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Grossmann M.,University of Melbourne | Grossmann M.,Endocrine Unit | Matsumoto A.M.,University of Washington | Matsumoto A.M.,Geriatric Research
Journal of Clinical Endocrinology and Metabolism | Year: 2017

Context: Middle-aged and older men (50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary-testicular axis pathology but have functional hypogonadism that is potentially reversible. Evidence Acquisition: Literature review from 1970 to October 2016. Evidence Synthesis: Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling. Conclusions: There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy. Copyright © 2017 by the Endocrine Society.


Grossmann M.,University of Melbourne | Grossmann M.,Endocrine Unit | Hoermann R.,University of Melbourne | Wittert G.,University of Adelaide | And 2 more authors.
Clinical Endocrinology | Year: 2015

Context The effects of testosterone treatment on glucose metabolism and other outcomes in men with type 2 diabetes (T2D) and/or the metabolic syndrome are controversial. Objective To perform a systematic review and meta-analysis of placebo-controlled double-blind randomized controlled clinical trials (RCT) of testosterone treatment in men with T2D and/or the metabolic syndrome. Data sources A systematic search of RCTs was conducted using Medline, Embase and the Cochrane Register of controlled trials from inception to July 2014 followed by a manual review of the literature. Study selection Eligible studies were published placebo-controlled double-blind RCTs published in English. Data extraction Two reviewers independently selected studies, determined study quality and extracted outcome and descriptive data. Data synthesis Of the 112 identified studies, seven RCTs including 833 men were eligible for the meta-analysis. In studies using a simple linear equation to calculate the homeostatic model assessment of insulin resistance (HOMA1), testosterone treatment modestly improved insulin resistance, compared to placebo, pooled mean difference (MD) -1·58 [-2·25, -0·91], P < 0·001. The treatment effect was nonsignificant for RCTs using a more stringent computer-based equation (HOMA2), MD -0·19 [-0·86, 0·49], P = 0·58). Testosterone treatment did not improve glycaemic (HbA1c) control, MD -0·15 [-0·39, 0·10], P = 0·25, or constitutional symptoms, Aging Male Symptom score, MD -2·49 [-5·81, 0·83], P = 0·14). Conclusions This meta-analysis does not support the routine use of testosterone treatment in men with T2D and/or the metabolic syndrome without classical hypogonadism. Additional studies are needed to determine whether hormonal interventions are warranted in selected men with T2D and/or the metabolic syndrome. © 2014 John Wiley & Sons Ltd.


Peppa M.,Endocrine Unit | Koliaki C.,Endocrine Unit | Raptis S.A.,National and Kapodistrian University of Athens | Raptis S.A.,Mellitus
Journal of Internal Medicine | Year: 2010

Peppa M, Koliaki C, Raptis SA (Athens University Medical School, Attikon University Hospital, Haidari, Athens; Hellenic National Diabetes Center for the Prevention, Research and Treatment of Diabetes Mellitus and its Complications (H.N.D.C), Athens, Greece). Adrenal incidentalomas and cardiometabolic morbidity: an emerging association with serious clinical implications (Review). J Intern Med 2010; 268: 555-566.Adrenal incidentalomas (AIs) represent adrenal masses that are incidentally discovered whilst investigating symptoms and signs unrelated to adrenal pathology. The onset and natural course of AIs are unknown, and the possible underlying cardiometabolic abnormalities have not been examined in depth. A growing body of clinical and experimental evidence supports the notion that both functioning and, paradoxically, nonfunctioning AIs are associated with a partially expressed or even full-blown metabolic syndrome (MS) phenotype, through yet unclear mechanisms. Subtle, subclinical or even profound adrenal hormone excess and an increased proinflammatory state might explain to some extent the development of MS disturbances. The emerging association between AIs and MS appears to be important in determining the optimal clinical management of these patients and raises speculation about the exact mechanisms of this interesting cause-effect relationship. © 2010 The Association for the Publication of the Journal of Internal Medicine.


