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Open access

Renato Cozzi, Maria Rosaria Ambrosio, Roberto Attanasio, Claudia Battista, Alessandro Bozzao, Marco Caputo, Enrica Ciccarelli, Laura De Marinis, Ernesto De Menis, Marco Faustini Fustini, Franco Grimaldi, Andrea Lania, Giovanni Lasio, Francesco Logoluso, Marco Losa, Pietro Maffei, Davide Milani, Maurizio Poggi, Michele Zini, Laurence Katznelson, Anton Luger, Catalina Poiana, and AME

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.

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Steinunn Arnardóttir, Jacob Järås, Pia Burman, Katarina Berinder, Per Dahlqvist, Eva Marie Erfurth, Charlotte Höybye, Karin Larsson, Oskar Ragnarsson, Bertil Ekman, and Britt Edén Engström

Objective

To describe the treatment and long-term outcomes of patients with acromegaly from all healthcare regions in Sweden.

Design and methods

Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991 to 2011. The latest clinical follow-up date was December 2012, while mortality data were collected for 28.5 years until June 2019.

Results

The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy, and 39% medical treatment. At the 5- and 10-year follow-ups, insulin-like growth factor 1 levels were within the reference range in 69 and 78% of patients, respectively. In linear regression, the proportion of patients with biochemical control including adjuvant therapy at 10 years follow-up increased over time by 1.23% per year. The standardized mortality ratio (SMR) (95% CI) for all patients was 1.29 (1.11–1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed between 1991 and 2000, SMR: 1.06 (0.85–1.33) nor between 2001 and2011, SMR: 0.87 (0.61–1.24). In contrast, non-controlled patients at the latest follow-up from both decades had elevated SMR, 1.90 (1.33–2.72) and 1.98 (1.24–3.14), respectively.

Conclusions

The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy, while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.

Open access

Charlotte J Green, Thomas Marjot, John Walsby-Tickle, Catriona Charlton, Thomas Cornfield, Felix Westcott, Katherine E Pinnick, Ahmad Moolla, Jonathan M Hazlehurst, James McCullagh, Jeremy W Tomlinson, and Leanne Hodson

Objective

Metformin is a first-line pharmacotherapy in the treatment of type 2 diabetes, a condition closely associated with non-alcoholic fatty liver disease (NAFLD). Although metformin promotes weight loss and improves insulin sensitivity, its effect on intrahepatic triglyceride (IHTG) remains unclear. We investigated the effect of metformin on IHTG, hepatic de novo lipogenesis (DNL), and fatty acid (FA) oxidation in vivo in humans.

Design and methods

Metabolic investigations, using stable-isotope tracers, were performed in ten insulin-resistant, overweight/obese human participants with NAFLD who were treatment naïve before and after 12 weeks of metformin treatment. The effect of metformin on markers of s.c. adipose tissue FA metabolism and function, along with the plasma metabolome, was investigated.

Results

Twelve weeks of treatment with metformin resulted in a significant reduction in body weight and improved insulin sensitivity, but IHTG content and FA oxidation remained unchanged. Metformin treatment was associated with a significant decrease in VLDL-triglyceride (TG) concentrations and a significant increase in the relative contribution of DNL-derived FAs to VLDL-TG. There were subtle and relatively few changes in s.c. adipose tissue FA metabolism and the plasma metabolome with metformin treatment.

Conclusions

We demonstrate the mechanisms of action of metformin whereby it improves insulin sensitivity and promotes weight loss, without improvement in IHTG; these observations are partly explained through increased hepatic DNL and a lack of change in FA oxidation.

Open access

Lucie Canaff, Vito Guarnieri, Yoojung Kim, Betty Y L Wong, Alexis Nolin-Lapalme, David E C Cole, Salvatore Minisola, Cristina Eller-Vainicher, Filomena Cetani, Andrea Repaci, Daniela Turchetti, Sabrina Corbetta, Alfredo Scillitani, and David Goltzman

Objective

The aim of this study was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma.

Design

We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants.

Methods

Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses.

Results

A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitrotranscriptional activity, including increased stimulation of the PTH promoter.

Conclusions

We provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.

