Figure 4.

Putative pathophysiological mechanism responsible for bilateral macronodular adrenal hyperplasia. Both gonads and adrenals originate from the adrenogonadal primordium. It can be speculated that the causative genetic mutations may alter differentiation and/or separation of the adrenogonadal primordium leading to the presence of pseudo-gonadal cells in the adrenals. Secretion of ACTH by intraadrenal pseudo-gonadal cells may progressively stimulate, via activation of MC2R, both cortisol secretion and growth of the adrenocortical tissue, leading to bilateral adrenal hyperplasia associated with hypercortisolism. In parallel, sustained activation of the PKA pathway consecutive to activation of MC2R by intraadrenal ACTH may activate expression of some illegitimate receptors. Activation of steroidogenesis by ligands of illegitimate receptors further reinforces cortisol hypersecretion through both an intrinsic stimulatory action and an indirect effect via local release of ACTH.