Endocrine Abstracts

IntroductionAdrenocortical Carcinoma (ACC) is a rare aggressive cancer which carries a poor prognosis. Adjuvant mitotane improves survival but is limited by poor response rates and resistance following tumour recurrence. Mitotane’s efficacy has been attributed to intracellular accumulation of toxic free cholesterol (FC) predominantly through inhibition of cholesterol storage through SOAT1. Yet SOAT1 specific inhibitors demonstrate inferior efficacy ...

Klotho (Kl), initially identified as an antiaging gene, plays a critical role in the regulation of renal and adrenal dependent fluid homeostasis. A previous study reported that haplodeficiency of Kl in mice resulted in increased aldosterone synthase (CYP11B2) expression, elevated plasma aldosterone and high blood pressure. This phenotype was presumed to result from diminished Kl expression in zona glomerulosa (zG) of the adrenal. To examine whether Kl expressed in zG is indeed...

The adrenal glands serve as central organs of the endocrine system by producing steroid hormone essential for organismal homeostasis. Mechanisms ensuring proper adrenal homeostasis and function are therefore crucial for maintaining human life. ACTH, released by the pituitary corticotrope, is required for the differentiation of the inner part of the adrenal cortex (the zona fasciculata) and the resultant stimulation of cortisol production. Perturbation of ACTH signaling can lea...

Background: Cushing’s syndrome (CS) is a rare but very severe condition with high morbidity and mortality. Patients are often diagnosed late in the course of the disease, many years after onset of symptoms. New approaches like extended screening of at risk populations, alternative biomarkers and clinical scores have been developed to improve diagnostic accuracy. However, there is still a debate, whether certain patient populations should be screened for CS outside the fra...

Background: Aldosterone-producing adenomas (APA) are a major cause of primary aldosteronism. Somatic mutations explain the excess aldosterone production in the majority of patients with APA with mutations in the potassium channel KCNJ5 the most prevalent. In contrast, mechanisms driving cell proliferation are largely unresolved.Objective: To identify genes that modulate cell growth in APAs.Methods: Quantitative transcripto...

In a previous study we found mutations in the main catalytic subunit of protein kinase A (PKA Cα) to be responsible for cortisol-secreting adrenocortical adenomas (ACAs). These mutations interfere with the formation of a stable holoenzyme, thus causing constitutive PKA activation. More recently, we identified additional mutations affecting PKA Cα in ACAs associated with overt Cushing syndrome: Ser213Arg_Leu212_Lys214insIle-Ile-Leu-Arg, Cys200_Gly201insVal, Trp197Arg,...

Introduction: Mutations activating USP8 have been detected in a high proportion of pituitary adenomas causing Cushing’s disease and have been linked to an increase of ACTH production in corticotroph cells. Whether USP8 mutations are involved in the tumorigenesis of the ectopic Cushing’s syndrome (ECS) caused by neuroendocrine tumors has not been studied.Patients and methods: In this work we evaluate the role of USP8 in a series of 17 t...

Recently, mutations in the PRKACA (catalytic subunit α of the PKA) gene have been identified as causative in 35% of adrenocortical adenomas (ACA) with overt Cushing’s syndrome (Beuschlein et al. 2014). These mutations lead to constitutive activation of PKA signaling and subsequently to an excessive production of cortisol. Protein kinase A is a heterotetramer consisting of two catalytic and two regulatory subunits with several isoforms (Cα, β, &#947...

Objective: To document influences of sampling of blood under supine fasting versus seated non-fasting conditions on diagnosis of pheochromocytoma using plasma concentrations of normetanephrine, metanephrine and methoxytyramine (P-NMN/MN/MTY).Design and methods: P-NMN/MN/MTY were measured by liquid chromatography with tandem mass spectrometry in 695 patients at five centers, two of which complied with requirements for supine sampling after an overnight fa...

In an attempt to define novel genetic loci involved in the pathophysiology of primary aldosteronism a mutagenesis screen after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. One of the established mouse lines with hyperaldosteronism was phenotypically and genetically characterized. Affected animals showed an increased aldosterone to renin ratio (males unaffected, 1.1±0.1 pg/ml per ng per ml per hour v...