Suppression of androgen action and the induction of gross abnormalities ofthe reproductive tract in male rats treated neonatally with diethylstilbestrol

This study evaluated whether androgen action is altered in rats treated neo natally with diethylstilbestrol (DES) at a dose that induced reproductive t ract abnormalities. Rats were treated on alternate days 2-12 with 10 mug DE S and studied on Day 18. DES-induced abnormalities included a 70% reduction in testis weight, distension and overgrowth of the rete, distension and re duction in epithelial height of the efferent ducts, underdevelopment of the epididymal duct epithelium, reduction in epithelial height in the vas defe rens, and convolution of the extra-epididymal vas. In DES-treated rats, and rogen receptor (AR) immunoexpression was virtually absent from all affected tissues and the testis, whereas AR expression in controls was intense in e pithelial and stromal cells. The DES-induced change in AR immunoexpression was confirmed by Western analysis for the testis. In rats treated neonatall y with 1 mug DES, reproductive abnormalities were absent or minor, except f or a 38% reduction in testis weight; loss of AR immunoexpression also did n ot occur in these rats. Treatment-induced changes in AR expression were par alleled by changes in Leydig cell volume per testis (91% reduction in the 1 0-mug DES group; no change in the 1-mug DES group). To test whether suppres sion of androgen production or action alone could induce comparable reprodu ctive abnormalities to 10 mug DES, rats were treated neonatally with either a potent gonadotropin-releasing hormone antagonist (GnRHa) or with flutami de (50 mg/kg/day). These treatments reduced testis weight (68% for GnRHa, 4 0% for flutamide), and generally retarded development of the reproductive t ract but failed to induce the abnormalities induced by 10 mug DES. GnRHa an d flutamide caused no detectable change in AR immunoexpression in target ti ssues, with the exception of minor changes in the testes of flutamide-treat ed males. GnRHa treatment caused a reduction (83%) in Leydig cell volume co mparable to that caused by 10 mug DES. Immunoexpression of estrogen recepto r alpha (ER alpha) in the efferent ducts and of ERP in all tissues studied were unaffected by any of the above treatments. Neonatal coadministration o f testosterone esters (TE; 200 mug) with 10 mug DES prevented most of the m orphological abnormalities induced by 10 mug DES treatment alone, though te stis weight was still subnormal (46% reduction in DES + TE vs 72% in DES al one and 49% with TE alone) and some lumenal distension was still evident in the efferent ducts. Coadministration of TE with DES prevented DES-induced loss of AR immunoexpression (confirmed for testis by Western blot analysis) . It is concluded that 1) reproductive tract abnormalities induced in the n eonatal male rat by a high (10 mug) dose of DES are associated with reduced AR expression and Leydig cell volume; 2) these changes are largely absent with a lower dose of DES (1 mug); 3) treatments that interfere with androge n production (GnRHa) or action (flutamide) alone failed to induce reproduct ive tract abnormalities or alter AR expression as did 10 mug DES; 4) a gros sly altered androgen:estrogen balance (low androgen + high estrogen) may un derlie the reproductive tract abnormalities, other than reduced testis weig ht, induced by high doses of DES.