Journal of the Endocrine Society

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ISSN / EISSN : 2472-1972 / 2472-1972
Current Publisher: The Endocrine Society (10.1210)
Total articles ≅ 7,464
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, Camilla Schalin-Jäntti, Outi Itkonen
Journal of the Endocrine Society; doi:10.1210/jendso/bvab106

Context Patients with serotonin-secreting neuroendocrine neoplasms (NENs) have increased serum 5-hydroxyindoleacetic acid (5HIAA) concentrations. Serum 5HIAA thus serves as a biomarker in NEN. Objective To evaluate an improved tandem mass spectrometric serum 5HIAA assay for diagnosis and follow-up of NEN in a clinical cohort. Design A retrospective study during 2016 - 2018 at the Diagnostic Center and Department of Endocrinology at Helsinki University Hospital, Finland. Methods Detailed patient data was obtained from 116 patients. Serum 5HIAA was analyzed by two different LC-MS/MS assays with samples prepared either by protein precipitation (PP) or solid phase extraction (SPE). 24-h urine 5HIAA samples (n=33) were analyzed by amperometric LC and the results were compared. Specificity and sensitivity were calculated by receiver operating characteristic (ROC) analysis. Results We achieved 5-10 000 nmol/l linearity and ≤2.5% variation with our new serum 5HIAA assay. In ROC analysis the area under curve (AUC) was 85% by serum assays (URL value 123 nmol/l) and 88% by the 24-h urine 5HIAA assay (URL value of 47.1 µmol), respectively. A difference (p<0.001) between patients with active NEN and patients in remission was found by all 5HIAA assays. Conclusion Serum 5HIAA by LC-MS/MS after protein precipitation performs equally well for the diagnosis of NEN as urinary 5HIAA LC assay. The outcome and sensitivity for serum and 24-h urine assays are convergent. Due to much more reliable and convenient sampling we recommend serum instead of 24-h urine 5HIAA for diagnosis and follow-up of NEN patients.
Alice Huang, Lenah Binmahfouz, Dale P Hancock, Paul H Anderson, Donald T Ward,
Journal of the Endocrine Society; doi:10.1210/jendso/bvab057

25-hydroxyvitamin D 1α-hydroxylase (encoded by CYP27B1), which catalyses the synthesis of 1,25-dihydroxyvitamin D3, is subject to negative or positive modulation by extracellular Ca 2+ (Ca 2+o) depending on the tissue. However, the Ca 2+ sensors and underlying mechanisms are unidentified. We tested whether calcium-sensing receptors (CaSRs) mediate Ca 2+o-dependent control of 1α-hydroxylase using HEK-293 cells stably expressing the CaSR (HEK-CaSR cells). In HEK-CaSR cells, but not control HEK-293 cells, co-transfected with reporter genes for CYP27B1-Photinus pyralis (firefly) luciferase and control Renilla luciferase, an increase in Ca 2+o from 0.5 to 3.0 mM induced a 2-3 fold increase in firefly-luciferase activity as well as mRNA and protein levels. Surprisingly, firefly-luciferase was specifically suppressed at Ca 2+o ≥ 5.0 mM, demonstrating biphasic Ca 2+o control. Both phases were mediated by CaSRs as revealed by positive and negative modulators. However, Ca 2+o induced simple monotonic increases in firefly-luciferase and endogenous CYP27B1 mRNA levels, indicating that the inhibitory effect of high Ca 2+o was post-transcriptional. Studies with inhibitors and the CaSR C-terminal mutant T888A identified roles for PKC, phosphorylation of T888, and ERK1/2 in high Ca 2+o-dependent suppression of firefly-luciferase. Blockade of both PKC and ERK1/2 abolished Ca 2+o-stimulated firefly-luciferase, demonstrating that either PKC or ERK1/2 is sufficient to stimulate the CYP27B1 promoter. A key CCAAT box (–74 bp to –68 bp), which is regulated downstream of PKC and ERK1/2 was required for both basal transcription and Ca 2+o-mediated transcriptional upregulation. The CaSR mediates Ca 2+o-dependent transcriptional upregulation of 1α-hydroxylase and an additional CaSR-mediated mechanism is identified by which Ca 2+o can promote luciferase and possibly 1α-hydroxylase breakdown.
, Tara Spence, Stuart J Frank, Raj Pandian, Andrew N Hoofnagle, Bob Argiropoulos, Julien L Marcadier
Journal of the Endocrine Society; doi:10.1210/jendso/bvab104

