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Acromegaly is characterized by high cardiovascular morbidity and mortality. Oxidative stress and endothelial dysfunction are underlying mechanisms of atherosclerosis. The aim of this study was to evaluate the blood redox status and endothelial function by means of nitric oxide (NO) levels in patients with acromegaly. Total antioxidant capacity (TAC), catalase activity and glutathione concentration (GSH), as measures of antioxidative capacity, total oxidized glutathione (GSSG) and thiobarbituric acid reactive substances (TBARS), as indices of oxidative stress, and NO levels were assessed in 15 patients with acromegaly (age 55.4 ± 10.5 years; 6 males) and 15 age- and sex-matched controls (age 58.4 ± 8.1 years; 7 males). Active disease was present in 12 patients: 11 on current pharmacotherapy and 1 newly diagnosed. Three acromegalics were in remission after successful treatment. Acromegalics as compared with controls had significantly lower levels of catalase activity (8.2 ± 5.8 vs. 51.3 ± 29.1 mmol/ml/min, p < 0.001), GSH (0.97 ± 0.54 vs. 1.41 ± 0.35 mmol/l, p = 0.006), GSSG (0.27 ± 0.19 vs. 2.04 ± 1.32 mmol/l, p = 0.002) and NO levels (6.0 ± 3.1 vs. 43.0 ± 29.8 mmol/l, p < 0.001), but higher TBARS (16.3 ± 8.9 vs. 10.1 ± 10.8, nmol/ml, p = 0.019). After adjustment for confounders, differences in catalase activity, NO levels and TBARS remained significant (p = 0.004, p < 0.001 and p = 0.025, respectively). No association between IGF-I/GH and oxidative stress markers was noticed, except for a positive correlation between nadir GH and GSSG (r² = 0.563, p = 0.036). Acromegaly is associated with increased levels of oxidative stress coupled by diminished antioxidant capacity and endothelial dysfunction indicated by the presence of decreased NO levels. [ABSTRACT FROM AUTHOR]

Objective: Estrogens play an important role in male physiology. We investigated the possible association of four single nucleotide polymorphisms in Estrogen Receptor α ( ESR1 ) and Estrogen Receptor β ( ESR2 ) genes with circulating levels of sex steroids and Sex Hormone Binding Globulin (SHBG) in men. Design and Methods: SHBG, total and calculated free testosterone (TT and cal FT), estradiol (E2) and free Estradiol (FE2) were determined in a population-based cohort of 170 apparently healthy Greek men. Body mass index (BMI), waist circumference (WC) and percentage of body fat ( % fat) content were measured in all participants. Genotyping for the Pvu II and Xba I polymorphisms of the ESR1 gene and for the Rsa I and Alu I polymorphisms of the ESR2 gene was performed. Results: Pvu II showed an association with E2 levels [median (IQR) pp 58.5 (42.1 - 73.4) pg / ml vs. Pp 48.8 (42.9 - 60.1) and PP 57.7 (44 - 70.5), p = 0.032], and with % fat [mean ± SD pp 24.6 ± 5.3 vs. Pp 22.4 ± 5.2 and PP 21.2 ± 6.7, p = 0.044], after adjustment for age and WC. Furthermore, the eff ect of Pvu II on E2 was independent of % fat (p = 0.038). A synergistic eff ect of the two ESR1 polymorphisms on E2 (p = 0.023), FE2 (p = 0.03) and % fat (p = 0.004) was present. Finally, a synergistic eff ect of the ESR1 and ESR2 genes on TT (p = 0.009), independent of age, WC and % fat also emerged. Conclusions: Genetic variation in ESR1 is associated with serum estradiol levels and body fat content regulation in men. Furthermore, a synergistic eff ect of ESR1 and ESR2 genes is exerted on serum testosterone levels. [ABSTRACT FROM AUTHOR]

