphic BCL1 variant. However, this study failed to demonstrate any significant impact of BCL1 GR polymorphism on the frequency of cortisol-dependent co-morbidities in patients with AI.

Long-term effects of thyroid fine-needle biopsy on the thyroid-related biochemical parameters.

AIMS: Thyroid fine-needle biopsy (FNB) is a simple, reliable, inexpensive and generally safe diagnostic procedure in the management of thyroid nodules. FNB may trigger biochemical alterations through destruction of thyroid follicles. We aimed to investigate long-term post-FNB alterations in serum thyroid-related parameters. METHODS: One hundred and ten consecutive patients with thyroid nodular disease were subjected to FNB. Thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3), thyroglobulin (Tg), thyroglobulin autoantibodies (anti-Tg), thyroid-peroxidase autoantibodies (anti-TPO) were measured in all subjects at baseline, 10 days, 2 and 6 months. Subsequently, patients were divided into subgroups according to the technique of FNB, the presence of disease characteristics as thyroid autoimmunity (Hashimoto's thyroiditis), goitre, singularity-maximum diameter-blood pattern of the nodule(-s), the number of passes and the administration of L-thyroxine (LT4). RESULTS: A significant increase in Tg, anti-Tg and FT3 levels was observed. These alterations were more prominent within patients with dominant nodule's maximum diameter ≥ 2 cm or without Hashimoto's thyroiditis. Tg and anti-Tg levels were significantly increased only in patients not being on LT4. On the other hand, FNB technique did not affect any of the measured parameters. CONCLUSION: Our data suggest that FNB results in statistically significant but clinically insignificant increases in Tg, anti-Tg and FT3 levels, implying a thyroid trauma of some level, more likely to happen in patients with larger nodules. The FNB technique used has no effect on the thyroid-related biochemical parameters.

Association of thyroid autoimmunity with acne in adult women.

BACKGROUND: During the last decades an increase has been observed regarding acne in adults and especially women. OBJECTIVE: To evaluate the association between thyroid disorder and the presence of post-adolescent acne in adult women, comparing with healthy controls. METHODS: 107 adult women with post-adolescent acne and 60 healthy controls were included. Complete blood count and standard biochemical profile of C-Reactive Protein (CRP) and levels of thyroid hormones and antibodies [triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), free T3 (FT3), free T4 (FT4), antithyroglobulin antibodies (anti-TG) and anti-thyroid peroxidase antibodies (anti-TPO)] were determined in all subjects of both the acne and control groups. A thyroid ultrasound was also performed. RESULTS: There was a statistically significant difference (P=0.008) in the prevalence of positive anti-TG antibodies, with 25.2% of the acne group and 8.3% of the control group having elevated (>40 U/mL) anti-TG levels, respectively. Adult women with acne had a statistically significant increased relative risk to have high levels of anti-TG in comparison with healthy controls (odds ratio 3.89, P=0.011). This association was independent of age. Values for TSH, FT4, FT3, T4 and anti-TPO did not significantly differ between the two groups. No significant difference was found regarding the thyroid ultrasound findings. Although there was no significant difference between cases and controls regarding CRP levels, it is interesting that we observed a significant elevation in CRP in those acne patients who had positive antithyroglobulin antibodies. CONCLUSIONS: It is likely that thyroid autoimmunity might be more frequent in the adult acne patients and this should be kept in mind when screening women with post-adolescent acne.

Cortisol levels and metabolic parameters in middle- and advanced- age subjects: associations with age.

BACKGROUND: It has been reported that morning cortisol levels increase with age, although there is some controversy in the literature. AIM: The aim of this study was to examine associations of cortisol levels with advancing age in an elderly population and investigate possible interactions with metabolic and hormonal parameters. SUBJECTS AND METHODS: From 372 subjects initially evaluated, we studied 251 ambulatory subjects aged 51-90 yr, median 71 yr (169 women), all permanent residents of a small town in southern Greece. Anthropometric parameters, glucose, insulin, cortisol, and biochemical parameters were recorded. RESULTS: Fasting cortisol levels (08:00-09:00 h) varied between 150.9- 854 nmol/l (mean 362.4 nmol/l). A significant association was found between age and cortisol levels (Spearman's rho =0.170, p=0.01). There was a positive correlation between cortisol levels and creatinine (Spearman's rho =0.144, p=0.023), homocysteine (Spearman's rho =0.283, p<0.001) and a negative correlation with body mass index (Spearman's rho =-0.128, p=0.047). Multivariate analysis showed that when creatinine was taken into account, the association of cortisol with age and with homocysteine was no longer significant. When, however, diabetic subjects were included in the analysis, the adjusted for creatinine association of cortisol with age was significant (ß=0.168, p<0.05). CONCLUSIONS: It is concluded that, in elderly ambulatory subjects, the reported associations between cortisol levels, age, and homocysteine may be affected by coexisting co-morbidities or possibly by a decline in renal function. In subsequent studies it is important that fasting glycemia is taken into account.

