Primary adrenal aetiologies account for 15–20% of the causes of endogenous Cushing's syndrome. The most common cause is unilateral adrenocortical cortisol producing adenoma, while bilateral adrenal hyperplasia is responsible for only 10% of cases of adrenal Cushing's syndrome.1 Primary adrenal hyperplasia includes cases of primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary bilateral micronodular adrenal hyperplasia. Both conditions generally causes low or suppressed levels of adrenocorticotropic hormone (ACTH), but differ characteristically in terms of genetic, clinical, hormonal, and radiological presentation2 (Fig. 1).

The new World Health Organization (WHO 2022) classification of adrenal cortical proliferations reflects translational advances in the fields of endocrine pathology, oncology and molecular biology and recognises the importance of structural and functional correlations.3 In this new classification, the causes of cortical nodular adrenal disease include (a) sporadic nodular adrenocortical disease, (b) bilateral micronodular adrenal cortical disease, and (c) bilateral macronodular adrenal cortical disease (corresponding to primary bilateral macronodular adrenal hyperplasia in this review). This classification highlights the importance the frequent genetic origin of PBMAH and suggests that the term hyperplasia is not appropriate due to the characteristic clonal and/or neoplastic pattern that the disease presents. However, the use of these terms is not yet widespread in clinical practice.

In this article, a series of 32 cases with PBMAH is described, focusing on the specific treatment of hypercortisolism in these patients. In addition, it contains a comprehensive review of the most important aspects of the epidemiology, diagnosis, genetics, pathophysiology and treatment of PMBAH, highlighting the latest developments in this field in the last years.