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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]

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]

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]

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]

Objective Underdiagnosis is an important issue in genetic lipodystrophies, which are rare diseases with metabolic, cardiovascular, gynecological, and psychological complications. We aimed to characterize the diagnostic pathway in these diseases from the patients' perspective. Design Cross-sectional study conducted through a self-reported patient questionnaire. Methods Patients with genetic lipodystrophy were recruited throughout the French national reference network for rare diseases of insulin secretion and insulin sensitivity. Patients completed a self-reported questionnaire on disease symptoms, steps leading to the diagnosis, and healthcare professionals involved. Descriptive analyses were conducted. Results Out of 175 eligible patients, 109 patients (84% women) were included; 93 had partial familial lipodystrophy and 16 congenital generalized lipodystrophy. Metabolic comorbidities (diabetes 68%, hypertriglyceridemia 66%, hepatic steatosis 57%), cardiovascular (hypertension 54%), and gynecologic complications (irregular menstruation 60%) were frequently reported. Median age at diagnosis was 30 years (interquartile range [IQR] 23-47). The overall diagnostic process was perceived as "very difficult" for many patients. It extended over 12 years (IQR 5-25) with more than five different physicians consulted by 36% of respondents, before diagnosis, for lipodystrophy-related symptoms. The endocrinologist made the diagnosis for 77% of the patients. Changes in morphotype were reported as the first symptoms by the majority of respondents. Conclusions Diagnostic pathway in patients with genetic lipodystrophy is rendered difficult by the multisystemic features of the disease and the lack of knowledge of non-specialized physicians. Training physicians to systematically include adipose tissue examination in routine clinical evaluation should improve diagnosis and management of lipodystrophy and lipodystrophy-associated comorbidities. [ABSTRACT FROM AUTHOR]

Importance: Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development.Objective: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. Design and participants: This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. Results: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. Conclusions and relevance: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life. [ABSTRACT FROM AUTHOR]

Objective: The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because insulinlike growth factor 1 (IGF-I) or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature. Design: Boys and girls (n = 429, 0.7-16 years) who attended our department for short statu re participated in this study. They were followed up for an average period of 9 years. At the end of follow-up after reaching the final height, a definitive diagnosis was assigned, and all the components of t ernary complex (IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and IGF-I/IGFBP-3 ratio) were evalua ted as biomarkers for the respective diagnosis. Results: All the components of the ternary complex were tightly correla ted with each other and were positively related to age. IGF-I, IGFBP-3, ALS, and IGF-I/IGFBP-3 ratio differed si gnificantly between GHD and normal groups. IGF-I and ALS levels were lower in GHD compared to children with familial short stature, while IGF-I and IGF-I/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-I and IGF-I/IGFBP-3 receiver operating curve cutoff points were unable to discriminate between GHD and normal group s or between GHD and CDGP groups. Conclusion: Despite the tight correlation among all the components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-I, ALS, and IGF-I/IGFBP-3 ratio in the distinction between GHD and CDGP or between GHD and normal groups but without usable discriminating power, making auxology as the primary criterion for establishing the d iagnosis. [ABSTRACT FROM AUTHOR]

Objective: Insulinomas are rare functional pancreatic neuroendocrine tumo urs. As previous data on the long-term prognosis of insulinoma patients are scarce, we studied the mor bidity and mortality in the Finnish insulinoma cohort. Design: Retrospective cohort study. Methods: Incidence of endocrine, cardiovascular, gastrointestinal and p sychiatric disorders, and cancers was compared in all the patients diagnosed with an insulinoma in Finland dur ing 1980-2010 (n = 79, including two patients with multiple endocrine neoplasia type 1 syndrome), vs 316 matched c ontrols, using the Mantel-Haenszel method. Overall survival was analysed with Kaplan-Meier and Cox regression anal yses. Results: The median length of follow-up was 10.7 years for the patients and 12.2 years for the controls. The long-term incidence of atrial fibrillation (rate ratio (RR): 2.07 (95% CI: 1.02-4.22)), intestinal obstruction (18.65 (2.09-166.86)), and possibly breast (4.46 (1.29-15.39) and kidney cancers (RR n ot applicable) was increased among insulinoma patients vs controls, P < 0.05 for all comparisons. Endocrine disorders and pancreatic d iseases were more frequent in the patients during the first year after insulinoma diagnosis, but not later on. The survival of patients with a nonmetastatic insulinoma (n = 70) was similar to that of controls, but for patients with dis tant metastases (n = 9), the survival was significantly impaired (median 3.4 years). Conclusions: The long-term prognosis of patients with a non-metastatic insu linoma is similar to the general population, except for an increased incidence of atrial fibrillation, intest inal obstruction, and possibly breast and kidney cancers. These results need to be confirmed in future studies. Metastatic insulinomas entail a markedly decreased survival. [ABSTRACT FROM AUTHOR]

Objectives: To determine trends in clinical practice for individuals with D SD requiring gonadectomy. Design: Retrospective cohort study. Methods: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019. Results: Data regarding gonadectomy were available in 668 (88%) individu als from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cas es (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (7 6%). The most common indication was mitigation of tumour risk in 172 (64%). Variatio ns in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergo ne gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), r espectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. Conclusions: The likelihood of gonadectomy depends on the underlying diagnos is, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all f orms of DSD will allow a better understanding of the variation in the practice of gonadectomy. [ABSTRACT FROM AUTHOR]

Objective: Transient neonatal diabetes mellitus (TNDM) is caused by activa ting mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We want ed to assess whether these different genetic aetiologies result in distinct clinical features. Design: Retrospective analysis of the Italian data set of patients wit h 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 value s, 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 K ATP/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 di abetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with K ATP 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 w ith macroglossia and/or umbilical hernia. Remission of diabetes without pharmaco logical therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remis sion of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy. [ABSTRACT FROM AUTHOR]

