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Journal: Endocrine connections

157

Background: The water deprivation test is the gold standard test to differentiate central or nephrogenic diabetes insipidus (DI) from primary polydipsia (PP) in patients with polyuria and polydipsia. Few studies have addressed the diagnostic performance of this test. Methods: The aim of this retrospective cohort study was to evaluate the diagnostic performance of the standard water deprivation test, including plasma arginine vasopressin (AVP) measurements, in 40 consecutive patients with polyuria. We compared initial test results to the final clinical diagnosis, i.e., no DI, central DI or nephrogenic DI. Median length of follow up was 8 years. In a subset of 10 patients, the novel marker copeptin (CP) was measured in plasma. Results: Using the final diagnosis as gold standard, a threshold for urine osmolality of > 800 mOsmol/kg after water deprivation yielded a sensitivity and specificity of 96% and 100% for diagnosing PP. Sensitivity increased to 100% if the cut off value for urine osmolalilty was set at 680 mOsmol/kg. Plasma AVP levels did not differ between patient groups and did not differentiate between central DI, nephrogenic DI or PP. In all three patients with central DI, plasma CP was <2.5 pmol/L with plasma osmolality > 290 mOsmol/kg, and >2.5 pmol/L in patients without DI. Conclusions: The optimal cut-off value for differentiating PP from DI during a water deprivation test was urine osmolality > 680 mOsmol/kg. Differentiating between central and nephrogenic DI should be based on clinical judgement since AVP levels did not discriminate.

Concepts: Cohort study, Diabetes mellitus, Type I and type II errors, Sensitivity and specificity, Diabetes insipidus, Nephrogenic diabetes insipidus

64

Concern has been raised over chemical induced disruption of ovarigenesis during fetal life resulting in long-lasting consequences only manifesting themselves much later during adulthood. A growing body of evidence suggest that prenatal exposure to the mild analgesic acetaminophen/paracetamol can cause such a scenario. In this Review, we therefore discuss three recent reports that collectively indicating that prenatal exposure in a window around 13.5 days post coitum in both rats and mouse can result in reduced female reproductive health. The combined data show that the exposure results in reduction in primordial follicles, irregular cycling, premature absence of corpus luteum, as well as reduced fertility, resembling premature ovarian insufficiency syndrome in humans that is linked to premature menopause. This could be problematic in the Western world where the age at childbirth is continuously being delayed and because acetaminophen is recommended during pregnancy for pain, fever. We therefore highlight an urgent need for more studies to verify these data including both experimental and epidemiological approaches.

Concepts: Pregnancy, Reproduction, Fetus, Uterus, Reproductive system, Fertility, Menstrual cycle, Corpus luteum

43

This review covers recent findings on the main categories of thyroid hormone disrupting chemicals and their effects on brain development. We draw mostly on epidemiological and experimental data published in the last decade. For each chemical class considered, we deal with not only the thyroid hormone disrupting effects but also briefly mention the main mechanisms by which the same chemicals could modify estrogen and/or androgen signalling, thereby exacerbating adverse effects on endocrine-dependent developmental programs. Further, we emphasize recent data showing how maternal thyroid hormone signalling during early pregnancy affects not only offspring IQ, but also neurodevelopmental disease risk. These recent findings add to established knowledge on the crucial importance of iodine and thyroid hormone for optimal brain development. We propose that prenatal exposure to mixtures of thyroid hormone-disrupting chemicals provides a plausible biological mechanism contributing to current increases in incidence of neurodevelopmental disease and IQ loss.

Concepts: Epidemiology, Developmental biology, Hormone, Luteinizing hormone, Chemistry, Chemical substance, Testosterone, Thyroid hormone

35

Neuroinflammatory responses are implicated in depression. The aim was to explore whether depression in patients with type 1 diabetes (T1D) was associated with high circulating galectin-3, controlling for metabolic variables, s-creatinine, life style factors, medication, and cardiovascular complications.

