Dual effect of estrogen on glomerular injury in hypercholesterolemic male Imai rats: its regulation by testosterone

Abstract

Background. Hypercholesterolemic Imai rats, especially males, spontaneously develop proteinuria and glomerulosclerosis. We previously studied the effect of estrogen on the development of glomerular injury in this rat strain and found that estrogen treatment showed a sex difference in its effect on glomerular injury, exerting dual effect, an attenuating effect in males and an exacerbatory effect in females. Because this dual effect seemed to be related to and regulated by testosterone, in the present study, we investigated whether estrogen's effect on glomerular injury differed in the presence and absence of testosterone, using castrated male Imai rats in experiment 1 (Exp 1), and testosterone-replaced castrated Imai rats in Exp 2.

Methods. In Exp 1, groups (G)1 and 2 were sham-operated and G3 and 4 were castrated at 6 weeks of age. G2 and 4 received estrogen. In Exp 2, G1 was sham-operated and G2 was castrated. G3 and 4 were castrated and received testosterone replacement therapy with G4 receiving additional estrogen therapy. Body weight, urinary protein, and serum constituents were investigated every 4 weeks, from 12 weeks through 24 weeks of age. At 24 weeks of age, the rats were studied morphologically.

Results. Estrogen treatment of control male rats attenuated glomerular injury to levels equal to those in castrated rats, but, conversely, the same treatment in castrated rats exacerbated the glomerular injury, with an increase in serum growth hormone (GH) levels. In Exp 2, testosterone replacement therapy abolished the attenuating effect of castration but estrogen treatment of testosterone-replaced castrated rats attenuated the glomerular injury with a reduction in serum GH levels.

Conclusions. The results suggest that a dual, attenuating and exacerbatory, effect of estrogen on glomerular injury is regulated by testosterone, and that up-regulation of GH by estrogen may contribute to the exacerbatory effect of estrogen.