Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene

It is well established that spermatogenesis is controlled by gonadotrophins and testosterone. However, a role for estrogens in male reproduction recen tly was suggested in adult mice deficient in estrogen receptor cu, These mi ce became infertile primarily because of an interruption of fluid reabsorpt ion by the efferent ductules of the epididymis, thus. leading to a disrupti on of the seminiferous epithelium [Hess,. R. A., Bunick, D., Lee, K. H., Ba hr, J., Taylor, J. A., Korach, K. S., and Lubabn, D. B. (1997) Nature (Lond on) 390, 509-512], Despite the demonstration of the aromatase enzyme, which converts androgens to estrogens, and estrogen receptors within the rodent seminiferous epithelium, the role of aromatase and estrogen in germ cell de velopment is unknown. We have investigated spermatogenesis in mice that lac k aromatase because of the targeted disruption of the cyp19 gene (ArKO). Ma le mice deficient in aromatase were initially fertile but developed progres sive infertility, until their ability to sire pups was severely impaired. T he mice deficient in aromatase developed disruptions to spermatogenesis bet ween 4.5 months and 1 year, despite no decreases in gonadotrophins or andro gens, Spermatogenesis primarily was arrested at early spermatogenic stages, as characterized by an increase in apoptosis and the appearance of multinu cleated cells, and there was a significant reduction in round and elongated spermatids, but no changes in Sertoli cells and earlier germ cells. In add ition, Leydig cell hyperplasia/hypertrophy was evident, presumably as a con sequence of increased circulating luteinizing hormone. Our findings indicat e that local expression of aromatase is essential for spermatogenesis and p rovide evidence for a direct action of estrogen on male germ cell developme nt and thus fertility.