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Eva C Coopmans, Joppe J Schneiders, Nour El-Sayed, Nicole S Erler, Leo J Hofland, Aart-Jan van der Lely, Patrick Petrossians, Julia Potorac, Ammar Muhammad, and Sebastian J C M M Neggers

Objective

T2-signal intensity and somatostatin (SST) receptor expression are recognized predictors of therapy response in acromegaly. We investigated the relationship between these predictors and the hormonal and tumoral responses to long-acting pasireotide (PAS-LAR) therapy, which were also compared with responsiveness to first-generation somatostatin receptor ligands (SRLs).

Design

The PAPE study is a cohort study.

Methods

We included 45 acromegaly patients initially receiving SRLs, followed by combination therapy with pegvisomant, and finally PAS-LAR. We assessed tumor volume reduction (≥25% from baseline), IGF-1 levels (expressed as the upper limit of normal), and T2-weighted MRI signal and SST receptor expression of the adenoma.

Results

Patients with significant tumor shrinkage during PAS-LAR showed higher IGF-1 levels during PAS-LAR (mean (S.D.): 1.36 (0.53) vs 0.93 (0.43), P = 0.020), less IGF-1 reduction after first-generation SRLs (mean (S.D.): 0.55 (0.71) vs 1.25 (1.07), P = 0.028), and lower SST2 receptor expression (median (IQR): 2.0 (1.0–6.0) vs 12.0 (7.5–12.0), P = 0.040). Overall, T2-signal intensity ratio was increased compared with baseline (mean (S.D.): 1.39 (0.56) vs 1.25 (0.52), P = 0.017) and a higher T2-signal was associated with lower IGF-1 levels during PAS-LAR (β: −0.29, 95% CI: −0.56 to −0.01, P = 0.045). A subset of PAS-LAR treated patients with increased T2-signal intensity achieved greater reduction of IGF-1 (mean (S.D.): 0.80 (0.60) vs 0.45 (0.39), P = 0.016).

Conclusions

Patients unresponsive to SRLs with a lower SST2 receptor expression are more prone to achieve tumor shrinkage during PAS-LAR. Surprisingly, tumor shrinkage is not accompanied by a biochemical response, which is accompanied with a higher T2-signal intensity.

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Dorte Glintborg, Henrik Bjarke Vaegter, Louise Lehmann Christensen, Emma Bendix, Thomas Graven-Nielsen, Per Grünwald Andersen, and Marianne Andersen

Background

Hypogonadism is prevalent during opioid treatment, but the effect of testosterone replacement treatment (TRT) on body composition, pain perception, and adrenal function is unclear.

Purpose

To measure changes in body composition, pain perception, quality of life, and adrenal function after TRT or placebo in opioid-treated men with chronic non-malignant pain.

Methods

Double-blind, placebo-controlled study in 41 men (>18 years) with total testosterone <12 nmol/L were randomized to 24 weeks TRT (Testosterone undecanoate injection three times/6 months, n = 20) or placebo (placebo-injections, n = 21).

Outcomes

Body composition (lean body mass and fat mass assessed by DXA), clinical pain intensity (numerical rating scale), and experimental pain perception (quantitative sensory assessment), quality of life (SF36), and adrenocorticotrophic hormone (ACTH) test. Data were presented as median (quartiles). Mann–Whitney tests were performed on delta values (24–0 weeks) between TRT and placebo.

Results

The median age was 55 years (46; 59) and total testosterone before intervention was 6.8 (5.0; 9.3) nmol/L. TRT was associated with change of testosterone levels: 12.3 (7.0; 19.9) nmol/L (P < 0.001 vs placebo), increased lean body mass: 3.6 (2.3; 5.0) kg vs 0.1 kg (−2.1; 1.5) during TRT vs placebo and decreased total fat mass: −1.2 (−3.1; 0.7) kg vs 1.2 kg (−0.9; 2.5) kg, both P < 0.003. Changed pain perception, SF36, and ACTH-stimulated cortisol levels were non-significantly changed during TRT compared with placebo.

Conclusions

Six months of TRT improved body composition in men with opioid-induced hypogonadism without significant changes in outcomes of pain perception, quality of life, or adrenal function.

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Rasmus Rørth, Peter Godsk Jørgensen, Henrik Ullits Andersen, Christina Christoffersen, Jens Peter Gøtze, Lars Køber, Peter Rossing, and Magnus Thorsten Jensen

Aims

Patients with type 1 diabetes have a high risk of cardiovascular disease. Yet, the importance of routine assessment of myocardial function in patients with type 1 diabetes is not known. Thus, we examined the prognostic importance of NT-proBNP and E/e′, an echocardiographic measure of diastolic function, in type 1 diabetes patients with preserved left ventricular ejection fraction (LVEF) and without known heart disease.

