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Aim: Sex differences have long been reported in schizophrenia leading to the hypothesis that sex hormones may be implicated in the pathophysiology of the disorder. We assessed gonadal hormones during the fasted state in drug-naïve patients with psychosis. Method: Fasting serum concentrations of follicular-stimulating hormone (FSH) and luteinizing hormone (LH), testosterone, free-testosterone, Sex Hormone Binding Globulin (SHBG) and oestradiol (E 2 ) were compared between a group of 55 newly diagnosed, drug-naïve, first-episode men with psychosis and a group of 55 healthy controls, matched for age, smoking status and BMI. Testosterone, free-testosterone and SHBG were compared between a group of 32 drug-naïve, first-episode females with psychosis and a group of 32 healthy controls matched for age, smoking status and BMI. Results: Testosterone and free-testosterone levels were significantly lower in the patients' group and SHBG levels significantly higher in the patients' group compared to those in healthy controls. The two female groups had similar values in the hormones which were measured. Conclusion: Our findings provide evidence of lower testosterone and free-testosterone levels and increased SHBG levels in drug-naïve, first-episode males with psychosis.KEY POINTSReduced testosterone and free-testosterone levels in drug-naive, first-episode males with psychosis.Increased SHBG levels in drug-naive first-episode males with psychosis.No difference in FSH, LH and E2 levels between drug-naive first episode males with psychosis and controls.No difference in testosterone, free-testosterone and SHBG levels between drug-naive, first-episode women with psychosis and controls.

Background: Obesity is associated with macrophage infiltration in adipose tissue that induces insulin resistance and contributes to the development of metabolic syndrome (MS). The aim of this study was to investigate whether circulating monocyte subsets (macrophage precursors) differ among obese subjects with MS [metabolically unhealthy obese (MUO)], obese subjects without MS [metabolically healthy obese (MHO)], and metabolically healthy lean (MHL) individuals. Methods: Fifty-eight obese (33 MUO, 25 MHO) and 25 MHL individuals participated in the study. Absolute blood counts of classical (Mon1A), intermediate (Mon2A), and nonclassical (Mon3A) monocyte subsets were measured by flow cytometry. Results: Increased proinflammatory monocyte counts (Mon2A, Mon3A) were observed in obese compared with MHL individuals ( P  = 0.001 and P  = 0.017 respectively). Mon2A count in MHO was lower compared with that in MUO subjects ( P  = 0.036) but higher compared with MHL controls ( P  = 0.032). Mon2A was positively associated with serum triglyceride levels ( r  = 0.328, P  = 0.023) and mean blood pressure (BP) ( r  = 0.457, P  = 0.001) in obese subjects. Among MS components, only the presence of elevated BP (≥130/85 mmHg) was independently associated with increased Mon2A in obese subjects ( P  < 0.001). Conclusions: Absolute counts of proinflammatory monocytes were lower in metabolically healthy compared with MUO individuals, but higher compared with healthy lean controls. The presence of low-grade inflammation suggests that "metabolically healthy" obesity is not a benign condition. ClinicalTrials.gov identifier: NCT03241394.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are an important asset in the armamentarium for the treatment of type 2 diabetes mellitus (type 2 DM). Incretin failure is a critical etiopathogenetic feature of type 2 DM, which, if reversed, results in improved glycaemic control. GLP-1 RAs are injectable peptides that resemble the structure and function of endogenous incretin GLP-1, but as they are not deactivated by the dipeptidyl peptidase-4 (DPP-4), their half-life is prolonged compared with native GLP-1. Based on their ability to activate GLP-1 receptor, GLP-1 RAs are classified as short-acting (exenatide twice-daily and lixisenatide once-daily), and long-acting (liraglutide once-daily and the once-weekly formulations of exenatide extended-release, dulaglutide, and albiglutide). Semaglutide, another long-acting, once-weekly GLP-1 RA, was recently approved by the FDA and EMA. Although all of these agents potently reduce haemoglobin A1C (HbA1c), there are unique features and fundamental differences among them related to fasting and postprandial hyperglycaemia reduction, weight loss potency, cardiovascular protection efficacy, and adverse events profile. It is imperative that current evidence be integrated and applied in the context of an individualised patient-centred approach. This should include not only glucose management but also targeting as many as possible of the pathophysiologic mechanisms responsible for type 2 DM development and progression.

