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Hershel Raff, Eric P Cohen and James Findling

The diagnosis of endogenous hypercortisolism (Cushing syndrome) is one of the most difficult problems in endocrinology. The signs and symptoms of Cushing syndrome overlap with many common medical disorders such as obesity and the metabolic syndrome. Another challenge to establishing a diagnosis of neoplastic/pathologic endogenous hypercortisolism is that many common disorders such as alcoholism and depression may cause a state of non-neoplastic/physiologic hypercortisolism (formerly known as pseudo-Cushing syndrome) and may lead to similar clinical and biochemical findings.

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Mirjam Christ-Crain

Diabetes insipidus (DI), be it from central or nephrogenic origin, must be differentiated from secondary forms of hypotonic polyuria such as primary polydipsia. Differentiation is crucial since wrong treatment can have deleterious consequences. Since decades, the gold standard for differentiation has been the water deprivation test, which has limitations leading to an overall unsatisfying diagnostic accuracy. Furthermore, it is cumbersome for patients with a long test duration. Clinical signs and symptoms and MRI characteristics overlap between patients with DI and primary polydipsia. The direct test including vasopressin (AVP) measurement upon osmotic stimulation was meant to overcome these limitations, but failed to enter clinical practice mainly due to technical constraints of the AVP assay. Copeptin is secreted in equimolar amount to AVP but can easily be measured with a sandwich immunoassay. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation and has led to a ‘revival’ of the direct test in the differential diagnosis of DI. We have shown that a baseline copeptin, without prior thirsting, unequivocally identifies patients with nephrogenic DI. In contrast, for the differentiation between central DI and primary polydipsia, a stimulated copeptin level of 4.9 pmol/L upon hypertonic saline infusion differentiates these two entities with a high diagnostic accuracy and is superior to the water deprivation test. Close sodium monitoring during the test is a prerequisite. Further new test methods are currently evaluated and might provide an even simpler way of differential diagnosis in the future.

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Emilia Sbardella, Carlotta Pozza, Andrea M. Isidori and Ashley B. Grossman

Introduction: The transition age is the period between childhood to adulthood, it refers to a broad set of physical, cognitive and sociocultural modifications, arbitrarily defined as starting in late puberty and ending with full adult maturation. Pituitary disorders in adolescence represent a challenge that requires careful management during the transition to adult care.

Methods: Given the complexity of care of pituitary disorders in the transition age, we have reviewed the relevant medical literature focusing on aetiology, clinical manifestations, treatment strategies of GH deficiency (GHD), hypogonadotrophic hypogonadism (HH) in male and female adolescents, central hypothyroidism (CH), central adrenal insufficiency (CAI) and cranial diabetes insipidus (CDI) at this time. The objective of the present review is to provide an up-to-date evaluation of the transition period, to evaluate specific needs of adolescents with chronic pituitary disease in order to optimise their management.

Results: We provide an overview of current clinical management of GHD, HH, CH, CAI and CDI in the transition age.

Conclusions: Specific changes occur in pituitary function during the transition period. A holistic approach including discussion of patients’ concerns and emotional support should constitute a key component of managing pituitary disorders in adolescence. Special transition clinics where paediatric and adult endocrinologists work together should be increasingly created and strengthened to bridge care, to promote continuity and adherence to treatment, and to limit potential negative development, metabolic, skeletal and cardiovascular sequelae of discontinuity of care among adolescents with pituitary disorders.

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Peter Wolf, Johanna Mayr, Hannes Beiglböck, Paul Fellinger, Yvonne Winhofer, Marko Poglitsch, Alois Gessl, Alexandra Kautzky-Willer, Anton Luger and Michael Krebs

Background

In patients suffering from primary adrenal insufficiency (AI) mortality is increased despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, mainly due to an increased cardiovascular risk. Since activation of the renin–angiotensin–aldosterone system (RAAS) plays an important role in the modulation of cardiovascular risk factors, we performed in-depth characterization of the RAAS activity.

Methods

Eight patients with primary AI (female = 5; age: 56 ± 21 years; BMI: 22.8 ± 2 kg/m2; mean blood pressure: 140/83 mmHg; hydrocortisone dose: 21.9 ± 5 mg/day; fludrocortisone dose: 0.061 ± 0.03 mg/day) and eight matched healthy volunteers (female = 5; age: 52 ± 21 years; BMI: 25.2 ± 4 kg/m2; mean blood pressure:135/84 mmHg) were included in a cross-sectional case–control study. Angiotensin metabolite profiles (RAS-fingerprints) were performed by liquid chromatography mass spectrometry.

