Progression of chronic renal disease is usually more rapid in males, both in humans and in experimental animals. Estrogen-replacement studies indicate that this may be related to the beneficial effects of estrogen on the lipoprotein profile. However, in hyperlipidemic analbuminemic rats (NAR), females are more prone to develop renal injury than males, and ovariectomy tends to decrease triglyceride levels and prevent renal disease. Therefore, we studied the effects of estrogen administration on lipoproteins, and the induction of renal injury in uninephrectomized female and male NAR. Ovariectomized and orchidectomized uninephrectomized NAR were treated with estradiol implants for 24 weeks. In an additional group of ovariectomized rats, the implant was removed after 12 weeks. Both in ovariectomized and orchidectomized NAR, estradiol caused severe hypercholesterolemia (9 to 12 mmol/liter) and hypertriglyceridemia (6 to 8 mmol/liter) after six weeks. Subsequently, these rats developed severe proteinuria, reaching 209 +/- 25 and 95 +/- 43 mg/day, respectively, after 24 weeks. At this point there was severe glomerular sclerosis, with a respective score of 107 +/- 21 and 61 +/- 33. In terminal blood samples the most pronounced increase in lipid levels were observed in very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL) and low density lipoproteins (LDL). In contrast, ovariectomized NAR and orchidectomized NAR without exogenous estrogen had much lower lipid levels (cholesterol 5 to 7 mmol/liter and triglycerides 1 to 2 mmol/liter) after six weeks. These rats, or ovariectomized NAR where the estrogen treatment had been withdrawn, had practically no proteinuria (4 +/- 1, 19 +/- 11, and 13 +/- 4 mg/day, respectively) or renal damage (glomerulosclerosis score 1 +/- 0.4, 5 +/- 3 and 3 +/- 1, respectively) after 24 weeks. Thus, in hypertriglyceridemic analbuminemic rats, estrogen-treatment causes further increases in both triglycerides and cholesterol. Most probably these changes contribute to the development of renal injury by estrogen in this model. This effect of estrogen, which has also been observed in the Zucker rat, is unique for the hypertriglyceridemic state and deserves further study.