Guerra A.,University of Salerno | Sapio M.R.,University of Salerno | Marotta V.,University of Naples Federico II | Campanile E.,University of Salerno | And 7 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: BRAFV600E is considered a primary event, a negative prognostic marker, and a site for pharmacological intervention in papillary thyroid carcinoma (PTC). We asked whether BRAFV600Ecan occur as a subclonal event in PTC and whether this and other oncogenes can coexist in the same tumor. Study Design: We determined by pyrosequencing the percentage of mutant BRAF, NRAS, and KRAS alleles in a series of conventional PTC. We also analyzed the BRAF mutation status in PTC cell clones in culture. Results: BRAFV600E alleles were present in 41 of 72 PTC (56.9%) in the range 44.7 to 5.1% of total BRAF alleles. In four PTC samples, mutant BRAF alleles were about 50%, being therefore compatible with a clonal heterozygous mutation. In 27 PTC samples, BRAFV600E alleles were in the range of 25 to 5.1%. This finding was confirmed after exclusion of the presence of a large contamination by lymphoreticular cells and by the analysis of PTC cells selected by laser capture. Analysis of clones derived from a single cell confirmed the presence of two distinct PTC populations with wild-type or mutated BRAF. Simultaneous subclonal BRAF and KRAS mutations were demonstrated in two PTC. Conclusions: These data demonstrate that clonal BRAFV600E is a rare occurrence in PTC, although frequently this cancer consists of a mixture of tumor cells with wild-type and mutant BRAF. These results suggest that BRAF mutation in PTC is a later subclonal event, its intratumoral heterogeneity may hamper the efficacy of targeted pharmacotherapy, and its association with a more aggressive disease should be reevaluated. Copyright © 2012 by The Endocrine Society.


Christin-Maitre S.,Endocrine Unit | Christin-Maitre S.,University Pierre and Marie Curie | Serfaty D.,Societe Francophone de Contraception | Chabbert-Buffet N.,University Pierre and Marie Curie | And 4 more authors.
Human Reproduction | Year: 2011

BACKGROUND: Nomegestrol acetate/17β-estradiol (NOMAC/E2) is a new monophasic oral contraceptive combining NOMAC (2.5 mg), a highly selective progesterone-derived progestogen, with E2 (1.5 mg), which is structurally identical to endogenous estrogen. The objective of this study was to compare the effects on ovarian activity of two different NOMAC/E 2 regimens. Methods This was a double-blind, randomized study. Healthy, premenopausal women (aged 1838 years, previous menstrual cycle length 28 ± 7 days) were randomized by computer-generated code to once-daily NOMAC/E2 for three consecutive 28-day cycles: either 24 days with a 4-day placebo interval (n = 40) or 21 days with a 7-day placebo interval (n = 37) per cycle. Follicular growth (primary outcome measure), plasma hormone profiles and bleeding patterns were assessed. Results There was no evidence of ovulation during treatment with either NOMAC/E2 regimen. The largest follicle diameter was significantly smaller in the 24-day group than in the 21-day group [mean (SD) mm in cycle 2: 9.0 (3.0) versus 11.3 (5.3) (P = 0.02); in cycle 3: 9.2 (3.0) versus 11.5 (6.0) (P = 0.04)]. Mean FSH plasma levels were significantly lower in the 24-day versus the 21-day group on Day 24 of cycles 1 and 2. Withdrawal bleeding duration was significantly shorter in the 24-day than in the 21-day group [mean (SD) days after cycle 1: 3.5 (1.3) versus 5.0 (2.6) (P = 0.002); after cycle 2: 3.9 (1.6) versus 4.8 (1.7) (P = 0.03)]. CONCLUSIONS The 24-day NOMAC/E2 regimen was associated with greater inhibition of follicular growth and shorter duration of withdrawal bleeding than the 21-day regimen, suggesting the shorter pill-free interval results in a greater margin of contraceptive efficacy and tolerability, and fewer withdrawal symptoms. © The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Giustina A.,University of Brescia | Mazziotti G.,University of Brescia | Mazziotti G.,Endocrine Unit | Torri V.,Instituto Of Ricerche Farmacologiche Mario Negri | And 3 more authors.
PLoS ONE | Year: 2012

