Most ovarian tumors in women occur upon aging. Follitropin receptor knockout (FORKO) mice are sterile and have age-dependent abnormalities including increased ovarian tumor incidence. To explore why atrophic ovaries of FORKO mice become tumorigenic later in life, we compared gene expression profiles by microarray at different ages. Here we show an unexpected ovarian expression of GDNF and its bimodal regulation. GDNF was down-regulated at a young age but up-regulated in aging FORKO mice prior to tumor appearance. Immunohistochemistry localized GDNF in the oocyte as well as somatic granulosa and stromal cells. GDNF protein also showed an age-dependent increase in the ovary, being lower in young mutants and increasing by 6 months. We found evidence for GDNF upregulation in GC tumors and a potential role for androgen. The peripheral expression pattern and functions of this powerful neurotropic factor suggest mediation of processes involved in pathology of ovarian compartments. (c) 2006 Elsevier Inc. All rights reserved.