We have already reported an equally attenuating effect of castration or estrogen administration on the development of focal segmental glomerulosclerosis (FSGS) in the animal models of a short-term experimental period ended at 24 weeks. In the present study, to clarify the importance of the experimental period in studying the pathogenesis of the development of FSGS, we investigated a long-term effect of castration or estrogen administration on FSGS using an experimental model of uninephrectomized Sprague-Dawley (SD) rats ended at 54 weeks. Thirty male SD rats received unilaterally right nephrectomy at 6 weeks of age. They were divided into three groups: group 1 was control; group 2 was castrated at 6 weeks, and group 3 was administered 0.2 mg estrogen subcutaneously once a month from 6 weeks of age. Body weight, urinary protein, serum albumin and other serum constituents were investigated every 12 weeks from 18 to 54 weeks of age. Each group was studied morphologically at the end of the experiment. Castration attenuated glomerular injury to the same extent as seen in the study of a short-term experimental period, while estrogen administration failed to attenuate glomerular injury, although each treatment equally suppressed an urinary excretion of a sex-related low-molecular-weight (LMW) protein. Castration reduced significantly kidney weight (KW), glomerular volume (GV) and serum growth hormone (GH) levels, but estrogen treatment failed to reduce KW and GV, and conversely elevated GH levels. These results suggest that a sex-related LMW protein influenced by castration or estrogen treatment may not play an important role in the development of FSGS and that an increase in plasma GH levels may contribute to the failure of an attenuating effect of estrogen on glomerular injury.