Objective: Hair cortisol (HF) and cortisone (HE) measurements reflect tissular exposure to cortisol over months and are increased in overt Cushing's syndrome (CS). No data is available in mild CS. We compared the diagnostic performance of HF and HE between patients with overt or mild CS. Design: Single centre retrospective study. Methods: HF&HE were measured by LC-MS/MS in 48 consecutive adult females with Cushing's disease (CD), ectopic ACTH syndrome, secreting adenomas and carcinomas, and adrenal incidentalomas. All had impaired dexamethasone suppression tests. Overt CS (n = 25) was diagnosed in front of specific symptoms, a mean UFC (>1.5 ULN) and increased midnight serum cortisol or salivary cortisol. Mild CS (n = 23) was diagnosed in patients lacking specific symptoms and displaying at least one additional biological abnormality including mildly increased UFC (≤1.5 ULN), increased midnight serum cortisol or salivary cortisol and supp ressed plasma ACTH in patients with adrenal tumours. In this study, 84 healthy subjects and obese patients served as controls. Results: HF and HE showed roughly similar performance in overt CS (92 a nd 100% sensitivity, 91 and 99% specificity, respectively). HF and HE were lower in mild CS but higher than in controls (P < 0.01). HE was correlated with midnight serum cortisol (P < 0.02) and volume of adrenal incidentalomas (P < 0.04) but not with UFC. HF and HE had 59% and 68% sensitivity, and 79 and 94% specificity, respectively, for the diagnosis of mild CS. Contrary to UFC, both HF and HE were in the range of overt CS in 11/23 patients with mild CS. Patients with mild CS and increased HE required more antihypertensive treatments and showed worser lipid profiles than patients with normal HE. Conclusions: HF and HE measurement performed better in overt than in mild CS but is a useful adjunct to diagnose mild CS and to identify adrenocortical incidentalomas responsible for excessive cortisol exposure. [ABSTRACT FROM AUTHOR]

Objective: Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP. Design and methods: This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years. Results: In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance. Conclusion: These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms. [ABSTRACT FROM AUTHOR]

Non-classic congenital adrenal hyperplasia (NCAH) is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline 17-hydroxyprogesterone measurement may be used for screening, but 17-hydroxyprogesterone measurement after ACTH stimulation is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOS-like picture and fertility issues. Many men with NCAH never seek medical attention and escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time, including fertility issues. Long-term treatment with glucocorticoids will improve the androgen symptoms but may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. The glucocorticoid doses should be kept low. However, complications seen in NCAH, assumed to be caused by the glucocorticoid treatment, may also be associated with long-term androgen exposure. Oral contraceptive pills are a common treatment option for young females with NCAH. Regular clinical monitoring to improve the clinical outcome is recommended. It is important to acknowledge that glucocorticoid treatment will lead to secondary cortisol insufficiency and the need for stress dosing. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted. [ABSTRACT FROM AUTHOR]

The strategy for diagnosis of primary aldosteronism (PA) in the hypertensive population includes firstly a screening step, based on the measurement of plasma aldosterone-to-renin ratio (ARR), a test which must have high sensitivity, and secondly a confirmatory step based on the demonstration of e xcessive aldosterone production independent of the renin-angiotensin-aldosterone system (RAAS) activity. The high proportion of false-positive ARR results and conversely of actual PA without a persistent elevation in baseline plasma aldosterone concentration necessitates the addition of a confirmatory step in the work-up of PA diagnosis. The present review focuses on the description of the different dynamic tests available for demonstrating autonomy of aldosterone secretion, on the performance and limitations of confirmatory tests and on possible strategies for PA diagnosis which may either include or avoid the confirmatory step for PA diagnosis. Large prospective studies co mparing different strategies with and without dynamic testing are mandatory to delineate clearly the role and limits of confirmatory tests in the work-up of PA. [ABSTRACT FROM AUTHOR]

While the ACTH1-24 test has some well-documented shortcomings, it is the most wid ely used test to diagnose primary and secondary adrenal insufficiency. However, this synthetic ACTH preparation is not readily available in some countries. Research from India has demonstrated that using a lo ng-acting porcine sequence ACTH has similar diagnostic performance to ACTH1-24 at around 25% of the cost. This may allow access to a robust t est for adrenal insufficiency to developing countries and potentially all ow thousands of patients to be identified and appropriately treated. [ABSTRACT FROM AUTHOR]

Objective: Primary aldosteronism (PA) is the most common endocrine form of arterial hypertension. The German Conn's Registry's purpose is to improve treatment outcomes of PA. We assessed whether key clinical, biochemical and epidemiological characteristics of newly diagnosed PA cases have changed over time, potentially indicating a different screening and referral practice in Germany evolving from 2008 to 2016. Design: The German Conn's Registry is a multicenter database prospectively analyzing morbidity and long-term outcome of patients with PA. Methods: Phenotypic changes between three year periods were calculated using Mann--Whitney U tests and Kruskal--Wallis tests for independent variables. Results: Over three time periods from 2008 to 2016, we noted a relative decrease of unilateral PA cases (67 vs 43%). Signifcantly more females were diagnosed with PA (33 vs 43%). Median daily defned drug doses decreased (3.1 vs 2.0) in the presence of unchanged SBP (150 vs 150 mmHg), plasma aldosterone (199 vs 173 ng/L) and PRC (3.2 vs 3.2 U/L). Median ARR values decreased (70 vs 47 ng/U) and median potassium levels at diagnosis (3.5 vs 3.7 mmol/L) increased as the percentage of normokalemic patients (25 vs 41%), indicating milder forms of PA. Conclusions: Our results are in accordance with an increased screening intensity for PA. We identifed a trend toward diagnosing milder forms, increasingly more females and less unilateral cases of PA. [ABSTRACT FROM AUTHOR]

