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Yaelle Elfassy, Alice Bongrani, Pierre Levy, Frantz Foissac, Soraya Fellahi, Céline Faure, Chloé McAvoy, Jacqueline Capeau, Joelle Dupont, Bruno Fève, Rachel Levy and Jean-Philippe Bastard

Objective: Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples.

Design: Male partners of infertile couples referred to four medical French centers were enrolled in years 2013-2016.

Methods: Subjects (n=160) aged 18-45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP.

Results: Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that body mass index, infertility duration, and adiponectin serum/SP ratio were independently associated with MS.

Conclusions: These results suggest an involvement of seminal adipokines to modulate fertility in men with MS, and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.

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Ravi Kumar Dutta, Thomas Arnesen, Anette Heie, Martin Walz, Piero Alesina, Peter Söderkvist and Oliver Gimm

Objective

To screen for CLCN2 mutations in apparently sporadic cases of aldosterone-producing adenomas (APAs).

Description

Recently, CLCN2, encoding for the voltage-gated chloride channel protein 2 (ClC-2), was identified to be mutated in familial hyperaldosteronism II (FH II). So far, somatic mutations in CLCN2 have not been reported in sporadic cases of APAs. We screened 80 apparently sporadic APAs for mutations in CLCN2. One somatic mutation was identified at p.Gly24Asp in CLCN2. The male patient had a small adenoma in size but high aldosterone levels preoperatively. Postoperatively, the patient had normal aldosterone levels and was clinically cured.

Conclusion

In this study, we identified a CLCN2 mutation in a sporadic APA comprising about 1% of all APAs investigated. This mutation was complementary to mutations in other susceptibility genes for sporadic APAs and may thus be a driving mutation in APA formation.

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Christa Flück, Anna Nordenström, S Faisal Ahmed, Salma R Ali, Marta Berra, Joanne Hall, Birgit Köhler, Vickie Pasterski, Ralitsa Robeva, Katinka Schweizer, Alexander Springer, Puck Westerveld, Olaf Hiort, Martine Cools and the COST Action BM1303 Working Group

The treatment and care of individuals who have a difference of sex development (DSD) have been revised over the past two decades and new guidelines have been published. In order to study the impact of treatments and new forms of management in these rare and heterogeneous conditions, standardised assessment procedures across centres are needed. Diagnostic work-up and detailed genital phenotyping are crucial at first assessment. DSDs may affect general health, have associated features or lead to comorbidities which may only be observed through lifelong follow-up. The impact of medical treatments and surgical (non-) interventions warrants special attention in the context of critical review of current and future care. It is equally important to explore gender development early and refer to specialised services if needed. DSDs and the medical, psychological, cultural and familial ways of dealing with it may affect self-perception, self-esteem, and psychosexual function. Therefore, psychosocial support has become one of the cornerstones in the multidisciplinary management of DSD, but its impact remains to be assessed. Careful clinical evaluation and pooled data reporting in a global DSD registry will allow linking genetic, metabolomic, phenotypic and psychological data. For this purpose, our group of clinical experts and patient and parent representatives designed a template for structured longitudinal follow-up. In this paper, we explain the rationale behind the selection of the dataset. This tool provides guidance to professionals caring for individuals with a DSD and their families. At the same time, it collects the data needed for answering unsolved questions of patients, clinicians, and researchers. Ultimately, outcomes for defined subgroups of rare DSD conditions should be studied through large collaborative endeavours using a common protocol.

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F P Paranhos-Neto, L Vieira Neto, M Madeira, A B Moraes, L M C Mendonça, I C B Lima, C L R Chagas, D A Lira, J F Spitz, J A M Guimarães, M E L Duarte and M L F Farias

Introduction

The role of vitamin D on bone microarchitecture and fragility is not clear.

Objective

To investigate whether vitamin D deficiency (25(OH)D <20 ng/mL) increases cortical bone loss and the severity of fractures.