Gender, age, puberty, and BMI related changes of TSH and thyroid hormones in schoolchildren living in a long-standing iodine replete area.

The aim of the work was to assess thyroid function in children and adolescents in an iodine replete area and to explore possible effects of age, gender, puberty, and adiposity. Thyrotropin (TSH), total triiodothyronine (T (3)), total thyroxine (T (4)), free thyroxine (FT (4)), and the T (4)/T (3) ratio were determined for 440 schoolchildren (200 boys and 240 girls), aged 5-18 years, living in an iodine replete region. Body Mass Index (BMI), BMI standard deviation score (BMI-SDS), and Body Surface Area (BSA) were calculated. In girls there was a negative correlation of TSH, T (3), and FT (4) values with age. In boys there was a negative correlation only of T (3) values with age. Girls had lower TSH, T (4), and T (3) values, whereas boys had only lower T (3) values at puberty compared to the prepubertal stage. Girls had lower TSH values than boys (p<0.03) only at puberty. BMI-SDS in boys and girls were 0.21 and 0.03, respectively. BMI-SDS was not related to TSH, T (4), or T (3) in either gender, whereas it was negatively related to T (4)/T (3) ratio in boys and to FT (4) in girls. We conclude that estrogens may exert a suppressive effect on the pituitary-thyroid axis after puberty. TSH values are not correlated with BMI-SDS, whereas T (4)/T (3) ratio in boys and FT (4) in girls are negatively correlated with BMI-SDS.

Multiple endocrine neoplasias: advances and challenges for the future.

Several important advances have been made over the last 2 years, since the last international workshop on multiple endocrine neoplasias (MENs) that was held in Marseilles, France (MEN2006). The series of articles that are included in this issue summarize the most important of these advances as they were presented in Delphi, Greece, during the 11th International Workshop on MENs, September 25-27, 2008 (MEN2008). This editorial summarizes some of these advances: the identification of the AIP, and the PDE11A and PDE8B genes by genome-wide association (GWA) studies as predisposing genes for pituitary and adrenal tumours, respectively, the discovery of p27 mutations in a new form of MEN similar to MEN type 1 (MEN 1) that is now known as MEN 4, the molecular investigations of Carney triad (CT), a disorder that associates paragangliomas (PGLs), gastrointestinal stromal tumour (GISTs), and pulmonary chondromas (PCH) with pheochromocytomas and adrenocortical adenomas and other lesions, and the molecular elucidation of the association of GISTs with paragangliomas (Carney-Stratakis syndrome) that is now known to be because of SDHB, SDHC, and SDHD mutations. Molecular investigations in Carney complex (another MEN also described by Dr. Carney, who during the meeting, along with Dr. Charles E. ('Gene') Jackson was honoured for his life-long and many contributions to the field) have also revealed the role of cyclic AMP signalling in tumorigenesis. As our knowledge of the molecular causes of MENs increases, the challenge is to translate these discoveries in better treatments for our patients. Indeed, new advances in the preventive diagnosis and molecular treatment of MEN 1 and MEN 2, respectively, continued unabated, and an update on this front was also presented at MEN2008 and is included in this issue.

Comparative topoisomerase IIa and ki 67 protein expression in papillary thyroid carcinoma based on tissue microarrays and image analysis.