Methods and results

Type 1 diabetes patients without known heart disease and LVEF ≥45% enrolled in the Thousand and 1 study were included and followed through nationwide registries. The risk of major cardiovascular events (MACE) and death associated with levels of NT-proBNP and E/e′ was examined. Of 960 patients, median follow-up of 6.3 years (Q1–Q3: 5.7–7.0), 121 (12%) experienced MACE and 51 (5%) died. Increased levels of both NT-proBNP and E/e′ were associated with worse outcomes (adjusted hazard ratios for MACE = 1.56 (1.23–1.98) and 4.29 (2.25–8.16) per Loge increase for NT-proBNP and E/e′, respectively). NT-proBNP and E/e′ combined significantly improved the discrimination power of the Steno T1D risk engine (MACE, C-index: 0.813 (0.779–0.847) vs 0.779 (0.742–0.816); P = 0.0001; All-cause mortality, C-index 0.855 (0.806–0.903) vs 0.828 (0.776–0.880); P = 0.03).

Conclusion

In patients with type 1 diabetes, preserved ejection fraction, and no known heart disease, NT-proBNP and E/e′ were associated with increased risk of MACE and all-cause mortality. The risks associated with NT-proBNP and E/e′ combined identified patients at remarkably high risk.

Open access

Jakob Skov, Daniel Eriksson, Ralf Kuja-Halkola, Jonas Höijer, Soffia Gudbjörnsdottir, Ann-Marie Svensson, Patrik K E Magnusson, Jonas F Ludvigsson, Olle Kämpe, and Sophie Bensing

Objective

Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases.

Design

Prospective twin cohort study.

Methods

We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto’s thyroiditis, atrophic gastritis, celiac disease, Graves’ disease, type 1 diabetes, vitiligo and Addison’s disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data.

Results

Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2–9.2) than in dizygotic twins (median HR: 2.4, range: 1.1–10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23–0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49–0.71) for Graves’ disease to 0.97 (95% CI: 0.91–1.00) for Addison’s disease.

Conclusions

Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.

Free access

Luis F de Castro, Diana Ovejero, and Alison M Boyce

Fibrous dysplasia/McCune–Albright Syndrome (FD/MAS), arising from gain-of-function mutations in Gαs, and cutaneous skeletal hypophosphatemia syndrome (CSHS), arising from gain-of-function mutations in the Ras/MAPK pathway, are strikingly complex, mosaic diseases with overlapping phenotypes. Both disorders are defined by mosaic skin and bone involvement, and both are complicated by increased FGF23 production. These similarities have frequently led to mis-diagnoses, primarily in patients with CSHS who are often assumed to have FD/MAS. The intriguing similarities in skeletal involvement in these genetically distinct disorders have led to novel insights into FGF23 physiology, making an understanding of FD/MAS and CSHS relevant to both clinicians and researchers interested in bone and endocrine disorders. This review will give an overview of FD/MAS and CSHS, focusing on the roles of mosaicism and FGF23 in the pathogenesis and clinical presentation of these disorders.

Free access

Livia Lamartina and Daria Handkiewicz-Junak

Each year, the proportion of thyroid cancer patients presenting with low-risk disease is increasing. The shift in the landscape of thyroid cancer presentation is forcing clinicians to re-evaluate not only management but also surveillance paradigms. During the follow-up, patients are stratified considering their response to treatment and classified into one of the following response categories: excellent, biochemical incomplete, structural incomplete, or indeterminate. These categories reflect a real-time prognosis and thereby substantially influence and personalise disease management. Although at present, no guideline recommends stopping differentiated thyroid carcinoma (DTC) surveillance at any particular time point, the relatively low prevalence of treatment failures in low-risk patients may prompt early discontinuation of surveillance in this subgroup. Therefore, this debate will present an overview of the controversies surrounding the surveillance of low-risk patients with DTC.

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Marco Mezzullo, Guido Di Dalmazi, Alessia Fazzini, Margherita Baccini, Andrea Repaci, Alessandra Gambineri, Valentina Vicennati, Carla Pelusi, Uberto Pagotto, and Flaminia Fanelli

Objective

To evaluate the independent impact of age, obesity and metabolic risk factors on 13 circulating steroid levels; to generate reference intervals for adult men.

Design

Cross-sectional study.

Methods

Three hundred and fifteen adults, drug-free and apparently healthy men underwent clinical and biochemical evaluation. Thirteen steroids were measured by LC-MS/MS and compared among men with increasing BMI. Moreover, the independent impact of age, BMI and metabolic parameters on steroid levels was estimated. Upper and lower reference limits were generated in steroid-specific reference sub-cohorts and compared with dysmetabolic sub-cohorts.

