Department of Reproducive Biology, Imperial College London, London, UK
Gonadectomy induces adrenal hyperplasia and tumorigenesis in certain inbred stains of mice, but its mechanism remains unclear. This adrenal response is apparently due to the post-gonadectomy elevation of gonadotrophins, because similar phenotype is observed in transgenic mice overexpressing luteinising hormone (LH) or chorionic gonadotrophin (hCG). Because the adrenal responsiveness to gonadectomy and high LH/hCG is strain dependent, we set out to unravel its genetic basis. Tumorigenic DBN 2J and non-tumorigenic C57BL/6J mice, as well as their F2 and backcrosses, were studied by whole genome linkage analysis. Gonadectomy induced similar up-regulation of adrenal LH receptors (LHR) in both parental strains and their crosses, irrespective of the tumor status, indicating that ectopic LHR expression is not the immediate cause of tumors. Linkage analysis revealed one major significant locus for the tumorigenesis on chromosome 8, modulated by epistasis with another quantitative trait locus on chromosome 18. Hence, postgonadectomy adrenal tumorigenesis in DBN2J mice is a dominant trait, not a direct consequence of adrenal LHR expression, but driven by a complex genetic architecture. Candidate genes in the tumorigenesis linkage region included Sfrp 1 (secreted frizzled-related protein 1), a tumor suppressor gene, which was down-regulated in the neoplastic areas. The gonadotrophin dependence of adrenal tumours ("gonadal rest") may be analogous to ACTH-dependence of adrenal rest tumours in the testis, and explained by the common embryonic origin of adrenal cortex and gonadal somatic cells. Our findings may have relevance to the human pathogenesis of macronodular adrenal hyperplasia and postmenopausal adrenocortical tumours.