Sexual dimorphism in benign adrenocortical tumours

Abstract

Benign adrenocortical tumours are the most common adrenal neoplasms. Evidence over the past few decades has highlighted sex differences in their prevalence, clinical characteristics, and treatment outcomes. Cortisol-producing adenomas causing either Cushing's syndrome, particularly those with PRKACA or GNAS somatic mutations associated with a more severe phenotype, or mild autonomous cortisol secretion (MACS) are more commonly observed in women. The mechanisms underpinning this sexual dimorphism remain to be fully elucidated. Studies in mice have revealed a protective role of androgens in males, leading to a decelerated growth rate of adrenocortical cells. Furthermore, evidence from human adrenal tumour tissue suggests that oestrogen, progesterone, and luteinising hormone/choriogonadotropin signalling in the adrenal cortex may play a role in adrenal tumourigenesis and steroid production. Clinically, this is supported by the increased incidence of cortisol-producing adrenocortical adenomas or nodular hyperplasia during puberty, pregnancy, and menopause. Notably, women with MACS seem to be more vulnerable to the harmful effects of cortisol excess and carry a higher mortality risk than men. Women with aldosterone-producing adenomas have a higher prevalence of somatic KCNJ5 mutations than men, and patients harbouring these mutations are likely to have more favourable clinical outcomes after adrenalectomy. In this review, we summarise the possible mechanisms behind the sexual dimorphism of benign adrenocortical tumours and provide an up-to-date overview of the sex-specific differences in their prevalence, clinical presentation, and outcomes, focusing on cortisol and aldosterone excess. Considering sexual dimorphism is crucial to guide diagnosis and management, and to counsel these patients for optimised care.

Keywords: Cushing's syndrome; adrenal tumour; mild autonomous cortisol secretion; primary aldosteronism; sexual dimorphism.

Graphical Abstract

Figure 1.

Adrenal cortex renewal from mouse models. The adrenal gland continuously regenerates itself by stem cell proliferation and migration from the capsule or subcapsular zona glomerulosa to the inner zone (centripetal migration model). In female mice, the capsular Gli1+ stem cells and the Axin2+/Shh+ progenitor cells are responsible for this process, whereas androgens inhibit the proliferation and migration of the Gli1+ stem cells in males. Other cells, including WT1-positive and nestin-positive progenitor cells, are also involved in replenishing the adrenal gland (not shown). As regenerated cells migrate to the inner zone, they mature into zona glomerulosa and fasciculata cells. Cell migration and zonal differentiation are influenced by the interaction between the Wnt and protein kinase A (PKA) signalling pathways. The Wnt pathway stimulates zona glomerulosa cell differentiation (with a lessening activation gradient from the zona glomerulosa to the zona fasciculata), while PKA signalling promotes the differentiation into zona fasciculata cells (with a lessening activation gradient from the zona fasciculata to the zona glomerulosa). The fate of adrenocortical cells is partially determined by the interplay between these 2 pathways.

Figure 2.

Putative mechanisms contributing to the sexual dimorphism of adrenocortical tumourigenesis. Factors potentially involved in the sexual dimorphism of adrenocortical tumours include (1) oestrogen, progesterone, and luteinizing hormone/choriogonadotropin signalling, (2) differences in the intra-adrenal immunological milieu (described in mouse models of adrenocortical carcinoma only), (3) possible differences in the stress response, and (4) differences in telomere attrition between sexes. The effects of androgens on adrenal gland formation, proliferation, and renewal are shown in Figure 1. Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; ER, nuclear oestrogen receptor; GPER, G protein-coupled oestrogen receptor; hCG, human chorionic gonadotropin; LH, luteinising hormone; LHCGR, luteinising hormone/choriogonadotropin receptor; mPR, membrane progesterone receptor; MR, melanocortin receptor; PR, nuclear progesterone receptor.