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Endocrine diagnostics currently depend on the ability to measure low and high concentrations of diagnostic hormones using immunoassays. This often is challenging in species other than humans, dogs, cats, and horses due to lack of validated assays and reference intervals. There are strategies to approach endocrine testing in zoo, wildlife, and zoologic companion animals but caution is needed in interpreting results. Newer techniques such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) may be more useful for all species, although technical hurdles remain for this method too., Competing Interests: Disclosure Drs D. Agnew and B.K. Petroff are employed by Michigan State University Veterinary Diagnostic Laboratory, which performs endocrine testing in animals., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: 1% of all breast cancer cases occur in men. There are significant differences regarding clinical behaviour and genetic profiles between female (FBC) and male breast cancer (MBC). Parameters for decision-making on treatment and prognosis are derived from FBC. Ki67 has a high value as a prognostic and predictive factor in FBC, but accurate Ki67 cut-off points for MBC are missing. In this study, we aimed to evaluate adequate examination methods and reliable cut-off points for Ki67 to assess the highest prognostic value for patient's overall survival (OS)., Methods: In this multicentric retrospective study, histological specimens were obtained from 104 male patients who were diagnosed and treated for primary invasive breast cancer. We applied three methods of Ki67 analysis: Tumor average scoring (TA), tumor border scoring (TB) and hot-spot scoring (HS). Calculated Ki67 cut-off points for each method were assessed as a threshold for patients' overall survival (OS)., Results: Ki67 cut-off points were 13.5 for the TA group, 22.5 for the HS group and 17.5 for the TB group. Only Ki67 TA cut-off calculations demonstrated statistical significance (p = 0.04). Ki67 expression analysis of TA showed that more than 90% of patients with low Ki67 levels (< 13.5) were alive after 5-year follow-up., Conclusion: Our findings demonstrate that determination of Ki67 expression in TA is the most reliable to define a cut-off point with high prognostic value. A Ki67 cut-off point of 13.5 shows highest statistical power to define luminal A subgroup and OS., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. It often causes symmetrical paresthesia, loss of sensation, and hyperalgesia. Without early intervention, it might lead to diabetic foot ulceration, gangrene, and subsequent amputation in people with diabetes. DPN is an insidious disease and often underdiagnosed. This paper reviews the current national and international prevalence of DPN, screening methods for early DPN, including quantitative sensory measurement, neurological function scoring system, confocal microscopy, and high-frequency ultrasound, and summarizes the related research progress, clinical application, and development prospects of these methods in recent years., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yu.)

Background: Macroprolactin is responsible for pseudohyperprolactinemia and is a common pitfall of the prolactin immunoassay. We aimed to determine the frequency of macroprolactinemia in Chinese hyperprolactinemic patients using monomeric prolactin discriminated by precipitation with polyethylene glycol (PEG)., Methods: Post-PEG monomeric prolactin gender-specific reference intervals were established for the Elecsys immunoassay method (Roche Diagnostics) using sera from healthy female (n = 120) and male (n = 120) donors. The reference intervals were validated using 20 macroprolactinemic (as assessed by gel filtration chromatography (GFC)) sera samples, and presence of monomeric prolactin was discriminated by GFC. Patients with high total prolactin were then screened by PEG precipitation to analyze macroprolactin. The demographic and biochemical details of patients with true hyperprolactinemia and macroprolactinemia were compared., Results: Reference intervals for monomeric prolactin in females and males were 3.4-18.5 and 2.7-13.1 ng/mL, respectively. Among 1140 hyperprolactinemic patients, macroprolactinemia was identified in 261 (22.9 %) patients while the other 879 (77.1 %) patients were diagnosed with true hyperprolactinemia. Menstrual disturbances were the most common clinical feature in both groups. Galactorrhea, amenorrhea, and visual disturbances occurred more frequently in true hyperprolactinemic patients (P < 0.05)., Conclusions: The prevalence of macroprolactin in Chinese patients with hyperprolactinemia was described for the first time. Monomeric prolactin concentration, along with a reference interval screening with PEG precipitation, provides a diagnostic approach for hyperprolactinemia with improved accuracy., (© 2021. The Author(s).)

Context: Serum inflammation-based scores reflect systemic inflammatory response and/or patients' nutritional status, and may predict clinical outcomes in cancer. While these are well-described and increasingly used in different cancers, their clinical usefulness in the management of patients with endocrine tumors is less known., Evidence Acquisition: A comprehensive PubMed search was performed using the terms "endocrine tumor," "inflammation," "serum inflammation-based score," "inflammatory-based score," "inflammatory response-related scoring," "systemic inflammatory response markers," "neutrophil-to-lymphocyte ratio," "neutrophil-to-platelet ratio," "lymphocyte-to-monocyte ratio," "Glasgow prognostic score," "neutrophil-platelet score," "Systemic Immune-Inflammation Index," and "Prognostic Nutrition Index" in clinical studies., Evidence Synthesis: The neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio are the ones most extensively investigated in patients with endocrine tumors. Other scores have also been considered in some studies. Several studies focused in finding whether serum inflammatory biomarkers may stratify the endocrine tumor patients' risk and detect those at risk for developing more aggressive and/or refractory disease, particularly after endocrine surgery., Conclusions: In this review, we summarize the current knowledge on the different serum inflammation-based scores and their usefulness in predicting the phenotype, clinical aggressiveness, and disease outcomes and prognosis in patients with endocrine tumors. The value of such serum inflammation-based scores in the management of patients with endocrine tumors has been emerging over the last decade. However, further research is necessary to establish useful markers and their cut-offs for routine clinical practice for individual diseases., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Endocrine tests are the cornerstone of diagnosing multiple diseases that primary care physicians are frequently faced with. Some of these tests can be affected by situations that affect the proper interpretation, leading to incorrect diagnoses and unnecessary treatment, such as the interference of biotin with thyroid function test, falsely elevated prolactin values in presence of macroprolactinemia or falsely normal due to the "hook effect" in macroprolactinomas. Recognizing these situations is essential for the clinician to make an adequate interpretation of these tests as well as an accurate diagnosis that guarantees the best outcomes for the patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alvarez-Payares, Bello-Simanca, De La Peña-Arrieta, Agamez-Gomez, Garcia-Rueda, Rodriguez-Arrieta and Rodriguez-Arrieta.)

Anti-Müllerian Hormone (AMH) is a 140 kDa homodimeric glycoprotein consisting of two identical subunits linked by disulphide bonds and is synthesised by the testes and ovaries. Its clinical applications are prediction of ovarian response and gonadotropin dose selection upon in vitro fertilization. In males, AMH is used to investigate sexual developmental disorders and gonadal function. AMH is commonly assayed by enzyme-linked immunosorbent assay or automated immunoassay formats that show variation between methods. This review applies fundamental chemical pathology concepts to explain the observed analytical variation of AMH measurement. We examine the lack of standardisation between AMH assays, the impact of antibody design on variable measurements, consider the analytical detection of AMH isoforms, review analytical interference in AMH measurement, and briefly assess systematic bias between AMH assays. The improved attempt at standardising AMH measurement by the recent approval of a WHO Reference Reagent offers promise for harmonising immunoassay results and establishing consensus medical cut-off points for AMH in disease. Standardisation, however, will need to redress the issue of poor commutability of standard reference material and further assign a standard reference procedure to quantify AMH standard reference material. The improvement of the analytical phase of AMH testing will support harmonised method development and patient care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Punchoo and Bhoora.)

