Differences of Sex Development (DSD) comprise a variety of congenital conditions characterized by atypical chromosomal, gonadal, or anatomical sex. Diagnosis and monitoring of treatment of patients suspected of DSD conditions include clinical examination, measurement of peptide and steroid hormones, and genetic analysis. This position paper on peptide hormone analyses in the diagnosis and control of patients with DSD was jointly prepared by specialists in the field of DSD and/or peptide hormone analysis from the European Cooperation in Science and Technology (COST) Action DSDnet (BM1303) and the European Reference Network on rare Endocrine Conditions (Endo-ERN). The goal of this position paper on peptide hormone analysis was to establish laboratory guidelines that may contribute to improve optimal diagnosis and treatment control of DSD. The essential peptide hormones used in the management of patients with DSD conditions are follicle-stimulating hormone, luteinising hormone, anti-Müllerian hormone, and Inhibin B. In this context, the following position statements have been proposed: serum and plasma are the preferred matrices; the peptide hormones can all be measured by immunoassay, while use of LC-MS/MS technology has yet to be implemented in a diagnostic setting; sex- and age-related reference values are mandatory in the evaluation of these hormones; and except for Inhibin B, external quality assurance programs are widely available.
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T H Johannsen, A-M Andersson, S F Ahmed, Y B de Rijke, R F Greaves, M F Hartmann, O Hiort, P-M Holterhus, N P Krone, A Kulle, M L Ljubicic, G Mastorakos, J McNeilly, A M Pereira, A Saba, S A Wudy, K M Main, A Juul and Working Group 3 of the European Cooperation in Science and Technology (COST) Action BM1303 ‘DSDnet’ and Work Package 5 ‘’ of the European Reference Network on Rare Endocrine Conditions
Daniela Esposito, Oskar Ragnarsson, Gudmundur Johannsson and Daniel S Olsson
Clinical features of acromegaly develop insidiously. Its diagnosis may therefore be delayed.
Our aim was to study diagnostic delay and its impact on morbidity and mortality in a nationwide cohort of patients with acromegaly.
Adult patients diagnosed with acromegaly between 2001 and 2013 were identified in the Swedish National Patient Registry. Diagnostic codes for predefined comorbidities associated with acromegaly were recorded between 1987 and 2013. Diagnostic delay was calculated as the time between the first registered comorbidity and the diagnosis of acromegaly.
A total of 603 patients (280 men, 323 women) with acromegaly were included. Mean (s.d.) diagnostic delay was 5.5 (6.2) years (median (minimum, maximum) 3.3 (0.0–25.9)) Diagnostic delay was 1–<5 years in 23% patients; 5–<10 years in 17%; and ≥10 years in 24%. No delay was recorded in 36% of patients. Overall, mean (s.d.) number of comorbidities was 4.1 (2.5) and was higher in patients with longer diagnostic delay (P < 0.0001). Overall, observed number of deaths was 61 (expected 42.2), resulting in a standardized mortality ratio (SMR) of 1.45 (95% CI: 1.11–1.86). Increased mortality was only found in patients with the longest diagnostic delay (1.76, 95% CI: 1.12–2.65). In the other groups, no statistically significant increase in mortality was recorded, with the numerically lowest SMR observed in patients without diagnostic delay (1.18; 95% CI: 0.68–1.92).
The diagnosis of acromegaly is delayed in most patients. Prolonged diagnostic delay is associated with increased morbidity and mortality.
Nils Bäcklund, Göran Brattsand, Marlen Israelsson, Oskar Ragnarsson, Pia Burman, Britt Edén Engström, Charlotte Høybye, Katarina Berinder, Jeanette Wahlberg, Tommy Olsson and Per Dahlqvist
The challenge of diagnosing Cushing’s syndrome (CS) calls for high precision biochemical screening. This study aimed to establish robust reference intervals for, and compare the diagnostic accuracy of, salivary cortisol and cortisone in late-night samples and after a low-dose (1 mg) dexamethasone suppression test (DST).
Design and methods
Saliva samples were collected at 08:00 and 23:00 h, and at 08:00 h, after a DST, from 22 patients with CS and from 155 adult reference subjects. We also collected samples at 20:00 and 22:00 h from 78 of the reference subjects. Salivary cortisol and cortisone were analysed with liquid chromatography-tandem mass spectrometry. The reference intervals were calculated as the 2.5th and 97.5th percentiles of the reference population measurements. Diagnostic accuracies of different tests were compared, based on areas under the receiver-operating characteristic curves.
The upper reference limits of salivary cortisol and cortisone at 23:00 h were 3.6 nmol/L and 13.5 nmol/L, respectively. Using these reference limits, CS was detected with a sensitivity (95% CI) of 90% (70–99%) and specificity of 96% (91–98%) for cortisol, and a 100% (84–100%) sensitivity and 95% (90–98%) specificity for cortisone. After DST, cortisol and cortisone upper reference limits were 0.79 nmol/L and 3.5 nmol/L, respectively. CS was detected with 95% (75–100%) sensitivity and 96% (92–99%) specificity with cortisol, and 100% (83–100%) sensitivity and 94% (89–97%) specificity with cortisone. No differences in salivary cortisol or cortisone levels were found between samples collected at 22:00 and 23:00 h.
Salivary cortisol and cortisone in late-night samples and after DST showed high accuracy for diagnosing CS, salivary cortisone being slightly, but significantly better.
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
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).
The PAPE study is a cohort study.
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.
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).
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.
Dorte Glintborg, Henrik Bjarke Vaegter, Louise Lehmann Christensen, Emma Bendix, Thomas Graven-Nielsen, Per Grünwald Andersen and Marianne Andersen
Hypogonadism is prevalent during opioid treatment, but the effect of testosterone replacement treatment (TRT) on body composition, pain perception, and adrenal function is unclear.
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.
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).
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.
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.
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.
Rasmus Rørth, Peter Godsk Jørgensen, Henrik Ullits Andersen, Christina Christoffersen, Jens Peter Gøtze, Lars Køber, Peter Rossing and Magnus Thorsten Jensen
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).
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.
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
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.
Prospective twin cohort study.
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.
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.
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.
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.
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.
Marco Mezzullo, Guido Di Dalmazi, Alessia Fazzini, Margherita Baccini, Andrea Repaci, Alessandra Gambineri, Valentina Vicennati, Carla Pelusi, Uberto Pagotto and Flaminia Fanelli
To evaluate the independent impact of age, obesity and metabolic risk factors on 13 circulating steroid levels; to generate reference intervals for adult men.
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.
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.
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.