Introduction: Transcription factor 7-like 2 (TCF7L2) gene variants rs12255372 and rs7903146 have been consistently shown to raise genetic risk for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the possible role of these variants in the development of impaired glucose metabolism (IGM), including impaired fasting glucose (IFG) or T2DM, in patients with metabolic syndrome (MS)., Patients and Methods: The study population consisted of 228 patients with MS who were divided into two groups. The first group consisted of 148 patients with MS and IGM [39M/109F, 59.8 ± 14.6 (mean ± SD) years] and the second group of 80 patients with MS and normoglycemia (NGM) (16M/64F, 56.1 ± 15.8 years). The diagnosis of MS was based on the criteria proposed by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) Scientific Statement. Anthropometric parameters including BMI and waist circumference were recorded and blood samples were obtained after overnight fasting for biochemical tests. The rs12255372 and rs7903146 TCF7L2 polymorphisms were genotyped in peripheral blood leucocytes., Results: Analysis of the distribution of the TCF7L2 polymorphic alleles revealed that the frequency of the T allele of the TCF7L2 variant rs12255372 was 38.2% in the study population, while the frequency of the T allele of the TCF7L2 rs7903146 variant was 35.3%. The T allele of the rs12255372 variant was more frequently present in patients with MS and IGM (48.3%) compared to patients with MS and NGM (19.4%, p < 0.001). Also, the T allele of rs7903146 was more frequently present in patients with MS and IGM (44.6%) compared to patients with MS and NGM (18.1%, p < 0.001). Logistic regression analysis followed and revealed that the presence of the T allele for both rs12255372 and rs7903146 TCF7L2 gene variants is a very powerful predictor of the presence of glucose disorders, increasing the risk more than fourfold in patients with MS and after adjustment for potential confounders, such as age, gender, BMI, and waist circumference (TCF7L2 rs12255372: Exp(B) 4.917, p < 0.001 and TCF7L2 rs7903146: Exp(B) 5.460, p < 0.001)., Conclusion: The presence of the rs12255372 and rs7903146 TCF7L2 gene variants plays an important role in the development of T2DM among individuals with MS. These findings support the notion that among subjects with MS, those who finally develop T2DM have a genetic predisposition to β-cell dysfunction.

Purpose of Review: To summarize recent data on the adverse reproductive consequences of androgen abuse, focusing on the recovery of reproductive function following androgen discontinuation., Recent Findings: Evidence is mostly based on case reports and observational studies. Androgen abuse leads to a state of hypogonadotropic hypogonadism associated with impaired spermatogenesis, testicular atrophy, gynecomastia as well as menstrual irregularities, virilization and subfertility. Recovery of the hypothalamic-pituitary-gonadal axis following androgen withdrawal depends on the type and characteristics of androgen administration (dose, duration of use) as well as those of the user (age, previous reproductive function). Biochemical and clinical features of hypogonadism may be evident months or even years following androgen discontinuation. To prevent androgen-related adverse effects and accelerate recovery of gonadal function, users take androgens in a cyclical fashion and use drugs such as human chorionic gonadotropin, antiestrogens and aromatase inhibitors, even though there is limited evidence to support efficacy of these strategies. As few studies refer to female androgen users, there is a lack of data concerning recovery from androgen-related reproductive side effects in women., Summary: Androgen abuse has profound and commonly under-recognized effects on the reproductive system; recovery following androgen withdrawal may be prolonged and occasionally incomplete.