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David J Handelsman, Reena Desai, Ann J Conway, Nandini Shankara-Narayana, Bronwyn G A Stuckey, Warrick J Inder, Mathis Grossmann, Bu Beng Yeap, David Jesudason, Lam P Ly, Karen Bracken, and Gary Allen Wittert

Context

The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known.

Objective

The aim of this study was to investigate the rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections.

Materials and Methods

Men (n = 303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo (P)-controlled randomized clinical trial of TU treatment were recruited for further 12 months while remaining blinded to treatment. Sex steroids (testosterone (T), dihydrotestosterone, oestradiol, oestrone) by liquid chromatography-mass sprectometry, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire, International Index of Erectile Function, and short form survey (SF-12)) were measured at entry (3 months after the last injection) and 6, 12, 18, 24, 40, and 52 weeks later.

Results

In the nested cohort of TU-treated men, serum T was initially higher but declined at 12 weeks remaining stable thereafter with serum T and SHBG at 11 and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carry-over higher scores in T-treated men but after 18 weeks showed no difference between T- and P-treated men. Initially, fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since the last injection.

Conclusions

After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since the last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

Open access

Nellie Y Loh, Edward Humphreys, Fredrik Karpe, Jeremy W Tomlinson, Raymond Noordam, and Constantinos Christodoulides

Objective

Epidemiological and clinical studies have highlighted important roles for sex hormones in the regulation of fat distribution and systemic metabolism. We investigated the bidirectional associations between bioavailable serum testosterone (BioT) in both sexes and oestradiol (E2) in men and adiposity and metabolic traits using Mendelian randomisation (MR).

Design and Methods

As genetic instruments for sex hormones, we selected all the genome-wide significant, independent signals from a genome-wide association studies (GWAS) in up to 425 097 European ancestry UK Biobank participants. European population-specific, summary-level data for adiposity, metabolic, and blood pressure traits were obtained from the largest publicly available GWAS. Sex-specific, two-sample MR analyses were used to estimate the associations of sex hormones with these traits and vice versa.

Results

In women, higher BioT was associated with obesity, upper-body fat distribution, and low HDL-cholesterol although, based on analyses modelling the sex hormone-binding globulin-independent effects of BioT, the last two associations might be indirect. Conversely, obesity and android fat distribution were associated with elevated serum BioT. In men, higher BioT was associated with lower hip circumference and lower fasting glucose. Reciprocally, obesity was associated with lower BioT and higher E2, while upper-body fat distribution and raised triglycerides were associated with lower E2.

Conclusions

Adipose tissue and metabolic dysfunction are associated with deranged sex hormone levels in both sexes. In women, elevated BioT might be a cause of obesity. Conversely, in men, higher BioT appears to have beneficial effects on adiposity and glucose metabolism.

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Eliza B Geer, John L Kilgallon, Karen J P Liebert, Allison Kimball, and Lisa B Nachtigall

Objectives

To assess the impact of virtual education programming for patients with acromegaly.

Design

We conducted a mixed methods study to evaluate patient attitudes, examine if patient-centered educational forums change these attitudes, and determine the role of virtual education as a means to learn about patients’ unmet needs, self-reported outcomes, and educational priorities.

Methods

The study included 653 total virtual program registrants. Of these, 78 patients with acromegaly were included in the analysis. The programs consisted of patient-centered livestream education by a multidisciplinary team of pituitary experts and patient presenters. Multiple-choice questions were used to assess attitudes before and after the event, and short answer surveys were used to collect care goals and unmet needs related to treatment.

Results

Attendance included participants from 37 countries. The number of patients who responded that they had no hope for improvement, had no choice in their treatment, and felt alone living with acromegaly each decreased significantly pre- to post-event (P  < 0.05). The number of patients who felt anxious about their acromegaly diagnosis remained unchanged. ‘Quality of life/mental health’ was the most common personal care goals concern followed by ‘medical therapies/tumor control.’ Perceived acromegaly unmet needs were evenly distributed, with five of six categories reported by over 20% of patients.

