Hypercholesterolemic Imai rats spontaneously develop proteinuria and glomerulosclerosis, especially in males. Estrogen administration attenuated glomerular injury in male Imai rats, and the aggravating effect of ovariectomy in female rats is found. To clarify whether this aggravating effect of ovariectomy is due to a lack of estrogen, we administered estrogen to ovariectomized female Imai rats. At 6 weeks of age, group 1 (control) was sham-operated and group 2 was ovariectomized. Groups 3 and 4 were ovariectomized and received estrogen replacement therapy (0.1 mg in group 3 and 0.2 mg in group 4 once a month subcutaneously). Body weight, urinary protein and serum constituents were investigated every month from 3 to 6 months of age. At 6 months of age, rats were studied morphologically. Estrogen replacement therapy increased serum estrogen to levels close to those of controls when 0.1 mg was used, or higher when 0.2 mg was used. Estrogen replacement therapy with 0.1 mg did not eliminate the aggravating effect of ovariectomy on glomerular injury and rather aggravated it, but conversely therapy with 0.2 mg attenuated glomerular injury and abolished the aggravating effect of ovariectomy. Estrogen replacement therapy markedly elevated serum GH levels dose-dependently. These results suggested that other hormones as well as estrogen may play a protective role of the ovary for the development of glomerular injury, and that estrogen seems to exert a dual effect on glomerular injury.