Project Details
Projekt
Genotype-steroidogenic phenotype relationships in patients with aldosteronomas and in experimental cell model systems
Applicant
Professor Jacques W.M. Lenders, Ph.D.
Subject Area
Endocrinology, Diabetology, Metabolism
Term
from 2011 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 189897882
Adrenal venous sampling (AVS) is the current method of choice to differentiate aldosterone-producing adenoma (APA) from bilateral hyperplasia (BAH) in patients with primary aldosteronism (PA). For this project we take advantage of ongoing studies at European centres that use AVS to determine the source of aldosterone secretion in PA patients. In the first funding period we showed that metanephrine in adrenal venous blood is a superior measure of selectivity than cortisol. Using a newly developed LC-MS/MS method, we also established that APAs and BAH have distinct steroid profiles and that APAs show considerable heterogeneity in these profiles. We will now determine whether steroid profiles and measurements of plasma metanephrine provide superior methods to determine aldosterone lateralisation over standard measurements of aldosterone and cortisol. Although it is increasingly clear that in many PA patients mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D play an important role, it is not fully clear if and how these mutations contribute to the phenotype (altered steroidogenesis and tumourigenesis). We will also examine whether heterogeneity in steroidogenic profiles in APAs reflects differences in underlying mutations. Influences of affected genes on steroidogenesis and tumourigenesis will be further examined using engineered cell culture systems. A potentially important practical implication of these studies is that the source of aldosterone secretion in PA patients can be equally or even better predicted by genotype/phenotype profiles than by AVS, thus obviating the use of AVS in the future.
DFG Programme
Clinical Research Units
Participating Persons
Professor Graeme Eisenhofer, Ph.D.; Privatdozent Dr. Holger S. Willenberg
