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The differential diagnosis of differences or disorders of sex development (DSD) belongs to the most complex fields in medicine. It requires a multidisciplinary team conducting a synoptic and complementary approach consisting of thorough clinical, hormonal and genetic workups. This position paper of EU COST (European Cooperation in Science and Technology) Action BM1303 'DSDnet' was written by leading experts in the field and focuses on current best practice in genetic diagnosis in DSD patients. Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step. Subsequently, further analyses comprise molecular studies of monogenic DSD causes or analysis of copy number variations (CNV) or both. Panels of candidate genes provide rapid and reliable results. Whole exome and genome sequencing (WES and WGS) represent valuable methodological developments that are currently in the transition from basic science to clinical routine service in the field of DSD. However, in addition to covering known DSD candidate genes, WES and WGS help to identify novel genetic causes for DSD. Diagnostic interpretation must be performed with utmost caution and needs careful scientific validation in each DSD case. [ABSTRACT FROM AUTHOR]

Disorders or differences in sex development (DSD) comprise a heterogeneous group of conditions with an atypical sex development. For optimal diagnosis, highly specialised laboratory analyses are required across European countries. Working group 3 of EU COST (European Cooperation in Science and Technology) Action BM 1303 'DSDnet' 'Harmonisation of Laboratory Assessment' has developed recommendations on laboratory assessment for DSD regarding the use of technologies and analytes to be investigated. This position paper on steroid hormone analysis in diagnosis and treatment of DSD was compiled by a group of specialists in DSD and/or hormonal analysis, either from participating European countries or international partner countries. The topics discussed comprised analytical methods (immunoassay/mass spectrometry-based methods), matrices (urine/serum/saliva) and harmonisation of laboratory tests. The following positions were agreed upon: support of the appropriate use of immunoassay- and mass spectrometry-based methods for diagnosis and monitoring of DSD. Serum/plasma and urine are established matrices for analysis. Laboratories performing analyses for DSD need to operate within a quality framework and actively engage in harmonisation processes so that results and their interpretation are the same irrespective of the laboratory they are performed in. Participation in activities of peer comparison such as sample exchange or when available subscribing to a relevant external quality assurance program should be achieved. The ultimate aim of the guidelines is the implementation of clinical standards for diagnosis and appropriate treatment of DSD to achieve the best outcome for patients, no matter where patients are investigated or managed. [ABSTRACT FROM AUTHOR]

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement. [ABSTRACT FROM AUTHOR]

Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous TSH is recommended by current clinical guidelines to detect occult disease with a maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of mass screening of newborns for congenital hypothyroidism of central origin (CH-C) by measurement of free thyroxine (FT4) and thyroid-stimulating hormone (TSH). Design: Questionnaire-based survey of CH-C patients born between 1999 and 2008 in Kanagawa prefecture, Japan. Methods: TSH and FT4 levels in dried blood spots on filter paper were measured using ELISA kits, and CH-C was diagnosed at FT4 levels below a cutoff of 0.7 ng/dl (9.0 pmol/l). Survey results were collated with the database created by the screening organizer Results: Twenty-four CH-C patients (18 males) were identified, 14 of whom had multiple pituitary hormone deficiencies (group M), eight had isolated CH-C (group I), and two had undetermined pituitary involvement (group U). In groups M, I, and U, the number of patients with FT4 levels below the cutoff value at screening was five (36%), seven (88%), and one (50%) respectively; other patients had been diagnosed clinically. Thus, 13 patients were true positives, while nine were false negatives, yielding screening sensitivity of 59.1% and positive predictive value of 11.5%. The calculated sensitivity was 81.8% at a higher cutoff value of 0.9 ng/dl (11.6 pmol/l). The overall incidence of CH-C was estimated at 1 in 30 833 live births, while that of CH of thyroidal origin (CH-T) is 1 in 3472 live births in Kanagawa prefecture (CH-T/CH-C, 8.9). Conclusions: Newborn screening with combined FT4 and TSH measurements can identify a significant number of CH-C patients before manifestation of clinical symptoms, but a more appropriate FT4 cutoff value should be considered. [ABSTRACT FROM AUTHOR]

The article discusses the challenges in determining rapid effects of steroids and its future prospects. It mentions that, it is believed that the classical steroid receptors are found to be involved in rapid actions but there are some evidences which suggest that unrelated structures are responsible for these rapid effects. The article further suggests that more work is to be done in order to identify clinical benefit of rapid steroid action.