Measuring total testosterone level is the first-line approach in assessing androgen excess in women. The main pitfalls in measuring testosterone relate to its low concentration and to the structural similarity between circulating androgens and testosterone, requiring accurate techniques with high specificity and sensitivity. These goals can be achieved by immunoassay using a specific anti-testosterone monoclonal antibody, ideally after an extraction step. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) will be commonly used for measuring testosterone, providing optimal accuracy with a low limit of detection. Yet, the pitfalls of these two techniques are well identified and must be recognized and systematically addressed. In general, laboratories using direct testosterone immunoassay and mass spectrometry need to operate within a quality framework and be actively engaged in external quality control processes and standardization, so as to ensure appropriate interpretation irrespective of the particular laboratory. Circulating testosterone is strongly bound to sex-hormone-binding globulin (SHBG), and SHBG levels are typically low in overweight hyperandrogenic patients. Thus, low SHBG may decrease circulating testosterone to normal values, which will mask androgen excess status. One way to avoid this pitfall, awaiting direct free testosterone assays that are yet to be developed, is to measure SHBG and calculate free testosterone. A few other pitfalls will be discussed in this review, including those of adrenal androgen exploration, with the aim of helping clinicians to better handle laboratory investigation of androgen excess disorders in women. [ABSTRACT FROM AUTHOR]

Objective: To investigate a probable impact of seasons on the diagnosis of GDM, as well as the specific effect of the environmental temperature on the diagnosis of this clinical entity. Patients and methods: Two observational studies, one retrospective and one prospective, were conducted in a referral center. Study A included retrospectively 7618 pregnant women who underwent a 3-h 100 g OGTT during the 3rd trimester of gestation. Study B prospectively included 768 pregnant women tested in the 3rd trimester of gestation with a 75 g OGTT. Temperature was recorded every day at 09:00 h. Results: Retrospective Study A: GDM prevalence differed significantly by season: winter = 28.1%, summer = 39.2%, spring = 32.4% and autumn = 32.4% (P < 0.0001). The odds ratio for being diagnosed with GDM was much higher during summer 1.65 (95% CI: 1.43-1.90), with spring and autumn following with 1.23 (95% CI: 1.08-1.39) compared to winter. Glucose levels during OGTT were measured: significantly increased blood glucose values were observed at 60, 120 and 180 min in summer, which remained significant after adjustment for age, gestational age, BMI, weight gain during pregnancy and blood pressure. Prospective Study B: At temperatures above 25°C, the average glucose 60-min and 120-min levels were increased. The relative risk for abnormal glucose values at 60 min, when the environmental temperature increased over 25°C, was 2.2 (1.5-3.3). Conclusions: GDM prevalence in Greece presents seasonal variation, with higher risk during summer due to post glucose load level variations. These variations could be attributed to differences in environmental temperature. [ABSTRACT FROM AUTHOR]

Pheochromocytoma in pregnancy is extremely rare. Early recognition is crucial as antepartum diagnosis can largely decrease maternal and fetal mortality rates. As symptoms of pheochromocytoma are rather similar to those of other far more common causes of hypertension during pregnancy, timely diagnosis is a challenge. In pregnant patients, similar to non-pregnant patients, increased plasma and/or 24-h urine (nor)metanephrine concentrations most reliably confirm the diagnosis of pheochromocytoma. MRI and ultrasound are the only imaging modalities that can be used safely during pregnancy to localize the tumor. During pregnancy, pretreatment consists of alpha blockade as usual. However, dosing of α-adrenergic receptor blockers during pregnancy is a challenge as hypertension must be treated while preserving adequate uteroplacental circulation. When the diagnosis is made within the first 24 weeks of pregnancy, it is generally recommended to remove the tumor in the second trimester, while resection is generally postponed till after delivery when the diagnosis is made in the third trimester and medical pretreatment is sufficient. Both during and after pregnancy, laparoscopic surgery is the preferred approach for resection of the tumor. There is no consensus in literature about the preferred route and timing of delivery. Therefore, in our opinion, decisions should be made on an individual basis by an experienced and dedicated multidisciplinary team. Over the last decades, maternal and fetal prognosis has improved considerably. Further increasing awareness of this rare diagnosis and treatment of these patients by a dedicated team in a tertiary referral hospital are critical factors for optimal maternal and fetal outcome. [ABSTRACT FROM AUTHOR]

Objective: To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; NCT00960128) between 2006 and 2016. Design: This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n = 425/61/316/119), France (n = 1404/188/970/206), Germany (n = 2603/351/1387/411) and the UK (n = 259/60/87/35). Methods: GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications. Results: In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown (P < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%). Conclusions: GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations. [ABSTRACT FROM AUTHOR]

Primary hyperparathyroidism (PHPT) is one of the most frequent endocrine diseases worldwide. Surgery is the only potentially curable option for patients with this disorder, even though in asymptomatic patients 50 years of age or older without end organ complications, a conservative treatment may be a possible alternative. Bilateral neck exploration under general anaesthesia has been the standard for the definitive treatment. However, significant improvements in preoperative imaging, together with the implementation of rapid parathyroid hormone determination, have determined an increased implementation of focused, minimally invasive surgical approach. Surgeons prefer to have a localization study before an operation (both in the classical scenario and in the minimally invasive procedure). They are not satisfied by having been referred a patient with just a biochemical diagnosis of PHPT. Imaging studies must not be utilized to make the diagnosis of PHPT. They should be obtained to both assist in determining disease etiology and to guide operative procedures together with the nuclear medicine doctor and, most importantly, with the surgeon. On the contrary, apart from minimally invasive procedures in which localization procedures are an obligate choice, some surgeons believe that literature on parathyroidectomy over the past two decades reveals a bias towards localization. Therefore, surgical expertise is more important than the search for abnormal parathyroid glands. [ABSTRACT FROM AUTHOR]

