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Anna Sjöström, Inga Bartuseviciene, and Charlotte Hoybye

Objective: The challenge of finding the rare patients with diabetes insipidus in need of vasopressin treatment is demanding. The guidelines for performing the fluid deprivation test and to interpret the results are abundant. We evaluated the discriminative capacity of the fluid deprivation test in patients with polyuria to define a cut off for a more effective discrimination between diabetes insipidus and other polyuria syndromes.

Research design and methods: Retrospective review and data collection of all ambulatory fluid deprivation tests, of patients with mild polyuria and polydipsia (< 3 L/day), performed between 2000–2018. Serum osmolality, urine osmolality, urine volumes and clinical information of diagnosis were retrieved from the patient’s medical records.

Results: The study group consisted of 153 patients , 123 were diagnosed with non-diabetes insipidus and 30 with diabetes insipidus. After 12 h fasting (baseline) median duration of the fluid deprivation test was 5 h (fasting range 12–21 h). At baseline there was a significant difference between median serum and urine osmolality between the groups (p < 0.05). The best cut-off for the diagnosis of diabetes insipidus, was the combination of < 400 mosmol/kg in urine and > 302 mosmol/kg in serum. With this cut-off a sensitivity of 90 % and specificity of 98 % was achieved.

Conclusion: Already after 12 h fasting our proposed cut off clearly differentiated between diabetes insipidus, and non- diabetes insipidus suggesting a possibility to considerably reduce the duration of the fluid deprivation test.

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Frédéric Illouz, Philippe Chanson, Emmanuel Sonnet, Thierry Brue, Amandine Ferriere, Marie-laure Raffin-sanson, Marie-Christine Vantyghem, Gerald Raverot, Mathilde Munier, Patrice Rodien, and Claire Briet

Objective: Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL.

Design: Retrospective study.

Methods: Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency.

Results: Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4-7) and for a median duration of 3 months (2.5-3). The TSH deficiency occurred after 1 to 3 injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency.

Conclusions: SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumor reduction is the aim of the treatment.

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Poupak Fallahi, Silvia Martina Ferrari, Giusy Elia, Francesca Ragusa, Sabrina Rosaria Paparo, Stefania Camastra, Valeria Mazzi, Mario Miccoli, Salvatore Benvenga, and Alessandro Antonelli

Tyrosine kinase inhibitors (TKIs) are emerging as potentially effective options in the treatment of cancer, acting on the pathways involved in growth, avoidance of apoptosis, invasiveness, angiogenesis, and local and distant spread. TKIs induce significant adverse effects, that can negatively affect patients’ quality of life. The most common adverse events (AEs) include fatigue, hand–foot skin reaction, decreased appetite, nausea, diarrhoea, hypertension, vomiting, weight loss, endocrinopaties and metabolic disorders.

Patients in therapy with TKIs can develop endocrine-metabolic disorders, including dyslipidemia (∼50%), diabetes (∼15–40%), and dysthyroidism (∼20%). In some cases, patients show an improved glycemia or hypoglycemia. The effects of TKIs on adrenal or gonadal function are still not completely known. It was shown a higher prevalence of subclinical hypocortisolism in patients treated with imatinib, while an increase of cortisol was reported in patients receiving vandetanib. Long-term treatment with imatinib could impact significantly the ovarian reserve and embryo developmental capacity.

It is important to evaluate patients, measure glucose levels, and manage hyperglycemia. Mild treatment-related hyperglycemia can be controlled modifying the diet and with exercise, while grade 3 and 4 hyperglycemia can lead to dose reductions and/or oral antihyperglycemic therapy.

Regarding thyroid dysfunctions, it is recommendable to measure the thyroid-stimulating hormone (TSH)/free thyroxine (FT4) levels before starting the therapy, and every 3–4 weeks during the first 6 months as changes in FT4 levels precede the changes in TSH by 3–6 weeks.

Additional studies are necessary to definitely clarify the mechanism of TKIs-induced endocrine-metabolic effects.