In this methodology editorial, the problem of censored survival (or time-to-event) data in clinical research is discussed. In case of censored observations, part of the observation time for some participants in a study is unobserved, which means that measures such as an average survival time cannot be calculated. Instead, censored survival time should explicitly be accounted for in the analysis of a study, for example using the Kaplan–Meier method. Implications of censoring and how to deal with it in the analysis of a study or when reading a research paper are discussed. [ABSTRACT FROM AUTHOR]

Researchers frequently come across sample size calculations in the scientific literature they read, in projects undertaken by their peers, and likely within their own work. However, despite its ubiquity, calculating a sample size is often perceived as a hurdle and not fully understood. This paper provides a brief overview of sample size estimation to guide readers, researchers, and reviewers through its fundamentals. [ABSTRACT FROM AUTHOR]

For many statistical methods that are commonly used in medical research, it is assumed that observations are independent. However, when this assumption is violated, alternative methods may be needed. In this paper, we describe why an analysis that ignores the dependencies within the data may provide biased results and outline possible alternatives. This paper aims to create awareness among researchers, readers, and reviewers for this possible source of bias in medical research. [ABSTRACT FROM AUTHOR]

Objective: Thyroglobulin measurement is the cornerstone of modern management of differentiated thyroid cancer, with clinical decisions on treatment and follow-up based on the results of such measurements. However, numerous factors need to be considered regarding measurement with and interpretation of thyroglobulin assay results. Design: The present document provides an integrated update to the 2013 and 2014 separate clinical position papers of our group on these issues. Methods: Issues concerning analytical and clinical aspects of highly-sensitive thyroglobulin measurement will be reviewed and discussed based on an extensive analysis of the available literature. Results: Thyroglobulin measurement remains a highly complex process with many pitfalls and major sources of interference, especially antithyroglobulin antibodies, need to be assessed, considered and, when necessary, dealt with appropriately. Conclusions: Our expert consensus group formulated 53 practical, graded recommendations for guidance on highly-sensitive thyroglobulin and TgAb in laboratory and clinical practice, especially valuable where current guidelines do not offer sufficient guidance. [ABSTRACT FROM AUTHOR]

Propensity score methods are popular to control for confounding in observational biomedical studies of risk factors or medical treatments. This paper focused on aspects of propensity score methods that often remain undiscussed, including unmeasured confounding, missing data, variable selection, statistical efficiency, estimands, the positivity assumption, and predictive performance of the propensity score model. [ABSTRACT FROM AUTHOR]

Importance: This proof-of-concept paper demonstrates that driver mutations can be detected in plasma in differentiated thyroid tumors, and we were able to detect mutations in up to 80% malignant thyroid nodules. Additionally, cancer subtypes could also be predicted using a 8-gene panel. In almost 90% follicular adenoma, rat sarcoma virus (RAS) mutations were detectable. There was a strong agreement between driver mutations found in plasma samples, FNAC materials, and histopathology samples. This has potential as a noninvasive, preoperative diagnostic tool (particularly of clinical importance in indeterminate nodules) and may help in detection of residual tumor after surgery. Future research is warranted to test the role of this tool to detect tumor recurrence. Objective: Ultrasonographic (USG) evaluation and fine-needle aspiration (FNA) are cornerstone for evaluation of thyroid neoplasm. Molecular technique including detection of driver mutation from FNA cytology (FNAC) material is an established modality. In this study, we explored the feasibility of using plasma cell--free nucleic acids to identify known driver mutations in differentiated thyroid neoplasm. Design: Patients presenting with thyroid nodules underwent USG with Thyroid Image Reporting and Data Systems scoring and FNAC (Bethesda classification). All patients in Bethesda 3, 4, 5, 6 underwent surgery and histopathological confirmation. Patients in Bethesda 2 (cosmetic concerns, compressive symptoms) underwent surgery, and rest were presumed benign on the basis of USG, FNAC features, and clinical followup.). Setting: Endocrinology clinic. Participants: Subjects with thyroid nodule. Intervention(s) or Exposure(s): None. Main Outcome(s) and Measure(s): Plasma sample, FNA, and histopathology material were evaluated for driver mutations (8-gene panel comprising BRAF-V600E, RET/PTC3, RET/PTC1, TERT promoter, HRAS, NRAS, KRAS, and PAX8-PPARG). Results: A total of 223 subjects were recruited; of these 154 were benign and 69 had differentiated thyroid cancer. We were able to detect driver mutation from plasma in 55 subjects (79.71%) of all malignant patients, and 11 patients in benign category had RAS mutation (follicular adenoma). Rest of the benign nodules did not have any detectable driver mutations. Conclusions and Relevance: Plasma might be a viable noninvasive alternative source for detection of driver mutations (8-gene panel) in subjects with differentiated thyroid tumors and may have significant clinical utility. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients. [ABSTRACT FROM AUTHOR]

Objective: Despite the improvements in ultrasound (US) and scintigraphy, 10-20% of patients with primary hyperparathyroidism (PHPT) still have discordant findings. We pe rformed a systematic review and meta-analysis to assess the safety and the diagnostic performance of US-guided PTH washout (FNA-PTH) in patients with PHPT, a suspected parathyroid lesion on US but negative or equivocal sc intigraphy. Methods: The review was registered on PROSPERO (CRD42019124249). PubMed , Scopus, CENTRAL and Web of Science were searched until February 2019. Original articles reporting complications and diagnostic performance of FNAPTH in biochemically and histopathologically diagnosed PHPT wer e selected. The risk of bias of included studies was assessed through QUADAS-2. Summary operating points were estima ted using a random-effects model. Results: Out of 2573 retrieved papers, nine cohort studies were include d in the review. No major procedure-related complications were found. Pooled sensitivity was 95% (95% CI: 9 1-98; I2: = 14%) and positive predictive value was 97% (95% CI: 93-100; I2: = 39%). There were not enough data for specificity and negative predictive value to perform a metaanalysis. However, pooling results of all lesions, they were es timated to be 83 and 73%, respectively. Conclusions: In patients with biochemically proven PHPT and discordant imaging, FNA-PTH was a safe and accurate procedure. In this specific setting of patients, FNA-PTH could b e used as a rule-in test for minimally invasive parathyroidectomy. [ABSTRACT FROM AUTHOR]

