Endocrine Abstracts

Cushing’s disease is caused by corticotroph adenomas of the pituitary. To explore molecular mechanisms of endocrine autonomy, we recently performed exome sequencing of 10 corticotroph adenomas1 identifying somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif enhancing proteolytic cleavage and catalytic activity of USP8. Cleaved USP8 led to increased EGF receptor deubiquitination impai...

Cushing's disease results from uncontrolled ACTH secretion by corticotroph adenomas of the pituitary, resulting in excess cortisol secretion. Numerous previous studies attempted to gain insight into the molecular mechanisms underlying the development of Cushing’s disease, but only few rare mutations have been reported. Recently, an exhaustive exome-wide screening has led us to identify somatic mutations in the ubiquitin-specific protease 8 (USP8) in 36% of adenomas...

In this session, the most recent publications related to the topic and published in 2013/2014 will be discussed and set into a clinical and problem-oriented context. In primary aldosteronism three Nature genetics papers have elucidated the genetic basis of aldosterone-producing adenomas. In addition, an important AVS expert consensus has been published (Hypertension 2014). Also, in 2014, a revised Endocrine Society Practice Guidline for primary aldosteronism is expected (JCEM...

We have recently reported that somatic mutations in the ubiquitin-specific protease 8 (USP8) are present in corticotropinomas of patients with Cushing’s disease and that these mutations reduced the interaction with 14-3-3. Mutant USP8 exhibited higher deubiquitination activity and potentiated EGFR-induced POMC expression (Reincke et al., Nat Genet 2014). To further study the prevalence of these mutations, we have analyzed 134 ACTH-producing corticotropin...

Background: Unilateral primary aldosteronism is the most common surgically correctable form of endocrine hypertension, usually diagnosed by adrenal vein sampling (AVS) or computed tomography (CT). We compared the outcomes of patients diagnosed by CT and AVS and determined if CT can reliably diagnose unilateral primary aldosteronism in young patients with an evident phenotype.Methods: Patient data were obtained from 18 internationally distributed centres ...

Objective: Clinical and histopathological assessment of a consecutive series of Munich patients operated between 2016 and 2018 for unilateral primary aldosteronism (PA).Background: Unilateral PA is the most common surgically curable form of hypertension mainly caused by an aldosterone-producing adenomas (APA). Somatic mutations in KCNJ5, CACNA1D, ATP1A1 or ATP2B3drive the aldosterone excess in the majority of APAs. Genetic variants in <...

A genome-wide association study indicated a correlation between a locus at 5q32 and high aldosterone to renin ratio in subjects from KORA F4 survey. As we considered the genes in this locus for their potential relevance for the etiology of primary aldosteronism, we observed significantly higher expression of one of them, SLC26A2, in mouse adrenal glands, even though the gene’s function in the adrenal was not reported in the literature. Using the human adrenocortical cell ...

Primary aldosteronism (PA) is a form of endocrine hypertension characterized by autonomous aldosterone secretion. Aldosterone-producing adenomas (APAs) are a significant cause of unilateral PA, where aldosterone overproduction is driven by a somatic mutation in an ion pump or channel. Multiple studies have shown that mutations in the KCNJ5 gene are the most prevalent in PA patients suffering from the unilateral subtype, and unilateral laparoscopic total adrenalectomy ...

In an attempt, to overcome the lack of preclinical models for adrenocortical carcinoma (ACC), we recently aimed at the development of patient-individual tumor models for ACC. During these studies one xenograft (MUC-1), derived from a neck metastasis of an ACC, showed extraordinary engraftment properties and sustained tumor growth over several passages in the murine host. During ongoing studies we investigated and compared all currently available xenograft models for ACC (NCI-H...

Medical treatment of adrenocortical carcinoma (ACC) is limited to common cytotoxic agents, which are usually given in combination with mitotane (M). Recently, we investigated together with M the effects of i) the classical EDP protocol (etoposide, doxorubicin, and cisplatin) and ii) a novel paclitaxel containing scheme PDP (paclitaxel, doxorubicin, and cisplatin) on human NCIh295 cells indicating anti-tumoral superiority of PDP-M over EDP-M regarding cell viability (P...