title: Nandrolone and stanozolol induce Leydig cell tumor proliferation through an estrogen-dependent mechanism involving IGF-I system.
abstract: 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.
authors.affiliation: Department of Pharmaco-Biology, University of Calabria, Cosenza, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Chimento
authors.forename: Rosa
authors.initials: R
authors.lastname: Sirianni
authors.forename: Fabiana
authors.initials: F
authors.lastname: Zolea
authors.forename: Arianna
authors.initials: A
authors.lastname: De Luca
authors.forename: Marilena
authors.initials: M
authors.lastname: Lanzino
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pezzi
mesh_terms: D045930:Anabolic Agents / Q000009:adverse effects / Q000494:pharmacology; D000728:Androgens / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007984:Leydig Cell Tumor / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D009277:Nandrolone / Q000009:adverse effects / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D013197:Stanozolol / Q000009:adverse effects / Q000494:pharmacology*; D013736:Testicular Neoplasms / Q000139:chemically induced / Q000473:pathology*
chemical_list: D045930:Anabolic Agents; D000728:Androgens; D047072:Aromatase Inhibitors; D019927:Cyclin E; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D013197:Stanozolol; D007334:Insulin-Like Growth Factor I; D009277:Nandrolone; D001141:Aromatase; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases