OR02-3 Endocrinological Crosstalk between Calcium Metabolism and Steroidogenesis in Primary Aldosteronism

Abstract

Introduction Primary aldosteronism (PA) accounts for 5-10% of all of the patients with hypertension and companies higher incidence of cardiovascular events. Calcium metabolic disorders including secondary hyperparathyroidism and osteoporosis were detected more frequently in PA patients than EH patients. Recently, it has been also reported that there was some interactive regulations between parathyroid gland and adrenal zona glomerulosa. However, its detailed mechanism has virtually remained unknown. Therefore, in order to clarify the association between Ca metabolic disorders and steroidogenesis as well as its clinical significance in PA patients, we analyzed expression profiles of Ca-related receptors in aldosterone-producing adenoma (APA), and compared the findings with clinicopathological parameters. PTH-induced steroidogenesis was also examined by in vitro study using H295R cell lines. Materials and methods Thirty formalin-fixed and paraffin-embeded APA and seventeen normal adrenal glands (NA) were examined for immunohistochemistry(IHC). 17 APA and 19 CPA cases were examined for mRNA expression levels of steroidogenic enzymes and Ca-related receptors by qRT-PCR. In vitro study was performed to analyze the responsiveness of steroidogenic enzymes by PTH treatment in H295R. Results Based on the results of IHC analysis, PTH1R and VDR were predominantly immunolocolized in the ZG among the normal adrenal cortex. VDR was positively correlated with CYP21A in normal ZG and CYP11B2 in APA. PTH1R was positively correlated with both CYP11B2 and CYP21A in APA. CaSR was inversely correlated with that of CYP11B2 in normal ZG. Both PTH1R and VDR mRNA levels were significantly higher in APA than in CPA. Also, their mRNA levels were positively correlated with CYP17A in APA. CaSR mRNA was detected in both APA and NA. For the clinical significance, VDR immunoreactivity was positively correlated with TRACP-5b. CaSR immunoreactivity was positively correlated with Bone Mineral Density (BMD). PTH1R immunoreactivity was inversely correlated with serum Ca level, and PTH1R mRNA level was positively correlated with urinary Ca. VDR mRNA level was inversely correlated with serum phosphate(P) and upregulated in KCNJ5 mutated APAs than wild type. CYP11A1 and CYP17A mRNA expression levels were significantly increased in cell line by PTH treatment. Discussion Results of our present study did demonstrate that PTH and Vitamin D could act on their receptors in APA, and could possibly activate aberrant pathways of “neoplastic” steroidogenesis including both aldosterone and cortisol, especially in stimulating CYP17A1 and CYP11A1. In addition, extracellular Ca level was closely associated with steroidogenesis in both normal ZG and PA. Finally, adrenal expression profiles of Ca-related receptors (VDR, CaSR and PTH1R) could be the predictive markers of Ca and bone metabolic disorders in PA patients.