Objective: Obesity and renal disease are both associated with low serum 25(OH)D. The aims of the present study were to (a) assess vitamin D status and compare serum vitamin D levels in overweight/obese versus normal-weight individuals according to eGFR and (b) assess the role of 25(OH)D in the development of secondary hyperparathyroidism (SHPT)., Design: Serum 25(OH)D, 1,25(OH) 2 D, parathyroid hormone (PTH), calcium, and phosphate were measured in 104 subjects with BMI > 25 kg/m 2 . Participants were categorized according to eGFR (ml/min/1.73m 2 ): G1 ≥ 60 (n = 53), G2 30-59 (n = 35), and G3 15-29 (n = 16). Fifty normal-weight individuals with comparable eGFR served as controls: G1-nw (n = 23), G2-nw (n = 18), and G3-nw (n = 9)., Results: 25(OH)D levels were lower in G1 compared to those in G1-nw (21.7 ± 6.5 vs 26.5 ± 7.0 ng/ml, p = 0.005), G2 versus G2-nw (19.0 ± 6.0 vs 25.0 ± 5.2 ng/ml, p = 0.001), and G3 vs G3-nw (15.8 ± 4.7 vs 20.3 ± 4.5 ng/ml, p = 0.030). 1,25(OH) 2 D and PTH levels were similar in obese/overweight versus normal-weight individuals in each of the eGFR categories. Factors independently associated with low 25(OH)D levels were BMI > 25 kg/m 2 , lower eGFR, and female gender. Mean 25(OH)D levels were < 30 ng/ml in both overweight and controls, in all eGFR groups. SHPT was universally observed when eGFR was < 30 ml/min/1.73m 2 ., Conclusions: Lower serum 25(OH)D but similar 1,25(OH) 2 D and PTH levels were observed in overweight/obese compared to normal-weight individuals. Even though vitamin D insufficiency was common across all eGFR categories, secondary hyperparathyroidism was more prevalent as eGFR declined.

We report the case of a patient with probable heterozygous familial hypercholesterolemia and mitotane-induced resistant hypercholesterolemia, despite combination therapy with rosuvastatin and ezetimibe. The patient was managed with the addition of evolocumab. Use of a proprotein convertase subtilisin-kexin type 9 inhibitor, should be considered in patients who develop mitotane-related hypercholesterolemia that cannot be managed with conventional lipid-lowering treatment., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: The pathophysiology of atherosclerosis in type 2 diabetes mellitus (T2DM) is multifactorial. The association of vascular indices with circulating biomarkers of inflammation and insulin resistance and their role in the long-term cardiovascular prognosis in T2DM patients were currently investigated., Patients and Methods: Patients with T2DM and poor glycemic control without known cardiovascular diseases (n=119) at baseline were enrolled and followed for about 9years. The end-point was the occurrence of any cardiovascular event (coronary heart disease, stroke, peripheral artery disease or cardiovascular death). Aortic pulse wave velocity (PWV), augmentation index (AIx), brachial flow-mediated dilation (FMD), hsCRP, Chitinase-3-like protein 1 (YKL-40), Neutrophil Gelatinase-Associated Lipocalin (NGAL), Fatty Acid Binding Protein (FABP-4) were assessed., Results: Higher YKL-40 and NGAL were associated with higher PWV, while higher YKL-40 and FABP-4 were related to higher AIx (p<0.05 for all). In univariate Cox regression analysis, PWV>10m/s, YKL-40>78ng/ml and NGAL>42ng/ml were associated with cardiovascular events (p<0.05 for all). In multivariate analysis, after adjusting for classical risk factors and glycemic control, increased NGAL, YKL-40 and PWV and decreased FMD (i.e. ≤2.2%) (p<0.05 for all) were independently associated with cardiovascular events., Conclusion: In T2DM patients without established cardiovascular disease, novel indices of vascular inflammation (NGAL and YKL-40) were associated with subclinical atherosclerosis (arterial stiffness) but also with adverse clinical prognosis. Arterial stiffness and endothelial dysfunction were also independently related to adverse prognosis., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Anabolic androgenic steroids (AAS) are testosterone derivatives used by athletes and recreational users to improve athletic performance and/or enhance appearance. Anabolic androgenic steroids use may have serious and potentially irreversible adverse effects on different organs and systems, including the reproductive system., Objective: This systematic review and meta-analysis aimed to critically assess the impact of AAS use on the reproductive system of athletes and recreational users., Methods: An electronic literature search was conducted using the databases MEDLINE, CENTRAL, and Google Scholar. Studies were included when the following criteria were fulfilled: participants were athletes or recreational users of any age, sex, level or type of sport; AAS use of any type, dose, form or duration; AAS effects on the reproductive system were assessed as stated by medical history, clinical examination, hormone and/or semen analysis. Random-effects meta-analysis was performed to assess the weighted mean difference (WMD) of serum gonadotropin (luteinizing hormone, follicle-stimulating hormone) and testosterone levels compared with baseline, during the period of AAS use, as well as following AAS discontinuation., Results: Thirty-three studies (three randomized clinical trials, 11 cohort, 18 cross-sectional, and one non-randomized parallel clinical trial) were included in the systematic review (3879 participants; 1766 AAS users and 2113 non-AAS users). The majority of the participants were men; only six studies provided data for female athletes. A meta-analysis (11 studies) was conducted of studies evaluating serum gonadotropin and testosterone levels in male subjects: (1) prior to, and during AAS use (six studies, n = 65 AAS users; seven studies, n = 59, evaluating gonadotropin and testosterone levels respectively); (2) during AAS use and following AAS discontinuation (four studies, n = 35; six studies, n = 39, respectively); as well as (3) prior to AAS use and following AAS discontinuation (three studies, n = 17; five studies, n = 27, respectively). During AAS intake, significant reductions in luteinizing hormone [weighted mean difference (WMD) -3.37 IU/L, 95% confidence interval (CI) -5.05 to -1.70, p < 0.001], follicle-stimulating hormone (WMD -1.73 IU/L, 95% CI -2.67 to -0.79, p < 0.001), and endogenous testosterone levels (WMD -10.75 nmol/L, 95% CI -15.01 to -6.49, p < 0.001) were reported. Following AAS discontinuation, serum gonadotropin levels gradually returned to baseline values within 13-24 weeks, whereas serum testosterone levels remained lower as compared with baseline (WMD -9.40 nmol/L, 95% CI -14.38 to -4.42, p < 0.001). Serum testosterone levels remained reduced at 16 weeks following discontinuation of AAS. In addition, AAS abuse resulted in structural and functional sperm changes, a reduction in testicular volume, gynecomastia, as well as clitoromegaly, menstrual irregularities, and subfertility., Conclusion: The majority of AAS users demonstrated hypogonadism with persistently low gonadotropin and testosterone levels, lasting for several weeks to months after AAS withdrawal. Anabolic androgenic steroid use results in profound and prolonged effects on the reproductive system of athletes and recreational users and potentially on fertility.