Adrenal incidentalomas (AIs) have been associated with an increased risk of metabolic syndrome and dyslipidemia, though evidence regarding the latter is limited. Lipid abnormalities in patients with AIs have been associated with subclinical hypercortisolism. The current study aims to test whether lipid profile in patients with AIs predicts "autonomous cortisol secretion" (ACS). Patients with AIs found on either computerized tomography (CT) or magnetic resonance imaging (MRI), were included in a prospective cohort study. All patients were followed up for at least three years. Alterations in their hormonal and lipid profiles were recorded. Ninety-four patients (69 women) harboring 111 AIs were included. There were no differences between patients with ACS and those without, with respect to their baseline lipid profile [total cholesterol, low-density-lipoprotein cholesterol (LDL-C), triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-HDL-C] and blood pressure (systolic and diastolic). Non-HDL-C concentrations decreased over time (Repeated Measures ANOVA, p=0.013), despite patients' body mass index (BMI) remaining unchanged. Logistic regression analysis revealed that the only predictor of ACS was the size of AIs, as calculated by CT or MRI. The current study demonstrated that lipid profile at baseline or during follow-up cannot predict ACS in patients with AIs. However, larger AIs may have a greater probability of ACS., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

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., (© 2016 John Wiley & Sons Ltd.)

Introduction: Intermittent parathyroid hormone (PTH) administration, acting through multiple signaling pathways, exerts an osteoanabolic effect on the skeleton that surpasses the effect of other antiosteoporotic agents. However, its efficacy is limited by the coupling effect and relatively common adverse events. Thus, the development of more sophisticated PTH receptor analogs seems imperative., Areas Covered: In this review, the authors summarize the role of PTH signaling pathway in bone remodeling. The authors also summarize investigational analogs targeting this pathway, which may be potential treatments for osteoporosis., Expert Opinion: β-arrestins are multifunctional cytoplasmic molecules that are decisive for regulating intracellular PTH signaling. Recently, in preclinical studies, arrestin analogs have achieved the anabolic bone effect of PTH without an accompanying increase in bone resorption. However, it is not yet known whether these analogs have adverse effects and there are no clinical data for their efficacy to date. On the other hand, several molecules derived either from PTH and PTH-related protein (PTHrP) molecules have been developed. Alternative routes of PTH 1 - 34 delivery (oral, transdermal), the PTH analog ostabolin and the N-terminal PTHrP analogs PTHrP 1 - 36 and abaloparatide, have recently been or are currently being tested in clinical trials and are more likely to become available for use in the near future.

Dopamine agonists (DA) are the mainstay of treatment for patients with prolactinomas. To describe the efficacy of treatment and the outcomes of DA withdrawal. Retrospective review of electronic medical records of patients with prolactinomas from 1985 to 2009. Seventy-nine patients (17 men/62 women), aged 35.3 ± 1.6 years at diagnosis were studied. The mean follow-up time was 84.7 ± 9.2 months (range 0-336). The mean initial size of microadenomas was 0.74 ± 0.10 cm (range 2.41 ± 0.39) and of macrodenomas 2.41 ± 0.39 cm (range 1.1-8) and serum prolactin (PRL) levels were 112 ± 19 and 263 ± 59 ng/ml, respectively (normal range 0-40). Fifty-one (65%) prolactinomas were micro- and 28 (35%) were macroadenomas. DA led to a decrease in adenoma size in 71% of them, while 53% of microadenomas were not visible during follow-up. In 26 patients, DA withdrawal was decided. After therapy of >24 months and a mean follow-up time of 49 ± 11 months (range 3-168), 15 subjects (58%) showed no recurrence of hyperprolactinemia. Higher remission rates, although not statistically significant, were observed with cabergoline (75%). The mean PRL levels before DA discontinuation were 12.2 ± 2.3 ng/ml (range 0.5-44.7) and after discontinuation they were significantly lower than pre-treatment values. Recurrence of hypeprolactinemia was evident during the first year in all but one patient. Remission rates were not associated with age or size of adenoma at diagnosis, initial or before DA discontinuation PRL levels and duration of treatment. DA withdrawal was followed by remission of hyperprolactinamia in about half of patients after >2 years of treatment.

Juvenile Paget's disease (JPD) is a rare, autosomal recessive osteopathy. Although it has phenotypic overlap with Paget's disease of bone (PDB), it is probably a distinct entity. Because of its rarity, optimal disease management has not yet been established by randomized controlled trials. However, clinical, biochemical, and radiographic improvement has been reported after treatment with antiresorptive agents, including calcitonin and bisphosphonates (BPs). Compared with other BPs, zoledronic acid (ZOL) has a higher affinity to bone mineral and is a stronger inhibitor of the enzyme farnesyl pyrophosphate synthase (the main target of nitrogen-containing BPs), properties that explain the prolonged effect of ZOL on bone turnover and render it a therapeutic option for JPD, similar to PDB. We describe hereby, for the first time in the literature, the case of a patient with JPD who developed severe hypocalcemia and secondary hyperparathyroidism following effective treatment with ZOL.