Design

Cross-sectional study of 287 elderly women with at least one prevalent low-impact fracture.

Methods

Biochemistry, X-rays to identify vertebral fractures (VFs) and to confirm non-vertebral fractures (NonVFs), and high-resolution peripheral quantitative computed tomography (HR-pQCT) to evaluate bone microstructure.

Results

Serum 25(OH)D levels were associated with body mass index (BMI: r = −0.161, P = 0.006), PTH (r = −0.165; P = 0.005), CTX (r = −0.119; P = 0.043) and vBMD at cortical bone (Dcomp: r = 0.132; P = 0.033) and entire bone (D100: r = 0.162 P = 0.009) at the distal radius, but not at the tibia. Age and PTH levels were potential confounding variables, but in the multiple linear regressions only BMI (95% CI: 0.11–4.16; P < 0.01), 25(OH)D (95% CI: −0.007 to 1.70; P = 0.05) and CTX (95% CI: −149.04 to 21.80; P < 0.01) predicted Dcomp, while BMI (95% CI: 1.13–4.18; P < 0.01) and 25(OH)D (95% CI: 0.24–1.52; P < 0.01) predicted D100. NonVFs predominated in patients with 25(OH)D <20 ng/mL (P = 0.013). Logistic regression analysis showed a decrease in the likelihood of presenting grade 2–3 VFs/NonVFs for every increase in 25(OH)D (OR = 0.962, 95% CI: 0.940–0.984; P = 0.001), BMI (OR = 0.932, 95% CI: 0.885–0.981; P = 0.007) and D100 at radius (OR = 0.994, 95% CI: 0.990–0.998; P = 0.005).

Conclusion

In elderly patients with prevalent fractures, vitamin D deficiency was associated with cortical bone loss and severity of fractures.

Free access

Terry J Smith and Luigi Bartalena

In this article, the two authors present their opposing points of view concerning the likelihood that glucocorticoids will be replaced by newly developed biological agents in the treatment of active, moderate-to-severe thyroid-associated ophthalmopathy (TAO). TAO is a vexing, disfiguring and potentially blinding autoimmune manifestation of thyroid autoimmunity. One author expresses the opinion that steroids are nonspecific, frequently fail to improve the disease and can cause sometimes serious side effects. He suggests that glucocorticoids should be replaced as soon as possible by more specific and safer drugs, once they become available. The most promising of these are biological agents. The other author argues that glucocorticoids are proven effective and are unlikely to be replaced by biologicals. He reasons that while they may not uniformly result in optimal benefit, they have been proven effective in many reports. He remains open minded about alternative therapies such as biologicals but remains skeptical that they will replace steroids as the first-line therapy for active, moderate-to-severe TAO without head-to-head comparative clinical trials demonstrating superiority. Despite these very different points of view, both authors are optimistic about the availability of improved medical therapies for TAO, either as single agents or in combination. Further, both agree that better treatment options are needed to improve the care of our patients with active moderate-to-severe TAO.

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Deborah Cosentini, Giuseppe Badalamenti, Salvatore Grisanti, Vittoria Basile, Ida Rapa, Sara Cerri, Andrea Spallanzani, Paola Perotti, Emanuela Musso, Marta Laganà, Vittorio Ferrari, Gabriele Luppi, Alberto Dalla Volta, Lorena Incorvaia, Sandra Sigala, Antonio Russo, Marco Volante, Massimo Terzolo and Alfredo Berruti

Objective: Temozolomide has shown a significant anti-proliferative activity on adrenocortical cancer (ACC) cells in vitro.

Design: On the basis of these results the drug was prescribed as second/third line in advanced metastatic ACC patients in 4 referral centers in Italy.

Methods: We retrospectively collected anagraphic, clinical and pathological data of patients with advanced ACC with disease progression to standard chemotherapy plus mitotane who were treated with temozolomide at the dose of 200 mg/m2/die given for 5 consecutive days every 28 days. The primary end-point was the disease control rate, defined as objective response or disease stabilization after 3 months. Secondary endpoints were overall survival (OS), progression free survival (PFS) and drug safety.