Proteinuric renal disease is prevalent in congenital or acquired forms of generalized lipodystrophy. In contrast, an association between familial partial lipodystrophy (FPLD) and renal disease has been documented in very few cases. A 22-year-old female patient presented with impaired glucose tolerance, hyperinsulinemia, hirsutism and oligomenorrhea. On examination, there was partial loss of subcutaneous adipose tissue in the face, upper and lower limbs, bird-like facies with micrognathia and low set ears and mild acanthosis nigricans. Laboratory investigations revealed hyperandrogenism, hyperlipidemia, elevated serum creatine kinase and mild proteinuria. A clinical diagnosis of FPLD of the non-Dunnigan variety was made; genetic testing revealed a heterozygous c.1045C > T mutation in exon 6 of the LMNA gene, predicted to result in an abnormal LMNA protein (p.R349W). Electromyography and muscle biopsy were suggestive of non-specific myopathy. Treatment with metformin and later with pioglitazone was initiated. Due to worsening proteinuria, a renal biopsy was performed; histological findings were consistent with mild focal glomerular mesangioproliferative changes, and the patient was started on angiotensin-converting enzyme inhibitor therapy. This is the fourth report of FPLD associated with the c.1045C > T missense LMNA mutation and the second with co-existent proteinuric renal disease. Patients carrying this specific mutation may exhibit a phenotype that includes partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy., Learning Points: Lipodystrophy is a rare disorder characterized by the complete or partial loss of subcutaneous adipose tissue, insulin resistance, diabetes mellitus and hyperlipidemia.Proteinuric renal disease is a prevalent feature of generalized lipodystrophy but rare in familial partial lipodystrophy.Patients carrying the c.1045C > T missense LMNA mutation (p.R349W) may present with familial partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.

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.)