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Massimo Terzolo, Soraya Puglisi, Giuseppe Reimondo, Christina Dimopoulou, and Günter K Stalla

The literature on an association between acromegaly and cancer is particularly abundant on either colorectal cancer or thyroid cancer, and an endless debate is ongoing whether patients with acromegaly should be submitted to specific oncology screening and surveillance protocols. The aim of the present work is to review the most recent data on the risk of either colorectal cancer or thyroid cancer in acromegaly and discuss the opportunity for specific screening in relation to the accepted procedures in the general population.

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Mijin Kim, Bo Hyun Kim, Hyungi Lee, Hyewon Nam, Sojeong Park, Min Hee Jang, Jeong Mi Kim, Eun Heui Kim, Yung Kyoung Jeon, Sang Soo Kim, and In Ju Kim

Objective: Little is known about the role of estrogen in thyroid cancer development. We aimed to evaluate the association between hysterectomy or bilateral salpingo-oophorectomy (BSO) and the risk of subsequent thyroid cancer.

Design: A nationwide cohort study.

Methods: Data from the Korea National Health Insurance Service between 2002 and 2017 were used. A total of 78,961 and 592,330 women were included in the surgery group and no surgery group, respectively. The surgery group was categorized into two groups according to the extent of surgery: hysterectomy with ovarian conservation (hysterectomy-only) and BSO with or without hysterectomy (BSO).

Results: During 8,086,396.4 person-years of follow-up, 12,959 women developed thyroid cancer. Women in the hysterectomy-only (adjusted hazard ratio = 1.7, P < 0.001) and BSO (adjusted hazard ratio = 1.4, P < 0.001) groups had increased risk of thyroid cancer compared to those in the no surgery group. In premenopausal women, hysterectomy-only (adjusted hazard ratio = 1.7, P < 0.001) or BSO (adjusted hazard ratio = 1.4, P < 0.001) increased the risk of subsequent thyroid cancer, irrespective of hormone therapy, whereas, there was no significant association between hysterectomy-only (P = 0.204) or BSO (P = 0.857) and thyroid cancer development in postmenopausal women who had undergone hormone therapy.

Conclusions: Our findings do not support the hypotheses that sudden or early gradual decline in estrogen levels is a protective factor in the development of thyroid cancer, or that exogenous estrogen is a risk factor for thyroid cancer.

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Andrea Lania, Maria Teresa Sandri, Miriam Cellini, Marco Mirani, Elisabetta Lavezzi, and Gherardo Mazziotti

Objective:

This study assessed thyroid function in patients affected by the coronavirus disease-19 (COVID-19), based on the hypothesis that the cytokine storm associated with COVID-19 may influence thyroid function and/or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly act on thyroid cells, such as previously demonstrated for SARS-CoV-1 infection.

Design and methods:

This single-center study was retrospective and consisted in evaluating thyroid function tests and serum interleukin-6 (IL-6) values in 287 consecutive patients (193 males, median age: 66 years, range: 27–92) hospitalized for COVID-19 in non-intensive care units.

Results:

Fifty-eight patients (20.2%) were found with thyrotoxicosis (overt in 31 cases), 15 (5.2%) with hypothyroidism (overt in only 2 cases), and 214 (74.6%) with normal thyroid function. Serum thyrotropin (TSH) values were inversely correlated with age of patients (rho −0.27; P < 0.001) and IL-6 (rho −0.41; P < 0.001). In the multivariate analysis, thyrotoxicosis resulted to be significantly associated with higher IL-6 (odds ratio: 3.25, 95% confidence interval: 1.97–5.36; P < 0.001), whereas the association with age of patients was lost (P = 0.09).

Conclusions:

This study provides first evidence that COVID-19 may be associated with high risk of thyrotoxicosis in relationship with systemic immune activation induced by the SARS-CoV-2 infection.

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I C M Pelsma, K M.j.a. Claessen, Pieternella E Slagboom, D van Heemst, A M Pereira, H Kroon, Yolande F M Ramos, M Kloppenburg, N R Biermasz, and Ingrid M Meulenbelt

Introduction

Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the potential role of the GH/IGF-1 axis in primary osteoarthritis (OA). We aimed to disentangle the role of IGF-1 levels in primary OA pathogenesis.