Conclusion

Our findings indicate that virtual education may have a significant positive effect on acromegaly patients’ perceptions of their disease. The lessons learned from these virtual programs may be used to inform future virtual education programming for acromegaly and other rare diseases.

Open access

Wiebke Schloetelburg, Ines Ebert, Bernhard Petritsch, Andreas Max Weng, Ulrich Dischinger, Stefan Kircher, Andreas Konrad Buck, Thorsten Alexander Bley, Timo Deutschbein, and Martin Fassnacht

Objective

Reliable results of wash-out CT in the diagnostic workup of adrenal incidentalomas are scarce. Thus, we evaluated the diagnostic accuracy of delayed wash-out CT and determined thresholds to accurately differentiate adrenal masses.

Design

Retrospective, single-center cohort study including 216 patients with 252 adrenal lesions who underwent delayed wash-out CT. Definitive diagnoses based on histopathology (n = 92) or comprehensive follow-up.

Methods

Size, average attenuation values of the adrenal lesions in all CT scan phases, and absolute and relative percentage wash-out (APW/RPW) were determined by an expert radiologist blinded for clinical data. Adrenal lesions with unenhanced attenuation values >10 Hounsfield units (HU) built a subgroup (n = 142). Diagnostic accuracy was calculated.

Results

The study group consisted of 171 adenomas, 32 other benign tumors, 11 pheochromocytomas, 9 adrenocortical carcinomas, and 29 other malignant tumors. All (potentially) malignant and 46% of benign lesions showed unenhanced attenuation values >10 HU. In this most relevant subgroup, the established thresholds of 60% for APW and 40% for RPW misclassified 35.9 and 35.2% of the masses, respectively. When we applied optimized cutoffs (APW >83%; RPW >58%) and excluded pheochromocytomas, we missed only one malignant tumor by APW and none by RPW. However, only 11 and 15% of the benign tumors were correctly identified.

Conclusions

Wash-out CT with the established thresholds for APW and RPW is insufficient to reliably diagnose adrenal masses. Using the proposed cutoff of 58% for RPW, malignant tumors will be correctly identified, but the added value is limited, namely 15% of patients with benign tumors can be prevented from additional imaging or even unnecessary surgery.

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Sahar Mohseni-Takalloo, Sara Beigrezaei, Zeinab Yazdanpanah, Seyede Hamide Rajaie, Sepideh Soltani, Tayebeh Zohrabi, Mojtaba Kaviani, Scott C Forbes, Julien S Baker, and Amin Salehi-Abargouei

Objective

There is no consensus of opinion if exercise beneficially affects sex hormones if added to weight-loss diets. The purpose of this study was to perform a systematic review and meta-analysis of controlled clinical trials to evaluate the effect of adding exercise to a hypo-caloric diet during a weight-loss program, on serum testosterone, estradiol, and sex hormone-binding globulin (SHBG) in adults with overweight/obesity.

Design

Systematic review and meta-analysis of the literature.

Methods

Online databases including PubMed/MEDLINE, EMBASE, Scopus, ISI Web of Science, and Google Scholar were searched up to April 2021. A random-effects model was applied to compare mean changes in sex hormones and SHBG between participants undergoing a hypo-caloric diet with or without exercise.

Results

In total, 9 eligible clinical trials with 462 participants were included. Out of these, seven, three, and four studies illustrated changes in testosterone, estradiol, and SHBG, respectively. The meta-analysis revealed that exercise had no significant effect on circulating testosterone (WMD = −0.03 nmol/L, 95% CI: −0.11, 0.06, P = 0.51), estradiol (WMD = −0.46 pg/mL, 95% CI: −1.57, 0.65, P = 0.42), and SHBG (WMD = 0.54 nmol/L, 95% CI: −2.63, 3.71, P = 0.74) when added to low-calorie diets.

Conclusion

The addition of exercise to a hypo-caloric diet provided no additional improvement in sex hormone profiles. Further, well-designed randomized controlled trials with longer follow-up periods in both sexes are recommended to confirm and expand the current results.

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Antoine Tabarin, Magalie Haissaguerre, Hélène Lassole, Arnaud Jannin, Anne-Cecile Paepegaey, Olivier Chabre, and Jacques Young