Background: The long-acting somatostatin analogue octreotide is used either as an adjuvant or primary therapy to lower growth hormone (GH) levels in patients with acromegaly and may also induce pituitary tumor shrinkage. Objective: We performed a meta-analysis to accurately assess the effect of octreotide on pituitary tumor shrinkage. Data Sources: A computerized Medline and Embase search was undertaken to identify potentially eligible studies. Study Eligibility Criteria: Eligibility criteria included treatment with octreotide, availability of numerical metrics on tumor shrinkage and clear definition of a clinically relevant reduction in tumor size. Primary endpoints included the proportion of patients with tumor shrinkage and mean percentage reduction in tumor volume. Data Extraction and Analysis: The electronic search identified 2202 articles. Of these, 41 studies fulfilling the eligibility criteria were selected for data extraction and analysis. In total, 1685 patients were included, ranging from 6 to 189 patients per trial. For the analysis of the effect of octreotide on pituitary tumor shrinkage a random effect model was used to account for differences in both effect size and sampling error. Results: Octreotide was shown to induce tumor shrinkage in 53.0% [95% CI: 45.0%-61.0%] of treated patients. In patients treated with the LAR formulation of octreotide, this increased to 66.0%, [95% CI: 57.0%-74.0%). In the nine studies in which tumor shrinkage was quantified, the overall weighted mean percentage reduction in tumor size was 37.4% [95% CI: 22.4%-52.4%], rising to 50.6% [95% CI: 42.7%-58.4%] with octreotide LAR. Limitations: Most trials examined were open-label and had no control group. Conclusions: Octreotide LAR induces clinically relevant tumor shrinkage in more than half of patients with acromegaly. © 2012 Giustina et al.


Peverelli E.,Endocrine Unit | Mantovani G.,Endocrine Unit | Lania A.G.,University of Milan | Spada A.,Endocrine Unit
Journal of Molecular Endocrinology | Year: 2013

The cyclic nucleotide cAMP is a universal regulator of a variety of cell functions in response to activated G-protein coupled receptors. In particular, cAMP exerts positive or negative effects on cell proliferation in different cell types. As demonstrated by several in vitro studies, in somatotrophs and in other endocrine cells, cAMP is a mitogenic factor. In agreement with this notion, it has been found that the mutations of genes coding for proteins that contribute to increases in the cAMP signaling cascade may cause endocrine tumor development. This review will discuss the central role of cAMP signaling in the pituitary, focusing on the cAMP pathway alterations involved in pituitary tumorigenesis, as well as on poorly investigated the aspects of cAMP cascade, such as crosstalk with the ERK signaling pathway and new cAMP effectors. © 2014 Society for Endocrinology.


Ooi C.P.,Endocrine Unit | Ooi C.P.,University Putra Malaysia | Loke S.C.,Endocrine Unit | Loke S.C.,University Putra Malaysia
Diabetic Medicine | Year: 2014

Aim: Colesevelam, a second-generation bile acid sequestrant, may be beneficial in controlling both glycaemia and lipids simultaneously. Our goal was to evaluate the systemic effects of colesevelam on Type 2 diabetes mellitus. Method: The original Cochrane review was conducted using the methodology for the systematic review of interventions of the Cochrane Collaboration in RevMan 5.2. We comprehensively searched the literature in several databases up to January 2012. Two reviewing authors independently selected and extracted the data, and then evaluated the quality of the randomized controlled trials that met the inclusion criteria. Results: Six randomized controlled trials were selected, which ranged from 8 to 26 weeks in duration. A total of 1450 participants were divided into two groups: those treated with colesevelam and no other anti-diabetic drug treatments/placebo, or with colesevelam added on to anti-diabetic drug treatments. The colesevelam added on to anti-diabetic agents demonstrated a statistically significant reduction in the fasting blood glucose (mean difference of -0.82 mmol/l, 95% CI -1.2 to -0.44), HbA1c (mean difference -0.5%, 95% CI -0.6 to -0.4) and LDL cholesterol (mean difference -0.34 mmol/l, 95% CI -0.44 to -0.23). There were no reported data on weight. Non-severe hypoglycaemic episodes were infrequently observed. Conclusion: The limited number of studies concerning the treatment with colesevelam added to anti-diabetic agents showed significant effects on glycaemic control; however, more research on the reduction of cardiovascular risks is required. Furthermore, long-term data on the health-related quality of life and all-cause mortality also need to be investigated. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.