Background: Primary thyroid lymphoma (PTL) is a rare malignancy, and its p rognosis depends significantly on its early diagnosis. While fine-needle aspiration (FNA) represents the gol d standard to identify differentiated thyroid carcinoma, its reliability for the detection of PTL is still unclear. Here, we conducted a systematic review and meta-analysis to evaluate the diagnostic performance of FNA in PTL. Research design and methods: A comprehensive literature search of PubMed/MEDLINE and Scopus databases was conducted to retrieve papers reporting histologically proven PT L undergone FNA. The last search was performed in February 2018 without language and time restrictions. Results: Thirty-two studies describing 593 PTL were included and the pooled FNA sensitivity was 0.48 (95% CI = 0.38- 0.58). FNA sensitivity was 0.51 in 20 studies published before 2010 and 0.39 in those published later, 0.50 in six articles with at least 20 cases and 0.44 in nine series enrolled after 2 000. This performance was similar in 12 articles including diffuse large B-cell lymphoma (0.54) and those six on marginal z one lymphoma (0.56). Remarkably, FNA sensitivity increased to 0.72 when considering also FNA reports suspicious for PTL reported in 14 articles. Heterogeneity among the series was found. Publication bias was not always detected. Conclusions: The present meta-analysis demonstrated that FNA has low sensit ivity in diagnosing PTL. However, this rate increased when considering also FNA reports suspicious for PTL, which is relevant from a clinical standpoint. This result could support indirectly the use of additional imaging and/or core biopsy when PTL is suspected. [ABSTRACT FROM AUTHOR]

The name of the study should properly reflect the actual conduct and analysis of the study. This short paper provides guidance on how to properly name the study design. The first dis tinction is between a trial (intervention given to patients to study its effect) and an observational study. For ob servational studies, it should further be decided whether it is cross-sectional or whether follow-up time is taken into a ccount (cohort or case-control study). The distinction prospective-retrospective has two disadvantages: prospective is often seen as marker of higher quality, which is not necessarily true; there is no unifying definition that makes a proper distinction between retrospective and prospective possible. [ABSTRACT FROM AUTHOR]

Objective: Thyroid surgery may lead to postoperative complications. The a im of this paper was to determine whether the rate of postoperative hypoparathyroidism (HPT) is influenced by whether surgery is staged. Design: Single-institution retrospective observational study. Methods: The clinical records of 786 patients treated at the Otolaryngo logy Unit of the Azienda USL-IRCCS di Reggio Emilia between January 1990 and December 2015 were reviewed. Pa tients were divided into two groups according to the surgical treatment received: group TT (637 patients, 81.04%) underwent single-stage total thyroidectomy; Group cT (149 patients, 18.96%) underwent loboisthmusectomy and delay ed completion total thyroidectomy. Transient and permanent HPT, assessed after 6 months of follow-up, were the p rimary endpoints. Risk factors of postoperative HPT were also analysed as secondary outcomes. Results: Rates of transient HPT in group TT were higher than those obse rved in group cT, (P = 0.0057). Analysis of risk factors identified sex as an independent risk factor for transie nt HPT only for group TT (P = 0.0012) and the number of parathyroid glands remaining in situ (PGRIS) as an independent risk factor for transient and perman ent HPT for group TT (P < 0.0001 and P = 0.0002, respectively). Conclusions: This study suggests that the risk of transient postoperative H PT is lower in patients that undergo completion thyroidectomy. Further independent risk factors for postoperative HPT are female sex and PGRIS score. In light of the growing use of conservative surgery for thyroid ne oplasms, these findings could help to adequately plan surgery in order to reduce endocrine complications. [ABSTRACT FROM AUTHOR]