Circulating plasma vitamin D metabolites are highly bound to vitamin D-binding protein (DBP), also known as group-specific component or Gc-globulin. DBP, encoded by the GC gene, is a member of the albumin family of globular serum transport proteins. We previously described a homozygous GC gene deletion in a patient with apparent severe vitamin D deficiency, fragility fractures and ankylosing spondylitis. Here, we report an unrelated patient free of fractures or rheumatologic disease, but with very low 25-hydroxyvitamin D and 1,25-hydroxyvitamin D, as well as undetectable DBP measured by liquid chromatography-tandem mass spectrometry. A whole gene deletion was excluded by microarray, and Sanger sequencing of GC revealed a homozygous pathogenic variant affecting a canonical splice site (c.702-1G>A). These findings indicate that loss of function variants in GC that eliminate DBP, and severely reduced total circulating vitamin D levels, do not necessarily result in significant metabolic bone disease. Together with our previous report, these cases support the free-hormone hypothesis, and suggest free vitamin D metabolites may serve as preferable indicators of bone and mineral metabolism, particularly when clinical suspicion of DBP deficiency is high.
César Ernesto Lam-Chung, Larissa López Rodríguez, Jazmín Arteaga Vázquez, Yanin Chávarri-Guerra, Rebeca Arízaga-Ramírez, Orlando Falcon Antonio, Jazmín De Anda González, María Aurelia López-Hernández, Jeffrey N Weitzel, Danielle Castillo, et al.
Journal of the Endocrine Society; doi:10.1210/jendso/bvab085

Objective Inherited MAX gene pathogenic variants (PVs) increase risk for pheochromocytomas (PCCs) and/or paragangliomas (PGLs) in adults and children. There is little clinical experience with such mutations. This report highlights an important approach. Methods Clinical assessment, including blood chemistry, imaging studies, and genetic testing were performed. Results A 38-year-old Hispanic woman was diagnosed with PCC in 2015, treated with adrenalectomy and referred to endocrinology clinic. Notably, she presented to her primary care physician three years earlier complaining of left flank pain, intermittent diaphoresis and holocranial severe headache. We confirmed severe hypertension (180/100 mmHg) over multiple antihypertensive regimens. Biochemical and radiological studies work-up revealed high plasma metanephrine of 255 pg/mL (normal range < 65), and plasma normetanephrine of 240 pg/mL (normal range < 196). A non-contrast computed tomography scan of the abdomen revealed a 4.2 x 4.3 x 4.9 cm, round-shaped and heterogenous contrast enhancement of the left adrenal gland, and a 2-mm nonobstructive left kidney stone. A presumptive diagnosis of secondary hypertension was made. After pharmacological therapy, laparoscopic left adrenalectomy was performed and confirmed the diagnosis of pheochromocytoma. Based on both her age, family history and a high suspicion for genetic etiology, genetic testing was performed which revealed the presence of a novel likely pathogenic variant involving a splice consensus sequence in the MAX gene, designated c.64-2A> G). Conclusion The phenotype of MAX PV-related disease and paraganglioma are highlighted. The novel c.64-2A> G mutation is reported here and should be considered on the diagnostic work-up of similar cases.
Xin Li Gong, Klemens Raile, Jolanta Slowikowska-Hilczer, Catherine Pienkowski, , Robert Roehle, Anna Nordenström,
Journal of the Endocrine Society; doi:10.1210/jendso/bvab103

Context Little is known about the physical health of individuals with 46,XY disorders of sex development (DSD). Objective To assess physical and reported subjective health of individuals with XY DSD. Design and methods As part of the dsd-LIFE study, patients with an XY DSD condition were analyzed in different diagnosis groups for metabolic parameters, comorbidities, metabolic syndrome, bone outcomes, and reported subjective health. Findings were evaluated by descriptive statistics. Results A total of 222 patients with XY DSD were included with a mean age of 28.8±12.2 years, mean height of 175.3±7.7 cm, mean weight of 74.3±20.0 kg and mean BMI of 24.1±6.0 kg/m 2. Obesity rate was not increased when descriptively compared to Eurostat data. Fourteen patients had metabolic syndrome (14/175; 8.0%). In descriptive comparison to data from the DECODE study and WHO, subjects fared better in the categories waist circumference, glucose, triglyceride, cholesterol and high-density lipoprotein. Of participants with available bone health data, 19/122 (15.6%) patients had a Z-score ≤ - 2.0 at lumbar spine indicating lowered bone mineral density (BMD). Mostly gonadectomized individuals with complete androgen insensitivity syndrome (CAIS) and no estrogen therapy had lowered BMD at lumbar spine. Individuals with XY DSD performed poorly in the category subjective health in descriptive comparison to Eurostat data. Conclusion Participants reported a lower subjective health status compared to Eurostat data but their overall metabolic health status was good. Decreased BMD at lumbar spine was especially present in gonadectomized individuals with CAIS and no estrogen therapy.
, , Irinel Stanciu, Cemre Robinson, Janet Y Lee, , , , Mary Scott Roberts, Stan Krolczyk, et al.
Journal of the Endocrine Society; doi:10.1210/jendso/bvab099

