TARGETED DISRUPTION OF THE ESTROGEN-RECEPTOR GENE IN MALE-MICE CAUSESALTERATION OF SPERMATOGENESIS AND INFERTILITY

The reproductive system of male mice homozygous for a mutation in the estrogen receptor (ER) gene (ER knock-out; ERKO) appears normal at the anatomical level. However, these males are infertile, indicating an e ssential role for ER-mediated processes in the regulation of male repr oduction. Adult ERKO male mice have significantly fewer epididymal spe rm than heterozygous or wild-type males. Although spermatogenesis is o ccurring in some seminiferous tubules of 3- to 5-month-old ERKO males, other tubules either have a dilated lumen and a disorganized seminife rous epithelium with few spermatogenic cells or lack a lumen and conta in mainly Sertoli cells. There are no obvious differences in seminifer ous tubules at 10 days of age between wild-type and ERKO mice, but the lumen in ERKO males is dilated in all seminiferous tubules by 20 days . However, spermatogenesis progresses and similar numbers of sperm are present in the cauda epididymis of ERKO and wild-type males until 10 weeks of age. Disruption of spermatogenesis and degeneration of the se miniferous tubules become apparent after 10 weeks in the caudal pole o f the testis and progresses in a wave to the cranial pole by 6 months. However, the seminal vesicles, coagulating glands, prostate, and epid idymis do not appear to be altered morphologically in ERKO mice. Serum testosterone levels are somewhat elevated, but LW and FSH levels are not significantly different from those in wild-type males. Sperm from 8- to 18-week-old mice have reduced motility and are ineffective at fe rtilizing eggs in vitro, In addition, ERKO males housed overnight with hormone-primed wild-type females produce significantly fewer copulato ry plugs than do heterozygous or wild-type males. These results sugges t that estrogen action is required for fertility in male mice and that the mutation of the ER in ERKO males leads to reduced mating frequenc y, low sperm numbers, and defective sperm function.