Objective: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFT-P) is an encapsulated follicular variant of papillary thyroid carcinoma (PTC) with nonaggressive clinical behavior. However, since its diagnosis is exclusively possible after surgery, it represents a clinical challenge. Neck ultrasound (US) shows good sensitivity and specificity in suggesting malignancy in thyroid nodules. However, little information is available about its ability in identifying NIFT-P. Design: The aim of this study was to evaluate the US features of NIFT-P, comparing them with other follicular-patterned thyroid tumors, and to test the ability of the main US risk stratification system (RSS) in identifying NIFT-P. Methods: We retrospectively evaluated 403 consecutive patients submitted to thyroid surgery, with positive histology for at least 1 nodule being NIFT-P, follicular variant of PTC (FV-PTC), follicular thyroid carcinoma (FTC), or follicular adenoma (FA). Results: The US features of NIFT-P (n = 116), FV-PTC (n = 170), FTC (n = 76), and FA (n = 90) were reported. Follicular variant of PTC and FTC more frequently showed irregular margins, presence of calcifications, "taller than wide" shape, and the absence of halo compared with NIFT-P. Furthermore, FTC and also FA were larger and more frequently hypoechoic than NIFT-P. Most cases (77%) showed an indeterminate cytology. Regardless of the US RSS considered, NIFT-P and FA were less frequently classified in the high-suspicious category compared with FV-PTC and FTC. Conclusions: Ultrasound features of NIFT-P are frequently superimposable to those of nodules with low suspicion of malignancy. The NIFT-P is almost never classified in the high-suspicious category according to the main US RSS. Therefore, although the preoperative identification of NIFT-P remains a challenge, neck US can be integrated in the algorithm of management of nodules with indeterminate cytology, suggesting a possible conservative approach in those with low-suspicious features. [ABSTRACT FROM AUTHOR]

Fertility and ovarian protection against chemotherapy-associated ovarian damage has formed a new field called oncofertility, which is driven by the pursuit of fertility protection as well as good life quality for numerous female cancer survivors. However, the choice of fertility and ovarian protection method is a difficult problem during chemotherapy and there is no uniform guideline at present. To alleviate ovarian toxicity caused by anticancer drugs, effective methods combined with an individualized treatment plan that integrates an optimal strategy for preserving and restoring reproductive function should be offered from well-established to experimental stages before, during, and after chemotherapy. Although embryo, oocyte, and ovarian tissue cryopreservation are the major methods that have been proven effective and feasible for fertility protection, they are also subject to many limitations. Therefore, this paper mainly discusses the future potential methods and corresponding mechanisms for fertility protection in chemotherapy-associated ovarian damage. [ABSTRACT FROM AUTHOR]

In a recent paper, Subramanian and collaborators reported a 52% increased risk of COVID-19 infection in women with polycystic ovary syndrome (PCOS) and an incidence nearly twice that of women without PCOS. The authors focused, as important factors of the increased prevalence of infection, both the inflammatory characteristic of PCOS and the increase in androgens that facilitate the entry of the virus into the cells of the target organs. We asked 200 consecutive, unvaccinated women with PCOS who had been followed with spirono lactone for more than 4 months, about COVID-19 infection and found only four patients who were infected. No ne of the infected patients were hospitalized and only one had fever and other manifestations of the syndrome, but the se symptoms resolved in a few days. The other three reported only mild or minimal symptoms. This observation needs confirmation with specific studies, considering the possibility that many other patients may have been infected by being asymptomatic and not swabbing for COVID-19. Spironolactone can increase the circulating angiotensin-converting enzyme 2 and antagonize the androgen receptor, preventing activation of transmembrane protease serine 2 in cel ls of the respiratory tract and other tissues. Drug also has potent anti-inflammatory and antithrombotic actions by antag onizing the mineralocorticoid receptor in target tissues and inflammatory cells. From Subramanian's study and rep orted observations, a proper evaluation of the use of spironolactone in COVID-19 in both PCOS and the general popu lation is urged. [ABSTRACT FROM AUTHOR]

Clinical endocrinologists have to deal frequently with adrenal incidentalomas in their practice. However, no comprehensive guidelines have been published by professional societies to guide assessment and management of adrenal incidentalomas and current recommendations are mainly based on the NIH state-of-the-science statement or expert opinions. An accompanying paper in this issue of the journal provides a critical revision of the relevant literature on this clinically important topic. The provocative conclusion of the authors is that current recommendations are burdened by high costs, little clinical benefit and also risk of inducing cancer. This paper has the merit to outline the limits of proposed protocols and to stimulate fruitful discussion; however, many aspects represent the personal view of the authors rather than evidence-based assumptions. The purpose of the present comment is to provide a more balanced view addressing the arguments that are condivisible and those that are based on inconsistent data. To add further to the argument of discussion, we also outline a clinically-oriented strategy for follow-up. In conclusion, the need for further research appears evident to define more efficient guidelines. [ABSTRACT FROM AUTHOR]

The incidence of differentiated thyroid carcinoma (DTC) has incr eased rapidly over the past several years. Thus far, the only conclusively established risk factor for developi ng DTC is exposure to ionizing radiation, especially when the exposure occurs in childhood. Since the number of chil dhood cancer survivors (CCS) is increasing due to improvements in treatment and supportive care, the number of patients who will develop DTC after surviving childhood cancer (secondary thyroid cancer) is also expected to rise. Currently, there are no recommendations for management of thyroid cancer specifically for patients who devel op DTC as a consequence of cancer therapy during childhood. Since complications or late effects from prior cancer treatment may elevate the risk of toxicity from DTC therapy, the medical history of CCS should be considered carefu lly in choosing DTC treatment. In this paper, we emphasize how the occurrence and treatment of the initial child hood malignancy affects the medical and psychosocial factors that will play a role in the diagnosis and treatment of a secondary DTC. We present considerations for clinicians to use in the management of patients with secondary DTC, based on the available evidence combined with experiencebased opinions of the authors. [ABSTRACT FROM AUTHOR]