Objective: Hyperprolactinaemia as a side effect of dopamine receptor blockers is common in patients with schizophrenia and other psychotic disorders and may lead to amenorrhoea, galactorrhoea, hypogonadism, subfertility and osteoporosis. The aim of our study was to determine whether hyperprolactinaemia occurs also in patients with schizophrenia and other psychotic disorders prior to any antipsychotic treatment., Methods: Serum prolactin, thyroid-stimulating hormone (TSH), triiodothyronine (T3), free tetraiodothyronine (FT4) and cortisol levels were measured in 40 newly diagnosed, drug naïve, patients with schizophrenia and other psychotic disorders and in 40 age and gender matched healthy subjects., Results: The median prolactin value was 12.5 ng/ml (range: 2-38 ng/ml) for patients and 8.6 ng/ml (range: 4-17.6 ng/ml) for healthy subjects (p = 0.011). Patients had lower levels of T3 compared to healthy controls (mean: 1.08 ng/ml, SD: 0.16 vs. 1.18 ng/ml, 0.18, respectively; p = 0.008). Serum TSH, FT4 and cortisol levels were similar between the two groups. Multiple regression analysis revealed that the difference in serum prolactin values was independent of thyroid function (TSH, FT4, T3) and serum cortisol levels., Conclusions: A higher serum prolactin level was found in drug naïve, newly diagnosed patients with schizophrenia and other psychotic disorders compared to healthy controls, prior to starting any antipsychotic treatment.

Diabetes and dyslipidemia are common in patients with psychosis; this association may be partly related to adverse metabolic effects of antipsychotic medications. We assessed glucose and lipid metabolism during the fasted state in drug-naïve patients with psychosis. Fasting serum concentrations of total cholesterol, triglycerides, high density lipoprotein (HDL), glucose, insulin, connecting peptide (C-peptide), homeostatic model assessment index (HOMA-IR), glycated hemoglobin (HbA1C) and serum cortisol were compared between a group of 40 newly diagnosed drug-naïve, first-episode patients with psychosis and a group of 40 healthy controls, matched for age, sex and BMI. Total cholesterol, triglycerides and fasting glucose levels were similar, whereas insulin and C-peptide levels were higher and HDL marginally lower in the patients' group compared to those in healthy controls. Drug-naïve patients with psychosis were more insulin resistant (as assessed by the HOMA-R index) compared to healthy controls. Serum cortisol did not differ between the two groups. There is evidence that drug-naïve, first-episode patients with psychosis are more insulin resistant compared to healthy controls., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Cushing's syndrome (CS) due to a corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) co-secreting tumor is very rare, and diagnosis can be difficult. We describe a case of CS caused by ectopic CRH and ACTH production from a pancreatic neuroendocrine tumor (pNET) and discuss possible pitfalls in the diagnosis. A 48-year-old woman presented with gradual increase in body weight, muscle weakness, and difficult to control hypertension. Laboratory and imaging investigations revealed ACTH-dependent hypercortisolemia and a 3-cm mass at the head of the pancreas. The patient underwent partial pancreatoduodenectomy. Histological examination revealed a well-differentiated pNET, expressing both CRH and ACTH. After a follow-up period of 18 months, she remains asymptomatic with no metastatic disease. This is the fourth case report of CS in adults due to an ectopic ACTH- and CRH-secreting pNET. Co-secretion of ACTH and CRH by the same tumor may cause diagnostic problems since investigation depends on which of the two hormones is secreted in greater amounts. Measurement of plasma CRH may help in establishing the diagnosis, especially in patients in whom endocrine tests are indicative of ectopic CS, whereas imaging findings are suggestive of pituitary hyperplasia.