Results

In patients suffering from primary AI, RAAS activity was highly increased with elevated concentrations of renin concentration (P = 0.027), angiotensin (Ang) I (P = 0.022), Ang II (P = 0.032), Ang 1-7 and Ang 1-5. As expected, aldosterone was not detectable in the majority of AI patients, resulting in a profoundly suppressed aldosterone-to-AngII ratio (AA2 ratio, P = 0.003) compared to controls. PRA-S, the angiotensin-based marker for plasma renin activity, correlated with plasma renin activity (r = 0.983; P < 0.01) and plasma renin concentration (r = 0.985; P < 0.001) and was significantly increased in AI patients.

Conclusions

AI is associated with a unique RAAS profile characterized by the absence of aldosterone despite strongly elevated levels of angiotensin metabolites, including the potent vasoconstrictor AngII. Despite state-of-the-art hormone replacement therapy, the RAAS remains hyperactivated. The contribution of Ang II in cardiovascular diseases in AI patients as well as a potential role for providing useful complementary information at diagnosis and follow up of AI should be investigated in future trials.

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Massimo Bongiovanni, Wc Faquin, Luca Giovanella, Cosimo Durante, Peter Kopp and Pierpaolo Trimboli

Objective: The second version of the Bethesda System for Reporting Thyroid Cytopathology endorsed the introduction of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as a distinct entity with low malignant potential into clinical practice. Consequently, the risk of malignancy (ROM) of cytological diagnoses has changed, but the magnitude of the change remains uncertain. The present systematic review was undertaken to obtain more robust information about the true impact of NIFTP on the ROM among patients undergoing surgery following a fine-needle aspiration cytology (FNAC) diagnosis of suspicious for malignancy (Bethesda V) or malignant (Bethesda VI). As they are managed surgically, these two diagnostic categories are the primary entities that are clinically impacted by the advent of NIFTP.

Design: Systematic review and meta-analysis.

Methods: A comprehensive literature search of online databases was performed in November 2018. The search was conducted looking for data of histologically proven NIFTP with preoperative FNAC.

Results: One-hundred-fifty-seven articles were identified and nine were included in the study. Overall, there were 13,752 thyroidectomies with a cancer prevalence of 45.7%. When NIFTP was considered non-malignant, the pooled risk difference for ROM was 5.5%. Applying meta-analysis, the pooled prevalence of NIFTP among nodules with FNAC of Bethesda V or Bethesda VI was 14% and 3%, respectively.

Conclusion: This meta-analysis shows that the inclusion of NIFTP leads to a reduction in the ROM for the Bethesda V and Bethesda VI FNAC diagnostic categories by 14% and 3%, respectively. Clinicians should be aware of these data to avoid overtreatment.

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David J. Torpy

Broersen et al. have, in this issue of EJE, provided an interesting retrospective cohort analysis of adrenal crises in adult Cushing’s syndrome patients (n=106 over 15 years; 19 patients with 41 crises), after pituitary or adrenal surgery (74 vs 26%) performed with at least initial cure of hypercortisolism. Adrenal crises (ACs) are a consequence of insufficient glucocorticoid tissue action. Glucocorticoid insufficiency may be absolute and follow from a lack of circulating cortisol, or relative where low cortisol concentrations are below tissue requirements, particularly in times of inflammatory stress where the immunomodulatory effects of cortisol are critical for survival. ACs are all too frequent in patients with adrenal insufficiency at 6-8% per annum, in patients with primary adrenal insufficiency and structural secondary insufficiency. Fortunately, given the high frequency of use of glucocorticoids for a myriad of disorders, ACs occur at much lower rates in patients who have glucocorticoid induced adrenal insufficiency.

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A Ziagaki, D Blaschke, W Haverkamp and U Plöckinger

Objective

Growth hormone (GH) deficiency is related to increased cardiovascular mortality. We studied clinical status, concentration of amino-terminal-pro B-type natriuretic-peptide (NT-proBNP) and echocardiographic parameters during long-term GH replacement (GH-R).

Methods

Fifty-one patients (29 females), 45.9 ± 11.3 years (mean ± s.d.), median follow-up 36.2 months, echocardiography and laboratory determinations initially and at 12-months intervals.

Results

At the last follow-up (last observation carried forward) (LFU (LOCF)) insulin-like growth-factor-1 standard deviation score (IGF-1 SDS) was ±1 in 92% of the patients. The median NT-proBNP declined significantly and stabilized (−40.5%) at LFU (LOCF) due to patients with a basal NT-proBNP >125 ng/L (indicative of heart failure). The basal NT-proBNP and the final IGF-1 SDS were significant predictors of the NT-proBNP at LFU (LOCF). Initially left ventricular enddiastolic diameter (LVEDD), left ventricular posterior wall diameter (LVPWD) and ejection fraction (EF) were normal, while interventricular septum diameter (IVSD) and left ventricular mass index (LVMi) were slightly increased. LVPWD and IVSD had significantly declined by year three. The LVMi was moderately to severely abnormal in 37.3 and 52.0% of patients initially and at LFU (LOCF). At LFU (LOCF) LVMi and IGF-1 were significantly correlated in the 14 male patients of this subgroup.