The use of recombinant human thyrotropin (rhTSH) testing in the diagnosis and therapy of differentiated thyroid cancer (DTC) has been adopted over the last two decades as an a lternative to the classical thyroid hormone withdrawal avoiding the threat of hypothyroidism. Serum thyroglobulin (Tg) measurement is crucial for monitoring DTC patients over time. Until about a decade ago, optimal sensitivity of Tg assays for the detection of smaller disease foci required Tg measurement after thyrotropin (TSH) stimulation, carried out following thyroid hormone withdrawal or rhTSH administration. In very recent years, significant improvements in assay technology have resulted in highly sensitive Tg (hsTg) assays, sufficiently sensitive to obviate the need for rhTSH stimulation in most DTC patients. The aim of this paper is to review and discuss, via a 'pros and cons' approach, the current clinical role of rhTSH to stimulate radioiodine (RAI) uptake for treatment and/or imaging purposes and to increase the clinical sensitivity of Tg measurement for monitoring DTC patients when high-sensitive Tg assays are available. [ABSTRACT FROM AUTHOR]

Purpose: To provide practice recommendations for the diagnosis and management of hypoparathyroidism in adults. Methods: Key questions pertaining to the diagnosis and management of hypoparathyroidism were addressed following a literature review. We searched PubMed, MEDLINE, EMBASE and Cochrane databases from January 2000 to March 2018 using keywords 'hypoparathyroidism, diagnosis, treatment, calcium, PTH, calcidiol, calcitriol, hydrochlorothiazide and pregnancy'. Only English language papers involving humans were included. We excluded letters, reviews and editorials. The quality of evidence was evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These standards of care for hypoparathyroidism have been endorsed by the Canadian Society of Endocrinology and Metabolism. Results: Hypoparathyroidism is a rare disease characterized by hypocalcemia, hyperphosphatemia and a low or inappropriately normal serum parathyroid hormone level (PTH). The majority of cases are post-surgical (75%) with nonsurgical causes accounting for the remaining 25% of cases. A careful review is required to determine the etiology of the hypoparathyroidism in individuals with nonsurgical disease. Hypoparathyroidism is associated with significant morbidity and poor quality of life. Treatment requires close monitoring as well as patient education. Conventional therapy with calcium supplements and active vitamin Danalogs is effective in improving serum calcium as well as in controlling the symptoms of hypocalcemia. PTH replacement is of value in lowering the doses of calcium and active vitamin D analogs required and may be of value in lowering long-term complications of hypoparathyroidism. This manuscript addresses acute and chronic management of hypoparathyroidism in adults. Main conclusions: Hypoparathyroidism requires careful evaluation and pharmacologic intervention in order to improve serum calcium and control the symptoms of hypocalcemia. Frequent laboratory monitoring of the biochemical profile and patient education is essential to achieving optimal control of serum calcium. [ABSTRACT FROM AUTHOR]

Over the past 20 years, the care for transgender adolescents has developed throughout many countries following the 'Dutch Approach' initiated in the 90s in pioneer countries as the Netherlands, United States and Canada, with increasing numbers of children and adolescents seeking care in transgender clinics. This medical approach has considerable positive impacts on the psychological outcomes of these adolescents, and several studies have been recently published underlining the relative safety of such treatments. This paper reviews the current standards of care for transgender children and adolescents with particular emphasis on disparities among countries and short-tomedium-term outcomes. Finally, it highlights ethical considerations regarding categorization of gender dysphoria, timing of treatment initiation, infertility and how to deal with the long-term consequences. [ABSTRACT FROM AUTHOR]

E Peverelli et al. Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients, European Journal of Endocrinology, Volume 161, Issue 5, Nov 2009, Pages 687–694, https://doi.org/10.1530/EJE-09-0677In the originally published version of this paper, the legend for Figure 2F incorrectly stated '(F) tumor sample of patient no. 13 with R867G variant and FS41X-truncating mutation (score=0).' It should have stated '(F) Higher magnification view of (E).'The journal and authors acknowledge the anonymous reader who identified and brought this error to the attention of the journal. [Extracted from the article]