Objective: Sunitinib is a tyrosine kinase inhibitor used in the therapy of pancreatic neuroendocrine tumors (PNETs), metastatic renal cancer and gastrointestinal stromal tumors. We describe a patient with PNET who presented with severe hypoglycemia following sunitinib administration., Case Report: A 64-year old man with known metastatic PNET presented with a history of recurring episodes of severe, life-threatening hypoglycemia 3 months after initiation of sunitinib treatment. Investigations during symptomatic hypoglycemia revealed inappropriately increased plasma insulin and C-peptide levels, consistent with endogenous hyperinsulinemia. No immune staining for insulin was observed in tissue samples from peritoneal metastatic tumor lesions, and serum anti-insulin antibodies were negative. Medical management with diazoxide, methylprednisolone and ocreotide was ineffective; continuous intravenous infusion of glucagon was required to maintain euglycemia. Following discontinuation of sunitinib there was gradual improvement in both the severity and frequency of the hypoglycemia. Six months later, the patient remained free of hypoglycemic episodes., Conclusions: We describe a patient with PNET who experienced severe, life-threatening hypoglycemia following sunitinib use. It is important that glucose levels of patients treated with sunitinib are monitored on a regular basis; those patients with diabetes may need to have their antidiabetic treatment adjusted to prevent hypoglycemia.

Objective: The main cause of death in patients with parathyroid carcinoma is parathyroid hormone (PTH)-induced hypercalcemia. To date, the management of hypercalcemia has been based on the use of bisphosphonates and calcimimetic agents. In recent reports, the use of denosumab has shown encouraging results in cases of refractory hypercalcemia of malignancy. Our objective is to present a case of successful management of resistant hypercalcemia due to parathyroid carcinoma with denosumab, to review similar cases from the literature, and to propose denosumab's use in the clinical management of PTH-induced refractory hypercalcemia., Methods: Presentation of a case report and review of the literature for cases of parathyroid carcinoma-mediated hypercalcemia successfully treated with denosumab., Results: A 71-year-old man with metastatic parathyroid carcinoma was referred to our department for uncontrolled hypercalcemia, resistant to treatment with bisphosphonates and cinacalcet. Treatment with denosumab (120 mg per month) in addition to cinacalcet (180 mg per day) resulted in normalization of calcium levels and maintenance within the normal range for an observation period of 11 months. Review of the literature revealed 4 case reports and a letter to the editor, all of which reported the successful treatment of resistant hypercalcemia associated with parathyroid carcinoma., Conclusion: Based on the above findings of the effectiveness of denosumab in controlling refractory hypercalcemia, its safety in renal failure and the fact that denosumab may reduce PTH-induced bone loss, we endorse its use in the management of hypercalcemia in patients with parathyroid carcinoma and perhaps other conditions with PTH-induced hypercalcemia.

Unlabelled: Aromatase is encoded by the CYP19 gene and catalyses the conversion of androgens to oestrogens, which in turn regulate skeletal homeostasis. CYP19 gene polymorphisms have been studied for their association with bone mineral density (BMD) in the general population with mixed results., Objective: To explore the influence of the CYP19 (TTTA)n repeat polymorphism on BMD and serum levels of osteoprotegerin (OPG), receptor activator of nuclear factor-κΒ ligand (RANKL), and bone metabolic markers in a Greek female population., Design: Cross-sectional study., Participants and Measurements: Two hundred and seventeen peri- and postmenopausal women aged 42-63 years were enrolled. All participants underwent spinal BMD evaluation by dual-energy X-ray absorptiometry (DXA). Genotyping of the (TTTA)n repeat polymorphism was performed by polymerase chain reaction. Levels of OPG, soluble RANKL (sRANKL) and bone metabolic markers were measured., Results: Genotype analysis revealed alleles having 7-12 TTTA repeats. Women carrying the (TTTA)11 and/or (TTTA)12 alleles had significantly higher spinal BMD than women not carrying these alleles in the total study population as well as in the subgroup of women with osteoporosis (P = 0·042 and P = 0·006, respectively). The aforementioned associations remained significant after adjustment for age, years since menopause, smoking and body mass index (P = 0·048 and P = 0·023, respectively, by multivariate analysis). Moreover, the urinary calcium to creatinine ratio was associated with the (TTTA)n polymorphism. No association of the (TTTA)n polymorphism with circulating levels of OPG, sRANKL was observed., Conclusions: The (TTTA)n polymorphism of the CYP19 gene is associated with spinal BMD in peri- and postmenopausal Greek women., (© 2014 John Wiley & Sons Ltd.)

