Adele Chimento and Rosa Sirianni contributed equally to this study.
Original Research Article
Nandrolone and stanozolol induce leydig cell tumor proliferation through an estrogen-dependent mechanism involving IGF-I system†
Article first published online: 23 JAN 2012
Copyright © 2011 Wiley Periodicals, Inc.
Journal of Cellular Physiology
Volume 227, Issue 5, pages 2079–2088, May 2012
How to Cite
Chimento, A., Sirianni, R., Zolea, F., De Luca, A., Lanzino, M., Catalano, S., Andò, S. and Pezzi, V. (2012), Nandrolone and stanozolol induce leydig cell tumor proliferation through an estrogen-dependent mechanism involving IGF-I system. J. Cell. Physiol., 227: 2079–2088. doi: 10.1002/jcp.22936
The authors have declared that no conflict of interest exists.
- Issue published online: 23 JAN 2012
- Article first published online: 23 JAN 2012
- Accepted manuscript online: 18 JUL 2011 08:15AM EST
- Manuscript Accepted: 7 JUL 2011
- Manuscript Received: 23 MAY 2011
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
Several substances such as anabolic androgenic steroids (AAS), peptide hormones like insulin-like growth factor-I (IGF-I), aromatase inhibitors and estrogen antagonists are offered via the Internet, and are assumed without considering the potential deleterious effects that can be caused by their administration. In this study we aimed to determine if nandrolone and stanozolol, two commonly used AAS, could have an effect on Leydig cell tumor proliferation and if their effects could be potentiated by the concomitant use of IGF-I. Using a rat Leydig tumor cell line, R2C cells, as experimental model we found that nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and estradiol (E2) production. When used in combination with IGF-I they were more effective than single molecules in inducing aromatase expression. AAS exhibited estrogenic activity and induced rapid estrogen receptor (ER)-dependent pathways involving IGF1R, AKT, and ERK1/2 phosphorylation. Inhibitors for these kinases decreased AAS-dependent aromatase expression. Up-regulated aromatase levels and related E2 production increased cell proliferation as a consequence of increased cyclin E expression. The observation that ER antagonist ICI182,780 was also able to significantly reduce ASS- and AAS + IGF-induced cell proliferation, confirmed a role for estrogens in AAS-dependent proliferative effects. Taken together these data clearly indicate that the use of high doses of AAS, as it occurs in doping practice, enhances Leydig cell proliferation, increasing the risk of tumor development. This risk is higher when AAS are used in association with IGF-I. To our knowledge this is the first report directly associating AAS and testicular cancer. J. Cell. Physiol. 227: 2079–2088, 2012. © 2011 Wiley Periodicals, Inc.