The increasing use of cross-sectional imaging, mainly CT, results in an accelerating number of incidental findings, for instance of adrenal tumours. Although most ‘adrenal incidentalomas’ are benign, it is important to identify the malignant and the hormone producing (functional) tumours. For a small fraction of adrenal incidentalomas, the diagnosis is apparent on imaging, but the large majority requires radiological characterisation. To this end, a previous joint European Society of Endocrinology and European Network for the Study of Adrenal Tumours publication in this jounal, recommends CT measurements of the native (non-contrast) tumour attenuation ≤10 Hounsfield units, consistent with a lipid-rich benign adrenocortical adenoma, and imaging at least 6 months apart, on which unchanged tumour size implies a benign tumour. Because of weak evidence, calculation of CT contrast medium washout was not recommended as a means for tumour characterisation, but this technique has nevertheless still been applied in several countries. The recent article by Schloetelburg et al. in this journal is important because, in the largest study to date, the authors confirm that calculation of CT contrast medium washout with established thresholds is insufficient to reliably characterise adrenal tumours. Their results are therefore expected to impact the management of these patients. [ABSTRACT FROM AUTHOR]

DESIGN: Data on lipids, body composition, and blood pressure (BP) from all published KIMS papers are summarized and compared with a literature review. RESULTS: KIMS data confirm and extend previous research showing that adults with GH deficiency (GHD) have an adverse cardiovascular risk profile. GHD patients have high levels of dyslipidemia, elevated body mass index, unfavorable waist-to-hip ratio and body composition, and a high risk of hypertension. These abnormalities are likely to explain the increased cardiovascular mortality observed in patients with hypopituitarism. When given GH replacement therapy, an improvement is seen in KIMS as well as earlier studies for lipid profile, body composition, and BP. The added value of the different KIMS papers over previous research is that KIMS involves a much larger number of patients, that lipid concentrations and IGF1 are measured in a single central laboratory, and that the effects of GH replacement therapy can be followed longer than the duration of earlier trials. By the large number of patients, KIMS gives insight into the effects of GH in different patients' subgroups such as elderly patients, patients with idiopathic GHD, patients with craniopharyngioma, patients after irradiation, and so on. In addition, KIMS has made it possible to calculate more exactly the influence of baseline parameters on these cardiovascular risk parameters and their response to GH. CONCLUSIONS: Taken together, data from KIMS confirm earlier knowledge about the important benefits of GH replacement therapy, but also on the use of GH in specific subgroups such as isolated GHD, patients above 65 years, and patients after irradiation. No subgroup yet has been identified as not responding well to GH. [ABSTRACT FROM AUTHOR]

When newborn screening (NBS) for congenital hypothyroidism (CH) using thyroid-stimulating hormone (TSH) as a primary screening test was introduced, typical TSH screening cutoffs were 20-50 U/L of whole blood. Over the years, lowering of TSH cutoffs has contributed to an increased prevalence of detected CH. However, a consensus on the benefit deriving from lowering TSH cutoffs at screening is lacking. The present paper outlines arguments both for and against the lowering of TSH cutoffs at NBS. It includes a review of recently published evidence from Australia, Belgium and Italy. A section focused on economic implications of lowering TSH cutoffs is also provided. One issue that bears further examination is the extent to which mild iodine deficiency at the population level might affect the association of neonatal TSH values with cognitive and developmental outcomes. A debate on TSH cutoffs provides the opportunity to reflect on how to make NBS for CH more effective and to guarantee optimum neurocognitive development and a good quality of life to babies with mild as well as with severe CH. All authors of this debate article agree on the need to establish optimal TSH cutoffs for screening programs in various settings and to ensure the benefits of screening and access to care for newborns worldwide. [ABSTRACT FROM AUTHOR]

Turner syndrome affects 25-50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting. [ABSTRACT FROM AUTHOR]

Objective: To summarize the current knowledge on epigenetic alterations in mother and offspring subjected to gestational diabetes (GDM) and indicate future topics for research. Design: Systematic review. Methods: We performed extensive searches in PubMed, EMBASE and Google scholar, using a combination of the search terms: GDM, gestational diabetes, epigenetic(s), methylation, histone modification, histone methylation, histone acetylation, microRNA and miRNA. Studies that compared women diagnosed with GDM and healthy controls were included. Two authors independently scanned the abstracts, and all included papers were read by at least two authors. The searches were completed on October 31st, 2016. Results: We identified 236 articles, of which 43 were considered relevant for this systematic review. Studies published showed that epigenetic alterations could be found in both mothers with GDM and their offspring. However, differences in methodology, diagnostic criteria for GDM and populations studied, together with a limited number of published studies and small sample sizes, preclude clear conclusions about the role of epigenetic modifications in transmitting risk from GDM mothers to their offspring. Conclusion: The current research literature suggests that GDM may have impact on epigenetic modifications in the mother and offspring. However, larger studies that include multiple cohorts of GDM patients and their offspring are needed. [ABSTRACT FROM AUTHOR]