PURPOSE: Topoisomerase II alpha (Topo IIa gene location 17q21) is a nucleic enzyme involved in the DNA replication, transcription and chromosome topological formation. Topo IIa inhibition strategies include specific chemotherapeutic agents such as anthracyclines. Our aim was to investigate potential protein alterations of the enzyme comparing them to ki 67 proliferation marker expression in papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: Using tissue microarray (TMA) technology, 50 specimens consisting of histologically confirmed PTCs (n=20), multi-nodular goiters (n=20) and also normal thyroid epithelia (n=10) were cored and re-embedded in the final paraffin block. Immunohistochemical analysis was performed using monoclonal anti-Topo IIa and anti-ki 67 (MIB-1) antibodies. Digital image analysis assay was also applied for the evaluation of the protein expression results (Nuclear Labeling Index-NLI). RESULTS: Topo IIa and ki 67 proteins were overexpressed in 4/20 (20%) and 14/20 (70%) cases, respectively. Concerning multi-nodular goiters, overexpression was observed in 2/20 and 4/20 specimens, respectively. Statistical association was assessed correlating ki 67 expression to pathology type, capsular invasion and also to vascular infiltration (p=0.001, p=0.008, and p=0.012, respectively). Topo IIa protein expression was strongly correlated only to capsular invasion (p=0.004). Overall expression of the examined markers demonstrated a medium concordance (kappa=0.27), but a strong association (p=0.001). CONCLUSION: Topo IIa and also ki 67 overexpression are correlated to an aggressive phenotype in PTC. Topo IIa overexpression maybe is a reliable marker for a rational application of targeted chemotherapeutic strategies in some subgroups of patients.

Hypothalamus-pituitary-adrenal (HPA) axis parameters and neurocognitive evaluation in patients with bipolar disorder.

Bipolar disorder is associated with neurocognitive impairment but the etiology of such impairment remains largely unknown. The present study aimed at investigating the performance of bipolar patients in various neuropsychological tasks within the framework of HPA axis hyperactivity model and also the impact of disease characteristics on neuropsychological functioning. Cognitive performance of 60 bipolar-I patients and 30 healthy controls was evaluated by using tasks from the CANTAB battery targeting visual memory, executive function and inhibitory control. Current symptoms were evaluated via administration of the Hamilton Depression Rating Scale (HAMD) and Young Mania Rating Scale (YMRS) whereas assessment of functioning was performed with the Global Assessment of Functioning (GAF). Basal cortisol levels were determined and all patients were administered the Dexamethasone Suppression Test (DST). Statistically significant differences between patients and controls were found in visuo-spatial associative learning and memory, planning, attentional set shifting and inhibitory control. Worse performance in visuospatial associative memory correlated with longer duration of illness and higher levels of basal cortisol. Poorer attentional set shifting was related to higher number of manic episodes. We found no relationship of neurocognitive measures with DST suppression status, current symptom severity or history of psychosis. The results of our study confirm the presence of cognitive deficits in bipolar disorder and provide evidence on the relation of cortisol with neuropsychological functioning, especially visuo-spatial associative memory. Moreover, we have found that number of previous manic episodes and duration of illness is associated with worse cognitive performance. It is known that neurocognitive deficits are evident in many patients with bipolar disorder. These deficits are often a cause of considerable distress and can lead to impairment of psychosocial and occupational functioning. The role of HPA axis needs to be further examined in bipolar disorder. Nevertheless, the identification of factors affecting neurocognitive functioning, like basal cortisol and number of manic episodes, may contribute to the implementation of more appropriate prevention strategies.

Severity of cardiovascular disease in postmenopausal women: associations with common estrogen receptor alpha polymorphic variants.

OBJECTIVE: Impaired estrogen action is a risk factor for coronary artery disease (CAD). Associations of CAD with estrogen receptor alpha (ER alpha) polymorphisms, which may influence sensitivity to estrogen, have been reported for men; the data concerning women are not conclusive. We investigated the association of common ER alpha polymorphisms with the severity of CAD and with metabolic and reproductive factors in postmenopausal women undergoing coronary angiography. METHODS: ER alpha polymorphisms at positions c.454-397 T>C (PvuII) and c.454-351 A>G (XbaI) were studied in 157 women (age 45-88 years). The severity of CAD was assessed by the number of arteries with >50% stenosis in the angiography. RESULTS: There was a significant association between the TT, TC, and CC genotypes (PvuII) and the severity of CAD (P=0.008); similar results were obtained for the XbaI polymorphism (P=0.021). These associations were independent of other risk factors for CAD. Women homozygous for the C allele had significantly higher triglyceride and insulin levels; they belonged more frequently to the group with a low number of births (n

Endogenous subclinical hyperthyroidism: Metabolic and cardiac parameters.

