Endocrine Abstracts

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...

Although primary aldosteronism (PA) is considered to be the most prevalent cause of secondary hypertension the underlying genetic mechanisms have been elucidated only for the rare familial forms of the disease. In an attempt to define novel genetic loci involved in the pathophysiology of PA a phenotype-driven mutagenesis screening after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. The aldosterone values ...

According to recent studies, primary aldosteronism is considered to be responsible for almost 10% of all cases of arterial hypertension. The genetic background of this common disease, however, has been elucidated only for the rare familial types whereas in the large majority of sporadic cases it still remains unclear. In an attempt to define novel genetic mechanisms of hyperaldosteronism we utilized a random mutagenesis screen after treatment with the alkylating agent N...

The tumorigenesis of Cushing’s disease is characterized by somatic mutations in the USP8 gene in almost half of the cases. USP8 encodes for ubiquitin specific protease 8, a deubiquitinase that rescues proteins involved in the regulation of ACTH synthesis in corticotroph cells. In the present study we tested the antisecretory and antiproliferative efficacy of a commercially available specific USP8 inhibitor (IC50 3.1 μM USP8; >90 μM USP7) in immortalized muri...

Introduction: Transcriptional regulation of gene expression by miRNAs is critical for the fine-tuning of adrenal stress response. However, its role in hypercortisolism has not been explored well. The study addresses this gap using adrenal samples of 3 patient groups from the German Cushing’s registry: Cortisol-Producing-Adenoma (CPA), Primary Bilateral Adrenal Hyperplasia (PBMAH) and controls (adrenal samples of patients with pheochromocytoma).Metho...

Background: Primary aldosteronism (PA) is the most frequent cause of endocrine hypertension associated with excess aldosterone production from one or both adrenal glands. Somatic or germline mutations in the KCNJ5 potassium channel cause an imbalance in intracellular ion homeostasis. This ultimately drives aldosterone overproduction in some sporadic forms of PA and a familial form of the disease (familial hyperaldosteronism type 3). Our objective was to identify small molecule...

Introduction: 11-ketotestosterone (11KT) and 11β-hydroxyandrostenedione (11OHA4) are new biomarkers for hyperandrogenic disorders. Steroids can be measured in saliva, allowing non-invasive sampling by patients. We modified a published LC-MS/MS method1 for quantification of 11-oxygenated androgens in saliva with respect to sample volume, extraction procedure and equipment, and assessed the potential impact of different sampling devices on results.<p class="a...

Background: Secondary hypogonadism (SH) is a common comorbidity of Cushing’s syndrome (CS) in men. There is a large overlap in associated symptoms and comorbidities between hypogonadism and hypercortisolism. To date, the influence of coexistent SH on clinical and biochemical parameters in CS is largely unknown and longitudinal data investigating its recovery during the remission phase are scarce.Hypothesis: We hypothesized that SH is a frequent and ...

Background: Symptoms of hyperandrogenism are common in patients with Cushing’s disease (CD), but they cannot be sufficiently explained by measured concentrations of circulating androgens. In this study we analyzed the contribution of 11-oxygenated (11o×C19) androgens to hyperandrogenemia in female patients with CD as well as the influence of treatment with steroidogenesis inhibitors osilodrostat and metyrapone on 11o×C19 and classic androgens.<p class="abste...

Introduction: Transcriptional regulation of gene expression by miRNAs is critical for the fine-tuning of stress response. However, its role in hypercortisolism has not been explored well. After exploring circulating miRNAs in Cushing’ Syndrome (CS) as biomarkers our aim was to investigate their origin and their role in adrenal tissue.Methods: Next generation sequencing (NGS) based miRNA profiling was performed in adrenal samples from patients of Ger...