When combined with the aromatase inhibitors, testosterone no longer protected against cell damage at normal concentrations and a significantly greater amount of damage was done at the higher concentrations. Neither aromatase inhibitor affected the three AAS (nortestosterone, stanozolol, gestrinone), which is consistent with their being considered nonaromatizable AAS. The androgen receptor antagonist flutamide reduced the damage done at the higher concentrations in all four AAS. The female steroids, estradiol and progesterone, both protected against cell death, though the protective effect of estrogen was lost at higher concentrations. These findings all support the suggestion that the increased vulnerability to NMDA is due to actions involving the androgen receptor. Interestingly, gestrinone actually became less toxic at the highest concentrations. The authors commented that the progesterone-like qualities of gestrinone may become more prominent at those concentrations.

    One last experiment was run to see if the effect required a long-term exposure to AAS or if the increased damage was realized immediately. To study this, the researchers exposed another round of brain cell cultures to NMDA, along with the various androgens, for 10 minutes and then looked for cell death. These cultures had not been previously exposed to any of the steroids. Testosterone did not significantly affect brain cell death; stanozolol did so only at the highest concentration; and gestrinone’s effects lessened as the concentration increased. Nortestosterone increased cell death at medium to high doses. This aspect of the experiment was relevant, as it supports a hypothesis that the effect is related to AAS activity at the membrane receptors (nongenomic) and not solely dependent upon the classic nuclear receptor complex (genomic). In other words, AAS do have some immediate effect and do not require days to weeks to act on certain parts of a cell’s metabolism. The more obvious effect of AAS, muscle growth, occurs over days to weeks and involves activation of specific genes in the muscle cell DNA. Similar effects occurring at the membrane receptors are seen with other hormones, including IGF-1 and insulin, which some users will stack with AAS. This increases the potential for problems in people who stack numerous anabolic agents and makes it difficult to predict the level of risk.

    So what is learned? AAS do not appear to be dangerous, even at high doses, in a pristine environment. However, if a chemical challenge is present, certain AAS may make brain cells (in a mouse, at least) more prone to damage and even cell death. The greatest danger appears to come from AAS that do not aromatize or if an aromatase inhibitor is used when AAS concentrations are elevated.