Context: Traditionally, low-dose dexamethasone suppression test (LDDST) was used to confirm the diagnosis of Cushing's syndrome (CS), and high-dose dexamethasone suppression test (HDDST) was used to differentiate Cushing's disease (CD) and ectopic adrenocorticotropin (ACTH) syndrome (EAS), but some studies suggested that HDDST might be replaced by LDDST. For the differential diagnosis of CS, dexamethasone suppression test was usually combined with other tests such as bilateral petrosal sinus sampling (BIPSS) and pituitary magnetic resonance imaging, but the optimal pathway to incorporate these tests is still controversial., Objectives: To develop an optimized pathway for the differential diagnosis of CD and EAS based on LDDST., Design and Setting: Single-center retrospective study (2011-2019)., Patients: Two hundred sixty-nine CD and 29 EAS patients with pathological diagnosis who underwent consecutive low- and high-dose DST., Results: For the differential diagnosis of CD and EAS, the area under curve (AUC) of LDDST using urine free cortisol (0.881) was higher than that using serum cortisol (0.685) (p < 0.001) in head-to-head comparison among a subgroup of 108 CD and 10 EAS. The AUC of LDDST (0.883) was higher than that of HDDST (0.834) among all the included patients. With the cutoff of <26%, the sensitivity and specificity of LDDST were 39.4% and 100%. We designed a new pathway in which BIPSS was only reserved for those patients with unsuppressed LDDST and adenoma <6mm, yielding an overall sensitivity of 97.7% and specificity of 86.7%., Conclusion: LDDST had similar value to HDDST in differentiating CD and EAS using the specific cutoff point. The pathway that combined LDDST and BIPSS could differentiate CD and EAS accurately., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Chen, Lu, Zhu, Zhang, Tong, Pan, Wang and Lu.)

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves' hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.

Competing Interests: DZ received research funds from the companies Wörwag, Novartis and Mitsubishi Tanabe, honoraria for lectures from the companies Meda, Wörwag, BerlinChemie, Takeda, Lilly Grünenthal, Procter & Gamble, Novaremed, Bayer, Nevro and Impeto Medical and honoraria for consulting from the companies Meda, Wörwag, Takeda, Berlin-Chemie, Pfizer, Trigo Care, Grünenthal, Procter & Gamble, Novaremed, Bayer, Nevro Astellas, Teva, Lilly, Biogen, Novartis, Mitsubishi Tanabe, Shire, Allergan and Mundipharma.

Competing Interests: S. Morbach: Within the last 3 years, Morbach has served on advisory boards of URGO GmbH (National Advisory Board DFU), Novo Nordisk Deutschland (Clinical Practitioners Advisory Board) and an international advisory board of Reapplix ApS and has received corresponding fees. He was also Vice President of the International Working Group on the Diabetic Foot Implementation and of D-FOOT International. He is a visiting researcher at the Institute for Health Services Research and Health Economics, Centre for Health and Society, Medical Faculty, Heinrich-Heine-University Düsseldorf. R. Lobmann has received research funding (personally or at his personal disposal) either directly or in the form of monetary benefits (personnel, equipment, etc.): Fa. Urgo (Explorer Study, E2-SubStudy) As a speaker he received a fee or as a passive participant he received a reimbursement of costs (travel or accommodation costs, paid participation fees): Honorarium adviser: Amgen, Astra Zeneca, Biotec, Böhringer Ingelheim, GWT-TUD GmbH, Lilly, Medac MSD Sharp & Domme GmbH, Novo Nordisk, Roche, Sanofi Aventis, Sciaric, URGO, Wörwag Pharma. Reimbursement of costs: Lilly, Urgo, Wörwag. He has been a paid consultant/internal training consultant or similar for: Abbott, Biotec, Böhringer Ingelheim, Lilly, Mölnlycke, Novo Nordisk, URGO, Wörwag Pharma. Membership and position in scientific societies/professional associations and possibly other associations relevant to this training measure: Member of the board of the ADBW, spokesman of the regional societies of the DDG, member of the Diabetes Advisory Board of the State Government of Baden Württemberg, delegate for D-Foot International, member of the board of the German Diabetes Society (DDG; 2016–2020), spokesman of the DDG Working Group on the Diabetic Foot (2010–2020). A. Risse has been active within the last 3 years in advisory boards of URGO GmbH and Neubourg Skin Care and has received corresponding fees. For lecture and training activities he received fees from the company Serag Wiesner and from the Zentralverband Podologie. He is chairman of the commission for EADV of DDG. M. Eckhard has worked for the following companies within the last 5 years and has received corresponding fees: Berlin-Chemie (lectures), Boehringer-Ingelheim (lectures and consulting), Lilly Deutschland (lectures and consulting), Novo Nordisk (lectures and consulting), Sanofi (lectures). Accompanying offices: Chairman of the Hessian Diabetes Society e.V. (HDG, Regional Society of DDG), Member of the Board of Directors of the DDG Working Group on the Foot e. V., Member of the Committee of DDG Diabetologists in the DDG. Professional status: Medical Director of the university diabetes center at the University Hospital Gießen and Marburg GmbH (UKGM, Gießen site), Chief Physician of the GZW Diabetes Clinic Bad Nauheim. H. Reike discloses that the Mariannen-Hospital has received support for events organized by him from the companies Novo Nordisk Deutschland, Lilly Deutschland, Beurer, Emmerich. M. Spraul has worked for the following companies within the last 3 years and has received corresponding fees: Lilly Germany (lectures and consulting), Novo Nordisk (lectures and consulting), Abbott (consulting), Astra Zeneca (lectures), Neubourg Skin Care (lectures and consulting). M. Spraul discloses that the Mathias-Spital has received support from the companies Novo Nordisk Deutschland and Neubourg Skin Care for events organized by him. G. Rümenapf and E. Müller have no conflicts of interest.

Competing Interests: LM has received fees and/or reimbursements from the following companies/institutions in the last 3 years: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly Pharma, Kassenärztliche Bundesvereinigung, Merck Inc., MSD Sharp & Dohme, Novo Nordisk, Praxisnetz Dormagen, Servier. He declares that he sees no conflict of interest with the article he has created. TE has received fees/cost reimbursements from Lilly, Novo Nordisk and Sanofi over the last 3 years. Within the scope of a consulting activity he received a fee from the companies Sanofi and Boehringer Ingelheim Pharma. He is also supported by a Novo Nordisk Postdoctoral Fellowship, which is carried out in cooperation with the Karolinska Institutet, and by a mentorship program of the European Foundation for the Study of Diabetes (EFSD), which is supported by an Educational grant from AstraZeneca. MG received fees/cost reimbursements/study grants from the following companies: Alexion, Astellas, Baxter, Bayer, Chiesi, AstraZeneca. B-WB and BI declare that they have no potential conflicts of interest.

Competing Interests: K. D. Lemmen: Lecture fees: Bayer, Novartis, Advisory Board, Pharm-Allergan. H.-P. Hammes: Lecture fees: Novartis, Bayer, MSD, Novo Nordisk, Boehringer Ingelheim, Sanofi. B. Bertram: no conflict of interest.