Objective: Acromegaly is frequently associated with altered facial appearance at the time of diagnosis. Furthermore, acromegaly is also associated with adverse psychological outcomes. We conducted a single-centre, cross-sectional study comparing patients with growth hormone vs non-functioning pituitary adenomas (NFA) to assess the association between morphometric changes and psychological outcomes and illness perception of patients with acromegaly. Methods: A seven-step scale was developed to grade morphometric changes based on facial photographs. In addition, all patients were asked to draw an image of their own body and an image of what they considered to be an average healthy body and complete seven psychological questionnaires. We recruited 55 consecutive patients in each of the two groups who had undergone surgery with or without radiation therapy (RT). Results: Our data showed that the clinician-rated morphometric scale was highly reliable in assessing facial changes, with 93/99 (Intraclass correlation coefficient (ICC)=0.95 (0.93-0.97)) graded as similar by independent raters. The mean (S.D.) grading for Acro and NFA patients on the clinician-rated morphometric scale were 3.5 (1.3) and 0.41 (0.35) respectively (P<0.0001). A higher clinician-rated morphometric score was also predictive of a poorer score on the drawing test. Conclusions: Our study demonstrates a correlation between physical changes associated with acromegaly and poor psychological outcomes, whereas no such correlation existed with modes of therapy, disease control status, RT, malignancy, initial or recent GH/IGF1 or secondary hormonal deficiency. Our data support the utility of the morphometric scale as a clinical tool for grading facial changes. [ABSTRACT FROM AUTHOR]

Context and objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic- pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations. Design: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients. Results: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01). Conclusions: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis. [ABSTRACT FROM AUTHOR]

Context: Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo-pituitary- adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 μg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost. Methods: We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting. Results: In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≤348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary. Conclusion: Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function. [ABSTRACT FROM AUTHOR]

Cushing's syndrome (CS) and acromegaly are endocrine diseases that are currently diagnosed with a delay of several years from disease onset. Novel diagnostic approaches and increased awareness among physicians are needed. Face classification technology has recently been introduced as a promising diagnostic tool for CS and acromegaly in pilot studies. It has also been used to classify various genetic syndromes using regular facial photographs. The authors provide a basic explanation of the technology, review available literature regarding its use in a medical setting, and discuss possible future developments. The method the authors have employed in previous studies uses standardized frontal and profile facial photographs for classification. Image analysis is based on applying mathematical functions evaluating geometry and image texture to a grid of nodes semi-automatically placed on relevant facial structures, yielding a binary classification result. Ongoing research focuses on improving diagnostic algorithms of this method and bringing it closer to clinical use. Regarding future perspectives, the authors propose an online interface that facilitates submission of patient data for analysis and retrieval of results as a possible model for clinical application. [ABSTRACT FROM AUTHOR]

Objective The prevalence of type 2 diabetes is increased in polycystic ovary syndrome (PCOS), but the prevalence of other diseases is not clarified. We aimed to investigate morbidity and medicine prescriptions in PCOS. Design A National Register-based study. Methods: Patients with PCOS (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital (OUH)) and one control population. Premenopausal women with PCOS underwent clinical and biochemical examination (PCOS OUH, n=1217). PCOS Denmark (n=19 199) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (n=57483). Main outcome measures Diagnosis codes and filled prescriptions. Results: The mean (range) age of the PCOS Denmark group and controls was 30.6 (12â€"60) years. Patients in PCOS Denmark had higher Charlson index, higher prevalence of diabetes, dyslipidemia, and hypertension than controls. PCOS was associated with a two times increased risk of stroke and thrombosis, whereas the risk of other cardiovascular diseases was not increased. Thyroid disease, asthma, migraine, and depression were more prevalent in PCOS Denmark vs controls, whereas fractures were rarer. Infertility was increased in patients compared with controls, but the mean number of births was higher in PCOS. Medicine prescriptions within all diagnosis areas were significantly higher in PCOS patients than in controls. In PCOS OUH, polycystic ovaries (PCO) and irregular menses were associated with a more adverse metabolic risk profile, but individual Rotterdam criteria were not associated with cardiometabolic diagnoses. Conclusion: Cardiometabolic and psychiatric morbidity were significantly increased in a Danish population with PCOS. Medical diseases are frequent also in young patients with PCOS. [ABSTRACT FROM AUTHOR]