Conclusion

Long-term GH-R of GHD positively affected ISVD and LVPWD. In a subgroup of patients with severe GHD, LVMi increased concomitantly to the decline in NT-proBNP and this was positively correlated to the final IGF-1 concentration. Whether this observation indicates a positive development in a structurally altered heart muscle (reversal of adverse remodelling) or poses a future risk for heart failure needs further follow-up.

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Germano Gaudenzi, Alessandra Dicitore, Silvia Carra, Davide Saronni, Carlotta Pozza, Elisa Giannetta, Luca Persani and Giovanni Vitale

Neuroendocrine neoplasms (NENs) are traditionally considered as a single group of rare malignancies that originate from the highly spread neuroendocrine system. The clinical management is complex due to the high heterogeneity of these neoplasms in terms of clinical aggressiveness and response to the therapy. Indeed, a multidisciplinary approach is required to reach a personalization of the therapy, including cancer rehabilitation. In this review, we discuss the possibility to adopt a precision medicine (PM) approach in the management of NENs. To this purpose, we summarize current knowledge and future perspectives about biomarkers and preclinical in vitro and in vivo platforms, potentially useful to inform clinicians about the prognosis and for tailoring therapy in patients with NENs. This approach may represent a breakthrough in the therapy and tertiary prevention of these tumors.

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Nicholas Russell and Mathis Grossmann

Evidence has been accumulating that, in men, some of the biological actions traditionally attributed to testosterone acting via the androgen receptor may in fact be dependent on its aromatization to estradiol (E2). In men, E2 circulates at concentrations exceeding those of postmenopausal women, and estrogen receptors are expressed in many male reproductive and somatic tissues. Human studies contributing evidence for the role of E2 in men comprise rare case reports of men lacking aromatase or a functional estrogen receptor alpha, short-term experiments manipulating sex steroid milieu in healthy men, men with organic hypogonadism or men with prostate cancer treated with androgen deprivation therapy (ADT) and from observational studies in community-dwelling men. The collective evidence suggests that, in men, E2 is an important hormone for hypothalamic–pituitary–testicular axis regulation, reproductive function, growth hormone insulin-like growth factor-1 axis regulation, bone growth and maintenance of skeletal health, body composition and glucose metabolism and vasomotor stability. In other tissues, particularly brain, elucidation of the clinical relevance of E2 actions requires further research. From a clinical perspective, the current evidence supports the use of testosterone as the treatment of choice in male hypogonadism, rather than aromatase inhibitors (which raise testosterone and lower E2), selective androgen receptor modulators and selective estrogen receptor modulators (with insufficiently understood tissue-specific estrogenic effects). Finally, E2 treatment, either as add-back to conventional ADT or as sole mode of ADT could be a useful strategy for men with prostate cancer.

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Yujiro Nakano, Takanobu Yoshimoto, Ryo Watanabe, Masanori Murakami, Tatsuya Fukuda, Kazutaka Saito, Yasuhisa Fujii, Takumi Akashi, Toshihiro Tanaka, Tetsuya Yamada, Mitsuhide Naruse and Yoshihiro Ogawa

Objective

The pathophysiology of aldosterone-producing adenomas (APAs) has been intensively investigated using genetic and epigenetic approaches. However, the role of miRNAs in APA is not fully understood. The present study profiled miRNAs in APAs as an exploratory approach to elucidate their pathophysiological roles in APAs.

Design

Tissues of APAs and other adrenocortical adenomas were obtained from patients who underwent adrenalectomy.

Methods

Candidate miRNAs differentially detected from samples were examined by whole miRNA sequencing. The expression of candidate miRNAs in APA tissues were further validated by real-time quantitative polymerase chain reaction (qPCR). Further, differential miRNA expression between APAs with and without KCNJ5 somatic mutations was examined. Prediction of miRNA target genes was performed by bioinformatics analysis. For specific miRNAs, correlation analysis between the levels of their target genes and CYP11B2 was analyzed in APA tissues.

Results

Our study determined differential expression of six miRNAs in APA or APA with KCNJ5 mutations. We further demonstrated that miR299 levels were negatively correlated with mRNA levels of CACNB2, which encodes the beta-subunit of the L-type calcium channel. Additionally, we found significant correlations among miR299, CACNB2, and CYP11B2 levels in APA tissues.

Conclusions

Our study suggests the possible pathophysiological involvement of specific miRNAs in calcium signaling and aldosterone hypersecretion in APAs. Further studies, including in vitro analyses, are required to clarify these findings.