Objective: To assess the potential association of the pentanucleotide (TAAAA)n repeat polymorphism in the promoter of SHBG gene with the age at menopause in a Greek female population., Study Design: Cross-sectional study. Two hundred and ten postmenopausal women aged 46-63 years were enrolled. The age at the last menstrual period and anthropometric parameters were recorded in all participants. Blood sampling for genotyping of the (TAAAA)n polymorphism of SHBG gene was performed., Main Outcome Measure(s): Frequency and association of the (TAAAA)n alleles with age at menopause., Results: The alleles with seven and eight TAAAA repeats were associated with the age at menopause. The age at menopause was higher in carriers than in non-carriers of the (TAAAA)7 allele (50.2±3.1 years vs. 48.0±4.8 years, p=0.026). Furthermore, the age at menopause was lower in women carrying the (TAAAA)8 allele (47.5±4.8 years) than in women not carrying this allele (48.8±4.4 years, p=0.048)., Conclusions: The (TAAAA)7 and (TAAAA)8 alleles of the SHBG (TAAAA)n polymorphism may contribute to variation in the timing of natural menopause in postmenopausal women of Northwestern Greece., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Glucocorticoids are commonly used in the treatment of patients with thyroid disorders, in particular Graves' ophthalmopathy. Thyrotoxic hypokalemic periodic paralysis (TPP) is an infrequent but potentially serious condition characterised by recurrent episodes of weakness associated with hypokalemia. We describe the development of acute hypokalemic paralysis in a middle-aged Caucasian man with recently diagnosed thyrotoxicosis and severe, active Graves' opthalmopathy who developed progressive flaccid paralysis 12 hours following intravenous administration of methylprednisolone. Rechallenge with the same dose after the patient had been rendered euthyroid did not provoke TPP. Clinicians should exercise caution when administering high-dose glucocorticoids during thyrotoxicosis as there is a risk of provoking hypokalemic paralysis in susceptible patients.

We have previously demonstrated that plasma glucose contributed 80% in the fed and 60% in the fasted state to lactose synthesis in humans, and de novo synthesis in the breast contributing to both the glucose and galactose moieties accounted for the remaining 20% and 40%, respectively, of lactose. The present study was conducted to determine, in lactating women, whether oral galactose is directly incorporated from plasma galactose into glucose and galactose in milk lactose or via conversion of galactose to glucose in the liver. Six healthy exclusively breast-feeding women (30 +/- 2 yr) (mean +/- SE) ingested galactose at 22 micromol x kg-1 x min-1 for 9 h after an overnight fast during infusion of [6,6-2H2]glucose and [1-13C]galactose. We observed that 69 +/- 6% of glucose and 54 +/- 4% of galactose in lactose were derived directly from plasma glucose, whereas 7 +/- 2% and 12 +/- 2% of glucose and galactose in lactose, respectively, were derived directly from plasma galactose. De novo synthesis of glucose and galactose via hexoneogenesis accounted for 25 +/- 8% and 35 +/- 6%, respectively. We conclude that during ingestion of galactose the contribution from plasma glucose to glucose and galactose in lactose was similar to that of a short-term fasting, but part of the de novo synthesis of glucose and galactose in the breast was replaced by direct uptake of galactose.

The development of cachexia is commonly seen in many pathological states and is associated with a markedly impaired prognosis. Loss of fat tissue appears to be of particular pathophysiological importance in this setting. Lipolysis is closely regulated in health; the major established pathways involving catecholamines (stimulation of lipolysis) and insulin (inhibition of lipolysis). The wasting process in cachexia is associated with marked metabolic dysfunction, and loss of this tight regulatory control. Natriuretic peptides are a family of related peptides with important vasodilatory, natriuretic and diuretic properties. It has recently been shown that natriuretic peptides are also potent stimuli for lipolysis in humans. In this respect, atrial and brain natriuretic peptide appear to have the greatest lipolytic effect, and are similar in potency to catecholamines. Elevated levels of circulating natriuretic peptides are found in several pathological states, and generally reflect disease severity. This article will provide a concise review of the regulation of lipolysis in humans, concentrating on the role of the natriuretic peptides. The relevance of natriuretic peptides to the development of cachexia will be discussed.