Gianatti E.J.,University of Melbourne | Gianatti E.J.,Endocrine Unit | Dupuis P.,University of Melbourne | Dupuis P.,Endocrine Unit | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Objective: The objective of the study was to assess the effect of T treatment on constitutional and sexual symptoms in men with type 2 diabetes (T2D).Design: This was a randomized double-blind, parallel, placebo-controlled trial.Setting: The study was conducted at a tertiary referral center.Patients: Men aged 35-70 years with T2D, a hemoglobin A1c less than 8.5%, and a total T level less than 12.0nmol/L(346 ng/dL) with mild to moderate aging male symptoms and erectile dysfunction.Intervention: Eighty-eight participants were randomly assigned to 40 weeks of im T undecanoate (n = 45) or matching placebo (n = 43).Main Outcome Measures: Constitutional symptoms using the aging male symptoms (AMS) score, sexual desire (question 17 AMS score), and erectile function (International Index of Erectile Function-5).Results: T treatment did not substantially improve aging male symptoms [mean adjusted difference (MAD) in change over 40 weeks across the T and placebo groups in AMS total score, -0.9(95% confidence interval [CI] -4.1, 2.2), P =.67] or sexual desire [MAD in question 17 AMS, -0.3 (95% CI -0.8, 0.2), P =.17]. Although compared with placebo, erectile function in men assigned to T was reduced [MAD in International Index of Erectile Function abridged version 5, -2.0 (95% CI -3.4, -0.6), P <.02], there was no significant difference between baseline and 40-week International Index of Erectile Function abridged version 5 scores if both groups were analyzed separately. At baseline, symptoms were worse in men with depression and microvascular complications but did not correlate with T levels.Conclusions: In this trial, T treatment did not substantially improve constitutional or sexual symptoms in obese, aging men with T2D with mild to moderate symptoms and modest reduction in T levels typical for the vast majority of such men. Copyright © 2014 by the Endocrine Society.


Kandasamy N.,University of Cambridge | Fugazzola L.,Endocrine Unit | Evans M.,University of Cambridge | Chatterjee K.,University of Cambridge | Karet F.,University of Cambridge
European Journal of Endocrinology | Year: 2011

Introduction: Pendred syndrome, a combination of sensorineural deafness, impaired organification of iodide in the thyroid and goitre, results from biallelic defects in pendrin (encoded by SLC26A4), which transports chloride and iodide in the inner ear and thyroid respectively. Recently, pendrin has also been identified in the kidneys, where it is found in the apical plasma membrane of non-α-type intercalated cells of the cortical collecting duct. Here, it functions as a chloride-bicarbonate exchanger, capable of secreting bicarbonate into the urine. Despite this function, patients with Pendred syndrome have not been reported to develop any significant acid-base disturbances, except a single previous reported case of metabolic alkalosis in the context of Pendred syndrome in a child started on a diuretic. Case report: We describe a 46-year-old female with sensorineural deafness and hypothyroidism, who presented with severe hypokalaemic metabolic alkalosis during inter-current illnesses on two occasions, and who was found to be homozygous for a loss-of-function mutation (V138F) in SLC26A4. Her acid-base status and electrolytes were unremarkable when she was well. Conclusion: This case illustrates that, although pendrin is not usually required to maintain acid-base homeostasis under ambient condition, loss of renal bicarbonate excretion by pendrin during a metabolic alkalotic challenge may contribute to life-threatening acid-base disturbances in patients with Pendred syndrome. © 2011 European Society of Endocrinology.

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