BACKGROUND: Subclinical hyperthyroidism (SH) is defined by suppressed TSH and normal levels of thyroid hormones. Endogenous subclinical hyperthyroidism (ESH) is probably less common than exogenous SH. Adverse effects of SH due to exogenous administration of thyroxine have been well studied, while the impact of ESH on the cardiovascular system and metabolic parameters remains controversial. METHODS: In a cross-sectional study, we examined patients with endogenous clinical hyperthyroidism (ECH; n=20), ESH (TSH<0.1 muU/mL, n=25), and mild ESH (TSH=0.1-0.3 muU/mL, n=32), as well as healthy controls (n=50). Biochemical and metabolic parameters influenced by thyroid hormones were assessed and cardiac parameters were studied using echocardiography and 24-hour ECG-blood pressure monitoring. RESULTS: Biochemical and metabolic parameters did not differ significantly between ESH and healthy subjects. The ECH group had significantly higher sex hormone-binding globulin, osteocalcin, and carboxy-terminal telopeptide levels than healthy subjects. No significant differences were noted in echocardiographic parameters between ESH patients and healthy subjects. The ECH group had a significantly higher heart rate, cardiac output, and cardiac index than the control group, as well as end-diastolic and end-systolic diameters of the left ventricle, and end-diastolic and end-systolic volumes of the left ventricle. The 24-hour ECG-blood pressure monitoring parameters did not differ significantly either between SH and healthy subjects while, in the ECH group, mean heart rate, maximum heart rate, and mean tachycardia episodes were significantly increased. CONCLUSION: Only subjects with ECH showed differences in metabolic and cardiac parameters from controls, while no significant effects were noted in the endogenous subclinical forms.

Association of dehydroepiandrosterone-sulfate with endothelial function in young women with polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to assess non-invasively endothelial function of young women with polycystic ovary syndrome (PCOS) in comparison with healthy age-matched women and a group of young women with idiopathic hirsutism (IH). The possible role of metabolic and hormonal parameters on endothelial function was also examined. DESIGN: Descriptive clinical trial. METHODS: Fifty-six women, 27 with PCOS, 16 with IH and 13 healthy age-matched women were studied. Endothelial function of resistance arteries was assessed by venous occlusion plethysmography. Metabolic and hormonal parameters were estimated in this study population. RESULTS: The duration of reactive hyperemia (durRH) was shorter in PCOS group when compared with normal controls (63.75 +/- 13.33 s vs 113.18 +/- 20.92 s, P = 0.036). A similar finding was observed when PCOS were compared with IH group (63.75 +/- 13.33 s vs 105 +/- 17.20 s, P = 0.05). The durRH did not differ between IH and control group (105 +/- 17.20 s vs 113.18 +/- 20.92 s, ns). A significant positive linear correlation was found between the durRH and dehydroepiandrosterone-sulfate (DHEA-S) levels (r = +0.48, P = 0.04) in the PCOS group. The basal insulin resistance index (HOMA) differed significantly between PCOS, IH and control groups. There was no significant correlation between durRH and HOMA index or testosterone levels in the PCOS group. CONCLUSIONS: Endothelial dysfunction may be an early sign of cardiovascular system abnormalities in young PCOS women. It is possible that increased DHEA-S levels may offer a cardioprotective advantage that attenuates the effects of cardiovascular risk factors that accompany PCOS.

Lack of suppression of plasma glucagon levels in late pregnancy persists postpartum only in women with previous gestational diabetes mellitus.