26

Chromogranin A (CgA) is the major soluble protein co-stored and co-released with catecholamines and can function as prohromone giving rise to several bioactive peptides. This review focuses on these molecules summarizing their physiological functions, their pathogenetic implications and their recent use as biomarkers in several pathological conditions. A thorough literature search of the electronic healthcare databases MEDLINE, from January 1985 to September 2013, was conducted to identify articles and studies concerned with CgA and its processing. The search strategies utilized key-words such Chromogranin A, Vasostatin-1 and 2, Chromofungin, Chromacin, Pancreastatin, Catestatin, WE-14, Chromostatin, GE-25, Parastatin and Serpinin, and was supplemented by the screening of references from included papers and review articles. A total of 209 English-language, peer-reviewed original articles or reviews were examined. The analysis of the retrospective literature suggested that CgA and its several bioactive fragments exert a broad spectrum of regulatory activities by influencing the endocrine, the cardiovascular and the immune systems and by affecting the glucose or calcium homeostasis. Since some peptides exert similar effects, but other elicit opposite responses, the regulation of the CgA processing is critical to maintain homeostasis, whereas an unbalanced production of peptides that exert opposing effects can have a pathogenetic role in several diseases. These clinical implications entail that CgA and its derived peptides are now used as diagnostic and prognostic markers or to monitor the response to pharmacological intervention not only in endocrine tumours, but also in cardiovascular, inflammatory and neuropsychiatric diseases.

Concepts: Immune system, Medicine, Cancer, Biology, Pathology, Physiology, Chromogranin A, Chromogranin

17

Cranial diabetes insipidus (CDI) is a treatable chronic condition that can potentially develop into a life-threatening medical emergency. CDI is due to the relative or absolute lack of the posterior pituitary hormone vasopressin (AVP), also known as anti-diuretic hormone. AVP deficiency results in uncontrolled diuresis. Complete deficiency can lead to polyuria exceeding 10 L/24 h. Given a functioning thirst mechanism and free access to water, patients with CDI can normally maintain adequate fluid balance through increased drinking. Desmopressin (DDAVP, a synthetic AVP analogue) reduces uncontrolled water excretion in CDI and is commonly used in treatment. Critically, loss of thirst perception (through primary pathology or reduced consciousness) or limited access to water (through non-availability, disability or inter-current illness) in a patient with CDI can lead to life-threatening dehydration. This position can be further exacerbated through the omission of DDAVP. Recent data have highlighted serious adverse events (including deaths) in patients with CDI. These adverse outcomes and deaths have occurred through a combination of lack of knowledge and treatment failures by health professionals. Here, with our guideline, we recommend treatment pathways for patients with known CDI admitted to hospital. Following these guidelines is essential for the safe management of patients with CDI.

17

Type 2 diabetes (T2D) is a serious disease. The gut microbiota has recently been identified as a new potential risk factor in addition to well-known diabetes risk factors. To investigate the gut microbiota composition in association with the dietary patterns in patients with different glucose tolerance we analyzed 92 patients: with normal glucose tolerance (n=48), prediabetes (preD, n=24), T2D (n=20). Metagenomic analysis was performed using 16SrRNA sequencing. The diet has been studied by a frequency method with a quantitative evaluation of food intake using a computer program. Microbiota in the samples was predominantly represented by Firmicutes, in a less degree by Bacteroidetes. Blautia was a dominanting genus in all samples. The representation of Blautia, Serratia was lower in preD than in T2D patients, and even lower in those with normal glucose tolerance. After the clustering of the samples into groups according to the percentage of protein, fat, carbohydrates in the diet, the representation of the Bacteroides turned to be lower and Prevotella abundance turned to be higher in carbohydrate cluster. There were more patients with insulin resistance, T2D in the fat-protein cluster. Using the Calinski-Harabasz index identified the samples with more similar diets. It was discovered that half of the patients with a high-fat diet had normal tolerance, the others had T2D. The regression analysis showed that these T2D patients also had a higher representation of Blautia. Our study provides the further evidence concerning the structural modulation of the gut microbiota in the T2DM pathogenesis depending on the dietary patterns.

