Endocrine Abstracts

The mechanisms regulating aldosterone secretion in primary aldosteronism (PA) independently from the renin-angiotensin axis include diverse genetic and molecular mechanisms. One mechanism results from the activation of aberrantly expressed GPCR which are diverse and highly prevalent in adrenal tissues of patients with PA, either from aldosteronoma or bilateral adrenal hyperplasia. The levels of expression of GPCR vary greatly between different PA tissues particularly for ACTH (MC2R) and serotonin (HTR4R) receptors with local increased presence of mast cells and serotonin production in adrenocortical tissues. Transcriptome studies or in vivo stimulation studies have identified greatly variable expression of GnRHR or LHCGR or aldosterone response to stimuli in approximately 30% of PA patients. In some, PA became evident during pregnancy or after menopause, following activation by placental hCG or increased levels of LH after menopause. In one case, repeated episodes of severe hypertension and hypokalemia with transient PA during pregnancy was secondary to LHCGR in an aldosteronoma revealed outside of pregnancy by stimulation with HCG during 5 days and again during adrenal vein sampling. The molecular mechanisms leading to aberrant GnRHR or LHCGR are not completely elucidated. Somatic β-catenin (CTNNB1) mutations was suggested to induce ectopic LHCGR and GnRHR during pregnancy or menopause, but not confirmed in several patients with aldosterone response to GnRH or LH tests in vivo. More recently, overexpression of those aberrant receptors required combined mutations of GNA11or GNAQin CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause. Thus, aldosterone secretion in patients with PA is not autonomous or constitutive despite the activation of aldosterone synthase by ion-channel or other genes mutations, but is dysregulated by the activation of diverse and variable aberrant expression of several GPCR by their ligands.