Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice

Research output: Contribution to journalResearch articleContributedpeer-review


  • Rodanthi Lyraki - , Université Côte d'Azur (Author)
  • Anaëlle Grabek - , Université Côte d'Azur (Author)
  • Amélie Tison - , Université Côte d'Azur (Author)
  • Lahiru Chamara Weerasinghe Arachchige - , Université Côte d'Azur (Author)
  • Mirko Peitzsch - , Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus Dresden (Author)
  • Nicole Bechmann - , Institute of Clinical Chemistry and Laboratory Medicine, Department of internal Medicine 3, University Hospital Carl Gustav Carus Dresden (Author)
  • Sameh A Youssef - , Utrecht University (Author)
  • Alain de Bruin - , Utrecht University (Author)
  • Elvira R M Bakker - , University Medical Center (UMC) Utrecht (Author)
  • Frank Claessens - , KU Leuven (Author)
  • Marie-Christine Chaboissier - , Université Côte d'Azur (Author)
  • Andreas Schedl - , Université Côte d'Azur (Author)


Female bias is highly prevalent in conditions such as adrenal cortex hyperplasia and neoplasia, but the reasons behind this phenomenon are poorly understood. In this study, we show that overexpression of the secreted WNT agonist R-spondin 1 (RSPO1) leads to ectopic activation of WNT/β-catenin signaling and causes sex-specific adrenocortical hyperplasia in mice. Although 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 regulation of the WNT-related genes Axin2 and Wnt4. Notably, genetic removal of androgen receptor (AR) from adrenocortical cells restores the mitogenic effect of WNT/β-catenin signaling. This is the first demonstration that AR activity in the adrenal cortex determines susceptibility to canonical WNT signaling-induced hyperplasia.


Original languageEnglish
JournalDisease models & mechanisms
Issue number6
Publication statusPublished - 1 Jun 2023

External IDs

PubMedCentral PMC10184674
Scopus 85159727530
Mendeley a8e751bf-0883-340d-89f7-bcfe764b17c8
ORCID /0000-0002-6932-333X/work/142239676



  • Male, Mice, Female, Animals, Wnt Signaling Pathway, Receptors, Androgen/genetics, beta Catenin/metabolism, Hyperplasia, Wnt Proteins/genetics, Adrenocortical hyperplasia, R-spondin signaling, Androgen receptor, Sexual dimorphism