Objective: Metabolic syndrome is a cluster of cardio-metabolic risk factors associated with an increased risk of cardiovascular disease and type 2 diabetes. In the last two decades, several definitions of metabolic syndrome have been proposed for the pediatric population; all of them agree on the defining components but differ in the suggested criteria for diagnosis. This review aims to analyze the current diagnostic criteria of metabolic syndrome in pediatrics with reference to their feasibility and reliability in clinical practice., Methods: The systematic research was conducted from January 2003 to June 2020 through MEDLINE via PubMed, Cochrane Library and EMBASE databases., Results: After the selection phase, a total of 15 studies (182 screened) met the inclusion criteria and are reported in the present review. Twelve studies were cross-sectional, two were longitudinal and one was a consensus report. The sample population consisted of multiethnic group or single ethnic group, including Turkish, European, Asian and Hispanic subjects., Conclusions: To date, there is not a univocal, internationally accepted pediatric definition of metabolic syndrome, which guarantees a high sensitivity and stability of the diagnosis. The definition proposed by IDF results the most straightforward and easy to use in clinical practice, having the unquestionable advantage of requiring measurements quickly accessible in clinical practice, without the adoption of multiple reference tables. Further research is needed to validate a new version of such definition which includes the diagnostic cut-off points recently suggested by published guidelines.

Objective: Glycosylated hemoglobin (HbA1c) has obvious clinical value in the diagnosis of diabetes, but the conclusions on the diagnostic value of diabetic retinopathy (DR) are not consistent. This study aims to comprehensively evaluate the accuracy of glycosylated hemoglobin in the diagnosis of diabetic retinopathy through the meta-analysis of diagnostic tests., Methods: Cochrane Library, Embase, PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), China Wanfang Database, Chinese Biomedical Literature Database (CBM) were searched until November, 2020. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess the quality of the included studies. The pooled sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR), diagnostic odds ratio (DOR) and areas under the receiver operating characteristic (ROC) curve were calculated by Stata 15.0 software., Results: After screening, 18 high-quality papers were included. The results of meta-analysis showed that the combined DOR = 18.19 (95% CI: 10.99-30.11), the sensitivity= 0.81 (95% CI): 0.75 ~ 0.87), specificity = 0.81 (95%CI: 0.72 ~ 0.87), +LR = 4.2 (95%CI: 2.95 ~ 6.00), -LR = 0.23 (95%CI: 0.17 ~ 0.31), and the area under the Summary ROC curve was 0.88 (95%CI:  0.85 ~ 0.90)., Conclusion: The overall accuracy of HbA1cC forin diagnosing diabetic retinopathy is good. As it is more stable than blood sugar and is not affected by meals, it may be a suitable indicator for diabetic retinopathy.

Objective: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features., Design: Retrospective analysis of the Italian data set of patients with TNDM., Methods: Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared., Results: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy., Conclusions: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Pituitary tumors are very complex and heterogeneous and have a very wide range of proliferative and aggressive behaviors, and how to define and classify these tumors remains controversial. This review summarizes the epidemiology and progress in the classification and definition of pituitary tumors, as well as controversial issues. Based on the results of radiologic and autopsy studies, the prevalence of pituitary tumors has recently increased significantly. However, the majority of pituitary tumors are incidentally discovered and asymptomatic, and such tumors are called pituitary incidentalomas. Most of these incidentalomas do not induce symptoms, remain stable in size, and do not need treatment. The recent revised classification strategies mainly depend on immunohistochemistry (IHC) to detect pituitary hormones and pituitary transcription factors; therefore, the accuracy of diagnosing pituitary tumors has improved. Although new classification strategies and definitions for pituitary tumors have been presented, there are still some controversies. The term pituitary neuroendocrine tumor (PitNET) was proposed by the International Pituitary Pathology Club, and this terminology can encompass the unpredictable malignant behavior seen in the subset of aggressive pituitary adenomas (PAs). However, some endocrinologists who oppose this change in terminology have argued that the use of tumor in the terminology is misleading, as it gives PAs a harmful connotation when the majority are not aggressive. Such terminology may add new ambiguity to the origin of PAs and unnecessary anxiety and frustration for the majority of patients with benign PAs. The classification of aggressive PAs mainly relies on subjective judgment of clinical behavior and lacks objective biomarkers and unified diagnostic criteria. However, the term "refractory" could more accurately represent the characteristics of these tumors, including their clinical behaviors, radiological features, and pathologic characteristics. Moreover, the diagnostic criteria for refractory PAs are stricter, more objective, and more accurate than those for aggressive PAs. Early identification of patients with these tumors through recognition and increased awareness of the definition of refractory PAs will encourage the early use of aggressive therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dai, Kang, Liu, Yao, Wang and Wang.)

Context: Discordant growth hormone (GH) and insulin-like growth factor-1 (IGF-1) values are frequent in acromegaly., Objective: To evaluate the impact of different GH cutoffs on discordance rate. To investigate whether the mean of consecutive GH measurements impacts discordance rate when matched to the last available IGF-1 value., Design: Retrospective study., Setting: Referral center for pituitary diseases., Patients: Ninety acromegaly patients with at least 3 consecutive evaluations for GH and IGF-1 using the same assay in the same laboratory (median follow-up 13 years)., Interventions: Multimodal treatment of acromegaly., Main Outcome Measures: Single fasting GH (GHf) and IGF-1 (IGF-1f). Mean of 3 GH measurements (GHm), collected during consecutive routine patients' evaluations., Results: At last evaluation GHf values were 1.99 ± 2.79 µg/L and age-adjusted IGF-1f was 0.86 ± 0.44 × upper limit of normality (mean ± SD). The discordance rate using GHf was 52.2% (cutoff 1 µg/L) and 35.6% (cutoff 2.5 µg/L) (P = 0.025). "High GH" discordance was more common for GHf <1.0 µg/L, while "high IGF-1" was predominant for GHf <2.5 µg/L (P < 0.0001). Using GHm mitigated the impact of GH cutoffs on discordance (GHm <1.0 µg/L: 43.3%; GHm <2.5 µg/L: 38.9%; P = 0.265). At receiver-operator characteristic curve (ROC) analysis, both GHf and GHm were poor predictors of IGF-1f normalization (area under the curve [AUC] = 0.611 and AUC = 0.645, respectively). The prevalence of disease-related comorbidities did not significantly differ between controlled, discordant, and active disease patients., Discussion: GH/IGF-1 discordance strongly depends on GH cutoffs. The use of GHm lessen the impact of GH cutoffs. Measurement of fasting GH levels (both GHf and GHm) is a poor predictor of IGF-1f normalization in our cohort., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: As the number of transgender (trans) people (including those who are binary and/or nonbinary identified) seeking gender-affirming hormone therapy rises, endocrinologists are increasingly asked to assist with interpretation of laboratory tests. Many common laboratory tests such as hemoglobin, iron studies, cardiac troponin, and creatinine are affected by sex steroids or body size. We seek to provide a summary of the impact of feminizing and masculinizing hormone therapy on common laboratory tests and an approach to interpretation., Cases: Case scenarios discussed include 1) hemoglobin and hematocrit in a nonbinary person undergoing masculinizing hormone therapy; 2) estimation of glomerular filtration rate in a trans woman at risk of contrast-induced nephropathy; 3) prostate-specific antigen (PSA) in a trans woman; and 4) chest pain in a trans man with a cardiac troponin concentration between the reported male and female reference ranges., Conclusions: The influence of exogenous gender-affirming hormone therapy on fat and muscle distribution and other physiological changes determines interpretation of laboratory tests that have sex-specific differences. In addition to affirmative practice to ensure a patient's name, gender, and pronoun are used appropriately, we propose that once individuals have commenced gender-affirming hormone therapy, the reference range of the affirmed gender be reported (and specified by treating clinicians) except for PSA or cardiac troponin, which are dependent on organ size. While suggestions may be challenging to implement, they also represent an opportunity to lead best practice to improve the quality of care and experiences of healthcare for all trans people., (© Endocrine Society 2020.)

Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine disorders in women and despite this, diagnostic challenges, delayed diagnosis, and less-than-optimal treatment regimens plague the condition. The International PCOS network, consisting of geographically diverse international experts in PCOS as well as consumers, engaged in a multi-year international evidence-based guideline development process that was jointly sponsored by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM). The guideline was published in 2018 and endorsed by more than 40 international societies involved in PCOS. Translation of this evidence-based guideline to medical practice and consumer groups remains a priority. However, there remain many challenges to both understanding the diagnosis and treatment of PCOS. Evidence suggests that both clinicians and consumers are not satisfied with the timeliness of diagnosis and treatment options. This review summarizes the important findings for diagnosis and treatment from the guidelines and expands on recent developments in the literature since its publication. Special attention to diagnosis at the ends of the reproductive spectrum are discussed and remaining areas of controversy are noted. Additionally, the review highlights some of the remaining challenges in the understanding and management of PCOS to help guide clinicians and investigators in this perplexing condition., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Diabetic microvascular complications of retinopathy, nephropathy and neuropathy may occur at hemoglobin A1c levels (HbA1c) below the 6.5% (48 mmol/mol) diagnostic threshold. Our objective was to assess the validity of the HbA1c diagnostic cutpoint of 6.5% based upon published evidence of the prevalence of retinopathy, nephropathy and neuropathy as markers of diabetes., Methods: Data Sources PubMed, Embase, Cochrane, Scopus and CINAHL from 1990-March 2019, grey literature sources. Study Selection All studies reported after 1990 (to ensure standardized HbA1c values) where HbA1c levels were presented in relation to prevalence of retinopathy, nephropathy or neuropathy in subjects not known to have diabetes. Data Extraction Studies were screened independently, data abstracted, and risk of bias appraised. Data Synthesis Data were synthesized using HbA1c categories of < 6.0% (< 42 mmol/mol), 6.0-6.4% (42-47 mmol/mol) and ≥ 6.5% (≥ 48 mmol/mol). Random-effects meta-analyses were conducted for retinopathy, nephropathy and neuropathy prevalence stratified by HbA1c categories. Random-effects multivariable meta-regression was conducted to identify predictors of retinopathy prevalence and sources of between-study heterogeneity., Results: Pooled mean prevalence was: 4.0%(95% CI: 3.2-5.0%) for retinopathy, 10.5% (95% CI: 4.0-19.5%) for nephropathy, 2.5% (95% CI: 1.1-4.3%) for neuropathy. Mean prevalence when stratified for HbA1c < 6.0%, 6.0-6.4% and ≥ 6.5% was: retinopathy: 3.4% (95% CI: 1.8-5.4%), 2.3% (95% CI: 1.6-3.2%) and 7.8%(95% CI: 5.7-10.3%); nephropathy: 7.1% (95% CI: 1.7-15.9%), 9.6% (95% CI: 0.8-26.4%) and 17.1% (95% CI: 1.0-46.9%); neuropathy: 2.1% (95% CI: 0.0-6.8%), 3.4% (95% CI: 0.0-11.6%) and 2.8% (95% CI: 0.0-12.8%). Multivariable meta-regression showed HbA1c ≥ 6.5% (OR: 4.05; 95% CI: 1.92-8.57%), age > 55 (OR: 3.23; 95% CI 1.81-5.77), and African-American race (OR: 10.73; 95% CI: 4.34-26.55), to be associated with higher retinopathy prevalence. Marked heterogeneity in prevalence estimates was found across all meta-analyses (Cochran's Q-statistic p < 0.0001)., Conclusions: The prevalence of nephropathy and moderate retinopathy was increased in subjects with HbA1c values ≥ 6.5% confirming the high specificity of this value for diagnosing T2DM; however, at HbA1c < 6.5% retinopathy increased at age > 55 years and, most strikingly, in African-Americans, suggesting there may be excess microvascular complication prevalence (particularly nephropathy) in individuals below the diabetes diagnostic threshold.

Objective: To investigate the impact of age, obesity and metabolic parameters on 13 circulating steroids in reproductive and menopausal age. To define reference intervals (RIs)., Design: Cross-sectional., Methods: Three hundred and twenty five drug-free, healthy and eumenorrheic women were selected from the general population. Independent relationships of LC-MS/MS-determined steroid levels with age, BMI and metabolic parameters were estimated. Reference sub-cohorts were defined for calculating upper and lower limits in reproductive age, menstrual phases and menopause, and these were compared with limits in dysmetabolic sub-cohorts., Results: Lower androgens, pro-androgens and estrogens, but higher cortisol and metabolites were found in menopausal compared to reproductive age women. Androgens and precursors decreased during reproductive age (P < 0.001-P = 0.002) but not after menopause. 17OH-progesterone decreased with BMI (P = 0.006) and glucocorticoids with waist circumference (P < 0.001P = 0.002) in reproductive age, but increased with triglycerides (P=0.011P=0.038) after menopause. Inverse associations of dihydrotestosterone with BMI (P=0.004) and HDL-cholesterol (P=0.010), estrone with total cholesterol (P=0.033) and estradiol with triglycerides (P=0.011) were found in reproductive age. After menopause, estrone increased with waist circumference (P<0.001) and decreased with insulin resistance (P=0.012). Ovarian steroid RIs were estimated in menstrual phases and menopause. Age- and reproductive status-specific RIs were generated for androgens, precursors and corticosteroids. Lower limits for reproductive age cortisol (P=0.020) and menopausal 11-deoxycortisol (P=0.003) in dysmetabolic sub-cohorts were reduced and increased, respectively, compared to reference limits., Conclusions: Obesity and dysmetabolism differently influence circulating steroids in reproductive and menopausal status. Age, menstrual and menopausal status-specific RIs were provided by LC-MS/MS for a broad steroid panel.

Diagnostic accuracy studies are fundamental for the assessment of diagnostic tests. Researchers need to understand the implications of their chosen design, opting for comparative designs where possible. Researchers should analyse test accuracy studies using the appropriate methods, acknowledging the uncertainty of results and avoiding overstating conclusions and ignoring the clinical situation which should inform the trade-off between sensitivity and specificity. Test accuracy studies should be reported with transparency using the STAndards for the Reporting of Diagnostic accuracy studies (STARD) checklist.

Background: Thyroid uptake and scan (TUS) is a clinical tool used for differentiation of thyrotoxicosis etiologies. Although guidelines recommend ordering a TUS for evaluation of low TSH levels, no specific value is defined. This study aimed to determine a TSH cutoff at which TUSs yield a greater likelihood of successful determination of etiology to avoid unnecessary testing., Methods: This was a retrospective study on 137 patients seen by an endocrinologist who underwent TUS for evaluation of low TSH (<0.4 μU/mL). A receiver operating curve analysis was performed to determine the TSH cutoff with maximal sensitivity and specificity for prediction of diagnostic utility., Results: Ninety percent of TUSs (n = 123) led to a diagnosis, while 10% (n = 14) were inconclusive or normal. Diagnoses included Graves' diseases (52%), toxic multinodular goiter (19%), thyroiditis (12%), and solitary toxic adenoma (7%). The median TSH value was 0.008 μU/mL (IQR 0.005, 0.011), and the median free T4 value was 1.7 μU/mL (IQR 1.3, 2.8). The ROC analysis produced an area under the curve of 0.86. The optimal TSH cutoff value was 0.02 μU/mL (sensitivity 80%, specificity 93%) for prediction of diagnostic yield., Conclusion: This study demonstrates that TSH is a useful predictor of the utility of TUS in yielding an etiology of thyrotoxicosis. Our analysis showed that TUS had a greater likelihood of determining an etiology when TSH was ≤0.02 μU/mL. This information can help clinicians avoid unnecessary cost and patient time burden when TUS is unlikely to aid in determining the etiology of thyrotoxicosis.

