Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment

Abstract

Bilateral adrenal hyperplasia is a rare cause of Cushing's syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades' findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5, and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy.

Keywords: ARMC5; Carney complex; Cushing’s syndrome; PKA pathway; PKRAR1A; bilateral adrenal hyperplasia; paracrine regulation; primary bilateral macronodular adrenal hyperplasia; primary pigmented micronodular adrenal; unilateral adrenalectomy.

Figure 1

Alteration of protein kinase A (PKA) pathway and ARMC5 in bilateral adrenal hyperplasia. (A) In normal adrenocortical cells, ACTH activates the MC2R receptor, leading to the activation of the Gα subunits of the G protein. The latter activates the adenylate cyclase (AC), which converts the ATP in cAMP. The phosphodiesterases (PDE) inactivates cAMP in AMP. The regulatory (R) subunits of the PKA bind the cAMP, leading to the release of the catalytic (C) subunits. The catalytic subunits phosphorylate their targets, including the cAMP Response Element-Binding protein (CREB), which activates genes involved in steroidogenesis. ARMC5 blocks the cell cycle in G1 phase and induces apoptosis. ARMC5 is degraded by Culin3. (B) In PPNAD and iMAD, the PKA pathway is activated by (1) mutations in the regulatory subunit R1α of PKA, (2) mutations in phosphodiesterases genes, and (3) duplication of the catalytic subunit Cα have also been described. (C) In PBMAH, the PKA pathway is activated by (1) ACTH locally produced by clusters of corticotropin adrenal cells, (2) mutations in the gene coding for MC2R, (3) mutations in gene GNAS coding for Gα, (4) aberrant expression of G-coupled protein receptors, (5) mutations in phosphodiesterase genes, (6) duplication of the catalytic subunit Cα, and (7) ARMC5 mutations, which lead to the activation of the cell cycle and the loss of apoptosis. Moreover, some mutations prevent its binding to Culin3 and its subsequent degradation. In addition, ARMC5 decreases the PKA activity.

Figure 2

Evolution of cortisol secretion in bilateral adrenal hyperplasia over time and impact of unilateral adrenalectomy.