The mediation of lesion-induced sprouting in the nervous system is a complex interaction of local membrane factors and circulating hormones. This series of studies examines the reactivity of the sprouting response of both male and female subjects under different hormonal conditions. Young adult male and female Sprague-Dawley rats which were gonadectomized (GDX) and adrenalectomized (ADX) underwent a unilateral entorhinal cortex lesion, which partially denervates the molecular layer of the ipsilateral hippocampal denate gyrus. At the time of the lesion, each animal received hormonal therapy. Fifteen days post-ERC-ablation the brains were analyzed for changes in reactive fiber outgrowth in the hippocampal commissural/associational afferents. Fiber outgrowth in females in the "asteroidal" (GDX/ADX) condition was unaffected. Asteroidal males demonstrated a decreased response. Gonadal steroid replacement, estrogen or testosterone, enhanced outgrowth in both asteroidal males and females. Glucocorticoid replacement suppressed outgrowth in both asteroidal males and females. Gonadal steroids clearly have neurotrophic activity which is interactive with glucocorticoid activity. Glucocorticoids under the GDX/ADX conditions in vivo have a negative impact on fiber outgrowth in both sexes. The effect of glucocorticoids is most dramatic when compared to the outgrowth of asteroidal animals without additional hormonal supplementation.