Introduction: The HbA1c has been considered as the 'gold standard' in diabetes diagnosis and management, however, age, gender and body mass index (BMI) might have certain effects on HbA1c. We are aiming to further investigate the correlation between age and HbA1c, and whether it was affected by gender and BMI., Methods: A cross-sectional survey including 135,893 nondiabetic individuals who took the physical examination between 2013 and 2017 was conducted. The subjects were grouped by gender, age and BMI, and the interactive and independent effects of the 3 factors on the HbA1c were detected. The median and 95% confidence interval (CI) of HbA1c levels were calculated., Results: The HbA1c levels gradually increased along with age, both in female and male, and there is a positive association between BMI and the HbA1c. The difference on HbA1c in gender was associated with both age and BMI, the age-related increase in HbAlc was accentuated in the subgroup with higher BMI, and there was a marked accentuation of the positive association between BMI and HbA1c as age increased. In almost all the young and middle-aged (aged 20-59) subgroups, the 97.5 th percentiles of HbA1c levels were lower than 6.5%, suggesting that the single HbA1c cutoff value is probably not applicable to the young and middle-aged population., Conclusions: We recommend that the effects of age, gender and BMI should be taken into consideration when using HbA1c for the diagnosis and management of diabetes, especially in the young and middle-aged population., Competing Interests: The authors declare no conflict of interest., (Thieme. All rights reserved.)

Introduction: The diagnosis of growth hormone deficiency (GHD) in adults is based on a reduced GH response to provocative tests, such as the insulin tolerance test (ITT) and the GH-releasing hormone (GHRH) + arginine (ARG) test. However, the cut-off limits of peak GH response in lean subjects are not reliable in obese patients; this is noteworthy since adult GHD is often associated with obesity. To date, there are no ITT cut-offs related to body mass index (BMI)., Objective: We aimed to evaluate the diagnostic cut-offs of GH response to the ITT in the function of BMI., Methods: The GH response to the ITT was studied in 106 patients with a history of hypothalamic-pituitary disease, a mean age of 48.2 ± 12.4 years, and a mean BMI of 26.8 ± 6.1 kg/m2). Patients were divided into lean, overweight, and obese groups according to their BMI. The lack of GH response to GHRH + ARG test was considered the gold standard for the diagnosis of GHD. The best GH cut-off in the ITT, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using receiver-operating characteristics curve (ROC) analysis., Results: The best GH cut-off in the ITT was 3.5 μg/L in lean subjects (SE 82.1%; SP 85.7%), 1.3 μg/L in overweight subjects (SE 74.1%; SP 85.7%), and 2.2 μg/L in obese subjects (SE 90.0%; SP 50.0%). The diagnostic accuracy was 97.2, 76.5, and 76.7%, respectively., Conclusions: Our data show that the ITT represents a reliable diagnostic tool for the diagnosis of adult GHD in lean subjects if an appropriate cut-off limit is assumed. Overweight and obesity strongly reduce the GH response to the ITT, GH BMI-related cut-off limits, and the diagnostic reliability of the test., (© 2020 S. Karger AG, Basel.)

Objective: Saline infusion testing (SIT) for confirmation of primary aldosteronism (PA) is based on impaired aldosterone suppression in PA compared to essential hypertension (EH). In the past, aldosterone was quantified using immunoassays (IA). Liquid chromatography tandem mass spectrometry (LC-MS/MS) is increasingly used in clinical routine. We aimed at a method-specific aldosterone threshold for the diagnosis of PA during SIT and explored the diagnostic utility of steroid panel analysis., Design: Retrospective cohort study of 187 paired SIT samples (2009-2018). Diagnosis of PA (n = 103) and EH (n = 84) was established based on clinical routine workup without using LC-MS/MS values., Setting: Tertiary care center., Methods: LC-MS/MS using a commercial steroid panel. Receiver operator characteristics analysis was used to determine method-specific cut-offs using a positive predictive value (PPV) of 90% as criterion., Results: Aldosterone measured by IA was on average 31 ng/L higher than with LC-MS/MS. The cut-offs for PA confirmation were 54 ng/L for IA (sensitivity: 95%, 95% CI: 89.0-98.4; specificity: 87%, 95% CI: 77.8-93.3; area under the curve (AUC): 0.955, 95% CI: 0.924-0.986; PPV: 90%, 95% CI: 83.7-93.9) and 69 ng/L for LC-MS/MS (79%, 95% CI: 69.5-86.1; 89%, 95% CI: 80.6-95.0; 0.902, 95% CI: 0.857-0.947; 90%, 95% CI: 82.8-94.4). Other steroids did not improve SIT., Conclusions: Aldosterone quantification with LC-MS/MS and IA yields comparable SIT-cut-offs. Lower AUC for LC-MS/MS is likely due to the spectrum of disease in PA and previous decision making based on IA results. Until data of a prospective trial with clinical endpoints are available, the suggested cut-off can be used in clinical routine.

Objective: Develop a consensus for the nomenclature and definition of adrenal histopathologic features in unilateral primary aldosteronism (PA)., Context: Unilateral PA is the most common surgically treated form of hypertension. Morphologic examination combined with CYP11B2 (aldosterone synthase) immunostaining reveals diverse histopathologic features of lesions in the resected adrenals., Patients and Methods: Surgically removed adrenals (n = 37) from 90 patients operated from 2015 to 2018 in Munich, Germany, were selected to represent the broad histologic spectrum of unilateral PA. Five pathologists (Group 1 from Germany, Italy, and Japan) evaluated the histopathology of hematoxylin-eosin (HE) and CYP11B2 immunostained sections, and a consensus was established to define the identifiable features. The consensus was subsequently used by 6 additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, United Kingdom, United States) for the assessment of all adrenals with disagreement for histopathologic diagnoses among group 1 pathologists., Results: Consensus was achieved to define histopathologic features associated with PA. Use of CYP11B2 immunostaining resulted in a change of the original HE morphology-driven diagnosis in 5 (14%) of 37 cases. Using the consensus criteria, group 2 pathologists agreed for the evaluation of 11 of the 12 cases of disagreement among group 1 pathologists., Conclusion: The HISTALDO (histopathology of primary aldosteronism) consensus is useful to standardize nomenclature and achieve consistency among pathologists for the histopathologic diagnosis of unilateral PA. CYP11B2 immunohistochemistry should be incorporated into the routine clinical diagnostic workup to localize the likely source of aldosterone production., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: (a) To evaluate the clinical performance of endocrine analytes using the sigma metrics (σ) model. (b) To redesign quality control strategies for performance improvement., Methods: The sigma values of the analytes were initially evaluated based on the allowable total error (TEa), bias, and coefficient of variation (CV) at QC materials level 1 and 2 in March 2018. And then, the normalized QC performance decision charts, personalized QC rules, quality goal index (QGI) analysis, and root causes analysis (RCA) were performed based on the sigma values of the analytes. Finally, the sigma values were re-evaluated in September 2018 after a series of targeted corrective actions., Results: Based on the initial sigma values, two analytes (FT3 and TSH) with σ > 6, only needed one QC rule (1 3S ) with N2 and R500 for QC management. On the other hand, seven analytes (FT4, TT4, CROT, E2, PRL, TESTO, and INS) with σ < 4 at one QC material level or both needed multiple rules (1 3S /2 2S /R 4S /4 1S /10 X ) with N6 and R10-500 depending on different sigma values for QC management. Subsequently, detailed and comprehensive RCA and timely corrective actions were performed on all the analytes base on the QGI analysis. Compared with the initial sigma values, the re-evaluated sigma metrics of all the analytes increased significantly., Conclusions: It was demonstrated that the combination of sigma metrics, QGI analysis, and RCA provided a useful evaluation system for the analytical performance of endocrine analytes., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals LLC.)