Concepts: Gut flora, Nutrition, Insulin, Diabetes mellitus type 2, Diabetes mellitus, Obesity, Insulin resistance, Metformin

12

Firemaster 550 (FM 550) is a flame retardant (FR) mixture that has become one of the most commonly used FRs in foam-based furniture and baby products. Human exposure to this commercial mixture, comprised of brominated and organophosphate components, is widespread. We have repeatedly shown that developmental exposure can lead to sex-specific behavioral effects in rats. Accruing evidence of endocrine disruption and potential neurotoxicity have raised concerns regarding the neurodevelopmental effects of FM 550 exposure, but the specific mechanisms of action remains unclear. Additionally, we observed significant, and in some cases sex-specific, accumulation of FM 550 in placental tissue following gestational exposure. Because the placenta is an important source of hormones and neurotransmitters for the developing brain, it may be a critical target of toxicity to consider in the context of developmental neurotoxicity. Using a mixture of targeted and exploratory approaches, the goal of the present study was to identify possible mechanisms of action in the developing forebrain and placenta. Wistar rat dams were orally exposed to FM 550 (0, 300, or 1,000 µg/day;) for 10 days during gestation and placenta and fetal forebrain tissue collected for analysis. In placenta, evidence of endocrine, inflammatory, and neurotransmitter signaling pathway disruption was identified. Notably, 5-HT turnover was reduced in placental tissue and fetal forebrains indicating that 5-HT signaling between the placenta and the embryonic brain may be disrupted. These findings demonstrate that environmental contaminants, like FM 550, have the potential to impact the developing brain by disrupting normal placental functions.

Concepts: Nervous system, Embryo, Fetus, Developmental biology, Placenta, Toxicity, Tyrosine, Nephrotoxicity

12

As the impact of high intensity interval training (HIIT) on systemic hormones in aging men is unstudied to date, we investigated whether total testosterone (TT), sex hormone binding globulin (SHBG), free testosterone (free-T), and cortisol (all in serum) were altered following HIIT in a cohort of 22 lifelong sedentary (62 ± 2 years) older men. As HIIT requires preconditioning exercise in sedentary cohorts, participants were tested at three phases, each separated by six weeks' training; baseline (phase A), following conditioning exercise (phase B), and post-HIIT (phase C). Each measurement phase used identical methods. TT was significantly increased following HIIT (~17%; P<0.001) with most increase occurring during preconditioning (~10%; P=0.007). Free-T was unaffected by conditioning exercise (P=0.102) but was significantly higher following HIIT compared to baseline (~4.5%; P=0.023). Cortisol remained unchanged from A to C (P=0.138). The present data indicate a combination of preconditioning and HIIT increases TT and SHBG in sedentary older males, with the HIIT stimulus accounting for a small but statistically significant increase in free-T. Further study is required to determine the biological importance of small improvements in free-T in aging men.

Concepts: Hormone, Obesity, Testosterone, Cortisol, Sex hormone-binding globulin, Puberty, Adrenal cortex, High-intensity interval training

8

Immunotherapy treatment with checkpoint inhibitors (CPI) (CTLA-4 and PD-1 inhibitors) significantly improves survival in a number of cancers. Treatment can be limited by immune-mediated adverse effects including endocrinopathies such as hypophysitis, adrenalitis, thyroiditis and diabetes mellitus. If endocrinopathies (particularly hypocortisolemia) are not recognized early, they can be fatal. The diagnosis and management of endocrinopathies can be complicated by simultaneous multi-organ immune adverse effects. Here, we present Endocrine Emergency Guidance for the acute management of the endocrine complications of checkpoint inhibitor therapy, the first specialty-specific guidance with Endocrinology, Oncology and Acute Medicine input and endorsed by the Society for Endocrinology Clinical Committee. We present algorithms for management: endocrine assessment and management of patients in the first 24 hours who present life-threateningly unwell (CTCAE grade 3-4) and the appropriate management of mild-moderately unwell patients (CTCAE grade 1-2) presenting with features compatible with an endocrinopathy. Other important considerations in relation to hypohysitis and the maintenance of glucocorticoid therapy are discussed.