Defective fasciculata zone function as the mechanism of glucocorticoid-remediable aldosteronism

Glucocorticoid-remediable aldosteronism is characterized by unusual sensitivity of aldosterone secretion to ACTH. Suppressibility by glucocorticoid and continued stimulability by exogenous ACTH has provided the basis for diagnosis and treatment of the disorder. A qualitative biochemical abnormality consisting of marked overproduction of the products of the cortisol C-18 oxidation pathway, 18-hydroxycortisol and 18-oxocortisol, has been examined in 10 patients with the disorder and compared to the normal C-18 oxidation products of corticosterone, aldosterone, and 18-hydroxycorticosterone. The technique, based on stable isotope dilution mass fragmentography, measured the tetrahydro urinary metabolites of aldosterone, 18-hydroxycorticosterone, and 18-oxocortisol and unmetabolized 18-hydroxycortisol. All 4 C-18 oxygenated corticosteroids were markedly elevated in the untreated state and showed rapid parallel suppression with low doses of glucocorticoid. The proportional changes in C-18 oxygenated cortisols together with aldosterone and 18-hydroxycorticosterone suggested the mechanism of a common catalytic site of a cytochrome P450 methyl oxidase serving both cortisol and corticosterone substrates. The ACTH-dependent secretion of the C-18 oxidation products of both corticosterone and cortisol in the disorder is attributed to the acquisition of methyl oxidase activity by the fasciculata zone, where there are abundant pools of these precursors.