Context: Application of ultrasound (US) to evaluate attainment and morphology of glandular tissue provides a new rationale for evaluating onset and progression of female puberty, but currently no hormone references complement this method. Furthermore, previous studies have not explored the predictive value of endocrine profiling to determine female puberty onset., Objective: To integrate US breast staging with hypothalamic-pituitary-gonadal hormone references and test the predictive value of an endocrine profile to determine thelarche., Design Setting and Participants: Cross-sectional sample of 601 healthy Norwegian girls, ages 6 to 16 years., Main Outcome Measures: Clinical and ultrasound breast evaluations were performed for all included girls. Blood samples were analyzed by immunoassay and ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify estradiol (E2) and estrone (E1) from the subpicomolar range., Results: References for E2, E1, luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin were constructed in relation to chronological age, Tanner stages, and US breast stages. An endocrine profile index score derived from principal component analysis of these analytes was a better marker of puberty onset than age or any individual hormone, with receiver-operating characteristic area under the curve 0.91 (P < 0.001). Ultrasound detection of nonpalpable glandular tissue in 14 out of 264 (5.3%) girls with clinically prepubertal presentation was associated with significantly higher median serum levels of E2 (12.5 vs 4.9 pmol/L; P < 0.05) and a distinct endocrine profile (arbitrary units; P < 0.001)., Conclusions: We provide the first hormone references for use with US breast staging and demonstrate the application of endocrine profiling to improve detection of female puberty onset., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Low-dose adrenocorticotropic hormone stimulation testing (LDST) can be used to diagnose central adrenal insufficiency. However, uncertainty remains over optimal times to draw serum cortisol levels., Objective: To determine optimal times to draw serum cortisol levels for the LDST in neonates., Design: A retrospective chart review of LDSTs performed on neonates from January 1, 2009 to September 30, 2017., Setting: Children's Hospital of Eastern Ontario (CHEO), a tertiary-care outborn pediatric center., Patients: Forty-nine patients were included: 23 (46.9%) born at term, 12 (24.5%) born very preterm to late preterm, and 14 (28.6%) born extremely preterm., Intervention: Cortisol levels were drawn at baseline and 15, 30, and 60 minutes following administration of Cortrosyn 1 mcg/kg (maximum dose 1 mcg)., Main Outcome Measure: Timing of peak cortisol level and marginal value of drawing a second and third cortisol sample at 15, 30, or 60 minutes was determined., Results: Cortisol peaked at 15-, 30-, and 60-minute sampling times for 4%, 27%, and 69% of patients, respectively. The probability that a failed LDST changes to a pass by adding a 15- or 30-minute sample to the superior 60 minute sample is 5.6% (1% to 25.8%) and 11% (3.1% to 32.6%), respectively, for a cortisol pass threshold of 18.1mcg/dL (500 nmol/L)., Conclusions: In contrast to studies of older children, we found that the majority of neonatal LDST cortisol peaks occurred at the 60-minute sampling time with the addition of a 30-minute sample providing substantial benefit. It is questionable if a 15-minute sample provides any benefit, making a case to revise LDST protocols to sample cortisol later for neonates., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: More than half of patients diagnosed with unilateral primary aldosteronism (UPA) suffer from persisting hypertension after unilateral adrenalectomy., Objective: The objective of this work is to develop and validate a nomogram-based preoperative score (NBPS) to predict clinical outcomes after unilateral adrenalectomy for UPA., Design and Setting: The NBPS was developed in an Asian cohort by incorporating predictors independently associated with remission of hypertension after unilateral adrenalectomy for UPA and validated in a Caucasian cohort., Participants: Participants comprised patients with UPA achieving complete biochemical success after unilateral adrenalectomy., Main Outcome Measure: Measurements included the predictive performance of the NBPS compared with 2 previously developed outcome prediction scores: aldosteronoma resolution score (ARS) and primary aldosteronism surgical outcome (PASO) score., Results: Ninety-seven of 150 (64.7%) patients achieved complete clinical success after unilateral adrenalectomy in the training cohort and 57 out of 165 (34.5%) in the validation cohort. A nomogram was established incorporating sex, duration of hypertension, aldosterone-to-renin ratio, and target organ damage. The nomogram showed good C indices and calibration curves both in Asian and Caucasian cohorts. The area under the receiver operating characteristic curve (AUC) of the NBPS for predicting hypertension remission in the training cohort was 0.853 (0.786-0.905), which was superior to the ARS (0.745 [0.667-0.812], P = .019) and PASO score (0.747 [0.670-0.815], P = .012). The AUC of the NBPS in the validation cohort was 0.830 (0.764-0.884), which was higher than the ARS (0.745 [95% CI, 0.672-0.810], P = .045), but not significantly different from the PASO score (0.825 [95% CI, 0.758-0.880], P = .911)., Conclusion: The NBPS is useful in predicting clinical outcome for UPA patients, especially in the Asian population., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Prader-Willi syndrome (PWS) is a complex hypothalamic disorder, combining hyperphagia, hypotonia, intellectual disability, and pituitary hormone deficiencies. Annual mortality of patients with PWS is high (3%). In half of the patients, the cause of death is obesity related and/or of cardiopulmonary origin. Health problems leading to this increased mortality often remain undetected due to the complexity and rareness of the syndrome., Objective: To assess the prevalence of health problems in adults with PWS retrospectively., Patients, Design, and Setting: We systematically screened 115 PWS adults for undiagnosed health problems. All patients visited the multidisciplinary outpatient clinic for rare endocrine syndromes at the Erasmus University Medical Center, Rotterdam, Netherlands. We collected the results of medical questionnaires, interviews, physical examinations, biochemical measurements, polygraphy, polysomnography, and radiology., Main Outcome Measures: Presence or absence of endocrine and nonendocrine comorbidities in relation to living situation, body mass index, genotype, and demographic factors., Results: Seventy patients (61%) had undiagnosed health problems, while 1 in every 4 patients had multiple undiagnosed health problems simultaneously. All males and 93% of females had hypogonadism, 74% had scoliosis, 18% had hypertension, 19% had hypercholesterolemia, 17% had type 2 diabetes mellitus, and 17% had hypothyroidism. Unfavorable lifestyles were common: 22% exercised too little (according to PWS criteria) and 37% did not see a dietitian., Conclusions: Systematic screening revealed many undiagnosed health problems in PWS adults. Based on patient characteristics, we provide an algorithm for diagnostics and treatment, with the aim to prevent early complications and reduce mortality in this vulnerable patient group., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Core Outcome Sets (COS) contain an agreed minimum set of outcomes to be measured and reported in all studies in a specific area, with the objective of standardizing outcome reporting. COS may minimize research waste by identifying outcomes important to key stakeholders, allowing for improved evidence synthesis, and facilitating translation of research findings to clinical practice. Over the past 5 years, there has been significant progress in developing COS relevant to studies of diabetes in pregnancy. This review summarizes work in this area, reviews the role of patient and public involvement in COS development, and suggests areas for future research., (© 2020 by the American Diabetes Association.)