Results

We observed lower steroid precursors and testosterone and increase in estrone levels in men with higher BMI ranges. By multivariate analysis, 17-hydroxyprogesterone and dihydrotestosterone decreased with BMI, while cortisol decreased with waist circumference. Estrone increased with BMI and systolic blood pressure. Testosterone decreased with worsening insulin resistance. 17-hydroxypregnenolone and corticosterone decreased with increasing total/HDL-cholesterol ratio. Age-related reference intervals were estimated for 17-hydroxypregnenolone, DHEA, 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol, cortisol and androstenedione, while age-independent reference intervals were estimated for progesterone, 11-deoxycorticosterone, testosterone, dihydrotestosterone, estrone and estradiol. Testosterone lower limit was 2.29 nmol/L lower (P = 0.007) in insulin resistant vs insulin sensitive men. Furthermore, the upper limits for dihydrotestosterone (−0.34 nmol/L, P = 0.045), cortisol (−87 nmol/L, P = 0.045–0.002) and corticosterone (−10.1 nmol/L, P = 0.048–0.016) were lower in overweight/obese, in abdominal obese and in dyslipidaemic subjects compared to reference sub-cohorts, respectively.

Conclusions

Obesity and mild unmedicated metabolic risk factors alter the circulating steroid profile and bias the estimation of reference limits for testosterone, dihydrotestosterone, cortisol and corticosterone. Applying age-dependent reference intervals is mandatory for steroid precursors and corticosteroids.

Free access

Nèle F Lenders, Ann I McCormack, and Ken K Y Ho

Gonadal steroids modulate the effects of GH, with oestrogens attenuating and androgens augmenting GH action. Whether these divergent effects influence the clinical manifestation, management and prognosis of acromegaly have not been carefully reviewed. This review examines whether there is a gender difference in epidemiology, presentation, quality of life (QoL), morbidity, treatments and mortality of acromegaly. Acromegaly is more common in women who present at an older age with longer diagnostic delay. At presentation, women have a higher GH relative to IGF-1 level than men. QoL is more adversely affected in women both before and after treatment. Prevalence of hypertension and diabetes are greater in women than in men with acromegaly. Treatment outcomes with SSAs are comparable between sexes, but women may require a higher dose of pegvisomant for equivalent response. Mortality in untreated acromegaly is more profoundly affected in women; however, improved treatments in recent decades have resulted in normalisation of standard mortality ratios in both sexes. We conclude that gender does matter in the management of acromegaly, with women presenting later in life, with greater diagnostic delay, higher prevalence of comorbidities and experiencing worse QoL.

Free access

Rolf H H Groenwold and Olaf M Dekkers

The results of observational studies of causal effects are potentially biased due to confounding. Various methods have been proposed to control for confounding in observational studies. Eight basic aspects of confounding adjustment are described, with a focus on correction for confounding through covariate adjustment using regression analysis. These aspects should be considered when planning an observational study of causal effects or when assessing the validity of the results of such a study.

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Mirko Peitzsch, Denise Kaden, Christina Pamporaki, Katharina Langton, Georgiana Constantinescu, Catleen Conrad, Stephanie Fliedner, Richard O Sinnott, Aleksander Prejbisz, Roland Därr, Jacques W M Lenders, Michael Bursztyn, and Graeme Eisenhofer

Objective

Sympathoadrenal activity is decreased during overnight rest. This study assessed whether urinary-free normetanephrine, metanephrine and methoxytyramine in overnight/first-morning urine collections might offer an alternative to measurements in 24-h collections or plasma for diagnosis of pheochromocytoma and paraganglioma (PPGL).

Design and methods

Prospective multicenter cross-sectional diagnostic study involving 706 patients tested for PPGL, in whom tumors were confirmed in 79 and excluded in 627 after follow-up. Another 335 age- and sex-matched volunteers were included for reference purposes. Catecholamines and their free O-methylated metabolites were measured in 24-h collections divided according to waking and sleeping hours and normalized to creatinine. Plasma metabolites from blood sampled after supine rest were measured for comparison.

Results

Urinary outputs of norepinephrine, normetanephrine, epinephrine and metanephrine in the reference population were respectively 50 (48–52)%, 35 (32–37)%, 76 (74–78)% and 15 (12–17)% lower following overnight than daytime collections. Patients in whom PPGLs were excluded showed 28 (26–30)% and 6 (3–9)% day-to-night falls in normetanephrine and metanephrine, while patients with PPGLs showed no significant day-to-night falls in metabolites. Urinary methoxytyramine was consistently unchanged from day to night. According to receiver-operating characteristic curves, diagnostic accuracy of metabolite measurements in overnight/first-morning urine samples did not differ from measurements in 24-h urine collections, but was lower for both than for plasma. Using optimized reference intervals, diagnostic specificity was higher for overnight than daytime collections at similar sensitivities.

Conclusions

Measurements of urinary-free catecholamine metabolites in first-morning/overnight urine collections offer an alternative for diagnosis of PPGL to 24-h collections but remain less accurate than plasma measurements.