Permanent effects of neonatal estrogen exposure in rats on reproductive hormone levels, sertoli cell number, and the efficiency of spermatogenesis inadulthood

This study aimed to identify the mechanism(s) for impairment of spermatogen esis in adulthood in rats treated neonatally with estrogens. Rats were trea ted (days 2-12) with 10, 1, or 0.1 mu g diethylstilbestrol (DES), 10 mu g e thinyl estradiol (EE), 10 mg/kg of a GnRH antagonist (GnRHa), or vehicle an d killed in adulthood. DES/EE caused dose-dependent reductions in testis we ight, total germ cell volume per testis, and Sertoli cell volume per testis . Sertoli cell number at 18 days of age in DES-treated rats was reduced dos e dependently. GnRHa treatment caused changes in these parameters similar t o those in rats treated with 10 mu g DES. Plasma FSH levels were elevated ( P < 0.001) to similar levels in all treatment groups regardless of differen ces in Sertoli cell number and levels of inhibin B; the latter reflected Se rtoli cell number, but levels were disproportionately reduced in animals tr eated with high doses of DES/EE. Neonatal estrogen treatment, but not GnRHa , caused dose-dependent reductions (40-80%) in plasma testosterone levels i n adulthood, but did not alter LH levels. Preliminary evidence suggests tha t the decrease in testosterone levels in estrogen-treated rats is not due t o reduced Leydig cell volume per testis. GnRHa-treated rats exhibited a significant increase in germ cell volume per Sertoli cell and a reduction in germ cell apoptosis, probably because of t he raised FSH levels. Despite similar raised FSH levels, rats treated with DES (10 or 1 mu g) or EE (10 mu g) had reduced germ cell volume/Sertoli cel l and increased germ cell apoptosis, especially when compared with GnRHa-tr eated animals. The latter changes were associated with an increase in lumen size per testis, indicative of impaired fluid resorption from the efferent ducts, resulting in fluid accumulation in the testis. Rats treated neonata lly with 0.1 mu g DES showed reduced germ cell apoptosis comparable to that in GnRHa-treated animals. The changes in apoptotic rate among treatment gr oups occurred across all stages of the spermatogenic cycle. It is concluded that 1) neonatal estrogen treatment results in dose-dependent alterations in Sertoli cell numbers, germ cell volume, efficiency of spermatogenesis, a nd germ cell apoptosis in adulthood; 2) the relatively poor spermatogenesis in estrogen-treated animals is most likely due to altered testis fluid dyn amics and/or altered Sertoli cell function; 3) as indicated by FSH (LII) an d testosterone levels, the hypothalamic-pituitary axis and Leydig cells are probably more sensitive than the Sertoli cells to reprogramming by estroge ns neonatally; and 4) elevated FSH levels in adulthood may improve the effi ciency of spermatogenesis.