The aim of the present study was to examine fasting (0') and postglucose glucagon levels in normal and gestational diabetes mellitus (GDM) pregnancy, as available data are somewhat conflicting. To this end we studied 18 women with GDM at 26-32 weeks of pregnancy and compared these with 26 normal pregnant women matched for age and BMI. We also examined glucagon suppressibility postpartum (2-4 months) in the same ex-GDM women, in whom normal glucose tolerance was confirmed (WHO criteria) and compared these with 17 controls matched for age and BMI. Glucose, insulin and glucagon levels were measured during a 100 or 75 g oral glucose tolerance test (OGTT) respectively. In pregnant women, baseline and 3 h after glucose ingestion, plasma glucagon levels were significantly higher (p < 0.05) in women with GDM compared to normal women. Interestingly, in normal pregnancy a significant increase (p < 0.01) of postglucose plasma glucagon levels at 1 and 2 h compared to baseline levels was observed, while there was no change in GDM pregnancy. In postpartum euglycaemic women, there was no difference in basal glucagon levels between the two groups. A differential glucagon response during OGTT was observed: in control women there was a significant glucagon suppression (p < 0.01) at 2 h, while there was a significant glucagon increase (p < 0.01) 1 h after glucose ingestion, in ex-GDM women. We conclude that (a) absence of the suppressibility of glucagon in ex-GDM women with normal OGTT may indicate insulin resistance and might be involved in the natural history towards glucose intolerance; and (b) nonsuppression of glucagon in normal late pregnancy as well as in pregnancy complicated by GDM may be due to "physiological" insulin resistance of the alpha cells during this period.

Study of the Trp64Arg polymorphism of the beta3-adrenergic receptor in Greek women with gestational diabetes.

OBJECTIVE: This study assessed whether the Trp(64)Arg polymorphism of the beta3-adrenergic receptor (beta3-AR), which has been associated with obesity, insulin resistance, weight gain, and earlier onset of type 2 diabetes, is more frequent in women who develop gestational diabetes mellitus (GDM) or whether it is associated with weight gain during pregnancy RESEARCH DESIGN AND METHODS: A total of 311 Greek pregnant women (180 with GDM and 131 without GDM [control]) who underwent a 100-g oral glucose tolerance test (OGTT) in the third trimester of pregnancy were genotyped for the beta3-AR Arg(64) polymorphism. Insulin levels were also determined during the OGTT. RESULTS: The frequency of Trp(64)Arg heterozygotes in this population was approximately 7% and was similar in the GDM and control groups (6.7 vs. 6.9%) as well as in the obese (BMI > or =27 kg/m2) and the nonobese (6.3 vs. 6.8%) subgroups. In the GDM group, BMI, fasting insulin resistance index, and diastolic blood pressure were significantly higher in Trp(64)Arg carriers; these differences were no longer observed when obesity was considered. In the 4 subgroups (control Trp(64)Trp and Trp(64)Arg and GDM Trp(64)Trp and Trp(64)Arg), a highly significant trend was evident of an increase in the percentage of subjects with shorter height. CONCLUSIONS: The frequency of the Arg(64) allele in Greek pregnant women is relatively rare compared with other ethnic groups and is probably not related to the development of GDM or obesity The observed tendency for shorter body height in Arg(64) carriers merits further evaluation in larger population samples.

Impaired endothelium-dependent vasodilatation in women with previous gestational diabetes.

OBJECTIVE: To assess whether otherwise healthy women with a history of gestational diabetes mellitus (GDM) may have abnormalities in endothelial function at a very early stage, before glucose intolerance occurs. RESEARCH DESIGN AND METHODS: A total of 33 women with previous GDM (17 nonobese [BMI < 27] and 16 obese [BMI > or = 27]) and 19 healthy nonobese women were examined. A 75-g oral glucose tolerance test was performed, and insulin levels and biochemical parameters were also measured. Using high-resolution ultrasound, we measured vasodilatory responses of the brachial artery during reactive hyperemia (endothelium-dependent vasodilatation), and after nitroglycerin administration, an endothelium-independent vasodilator. RESULTS: Flow-mediated dilatation (FMD) was significantly and equally decreased in both groups of women with previous GDM, compared with control subjects (1.6 +/- 3.7% in the nonobese GDM group and 1.6 +/- 2.5% in the obese GDM group vs. 10.3 +/- 4.4% in control subjects, P < 0.001). FMD correlated inversely with serum uric acid levels, BMI, serum total cholesterol, and basal insulin resistance (homeostasis model assessment). Nitrate-induced dilatation was significantly decreased only in the obese GDM group compared with control subjects, (21.4 +/- 5.1 vs. 27.9 +/- 9.5, P < 0.05). CONCLUSIONS: Endothelial dysfunction, which is considered as a very early index of atherogenesis, is already present in both obese and nonobese women with a history of GDM, even when they have normal glucose tolerance.