Introduction: Adrenal incidentalomas (AIs) constitute an emerging clinical entity due to the increased use of abdominal imaging for diagnostic purposes. Most often it consists of benign-nonfunctioning lesions and an increase in size during follow-up is reported in about 9% (0-26%), whereas their functional evolution is rare., Materials and Methods: Sixty-four patients (22 males and 42 females; mean age 61.6 ± 1.2 years), with AIs and follow-up of 3.1 ± 0.4 years (range 0-19) were retrospectively evaluated. The patients underwent basal and dynamic evaluation of the hypothalamic-pituitary-adrenal axis, renin-angiotensin-aldosterone system and adrenomedullary function. Mass enlargement and adrenal hyperfunction were estimated at yearly intervals., Results: Adrenalectomy was performed in 5 patients (4 benign cortical adenomas and 1 pheochromocytoma). Abnormal manifestation, based on clinical, laboratory and histological evaluation, was observed in 4 patients [1 (1.56%) with SCS, 2 (3.12%) with pheochromocytoma and 1 (1.56%) with aldosteronoma], 3 of which were diagnosed at their initial evaluation and 1 at the 3 (rd) year of follow-up. The remainders [60 patients (93.75%)] were harbouring a non-secretory mass (8 potential myelolipomas, 8 nodular hyperplasias, 3 cystic lesions). Eleven patients (17.2%) had bilateral AIs. Mass enlargement (5-13 mm) was observed in 9 patients (14%), ≥10 mm 4 (6.25%), while mass shrinkage (5-19 mm) in 3 (4.7%) during follow-up. No hormonal evolution was noticed., Conclusions: AIs present usually as benign, non-secretory lesions. Criteria for surgical intervention were met at initial assessment for the majority of AIs. Size alterations during follow-up are uncommon and functional evolution is rare., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

High serum homocysteine (HCY) and indirectly deficiency of folate and/or vitamin B(12) stimulate bone resorption and adversely affect collagen cross-linking. The aim of this study was the evaluation of serum levels of HCY, folate and vitamin B(12) in patients with Paget's disease of bone (PDB) and the effect of zoledronic acid (ZOL) on their serum levels. Nine consecutive patients with polyostotic PDB (median age 66 years) received a single 5-mg ZOL infusion. Blood samples for HCY, folate, vitamin B(12), 25-hydroxyvitamin D (25-OH-D), total serum alkaline phosphatase (TSAP), bone-specific serum alkaline phosphatase (BSAP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were obtained at baseline and 3, 6 and 12 months after ZOL infusion. Twelve age-, gender- and BMI-matched healthy individuals were recruited for the control group at baseline assessment. Patients with PDB had significantly higher serum HCY (p = 0.028), folate (p < 0.001) and bone markers [TSAP (p < 0.001), BSAP (p < 0.001) and CTX (p < 0.001)] compared with the control group at baseline. In the pagetic group, serum HCY significantly decreased 3 months after ZOL infusion and remained essentially unchanged up to the end of the study (p = 0.005). Serum vitamin B(12) and folate remained unaffected throughout the study. Our data suggest that serum HCY levels are increased in patients with PDB. A single ZOL infusion results in a decrease in HCY levels that might represent another mechanism for the reduction of the activity of PDB achieved by ZOL.

