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.

Nandrolone and stanozolol upregulate aromatase expression and further increase IGF-I-dependent effects on MCF-7 breast cancer cell proliferation

“…The combination of nandrolone and stanozolol with IGF-I increased E2 production to levels higher than those obtained with the use of each single agent. We have recently shown that the two AAS increase IGF-I production in a tumor Leydig cell line (Chimento et al, 2012) and potentially a similar effect could also occur in MCF-7 cells. Thus, when IGF-I was used in combination with nandrolone and stanozolol, the amount of IGF-I available to the cells was higher than the concentration used to originally treat the cells.…”

“…Clinical reports highlight a link between AAS abuse and different kinds of cancer, such as hepatocellular adenomas and adenocarcinomas (Socas et al, 2005). In addition, we have recently reported that AAS, through the activation of estrogen-dependent pathways, are involved in the progression of a type of testicular cancer (Chimento et al, 2012). To date no data regarding the relationship between AAS abuse and breast cancer risk are available.…”

Annual banned‐substance review: analytical approaches in human sports drug testing

“…[23] The attraction of anabolic agents apparently continues to be unconfined among cheating athletes and recreational sportsmen and women despite numerous comprehensive and new reports on health risks attributed to the abuse of AAS, [24,25] ranging from acne fulminans [26] over cardiovascular issues [27][28][29][30][31] to increased risk of breast and Leydig cell cancer [32,33] as well as psychic disorders and dependence. [23] The attraction of anabolic agents apparently continues to be unconfined among cheating athletes and recreational sportsmen and women despite numerous comprehensive and new reports on health risks attributed to the abuse of AAS, [24,25] ranging from acne fulminans [26] over cardiovascular issues [27][28][29][30][31] to increased risk of breast and Leydig cell cancer [32,33] as well as psychic disorders and dependence.…”

Illicit use of androgens and other hormones

“…This is a matter of concern, since both androgens [44, 45] and HGH [46–49] exhibit cardiac toxicity, raising the specter of synergistic cardiotoxic effects in individuals combining these hormones. Synergistic effects might influence other organ systems as well; one new report suggests that androgens might interact with IGF-1 to enhance Leydig cell proliferation, with a possible increased risk of testicular cancer [25]. …”

“…These studies include, for example, investigations of androgen effects in animal models, including several new studies of mechanisms for androgen-induced aggression [17–20] and possible androgen-related depression [21]. Recent animal studies have also pursued mechanisms of the performance-enhancing effects of androgens (for review see [22]), as well as androgen-induced adverse effects, including cardiac [23], neuronal [24], and possible carcinogenic effects [25]. We will not attempt a complete review of these animal studies here, since this review is focused primarily on illicit human androgen use, but important animal studies of immediate relevance to human androgen abuse are mentioned in the text that follows.…”