Background: A growth hormone (GH) stimulation test is the recommended method for evaluating GH levels in children with possible GH deficiency (GHD). However, serial measurements of nocturnal spontaneous GH secretion are also performed. Divergent results from these tests have been reported, but with variable frequencies., Objectives: To investigate whether performing one or two GH tests is associated with the probability to diagnose a child with GHD; the frequency of divergent results in the arginine-insulin tolerance test (AITT) and the nocturnal spontaneous test using different cut-off levels, and whether refractoriness may explain some of the discordance., Methods: In a population-based setting, the medical records of all short children evaluated for possible GHD during January 1993-February 2017 were reviewed. Twenty-one patients had been evaluated with one GH test only and 102 children had been evaluated with a spontaneous nocturnal GH test followed immediately by a complete AITT. Divergent results were defined as having a pathological response on only one of the tests when using 3, 5, 7, and 10 µg/L as cut-offs for peak GH on both tests, 1.1 and 3.3 µg/L for mean nocturnal values and receiver operating characteristic curves-derived cut-offs for nocturnal values., Results: Children evaluated with one test only were more often diagnosed with GHD compared with children evaluated with both tests (48 vs. 19%, p = 0.019). Divergent results were found in 6-42% of the patients, with higher frequencies seen when higher cut-offs were applied. A higher proportion of patients with stimulated peak values ≤ 7 and ≤ 5 µg/L had a spontaneous peak within 2 h before the start of the AITT compared with patients with higher stimulated peak values (68 vs. 45%, p = 0.026, and 77 vs. 48%, p = 0.033, respectively)., Conclusions: Divergent results between AITT and nocturnal spontaneous secretion are common in short children, dependent on the cut-offs applied and partly due to refractoriness. Performing both tests decreases the risk of over diagnosing GHD in short children., (Copyright © 2020 Lennartsson, Nilsson and Lodefalk.)

Objective: The need for personalization of the reference values of thyroid function tests has been previously suggested. We aimed at determining TSH reference values in a large cohort of children according to age, sex, BMI, and ethnicity., Design: A population-based cohort study., Methods: The study cohort included 75 549 healthy children aged 5-18 years. Data analyzed included age, gender, TSH, FT4 levels, BMI and ethnicity. Multivariate logistic regression analysis examined the associations between the study parameters., Results: TSH in the Jewish population is lower than in the non-Jewish population (median: 2.1 IU/L (IQR: 1.5) vs 2.2 IU/L (IQR: 1.5), P < 0.0001). TSH is significantly affected by BMI for children defined as underweight, normal weight, overweight or obese, levels increased as weight diverged from the normal range (median levels: 2.1 IU/L (IQR: 1.4), 2.0 IU/L (IQR: 1.3), 2.1 IU/L (IQR: 1.4), 2.4 (IQR: 1.5), respectively, P < 0.001). The 2.5 percentile is affected by gender and BMI (P < 0.02 and P < 0.001, respectively), while the 97.5 percentile is affected by ethnic origin and BMI (P < 0.001 for both). New TSH reference intervals (RI) adjusted according to BMI and ethnicity are suggested. Comparison of the old and new RI demonstrate the significance of RI personalization: 25.1% of the children with TSH levels above the old RI are within the new RI, while 2.3% of the children who were in the old RI are below the new RI., Conclusions: TSH reference values in children are affected by BMI and ethnicity. Reference values should be individualized accordingly to improve future clinical decision-making and treatment.

Objective: To explore the meal response of circulating succinate in patients with obesity and type 2 diabetes undergoing bariatric surgery and to examine the role of gastrointestinal glucose sensing in succinate dynamics in healthy subjects., Research Design and Methods: Cohort I comprised 45 patients with morbid obesity and type 2 diabetes (BMI 39.4 ± 1.9 kg/m 2 ) undergoing metabolic surgery. Cohort II was a confirmatory cohort of 13 patients (BMI 39.3 ± 1.4 kg/m 2 ) undergoing gastric bypass surgery. Cohort III comprised 15 healthy subjects (BMI 26.4 ± 0.5 kg/m 2 ). Cohorts I and II completed a 2-h mixed-meal tolerance test (MTT) before the intervention and at 1 year of follow-up, and cohort II also completed a 3-h lipid test (LT). Cohort III underwent a 3-h oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI) study., Results: In cohort I, succinate response to MTT at follow-up was greater than before the intervention ( P < 0.0001). This response was confirmed in cohort II with a greater increase after 1 year of surgery ( P = 0.009). By contrast, LT did not elicit a succinate response. Changes in succinate response were associated with changes in the area under the curve of glucose ( r = 0.417, P < 0.0001) and insulin ( r = 0.204, P = 0.002). In cohort III, glycemia, per se, stimulated a plasma succinate response ( P = 0.0004), but its response was greater in the OGTT ( P = 0.02; OGTT versus IIGI)., Conclusions: The meal-related response of circulating succinate in patients with obesity and type 2 diabetes is recovered after metabolic surgery., (© 2020 by the American Diabetes Association.)

Background and Aim: Diabetic ketoacidosis (DKA) is a serious medical emergency once considered typical of type 1 diabetes (T1DM), but now reported to occur in type 2 and GDM patients as well. DKA can cause severe complications and even prove fatal. The aim of our study was to review recent international and national guidelines on diagnosis, clinical presentation and treatment of diabetic ketoacidosis, to provide practical clinical recommendations., Methods and Results: Electronic databases (MEDLINE (via PUB Med), Scopus, Cochrane library were searched for relevant literature. Most international and national guidelines indicate the same accurate flow chart to diagnose, to evaluate from clinical and laboratory point of view, and treat diabetic ketoacidosis., Conclusion: Prompt diagnosis, rapid execution of laboratory analysis and correct treatment are imperative to reduce the mortality related to diabetic ketoacidosis. These recommendations are designed to help healthcare professionals reduce the frequency and burden of DKA., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020. Published by Elsevier B.V.)

The differential diagnosis of diabetes insipidus involves the distinction between central or nephrogenic diabetes insipidus and primary polydipsia. Differentiation is important because treatment strategies vary; the wrong treatment can be dangerous. Reliable differentiation is difficult especially in patients with primary polydipsia or partial forms of diabetes insipidus. New diagnostic algorithms are based on the measurement of copeptin after osmotic stimulation by hypertonic saline infusion or after nonosmotic stimulation by arginine and have a higher diagnostic accuracy than the water deprivation test. Treatment involves correcting preexisting water deficits, but is different for central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia., Competing Interests: Competing interests M. Christ-Crain received speaking honoraria from Thermo Fisher AG, the manufacturer of the copeptin assay., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Parathyroid gland excision specimens are common and sometimes underestimated cases that many surgical pathologists encounter regularly. In the vast majority of cases, these will be spot diagnoses of sporadic primary parathyroid adenomas or, perhaps, hyperplasias commonly in the setting of renal failure. However, a small but significant number of parathyroid gland excisions may be due to heritable disease. In most cases, hereditary disease is suspected by the referring clinicians. Nevertheless, a subset of these are undetected which is significant, particularly in the setting of the multiple endocrine neoplasia (MEN), and the hyperparathyroidism jaw tumour (HPT-JT) syndromes. There have been recent advances in recognition of the morphological and immunohistochemical characteristics of these tumours and hyperplasias. While hereditary kindreds are over-represented at specialist referral centres, with awareness of the characteristic clinical and morphological features, the general surgical pathologist is frequently able to suggest the possibility of hereditary parathyroid disease. We therefore provide a succinct guide for pathologists to increase the recognition of hereditary parathyroid disease.