Lactose is the major osmotic agent in milk. Therefore, lactose synthesis indirectly regulates milk volume. The aim of this study was to determine the source of glucose and galactose in lactose. Six healthy lactating women were studied twice, during a 24-h fast and during ingestion of a mixed macronutrient drink (Sustacal) using [U-13C]glucose and [2-13C]glycerol. Six additional lactating women were studied on one single occasion during ingestion of glucose labeled with [1-13C]glucose. Using the ratios of [13C6] enrichments of glucose in lactose and plasma glucose and that of galactose in lactose and plasma glucose, we determined that 98 +/- 3% of glucose and 68 +/- 7% of galactose in lactose were derived from plasma glucose in the fed state, and 72 +/- 4 and 51 +/- 3%, respectively, after a 24-h fast. Virtually identical results (97 +/- 6 and 64 +/- 4%, respectively) were obtained during the glucose feeding study. On the basis of the [13C1] enrichment of glucose and galactose in lactose (derived from [2-13C]glycerol), glycerol contributes to the production of galactose but not glucose within the breast. Thus, plasma glucose is an important source of lactose, but significant amounts of glucose and galactose in lactose are generated within the breast, a process denoted hexoneogenesis. In this process, glycerol is a precursor for milk galactose but not glucose.

The aim of these studies was to determine the metabolic adaptation to fasting and feeding during lactation. Normal lactating (L) and nonlactating (NL) women (n = 6 each) were studied using infusions of [U-13C]glucose and [2-13C]glycerol during: 1) a 24-h fast, and 2) ingestion of Sustacal (protocol 1). In addition, 8 L and 6 NL women were studied during infusion of [6,6-2H2]glucose and ingestion of a glucose meal containing [1-13C]glucose (protocol 2). Protocol 1: Glucose production rate (GPR) during fasting was 33% higher in the L women (12.5 +/- 1.0 vs. 9.4 +/- 0.5 micromol x kg(-1) x min(-1); P < 0.03). Fractional gluconeogenesis (GNG), GNG rate, glucose, lactate, beta- hydroxybutyrate, FFA, insulin, and C-peptide were similar in both groups during feeding and fasting, but glycogenolysis was 50% higher in fasting L women. Protocol 2: Although GPR was slightly increased in the L group (L, 1.8 +/- 0.2 micromol x kg(-1) x min(-1); NL, 1.2 +/- 0.2 micromol x kg(-1) x min(-1); P < 0.04), no other differences were observed in splanchnic and systemic metabolism of ingested glucose between L and NL women. Insulin concentrations were lower in L women compared with controls (L, 15 +/- 3 microU/ml; NL, 28 +/- 6 microU/ml; P = 0.05). In conclusion, the increased glucose demands of lactation are met by increased GPR as a result of increased glycogenolysis but not GNG or by increased use of FFA. During feeding, lactating women handle oral carbohydrates normally but have increased insulin sensitivity.

There is controversy about the correct dose and form of thyroid hormone therapy for patients with hypothyroidism. Despite restoration of serum thyrotropin (TSH) concentrations to normal, many patients complain of excessive weight gain. We have compared weight at diagnosis of hyperthyroidism with that when euthyroid, evidenced by a stable, normal serum TSH concentration, with or without thyroxine (T4) replacement therapy, in patients treated with an 18-month course of antithyroid drugs (43 patients), surgery (56 patients), or 13I (34 patients) for Graves' disease. In addition, weights were recorded before and after treatment of 25 patients with differentiated thyroid carcinoma by total thyroidectomy, 131I, and long-term T4 suppressive therapy, resulting in undetectable serum TSH concentrations. Mean weight gain in patients with Graves' disease who required T4 replacement therapy following surgery was significantly greater than in those of the same age, sex, and severity of hyperthyroidism rendered euthyroid by surgery (3.9 kg) (p < 0.001) or at the end of a course of antithyroid drugs (4.1 kg) (p < 0.001). Weight gain was similar in those requiring T4 replacement following surgery or 131T therapy (10.4 versus 10.1 kg). In contrast, ablative therapy combined with suppression of TSH secretion by T4 in patients with differentiated thyroid carcinoma did not result in weight gain. The excessive weight gain in patients becoming hypothyroid after destructive therapy for Graves' disease suggests that restoration of serum TSH to the reference range by T4 alone may constitute inadequate hormone replacement.