Objective: Pediatric patients with sellar masses such as craniopharyngioma (CP) or cyst of Rathke's pouch (CRP) frequently suffer disease- and treatment-related sequelae. We analyzed the impact and prognostic relevance of initial hydrocephalus (HY) and hypothalamic involvement (HI) on long-term survival and functional capacity (FC) in children with CP or CRP. Subjects and methods: Using retrospective analysis of patient records, presence of initial HY or HI was assessed in 177 pediatric patients (163 CP and 14 CRP). Twenty-year overall survival (OS) and progression-free survival (PFS), FC, and BMI were analyzed with regard to initial HY, degree of resection, or HI. Results: Of the 177 patients, 105 patients (103/163 CP and 2/14 CRP) presented with initial HYand 96 presented with HI. HYat diagnosis was associated (PZ0.000) with papilledema, neurological deficits, and higher BMI at diagnosis and during followup. OS, PFS, and FC were not affected by HY at initial diagnosis. HI at diagnosis (96/177) had major negative impact on longterm prognosis. Sellar masses with HI were associated with lower OS (0.84G0.04; PZ0.021), lower FC (PZ0.003), and higher BMI at diagnosis and last follow-up (PZ0.000) when compared with sellar masses without HI (OS: 0.94G0.05). PFS was not affected by HI or degree of resection. Conclusions: Initial HY has no impact on outcome in patients with sellar masses. OS and FC are impaired in survivors presenting with initial HI. PFS is not affected by HY, HI, or degree of resection. Accordingly, gross-total resection is not recommended in sellar masses with initial HI to prevent further hypothalamic damage. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is the most common cause of secondary hypertension. In this review, we discuss the diagnosis and management of PA during pregnancy based on the literature. As aldosterone and renin are physiologically increased during pregnancy and confirmation tests are not recommended, the diagnosis of PA during pregnancy relies on a repeatedly suppressed plasma renin level. Mineralocorticoid receptor antagonists (MRAs) are the most effective drugs to treat hypertension and hypokalemia in patients with PA. However, spironolactone (FDA pregnancy category C) might lead to undervirilization of male infants due to the anti-androgenic effects. Although data in the literature are very limited, treatment with spironolactone is not recommended. Eplerenone (FDA pregnancy category B) is a selective MRA without anti-androgenic potential. If MRA treatment is required in pregnancy, eplerenone appears to be a safe and effective alternative, although symptomatic treatment with approved antihypertensive drugs and supplementation with potassium is the first choice. In case of aldosterone-producing adenoma, laparoscopic adrenalectomy is a therapeutic option in the second trimester of pregnancy. [ABSTRACT FROM AUTHOR]

Objective: The role of cortisol in the prediction of mortality risk in critical illness is controversial in the literature. The aim of this study was to evaluate the prognostic value of cortisol concentrations in a mixed population of critically ill patients in medical emergencies. Design: In this prospective, observational study, measurement of total (TC) and free cortisol (FC) levels was made in the serum samples of 69 critically ill patients (39 males and 30 females, median age of 74 years) at admission (0 h) and 6, 24, 48, and 96 h after admission. Methods: Cortisol levels were determined using HPLC coupled high-resolution ESI-TOF mass spectrometry. The severity of disease was calculated by prognostic scores. Statistical analyses were performed using the SPSS 22.0 software. Results: The range of TC varied between 49.9 and 8797.8 nmol/l, FC between 0.4 and 759.9 nmol/l. The levels of FCat0, 6, 24, and 48 h and TC at 0, 6 h were significantly elevated in non-survivors and correlated with the predicted mortality. The prognostic value of these cortisol levels was comparable with the routinely used mortality scores. In predictive models, FC at 6, 24, and 48 h proved to be an independent determinant of mortality. Conclusions: The predictive values of FC in the first 2 days after admission and TC within 6 h are comparable with the complex, routinely used mortality scores in evaluating the prognosis of critically ill patients. The cortisol response probably reflects the severity of disease. [ABSTRACT FROM AUTHOR]

Context: Cutoff limits of GH stimulation tests to diagnose GH deficiency (GHD) in children and adolescents are not sufficiently validated by clinical studies due to discrepancies in the performance of GH immunoassays and lack of available study populations. Objective: We aimed to establish new cutoff limits for GH stimulation tests based on clinical evidence and compared these immunoassay-based values with an antibody-independent mass spectrometric method. Design and setting: In a retrospective study, GH cutoff limits for eight different immunoassays and isotope dilution mass spectrometry (ID-MS) were calculated from hGH peak concentrations of short-statured children with and without GHD. Patients: We compared the serum GH peak concentrations at GH stimulation test of 52 short-statured children and adolescents, who have normal GH secretion at initial workup and normal growth in the follow-up, with the serum GH peak concentrations of 44 GHD patients in the same age range, in order to optimize the cutoff limit calculation. Results: Discriminant analysis of re-measured GH led to a new cutoff limit of 7.09 mg/l using the iSYS assay (IDS) and the limits for the other seven hGH assays varied between 4.32 and 7.77 mg/l. For ID-MS, cutoffs of 5.48 mg/l (22k GH) and 7.43 mg/l (total GH) were ascertained. Conclusion: The establishment of method-specific clinical evidence-based GH cutoff limits is of importance to ensure adequate clinical diagnosis and treatment of children and adolescents with GHD. ID-MS may become an important tool for providing both reliable and sustainable SI traceability of GH measurements in the future. [ABSTRACT FROM AUTHOR]

Hyponatraemia, defined as a serum sodium concentration !135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice. [ABSTRACT FROM AUTHOR]

Objective: To determine the diagnostic value of a ghrelin test in the diagnosis of GH deficiency (GHD) shortly after aneurysmal subarachnoid hemorrhage (SAH). Design: Prospective single-center observational cohort study. Methods: A ghrelin test was assessed after the acute phase of SAH and a GH-releasing hormone (GHRH)-arginine test 6 months post SAH. Primary outcome was the diagnostic value of a ghrelin test compared with the GHRH-arginine test in the diagnosis of GHD. The secondary outcome was to assess the safety of the ghrelin test, including patients' comfort, adverse events, and idiosyncratic reactions. Results: Forty-three survivors of SAH were included (15 males, 35%, mean age 56.6±11.7). Six out of 43 (14%) SAH survivors were diagnosed with GHD by GHRH-arginine test. In GHD subjects, median GH peak during ghrelin test was significantly lower than that of non-GHD subjects (5.4 vs 16.6, P=0.002). Receiver operating characteristics analysis showed an area under the curve of 0.869. A cutoff limit of a GH peak of 15 μg/l corresponded with a sensitivity of 100% and a false-positive rate of 40%. No adverse events or idiosyncratic reactions were observed in subjects undergoing a ghrelin test, except for one subject who reported flushing shortly after ghrelin infusion. Conclusion: Owing to its convenience, validity, and safety, the ghrelin test might be a valuable GH provocative test, especially in the early phase of SAH. [ABSTRACT FROM AUTHOR]