Methods

Patients from the Genetics osteoARthritis and Progression (GARP) Study with familial, generalized, symptomatic OA (N=337, mean age 59.8±7.4 years, 82% female) were compared to Leiden Longevity Study (LLS) controls (N=456, mean age 59.8±6.8 years, 51% female). Subjects were clinically and radiographically assessed, serum IGF-1 levels were measured, and 10 quantitative trait loci (QTL) in the FOXO3, IGBP3/TNS3, RPA3, SPOCK2 genes, previously related to serum IGF-1 levels, were genotyped. Linear or binary logistic generalized estimating equation models were performed.

Results

Serum IGF-1 levels were increased in OA patients, with male patients exhibiting the strongest effect (males OR=1.10 (1.04-1.17), P=0.002 vs. females OR=1.04 (1.01-1.07), P=0.02). Independent of the increased IGF-1 levels, male carriers of the minor allele of FOXO3 QTL rs4946936 had lower risk to develop hip OA (OR=0.41 (0.18-0.90), P=0.026). Additionally, independent of IGF-1 levels, female carriers of the minor alleles of RPA3 QTL rs11769597 had higher risk to develop knee OA (OR=1.90 (1.20-2.99), P=0.006).

Conclusion

Patients with primary OA had significantly higher IGF-1 levels compared to controls. Moreover, SNPs in the FOXO3 and RPA3 genes were associated with an altered risk of OA. Therefore, altered IGF-1 levels affect the development of OA, and are potentially the result of the pathophysiological OA process.

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Olaf M Dekkers and Rolf H.h. Groenwold

Immortal time bias should always be considered in an observational study if exposure status is determined based on a measurement or event that occurs after baseline. This bias can lead to an overestimation of an effect, but also to an underestimation, which is explained Several approaches are illustrated that can be used to avoid immortal time bias in the analysis phase of the study; a time-dependent analysis to avoid immortal time bias optimizes the use of available information.

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Adina F Turcu, Diala El-Maouche, Lili Zhao, Aya T Nanba, Alison Gaynor, Padma Veeraraghavan, Richard J Auchus, and Deborah P Merke

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João Pedro Ferreira, Zohra Lamiral, Constance Xhaard, Kévin Duarte, Emmanuel Bresso, Marie-Dominique Devignes, Edith Le Floch, Claire Dandine Roulland, Jean-François Deleuze, Sandra Wagner, Bruno Guerci, Nicolas Girerd, Faiez Zannad, Jean-Marc Boivin, and Patrick Rossignol

Objective:

Determining the factors associated with new-onset pre-diabetes and type 2 diabetes mellitus (T2D) is important for improving the current prevention strategies and for a better understanding of the disease.

Design:

To study the factors (clinical, circulating protein and genetic) associated with new onset pre-diabetes and T2D in an initially healthy (without diabetes) populational familial cohort with a long follow-up (STANISLAS cohort).

Methods:

A total of 1506 participants attended both the visit 1 and visit 4, separated by ≈20 years. Over 400 proteins, GWAS and genetic associations were studied using models adjusted for potential confounders. Both prospective (V1 to V4) and cross-sectional (V4) analyses were performed.

Results:

People who developed pre-diabetes (n = 555) and/or T2D (n = 73) were older, had higher BMI, blood pressure, glucose, LDL cholesterol, and lower eGFR. After multivariable selection, PAPP-A (pappalysin-1) was the only circulating protein associated with the onset of both pre-diabetes and T2D with associations persisting at visit 4 (i.e. ≈20 years later). FGF-21 (fibroblast growth factor 21) was a strong prognosticator for incident T2D in the longitudinal analysis, but not in the cross-sectional analysis. The heritability of the circulating PAPP-A was estimated at 44%. In GWAS analysis, the SNP rs634737 was associated with PAPP-A both at V1 and V4. External replication also showed lower levels of PAPP-A in patients with T2D.

Conclusions:

The risk of developing pre-diabetes and T2D increases with age and with features of the metabolic syndrome. Circulating PAPP-A, which has an important genetic component, was associated with both the development and presence of pre-diabetes and T2D.