Objective: To investigate the differences in bone turnover between diabetic patients and controls. Design: A systematic review and meta-analysis. Methods: A literature search was conducted using the databases Medline at PubMed and EMBASE. The free text search terms 'diabetes mellitus' and 'bone turnover', 'sclerostin', 'RANKL', 'osteoprotegerin', 'tartrate-resistant acid' and 'TRAP' were used. Studies were eligible if they investigated bone turnover markers in patients with diabetes compared with controls. Data were extracted by two reviewers. Results: A total of 2881 papers were identified of which 66 studies were included. Serum levels of the bone resorption marker C-terminal cross-linked telopeptide (--0.10 ng/mL (--0.12, --0.08)) and the bone formation markers osteocalcin (--2.51 ng/mL (--3.01, --2.01)) and procollagen type 1 amino terminal propeptide (--10.80 ng/mL (--12.83, --8.77)) were all lower in patients with diabetes compared with controls. Furthermore, s-tartrate-resistant acid phosphatase was decreased in patients with type 2 diabetes (--0.31 U/L (--0.56, --0.05)) compared with controls. S-sclerostin was significantly higher in patients with type 2 diabetes (14.92 pmol/L (3.12, 26.72)) and patients with type 1 diabetes (3.24 pmol/L (1.52, 4.96)) compared with controls. Also, s-osteoprotegerin was increased among patients with diabetes compared with controls (2.67 pmol/L (0.21, 5.14)). Conclusions: Markers of both bone formation and bone resorption are decreased in patients with diabetes. This suggests that diabetes mellitus is a state of low bone turnover, which in turn may lead to more fragile bone. Altered levels of sclerostin and osteoprotegerin may be responsible for this. [ABSTRACT FROM AUTHOR]

There are different ways to quantify the relation between two or more continuous variables. Some researchers use correlation coefficients; others will apply regression methods such as linear regression. In this paper, we show that the choice between correlation and regression is not purely a statistical one but largely depends on the research aims. Importantly, one should always inspect the data before using either of the two methods. [ABSTRACT FROM AUTHOR]

In almost all medical research, more than a single hypothesis is being tested or more than a single relation is being estimated. Testing multiple hypotheses increases the risk of drawing a false-positive conclusion. We briefly discuss this phenomenon, which is often called multiple testing. Also, methods to mitigate the risk of false-positive conclusions are discussed. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS. [ABSTRACT FROM AUTHOR]

Hirsutism is a common medical complaint among women of reproductive age, and it affects the majority of women with the polycystic ovary syndrome (PCOS). Increased rate of androgen production and its availability in tissue represent the main pathophysiological mechanisms responsible for hirsutism. In addition, androgens may be generated de novo in the hair follicle; therefore, circulating androgen levels do not quantify the real exposure of the hair follicle to androgens, as a quota is locally generated. Hirsutism is a clinical sign and not a disease in itself; its presence does not therefore necessarily require treatment, particularly in mild-to-moderate forms, and when an affected woman does not worry about it. Physicians should decide whether hirsutism is to be treated or not by evaluating not only the severity of the phenomenon but also the subjective perception of the patient, which does not necessarily correspond to the true extent of hair growth. In any case, a physician should manage a woman with hirsutism only on the basis of a diagnosis of the underlying cause, and after a clear explanation of the efficacy of each therapeutic choice. Cosmetic procedures and pharmacological intervention are commonly used in the treatment of hirsutism and are discussed in this paper. Importantly, there are different phenotypes of women with hirsutism and PCOS that may require specific attention in the choice of treatment. In particular, when obesity is present, lifestyle intervention should be always considered, and if necessary combined with pharmacotherapy. [ABSTRACT FROM AUTHOR]

Transition in health care for young patients with Turner's syndrome (TS) should be perceived as a staged but uninterrupted process starting in adolescence and moving into adulthood. As a condition associated with high risk of short stature, cardiovascular diseases, ovarian failure, hearing loss and hypothyroidism, TS requires the attention of a multidisciplinary team. In this review paper, we systematically searched the relevant literature from the last decade to discuss the array of problems faced by TS patients and to outline their optimal management during the time of transfer to adult service. The literature search identified 233 potentially relevant articles of which 114 were analysed. The analysis confirmed that all medical problems present during childhood should also be followed in adult life. Additionally, screening for hypertension, diabetes mellitus, dyslipidaemia, and osteoporosis is needed. After discharge from the paediatric clinic, there is still a long way to go. [ABSTRACT FROM AUTHOR]

Acromegaly is predominantly caused by a pituitary adenoma, which secretes an excess of GH resulting in increased IGF1 levels. Most of the GH assays used currently measure only the levels of the 22 kDa form of GH. In theory, the diagnostic sensitivity may be lower compared with the previous assays, which have used polyclonal antibodies. Many GH-secreting adenomas are plurihormonal and may co-secrete prolactin, TSH and a-subunit. Hyperprolactinaemia is found in 30-40% of patients with acromegaly, and hyperprolactinaemia may occasionally be diagnosed before acromegaly is apparent. Although trans-sphenoidal surgery of a GH-secreting adenoma remains the first treatment at most centres, the role of somatostatin analogues, octreotide long-acting repeatable and lanreotide Autogel as primary therapy is still the subject of some debate. Although the normalisation of GH and IGF1 levels is the main objective in all patients with acromegaly, GH and IGF1 levels may be discordant, especially during somatostatin analogue therapy. This discordance usually takes the form of high GH levels and an IGF1 level towards the upper limit of the normal range. Pasireotide, a new somatostatin analogue, may be more efficacious in some patients, but the drug has not yet been registered for acromegaly. Papers published on pasireotide have reported an increased risk of diabetes mellitus due to a reduction in insulin levels. Pegvisomant, the GH receptor antagonist, is indicated - alone or in combination with a somatostatin analogue - in most patients who fail to enter remission on a somatostatin analogue. Dopamine-D2-agonists may be effective as monotherapy in a few patients, but it may prove necessary to apply combination therapy involving a somatostatin analogue and/or pegvisomant. [ABSTRACT FROM AUTHOR]

