Pre-pubertal onset of diabetes mellitus (DM) in male rats delays diabetic renal hypertrophy and suppresses renal transforming growth factor beta (TGF-) when compared to onset in adult males. Because there are sex differences in normal and pathologic renal growth, we performed similar experiments in female rats and examined the effects of prior ovariectomy. As in male rats, adult onset of DM increased renal weight ~35%, total renal TGF- ~35%, and mRNA for TGF- inducible gene H3 (IG-H3) ~200%. TGF- levels did not increase with DM in pre-pubertal animals, but renal weight increased ~40%, similar to the enlargement seen in adults. In nondiabetic rats, ovariectomy suppressed renal TGF- levels by 25-50% in both age groups, but IG-H3 was stable in younger animals and increased by ~200% in older animals following ovariectomy. Ovariectomy increased kidney weight ~10% in both age groups. DM further increased kidney weight by an additional 40% following ovariectomy with ~150% increase in IG-H3, even though TGF- levels were not significantly increased. Pre-pubertal (~99% lower), diabetic (~50% lower), and ovariectomized rats (~90% lower) all tended toward lower estradiol levels than intact adults, though not all differences were statistically significant. Both pre-pubertal onset and ovariectomy suppress TGF- in the kidneys of female rats with DM compared with adult onset animals, but these states have no effect on renal enlargement. Production of the extracellular matrix component IG-H3 is dissociated from TGF- under these conditions. These observations may help explain some of the sex differences demonstrated in progressive kidney diseases, including DM.