Results: Twenty-eight patients have been included in the study. Ten patients (35.8%, 95% CI 17.8-53.8) obtained a disease control from temozolomide treatment. In particular, 1 patient had a complete response, 5 patients a partial response and 4 patients stable disease. Median PFS was 3.5 months and median OS 7.2 months. Disease response was more frequently observed in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene. Temozolomide therapy was well tolerated and most toxicities were limited to grade G1-2 according to WHO criteria.

Conclusion: Temozolomide was found active in the management of advanced ACC patients. The disease control rate obtained, however, was short lived and the prognosis of treated patients was poor.

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Sandeep Dhindsa, Husam Ghanim, Kelly Green, Sanaa Abuaysheh, Manav Batra, Antoine Makdissi, Ajay Chaudhuri, Sartaj Sandhu and Paresh Dandona

Abstract

Aims: Insulin has anabolic effects on skeletal muscle. However, there is limited understanding of the molecular mechanisms underlying this effect in humans. We evaluated whether the skeletal muscle expression of satellite cell activator Fibroblast growth factor 2 (FGF2) and muscle growth and differentiation factors are modulated acutely by insulin during euglycemic hyperinsulinemic clamp (EHC).

Design and methods: This is a secondary investigation and analysis of samples obtained from a previously completed trial investigating the effect of testosterone replacement in males with hypogonadotropic hypogonadism and type 2 diabetes. Twenty men with type 2 diabetes underwent quadriceps muscle biopsies before and after 4 hours of EHC.

Results: The infusion of insulin during EHC raised the expression of myogenic growth factors, myogenin (by 72±20%) and myogenin differentiation protein (MyoD; by 81±22%). Insulin reduced the expression of muscle hypertrophy suppressor, myogenic regulatory factor 4 (Mrf4) by 34±14%. In addition, there was an increase in expression of FGF receptor 2, but not FGF2, following EHC. The expression of myostatin did not change.

Conclusions: Insulin has an acute potent effect on expression of genes that can stimulate muscle differentiation and growth.

Open access

Fahim Ebrahimi, Andrea Widmer, Ulrich Wagner, Beat Mueller, Philipp Schuetz, Mirjam Christ-Crain and Alexander Kutz

OBJECTIVE Adrenal insufficiency in the outpatient setting is associated with excess morbidity, mortality, and impaired quality of life. Evidence on its health-care burden in medical inpatients is scarce. The aim of this study was to assess the health-care burden of primary (PAI) and secondary adrenal insufficiency (SAI) among hospitalized inpatients.

DESIGN and METHODS In this nationwide cohort study, adult medical patients with either PAI or SAI hospitalized between 2011 and 2015 were compared with propensity-matched (1:1) medical controls, respectively. The primary outcome was 30-day all-cause in-hospital mortality. Main secondary outcomes included ICU admission rate, length-of-hospital stay, 30-day- and 1-year all-cause readmission rates.

RESULTS In total, 594 hospitalized cases with PAI and 4`880 with SAI were included. Compared with matched controls, in-hospital mortality was not increased among PAI or SAI patients, respectively. Patients with adrenal insufficiency were more likely to be admitted to ICU (PAI: OR 1.9 [95%CI, 1.27 to 2.72], and SAI: OR 1.5 [95%CI, 1.35 to 1.75]). Length of hospital stay was prolonged by 1.0 days in PAI patients (8.9 vs. 7.9 days [95%CI, 0.06 to 1.93]), and by 3.3 days in SAI patients (12.1 vs. 8.8 days [95%CI, 2.82 to 3.71]), when compared to matched controls. Patients with SAI were found to have higher 30-day and 1-year readmission rates (14.1% vs. 12.1% and 50.0% vs.40.7%; p<0.001) than matched controls.