One hundred years have passed since Harvey Williams Cushing presented the first patient with the syndrome that bears his name. In patients with Cushing's syndrome (CS), body composition and lipid, carbohydrate and protein metabolism are dramatically affected and psychopathology and cognitive dysfunction are frequently observed. Untreated patients with CS have a grave prognosis with an estimated 5-year survival of only 50%. Remission can be achieved by surgery, radiotherapy and sometimes with medical therapy. Recent data indicate that the adverse metabolic consequences of CS are present for years after successful treatment. In addition, recent studies have demonstrated that health-related quality of life and cognitive function are impaired in patients with CS in long-term remission. The focus of specialised care should therefore be not only on the diagnostic work-up and the early postoperative management but also on the long-term follow-up. In this paper, we review the long-term consequences in patients with CS in remission with focus on the neuropsychological effects and discuss the importance of these findings for long-term management. We also discuss three different phases in the postoperative management of surgically-treated patients with CS, each phase distinguished by specific challenges: the immediate postoperative phase, the glucocorticoid dose tapering phase and the long-term management. The focus of the long-term specialised care should be to identify cognitive impairments and psychiatric disorders, evaluate cardiovascular risk, follow pituitary function and detect possible recurrence of CS. [ABSTRACT FROM AUTHOR]

Background: The beneficial effects of recombinant human GH (rhGH) therapy in GH deficient (GHD) adults are well-established in the short term. However, data documenting the effects during prolonged follow-up are relatively scarce. Objective: To evaluate the reported effects of rhGH replacement (≥ 5 years) in GHD adults on biochemical and anthropometric parameters, quality of life (QoL), bone metabolism, muscle strength, serious adverse events and mortality. Methods: We conducted a systematic literature search. Quality assessment of retrieved papers was performed using a quality assessment based on the modified STROBE statement. Results: We included 23 prospective studies with a rhGH treatment duration ranging from 5 to 15 years. Overall, beneficial effects were reported on QoL, body composition, lipid profile, carotid intima media thickness and bone mineral density. In contrast, the prevalence of the metabolic syndrome, glucose levels, BMI and muscle strength were not, or negatively, influenced. Most of the studies were uncontrolled, lacked the presence of a control group (of non-treated GHD patients), and reported no data on lipid-lowering and anti-diabetic medication. Overall mortality was not increased. Conclusion: rhGH treatment in adult GHD patients is well-tolerated and positively affects QoL in the long term. However, the metabolic and cardiovascular effects during long-term treatment are variable. The low numbers of long-term studies and studied patients and lack of control data hamper definite statements on the efficacy of prolonged treatment. Therefore continuous monitoring of the effects of rhGH replacement to enable an adequate risk-benefit analysis that may justify prolonged, potentially life-long, treatment is advisable. [ABSTRACT FROM AUTHOR]

The authors and the journal apologize for an error in the above paper which appeared in 158 (5) 669–676. In this paper, on page 671, the fifth sentence should appear as follows ‘Each mixture consisted of 1 µl (8 ng) genomic DNA, 0.125 µl 40* assay mix (Applied Biosystems), and 2.5 µl TaqMan Universal Master Mix (Applied Biosystems)’. [ABSTRACT FROM AUTHOR]

The authors and the journal apologize for an error in the above paper which appeared in 157 (1) (109–112). In this paper on page 110, the hydrocortisone doses given in Fig. 1A were incorrect. The correct hydrocortisone doses were 0.5 (08–12 h), 0.2 (12–20 h), 0.05 (20–02 h) and 1.0 mg/m2body surface area/hour (02–08 h). [ABSTRACT FROM AUTHOR]

The GH/IGF1 axis may play an important role in cognitive function. This theory is supported by the finding that both GH and IGF1 receptors are located in several brain areas such as the hippocampus, a brain area that is known to play an essential role in cognitive processes, especially memory and learning. However, the exact mechanism by which the GH/IGF1 axis influences the cognitive functions is still unknown. Furthermore, little is known about the cognition in adults with both childhood-onset and adult-onset GH deficiency (CO-GHD and AO-GHD). Recent data indicate that cognitive function, particularly attention and memory, in adults with GHD might be impaired. To date, only a limited number of studies have been conducted to study the effects of GH replacement therapy on cognitive function in adults with GHD. In this paper, the results of studies on cognitive functioning in GHD patients, in particular the results of the studies performed in adults with CO-GHD, and the effects of GH replacement therapy in these patients, will be discussed. [ABSTRACT FROM AUTHOR]