Background: This study aimed to evaluate the discriminative abilities of glycosylated hemoglobin (HbA1c) and to examine the optimal HbA1c cutoff values for diabetes and prediabetes in Chinese adults., Methods: Data of a population-based cohort of Chinese adults aged ≥40 years living in Jiading District in Shanghai were used. At baseline, 9389 and 7241 participants were included to identify the optimal HbA1c cutoff values for diabetes and prediabetes, respectively using the 1999 World Health Organization criteria as reference. In addition, the follow-up data on incident diabetes of 4538 participants were used to determine the HbA1c cutoff value for prediabetes using the development of diabetes as reference. The discriminative abilities of HbA1c were evaluated using receiver operating characteristic (ROC) curves, and the optimal cutoff values were determined by Youden's index., Results: The areas under the ROC curves were 0.849 for diabetes, 0.614 for prediabetes using baseline data, and 0.648 for prediabetes using follow-up data. An HbA1c cutoff value of 6.0% had the largest Youden's index to diagnose diabetes with a sensitivity of 70.2% and a specificity of 87.4%. An HbA1c cutoff value of 5.6% was indicated for prediabetes using both baseline and follow-up data. However, the sensitivity and specificity were both low (55.4% and 61.1% using an oral glucose tolerance test as reference, 64.6% and 57.1% using incident diabetes as reference)., Conclusions: An HbA1c value ≥6.0% could be used to detect diabetes in Chinese adults aged ≥40 years. However, although an HbA1c value of 5.6% to 5.9% was indicated in this study, the overall discrimination of HbA1c for prediabetes was poor., (© 2020 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Objective: Various organizations have highlighted the need to examine whether abdominal obesity cut points are appropriate for identification of cardiovascular risk among ethnic minority adults, particularly Hispanic/Latino adults living in Western societies. This study aimed 1 ) to establish optimal definitions for abdominal obesity among Hispanics/Latinos and 2 ) to determine the level of agreement between the presence of metabolic syndrome diagnosed by the current Joint Interim Statement (JIS) definition and an updated definition with optimal abdominal obesity cut points., Research Design and Methods: The sample included 16,289 adults who self-identified as Hispanic/Latino ages 18-74 years enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Receiver operating characteristic curves were used to derive sensitivity and specificity values. The largest sum of sensitivity plus specificity was used to determine appropriate cut points., Results: Among U.S. Hispanic/Latino adults, waist circumference cut points of >102 cm in men (in line with current JIS criteria) and >97 cm (9 points higher than JIS criteria) in women provide optimal discrimination for cardiovascular risk as judged by the presence of coronary heart disease. When using these cut points to create an updated metabolic syndrome definition among women, we found disagreement between our updated definition and the current JIS criteria. The prevalence of the metabolic syndrome was overestimated by ∼5 percentage points among women based on JIS criteria in comparison with our definition., Conclusions: Our results suggest that the current recommendations for waist circumference cut points may not be appropriate for U.S. Hispanic/Latino women., (© 2020 by the American Diabetes Association.)

In Japan, primary aldosteronism (PA) is diagnosed if any one of the captopril challenge test (CCT), saline infusion test (SIT), furosemide-upright test (FUP), and oral salt-loading test (OST) is positive. The present study aimed to investigate if parameters of CCT, the safest confirmatory test, could predict decisions of other tests and propose the next test to diagnose PA in CCT-negative patients. In a cross-sectional design, 142 patients, who were referred to our hospital for the scrutiny of PA and underwent at least two confirmatory tests, were enrolled. While 123 patients underwent all of the CCT, SIT, and FUP, the OST was successfully done in only six patients and excluded from further analyses. CCT parameters showing correlations of higher degrees with SIT and FUP parameters were selected, and their powers to predict SIT and FUP decisions were investigated by receiver operating characteristic analyses. Proposals of the next test based on the CCT parameters were validated with SIT and FUP decisions in subsets of CCT-negative patients divided by cut-offs of the CCT parameters. The plasma aldosterone concentration and plasma renin activity 60 min after the load of CCT (CCT60-PAC and CCT60-PRA) were selected, and CCT60-PAC ≤59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h could predict negativities of SIT and FUP, respectively, with >95% specificities. Based on the validation, the present study suggested the SIT as the next test to be done if the CCT-negative patient belonged to the subset with CCT60-PAC >59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h, otherwise the FUP should be selected.

With this review, we aim to focus the attention on some established as well as new concepts for the metabolic syndrome (MetS) in children and adolescents spanning from definition to recommendations for the diagnostic approach. Even though there is no international commonly used definition of the metabolic syndrome in children and adolescents, all definitions include obesity as precondition for the development of MetS even in children. Obesity is one of the major cardiometabolic risk factors and it is strongly linked to other metabolic diseases like hyperlipidemia, hyperinsulinemia as well as hypertension. The metabolic syndrome is commonly known as a constellation of the mentioned morbidities. Pediatricians and researchers agree that early diagnosis and early interventions of the MetS are important to improve the prevention of cardiovascular disease and type 2 diabetes in adulthood. However, this requires appropriate screening tools for children and adolescents at risk for the MetS and its comorbidities. Due to controversies regarding the definition of MetS and the lack of consensus thresholds for the single components in children and adolescents, there is no internationally accepted diagnostic pathway for MetS available. However, several consensus statements and national guidelines for the assessment of obesity and its comorbidities in children and adolescents are available. Obesity seems to be the driving factor for the development of the other risk factors of MetS. In order to avoid conflicts concerning the definition of overweight and obesity, we recommend using the WHO definition of overweight (one standard deviation body mass index for age and sex and obesity; two standard deviations body mass index for age and sex) in children and adolescents.

Modern ICSI (intracytoplasmic sperm injection) cycles' outcomes are difficult to predict. Whether human chorionic gonadotrophin (hCG) or luteinizing hormone (LH) serum levels 24 h prior to oocyte retrieval are correlated with retrieval and subsequent cycle results is unclear. An observational historic cohort study of 645 fresh ICSI cycles was conducted. After controlled oocyte stimulation, and 10-12 h after a self-administered trigger, serum levels of hCG (hCG trigger n  = 563) and LH (GnRHa trigger n  = 82) were measured. Correlations between pre-retrieval hormone levels and cycle results were assessed. No correlation ( p  > .12) was found between serum pre-retrieval hCG levels or LH levels (in GnRHa-triggered cycles) and total oocytes, M2, M1 + M2 or oocyte maturity rates (OMR) for any of the stimulation protocols. ROC (receiver operator curve) analysis for fertilization rates showed a possible cutoff for LH levels. Pregnancy rates (PR) were higher in rising hCG groups; a cutoff of 117 IU/L was associated with an increase in PR (30.9% to 45.6%) and a moderate sensitivity and specificity (60.6% and 55.0%). However, HCG was not predictive of pregnancy in a logistic regression model. We conclude that preretrieval hCG serum levels are not useful for pre-retrieval estimation of aspiration results but might have a role in prediction of pregnancy.