Background: Little is known about Sheehan's syndrome (SS), even though it is believed that its incidence is low. The aims of this study were to determine the clinical features and diagnostic delay of SS and to ascertain whether early signs could have allowed earlier diagnosis. Subjects and methods: All patients with SS diagnosed in reference units in the southeast of France between 1980 and 2011 were recruited for this study. Data on obstetrical history, clinical symptoms suggestive of hypopituitarism, early signs, hormone analysis, and magnetic resonance imaging were collected. Results: Of the 40 women found to have SS, 39 were studied. Mean delay in the diagnosis of SS was 9±9.7 years. We found that four of the 35 assessable patients were diagnosed with agalactia, 16 of the 29 assessable oneswithamenorrhea,19 of the 39with hypothyroidism, eightwith acute adrenal insufficiency, and 15 with asthenia. Among the patients for whom there was a diagnostic delay of more than 1 year (n=28), seven had headaches during the postpartum period, all assessable patients had agalactia, six of the 22 assessable ones had amenorrhea, seven of 28 had hypothyroidism, and 12 of 28 had asthenia. Conclusion: Most signs of SS are aspecific and classical signs such as agalactia and amenorrhea are often difficult to detect, which can explain the long diagnostic delay. We suggest that allwomen failing to lactate after postpartum hemorrhage (PPH) should be evaluated by measuring prolactin levels and women with signs suchas amenorrhea and asthenia, even several years after PPH, should undergo ablood test including assessment of thyroxine, TSH, 0800 h ACTH-cortisol, and IGF1 levels. [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between family history of diabetes and frequency of diabetic ketoacidosis (DKA) at diagnosis and to analyze the possible association between HLA genotypes and DKA. Design and methods: We recruited 510 children and adolescents aged < 17 years with type 1 diabetes (T1D) and collected information on first-degree relative (FDR) history of T1D. DKA and severe DKA were defined as blood pH < 7.30 and < 7.10 at diabetes onset respectively. Risk categories for developing T1D were determined according to various HLA DQA1-DQB1 haplotype combination genotypes. Results: The frequency of DKA and severe DKA at diagnosis was 34.7 and 7.2% respectively. DKA was more frequent in younger patients (< 2 years (60.0%; P< 0.001)) and occurred less in children with at least one FDR affected by T1D (13.0 vs 37.4%, P<0.001). The logistic regression showed that age at diagnosis (< 2 years) and increased HLA-associated risk genotypes were independent predictors of DKA (P<0.01, odds ratio (OR)=1.068 (95% confidence interval (CI) 1.021-1.117); P< 0.05, OR=1.606 (95% CI 1.034-2.475)). Introducing the presence of T1D in at least one FDR in the logistic model, a significant association between DKA and age at diagnosis (< 2 years; P< 0.01, OR=1.072 (95% CI 1.024-1.123)) and absence of FDRs with T1D (P=0.001, OR=4.287 (95% CI 1.770- 10.383)) was found, but no more with increased HLA-associated risk genotype (P=0.06, OR=1.550 (95% CI 0.992-2.423)). Conclusions: HLA-associated high-risk genotypes are associated with a high chance of presenting DKA at diabetes onset. However, having at least one FDR with T1D reduced the risk of DKA regardless of HLA genotype. [ABSTRACT FROM AUTHOR]

Design: To evaluate the efficacy of the main tools in the diagnostic localization of hyperfunctioning parathyroids (HP) in primary hyperparathyroidism (pHPT) with concomitant thyroid diseases. Methods: Forty-three patients with pHPT associated with nodular goiter (NG, n=32) and/or autoimmune thyroid diseases (AITDs, n=11) for a total of 63 neck lesions were considered. Sixteen patients displaying HP (16 lesions), unequivocally localized by sestaMIBI scintigraphy (MIBI) and neck ultrasound (US) (group I), were compared with 27 patients (47 neck lesions) displaying equivocal parathyroid localization (group II). In all cases, neck US, MIBI scan, cytology, and parathyroid hormone assay in fine-needle aspiration washout fluid (FNA-PTH) were performed. All patients finally underwent surgery. Results: According to histological examination, high FNA-PTH values (>103 pg/ml) correctly identified all HP in both groups of patients (100% of sensitivity and specificity). Both MIBI and US correctly identified all HP only in group I patients; in contrast, four patterns of mismatch between these techniques were observed in group II patients, leading to low diagnostic performances of neck US (71.4% sensitivity and 78.9% specificity) and of MIBI scan (35.7% sensitivity and 42.1% specificity). The latter was due to both false-negative (mainly in AITD) and false-positive (mainly in NG) scan images. Conclusions: Coexistent thyroid diseases are responsible for mismatch between MIBI and US images resulting in equivocal HP localization. In these cases, FNA-PTH resulted in the most accurate tool to identify HP. However, although safe, it should be advised only to patients with uncertain HP localization. [ABSTRACT FROM AUTHOR]

Objective: Insulin tolerance test (ITT) is the test of reference for the diagnosis of adult GH deficiency (GHD), although GHRH in combination with arginine (ARG) or GH secretagogues are considered equally reliable tests. Testing with GH secretagogue alone is, anyway, a potent stimulus exploring the integrity of hypothalamic pathways controlling somatotropic function. We therefore aimed to determine the diagnostic reliability of testing with ghrelin, the natural GH secretagogue. Methods: We studied the GH response (every 15 min from -15 to +120 min) to acylated ghrelin (1 μg/kg i.v. at 0 min) in 78 patients with a history of pituitary disease (49 male, 29 female; age (mean±S.D.): 52.1±18.7 years; BMI: 26.7±5.3 kg/m²). The lack of GH response to GHRH+ARG and/or ITT was considered the gold standard for the diagnosis of GHD. The best GH cut-off to ghrelin test, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using the receiver-operating characteristic curve analysis. Results: The best GH cut-off to ghrelin test was 7.3 μg/l in lean subjects (SE 88.2%, SP 90.9%), 2.9 μg/l in overweight subjects (SE 92.6%, SP 100%) and 0.6 μg/l in obese subjects (SE 50%, SP 100%). The diagnostic accuracy was 89.3, 94.1 and 62.5% respectively. Conclusions: Our data show that testing with acylated ghrelin represents a reliable diagnostic tool for the diagnosis of adult GHD, in lean and overweight subjects, if appropriate cut-off limits are assumed. Obesity strongly reduces GH response to ghrelin, GH weight-related cut-off limit and diagnostic reliability of the test. [ABSTRACT FROM AUTHOR]