Purpose Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism caused by typically small endocrine tumors that secrete fibroblast growth factor 23 (FGF23). TIO is characterized clinically by progressive musculoskeletal pain, fatigue, proximal muscle weakness, and multiple fractures, leading to long-term disability. Misdiagnosis and delayed diagnosis are common because of the non-specific symptoms, and several years may elapse before patients receive an accurate diagnosis and appropriate treatment. Thus, it is vital that awareness of the appropriate recognition and management of TIO is increased among healthcare professionals who may encounter patients with suspected TIO. Methods A roundtable meeting was held on 10 January 2020 in Dallas, TX, USA to gather perspectives on the diagnosis and treatment of TIO. The following topics were considered: clinical presentation, patient history, differential diagnosis, laboratory assessment, imaging, venous sampling, and treatment. Results This report provides a summary of our collective experiences in the management of TIO. Main conclusions Laboratory tests are mandatory to expedite TIO diagnosis and should include measurement of fasting serum phosphorus, renal phosphate reabsorption, serum 1,25-dihydroxyvitamin D, and serum FGF23 levels. Functional and anatomical imaging are essential to locate the FGF23-secreting tumor(s) causing TIO. Surgical resection is often a curative treatment when the tumor can be localized; however, better management of non-operable patients with targeted therapies is needed. Further efforts to increase awareness of TIO within the medical community, and education on recommended diagnostic and treatment pathways are required to improve the management of this debilitating disease.
, Bicky Thapa, Monica Flores, Ramsha Ahmed, Shab E Gul Rahim, Maryam Amir, Mohammad Alomari, Pravallika Chadalavada, Shannon L Morrison, James F Bena, et al.
Journal of the Endocrine Society; doi:10.1210/jendso/bvab100

Context Immune checkpoint inhibitors (ICIs) have gained a revolutionary role in management of many advanced malignancies. However, immune-related endocrine events (irEEs), have been associated with their use. irEEs have non-specific clinical presentations and variable timelines, making their early diagnosis challenging. Objective To identify risk factors, timelines, and prognosis associated with irEEs development. Design and setting Retrospective observational study within the Cleveland Clinic center. Patients Metastatic cancer adult patients who received ICIs were included. Methods 570 charts were reviewed to obtain information on demographics, ICIs used, endocrine toxicities, cancer response to treatment with ICI, and overall survival. Main Outcome Measures Incidence of irEEs, time to irEEs development, and overall survival of patients who develop irEEs. Results The final cohort included 551 patients. The median time for the diagnosis of irEEs was 11 weeks. Melanoma was associated with the highest risk for irEEs (31.3%). Ipilimumab appeared to have the highest percentage of irEEs (29.4%), including the highest risk of pituitary insufficiency (11.7%), the most severe (Grade 4 in 60%) and irreversible (100%) forms of irEEs. 45 % of patients with irEEs had adequate cancer response to ICI compared to 28.3 % of patients without irEEs (p= 0.002). Patients with irEEs had significantly better survival compared to patients without irEEs (P <0.001). Conclusions In the adult population with metastatic cancer receiving treatment with ICI, irEEs development may predict tumor response to immunotherapy and a favorable prognosis. Ipilimumab use, combination ICI therapy, and melanoma are associated with a higher incidence of irEEs.
Cole D Davidson, Eric L Bolf, Noelle E Gillis, Lauren M Cozzens, Jennifer A Tomczak,
Journal of the Endocrine Society; doi:10.1210/jendso/bvab102

Thyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. Anaplastic thyroid cancer (ATC) is highly aggressive, dedifferentiated, and patients have a median survival of fewer than six months. Oncogenic alterations in ATC include aberrant PI3K signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and Akt amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) is strongly associated with ATC. TRβ is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85⍺. However, the role of TRβ in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRβ indeed suppresses PI3K signaling in ATC cell lines through unreported genomic mechanisms including a decrease in RTK expression and increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRβ in ATC cell lines enables an increase in the efficacy of the competitive PI3K inhibitors LY294002 and buparlisib on cell viability, migration, and suppression of PI3K signaling. These findings not only uncover additional tumor suppressor mechanisms of TRβ but shed light into the implication of TRβ status and activation on inhibitor efficacy in ATC tumors.
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