The main aim of this study was to determine the effect of zoledronic acid (ZOL) on parameters of dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) in unaffected bones of patients with Paget's disease of bone (PDB). The secondary aim was the association of bone markers and Dickkopf (DKK)-1 with parameters of DXA and QUS. Ten consecutive patients with polyostotic PDB (median age: 63 yr) received a single 5-mg ZOL infusion. The patients were subjected to calcaneal QUS and DXA of both lumbar spine (LS) and femoral neck (FN). Blood samples for serum bone markers and DKK-1 were serially obtained for 12 mo. There was a significant increase in LS (p=0.005) and FN bone mineral density (BMD) (p=0.021) 12 mo after ZOL infusion. QUS parameters remained unaffected throughout the study. A significant correlation between broadband ultrasound attenuation and DKK-1 (p<0.001) and between speed of sound and DKK-1 (p=0.033) at baseline was found, which remained significant after adjustment for gender, age, and body mass index. Our data suggest that a single ZOL infusion significantly increases nonpagetic BMD 12 mo after treatment but has no effect on QUS parameters or DKK-1. Significant correlations were observed between QUS parameters and DKK-1 at baseline., (The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Objective To evaluate the effect of strontium ranelate (SR) on bone turnover markers in women with established osteoporosis previously treated with teriparatide (TPTD--recombinant human PTH 1-34). DESIGN PATIENTS: Twenty-two postmenopausal Caucasian women (aged 65.7 +/- 1.7 years) with established osteoporosis previously treated with TPTD 20 microg daily for 18 months were randomly assigned to receive either SR (SR group, n = 11) or calcium and vitamin D (control group, n = 11)., Measurements: Blood samples for serum N-terminal propeptide of type 1 collagen (P1NP), C-terminal telopeptide of type 1 collagen (CTx) and total alkaline phosphatase (ALP) were obtained from all women before (pre-TPTD) and after (post-TPTD) TPTD administration, as well as 6 months after SR or calcium/vitamin D administration (post-SR/Ca)., Results: Serum P1NP, CTx and total ALP increased significantly after TPTD treatment and decreased at the end of the study in both SR and control groups, with no difference between them., Conclusions: SR following TPTD administration acts predominantly as an antiresorptive agent with no evidence of additional osteoanabolic action. In this setting, SR is not more effective than Ca/vitamin D as far as bone turnover markers are concerned.

Introduction: Thyroid nodules are a common diagnostic challenge mainly because of the need to exclude thyroid malignancy. The aim of this study was to evaluate the usefulness of demographic, ultrasonographic and scintigraphic findings in differentiating benign from malignant thyroid lesions in patients presenting with thyroid nodules., Materials and Methods: 941 patients, who presented with palpable thyroid nodules and underwent at least one fine-needle aspiration biopsy (FNAB), were retrospectively evaluated., Results: The thyroid was assessed by ultrasonography (US) in 796 patients and by scintigraphy (SC) in 774 patients. The final diagnostic outcome was established after surgery (n=183) or after a minimum of one-year clinical follow-up period. Higher rates of malignancy were observed in male gender (p<0.001), in patients presenting with a solitary nodule in US (p<0.001), in nodules with maximum diameter > or =4.5 cm in US (p=0.024) and in nodules detectable by SC (p=0.006). There were no statistical differences in the rates of malignancy among cystic, solid or mixed nodules in US or among "hot", "warm" or "cold" nodules in SC., Conclusions: Male gender, solitary nodule and nodule diameter > or =4.5 cm can serve as adjuncts to FNAB in predicting the risk of thyroid malignancy in patients presenting with thyroid nodules.

Purpose: Serum thyrotropin (TSH) is a well-established growth factor for thyroid nodules and suppression of TSH concentrations by administering exogenous thyroxine may interfere with the growth of established nodules as well as the formation of new thyroid nodules. The aim of this study was to investigate whether serum TSH at presentation is a predictor of thyroid malignancy in patients with thyroid nodules., Methods: A total of 565 patients without overt thyroid dysfunction, who presented with palpable thyroid nodule(s) between 1988 and 2004 and underwent at least one fine-needle aspiration biopsy, were retrospectively evaluated., Results: The final diagnostic outcome was established after surgery (n = 122) or after a minimum of 1-year clinical follow-up period. Higher rates of malignancy were observed in patients with serum TSH in the upper tertile of the normal range (P = 0.026). Binary logistic regression analysis revealed significantly increased adjusted odds ratios for the diagnosis of malignancy in patients with serum TSH 1.5-4.0 mIU/l when compared to those with either TSH 0.4-0.8 mIU/l (P = 0.005) or TSH 0.9-1.4 mIU/l (P = 0.007)., Conclusions: The risk of malignancy in thyroid nodules increases in parallel with TSH concentrations within the normal range. TSH concentration at presentation is an independent predictor of thyroid malignancy.