Objective: Thyroid proteomics is a new direction in thyroid cancer research aiming at etiological understanding and biomarker identification for improved diagnosis. Methods: Two-dimensional electrophoresis was applied to cytosolic protein extracts from frozen thyroid samples (ten follicular adenomas, nine follicular carcinomas, ten papillary carcinomas, and ten reference thyroids). Spots with differential expression were revealed by image and multivariate statistical analyses, and identified by mass spectrometry. Results: Aset of 25 protein spots significant for discriminating between the sample groupswas identified. Proteins identified for nine of these spots were studied further including 14-3-3 protein beta/alpha, epsilon, and zeta/delta, peroxiredoxin 6, selenium-binding protein 1, protein disulfide-isomerase precursor, annexin A5 (ANXA5), tubulin alpha-1B chain, and a1-antitrypsin precursor. This subset of protein spots carried the same predictive power in differentiating between follicular carcinoma and adenoma or between follicular and papillary carcinoma, as compared with the larger set of 25 spots. Protein expression in the sample groups was demonstrated by western blot analyses. For ANXA5 and the 14-3-3 proteins, expression in tumor cell cytoplasm was demonstrated by immunohistochemistry both in the sample groups and an independent series of papillary thyroid carcinomas. Conclusion: The proteins identified confirm previous findings in thyroid proteomics, and suggest additional proteins as dysregulated in thyroid tumors. [ABSTRACT FROM AUTHOR]

Context: The diagnostic accuracy of tests used to diagnose GH deficiency (GHD) in adults is unclear. Objective: We conducted a systematic review and meta-analysis of studies that provided data on the available diagnostic tests. Data sources: We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Sciences, and Scopus) through April 2011. Study selection: Review of reference lists and contact with experts identified additional candidate studies. Reviewers, working independently and in duplicate, determined study eligibility. Data extraction: Reviewers, working independently and in duplicate, determined the methodological quality of studies and collected descriptive, quality, and outcome data. Data synthesis: Twenty-three studies provided diagnostic accuracy data; none provided patient outcome data. Studies had fair methodological quality, used several reference standards, and included over 1100 patients. Several tests based on direct or indirect stimulation of GH release were associated with good diagnostic accuracy, although most were assessed in one or two studies decreasing the strength of inference due to small sample size. Serum levels of GH or IGF1 had low diagnostic accuracy. Pooled sensitivity and specificity of the two most commonly used stimulation tests were found to be 95 and 89% for the insulin tolerance test and 73 and 81% for the GHRHCarginine test respectively. Metaanalytic estimates for accuracy were associated with substantial heterogeneity. Conclusion: Several tests with reasonable diagnostic accuracy are available for the diagnosis of GHD in adults. The supporting evidence, however, is at high risk of bias (due to heterogeneity, methodological limitations, and imprecision). [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. DESIGN: A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT: Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. MANAGEMENT: Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Pretibial myxedema (PM) is a manifestation of Graves' disease (GD). Currently, its diagnosis depends on physicians' observation and biopsy. No satisfactory, objective, and non-invasive tool is available to record and investigate lesions. Digital infrared thermal imaging (DITI) detects surface temperature, and sonography reflects composition changes in soft tissue. This study was aimed to observe changes in DITI and sonography in PM, and to evaluate their clinical usefulness. METHODS: Nineteen GD patients with PM, 22 GD patients with mild diffuse non-pitting edema over lower legs, 46 GD patients with normal appearance of lower legs, and 14 normal volunteers were recruited for observation with DITI; 8, 21, 21, and 11 of them respectively also received soft tissue sonography for investigating the pathogenesis of DITI change. RESULTS: Lower leg temperatures of normal volunteers decreased gradually from proximal to distal parts. In all 19 patients with PM, DITI showed abnormally low focal temperatures over the lesions. In GD patients with mild diffuse non-pitting edema and GD patients with normal appearance of lower legs, DITI showed abnormally low focal temperature in 90.9 and 65.2% of the patients respectively. Areas of clinically visible PM and low focal temperature detected by DITI were sonographically characterized with increased skin thickness, hypoechoic substance deposition in the cutaneous tissue, and blurred boundary lines between dermis and subcutaneous tissue. TSH receptor antibody level correlated positively and significantly with skin thickness change and adjusted temperature difference between the center of temperature defect and the surrounding skin (P=0.046 and 0.033 respectively). CONCLUSIONS: By using DITI and sonography, we detected characteristic changes in PM. These techniques are helpful in recording and may be useful tools to detect early changes of PM. [ABSTRACT FROM AUTHOR]

The article reports on a study to investigate the prevalence of hepatocyte nuclear factor 4 alpha (HNF4A) mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). The study included 220 patients with HH responsive to diazoxide, who underwent sequencing of the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes and were diagnosed with hyperinsulinism (HI). The study reveals that HNF4A mutations are one of the most common cause of diazoxide responsive HH.

