Adrenal cortex size, homeostasis and tumorigenesis is regulated by gonadal hormones via androgen receptor/β-catenin signalling crosstalk

Female bias is highly prevalent among adrenal cortex hyperplasia and neoplasia, but the reasons behind this phenomenon are poorly understood. In this article, we show that overexpression of the secreted WNT agonist R-spondin-1 leads to ectopic activation of WNT/β-catenin signalling and causes sex-specific adrenocortical hyperplasia in mice. While female adrenals show ectopic proliferation, male adrenals display excessive immune system activation and cortical thinning. Using a combination of genetic manipulations and hormonal treatment, we show that gonadal androgens suppress ectopic proliferation in the adrenal cortex and determine the selective activation of WNT-related genes Axin2 and Wnt4. Notably, genetic removal of androgen receptor (AR) from adrenocortical cells restores the mitogenic effect of WNT/β-catenin signalling. This is the first demonstration that AR activity in the adrenal cortex determines susceptibility to canonical WNT signalling-induced hyperplasia.TeaserActivation of R-spondin signaling in the adrenal cortex leads to a sexually dimorphic phenotype causing tumors in females and immune cell recruitment in males