CONCLUSIONS While no difference in in-hospital mortality was found, adrenal insufficiency was associated with prolonged length of hospital stay, and substantially higher rates of ICU admission and hospital readmission.

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J E Lake, P Debroy, D Ng, K M Erlandson, L A Kingsley, F J Palella Jr, M J Budoff, W S Post and T T Brown

Objectives

Adipose tissue (AT) density measurement may provide information about AT quality among people living with HIV. We assessed AT density and evaluated relationships between AT density and immunometabolic biomarker concentrations in men with HIV.

Design

Cross-sectional analysis of men enrolled in the Multicenter AIDS Cohort Study.

Methods

Abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density (Hounsfield units, HU; less negative = more dense) were quantified from computed tomography (CT) scans. Multivariate linear regression models described relationships between abdominal AT density and circulating biomarker concentrations.

Results

HIV+ men had denser SAT (−95 vs −98 HU HIV−, P < 0.001), whereas VAT density was equivalent by HIV serostatus men (382 HIV−, 462 HIV+). Historical thymidine analog nucleoside reverse transcriptase inhibitor (tNRTI) use was associated with denser SAT but not VAT. In adjusted models, a 1 s.d. greater SAT or VAT density was associated with higher levels of adiponectin, leptin, HOMA-IR and triglyceride:HDL cholesterol ratio and lower hs-CRP concentrations in HIV− men. Conversely, in HIV+ men, each s.d. greater SAT density was not associated with metabolic parameter improvements and was significantly (P < 0.05) associated with higher systemic inflammation. Trends toward higher inflammatory biomarker concentrations per 1 s.d. greater VAT density were also observed among HIV+ men.

Conclusions

Among men living with HIV, greater SAT density was associated with greater systemic inflammation independent of SAT area. AT density measurement provides additional insight into AT density beyond measurement of AT quantity alone, and may have implications for metabolic disease risk.

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Bu Beng Yeap, Jennie Hui, Matthew Knuiman, S A Chubb, Ken K Y Ho, Leon Flicker, Mark L. Divitini, Gillian M Arscott, Stephen Twigg, Osvaldo Almeida, Graeme Hankey, Jonathan Golledge and John Beilby

Objective: Effects of insulin-like growth factor 1 (IGF1) and its binding proteins (IGFBPs) on ageing, and their interaction with sex hormones, remain uncertain. We examined associations of plasma IGF1, IGFBP1, IGFBP3, estradiol and testosterone, with leucocyte telomere length (LTL), a marker of biological age, in 2999 community-dwelling men aged 70-84 years.

Methods: Plasma IGF1, IGFBP1 and IGFBP3 measured using immunoassay, sex hormones using mass spectrometry. LTL measured by PCR, expressed as ratio of telomeric to single-copy control gene DNA (T/S ratio). Linear regression models adjusted for age and cardiometabolic risk factors, median splits defined low/high groups.

Results: Mean age was 76.7±3.2 years. IGF1 and IGFBP3 showed age-adjusted correlations with LTL (coefficient 0.59, p=0.001 and 0.45, p=0.013 respectively), IGFBP1 did not. In multivariable-adjusted models IGF1 and IGFBP3 (but not IGFBP1) were associated with LTL (T/S ratio 0.015 higher per 1SD increase in IGF1, p=0.007, and 0.011 per 1SD IGFBP3, p=0.049). IGF1 and estradiol were independently associated with longer telomeres (T/S ratio 0.012 higher per 1SD increase in estradiol, p=0.027, when included in model with IGF1). Testosterone was not associated with LTL. Men with both high IGF1 (>133 ug/L) and high estradiol (>70 pmol/L) had longer LTL compared to men with lower values (multivariable-adjusted T/S ratio 1.20 vs 1.16, p=0.018).

Conclusions: Higher IGF1 and IGFBP3 are independently associated with longer telomeres in older men. Additive associations of higher IGF1 and higher estradiol with telomere length are present. Further studies are needed to determine whether these hormonal exposures cooperate to slow biological ageing.