OBJECTIVE: To examine the factors causing inadequate cortisol responses to the 1 µg ACTH stimulation test. DESIGN: Random test assignment (by age and gender) at 0800 or 1600 h. METHODS: We recruited 20 healthy adults to each of the three age groups (55 years; half females in each group). ACTH stimulation tests were performed in an outpatient clinic at the NIH Clinical Research Center. Plasma cortisol was measured just before, and 30 and 60 min after the administration of 1 µg ACTH (1–24). The ACTH concentration in diluted and administered solutions was measured. RESULTS: Twenty-five volunteers (19 at 1600 h) had a subnormal cortisol response (peak cortisol 10.4–17.5 µg/dl), using a criterion <18 µg/dl (497 nmol/l), for a specificity of 58% (confidence interval (CI) 45–71%). Afternoon testing had a significant impact on failure rates (odds ratio 6.98, CI 2.17–22.43), while gender and age did not. The stock solution contained 1 µg ACTH, but after administration through tubing it contained only 0.5–0.8 µg. CONCLUSIONS: The high rate of abnormal results, especially in the afternoon, and loss of ACTH through tubing suggest that morning testing and minimal tubing should be adopted to avoid an inappropriate diagnosis of adrenal insufficiency. Earlier time points and standardized protocols would facilitate comparison of studies. [ABSTRACT FROM AUTHOR]

Previous work has examined potential links between the etiology of GH deficiency (GHD) and the baseline characteristics of the patients including biochemical and psychometric parameters. Using an update of the KIMS pharmaco-epidemiological database (Pfizer International Metabolic Database), we addressed the question how well such results can be generalized and whether regional differences may play a role. From 30 different countries, 13 167 GH-deficient patients were included in KIMS at the data close in December 2008. In order to explore country-specific differences of baseline characteristics documented in KIMS, separate analyses of baseline characteristics of adult-onset GHD patients (n=7708) were performed for the six largest contributing European countries and the United States. This analysis revealed striking regional variations in the pathogenesis of the disease, clinical characteristics such as body mass index, and in the classical features of the metabolic syndrome such as blood pressure or lipid status between countries. Moreover, the approach to endocrine function testing was widely different between countries, as well as the distribution of etiologies of GHD. These data suggest that a complex relation between biochemical and clinical signs of GHD exists, and that the spectrum of adult GHD syndrome is influenced by regional diagnostic and clinical particularities. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In patients with adrenal incidentalomas, hormonally active masses need to be considered, particularly cortisol-producing adenomas (CPA), aldosterone-producing adenomas, and pheochromocytomas. The screening for hypercortisolism relies on confirming excess cortisol secretion and insufficient suppression after dexamethasone. Because of its high correlation with free cortisol and its stress-free collection, salivary cortisol (SaC) may offer advantages over serum cortisol (SeC). We evaluated the value of SaC and SeC for the diagnosis of CPA. DESIGN: Comparative study between 2001 and 2006. METHODS: Thirty-eight patients with confirmed CPA were compared with 18 healthy subjects as well as 48 control patients suffering from aldosterone-producing adenomas (n=13), pheochromocytomas (n=16), or nonfunctioning adenomas (n=19). Sampling of saliva and serum was performed at 2300 and at 0800 h following low-dose dexamethasone suppression. Receiver operating characteristics analysis was used to calculate thresholds with at least 95% sensitivity for CPA. RESULTS: Regarding the cutoffs for late-night cortisol, SaC (4.8 nmol/l, sensitivity 97%, specificity 69%) was slightly more specific than SeC (115 nmol/l, sensitivity 97%, specificity 63%). In contrast, the cutoff for dexamethasone-suppressed SaC (3.7 nmol/l, sensitivity 97%, specificity 83%) was slightly less specific than SeC (94 nmol/l, sensitivity 97%, specificity 88%). However, the latter cutoffs demonstrated greater specificity when compared with the cutoffs for late-night cortisol. CONCLUSION: The diagnostic accuracy of SaC is as good as SeC. Owing to its higher specificity, dexamethasone-suppressed cortisol is preferable to late-night cortisol when screening for Cushing's syndrome in patients with adrenal incidentalomas. [ABSTRACT FROM AUTHOR]

Background: A low serum total IGF1 is considered as a diagnostic indicator of GH deficiency (GHD) in the presence of hypopituitarism. Introduction of IRMA and chemiluminescent immunometric assay (CLIA) IGF1 immunoassays has introduced endogenous antibodies as a new source of interference. In general, this goes unnoticed and might lead to unnecessary diagnostic and therapeutic interventions. Case: A 56-year-old man was referred with a decline in physical performance, unexplained osteopenia, and weight loss of 3 kg over the past 8 months. Although clinical signs and symptoms were unremarkable, laboratory results pointed to secondary hypothyroidism and secondary hypogonadism. In addition, the serum total IGF1 level (CLIA; Siemens Medical Solutions Diagnostics) was in the low normal range. Two GH stimulation tests were performed, but these tests did not support the diagnosis GHD. Moreover, IGF1 bioactivity measured by the kinase receptor activation assay was normal. Interference of heterophilic antibodies was considered. After pretreatment with specific heterophilic blocking tubes that contain blocking reagents to eliminate heterophilic antibodies, serum-free thyroxine, testosterone, and IGF1 levels turned out to be normal. Conclusion: To the best of our knowledge,we here describe the first case in the literature of a patient with low serum total IGF1 levels due to interference from heterophilic antibodies in the used IGF1 immunoassay.When confronted with low-IGF1 levels that do not fit the clinical picture, interference of heterophilic antibodies should be considered in the differential diagnosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: 17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns. DESIGN: GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography–tandem mass spectrometry method (LC–MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody. RESULTS: There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC–MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S- and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited. CONCLUSIONS: Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated. [ABSTRACT FROM AUTHOR]