Altered structure and function of reproductive organs in transgenic male mice overexpressing human aromatase

Aromatization of androgens is a key step in estrogen production, and it reg ulates the delicate balance between estrogens and androgens in the gonads a nd sex steroid target tissues. In the present study, we generated transgeni c mice (AROM(+)) bearing the human ubiquitin C promoter/human P450 aromatas e fusion gene. AROM(+) male mice are characterized by an imbalance in sex h ormone metabolism, resulting in elevated serum E, concentrations, combined with significantly reduced testosterone and FSH levels, and elevated levels of PRL and corticosterone. AROM+ males present a multitude of severe struc tural and functional alterations in the reproductive organs, such as crypto chidism associated with Leydig cell hyperplasia, dysmorphic seminiferous tu bules, and disrupted spermatogenesis. The males also have small or rudiment ary accessory sex glands with abnormal metaplasia, and edema in the ejacula tory ducts and vas deferens. In addition, the abdominal muscle wall is thin , and the adrenal glands are enlarged, with cortical hyperplasia. Some of t he abnormalities, such as undescended testes and undeveloped prostate, rese mble those observed in animals exposed perinatally to high levels of exogen ous estrogen, indicating that the elevated aromatase activity results in ex cessive estrogen exposure during early phases of development. Some of the d isorders in the reproductive organs, furthermore, can be explained by the f act that AROM(+) males are hypoandrogenic, and have elevated levels of seru m PRL and corticosterone. Thus, the AROM+ mouse model provides a novel tool to investigate the consequences of a prolonged increase in conversion of a ndrogens to estrogens which results in complex hormonal disturbances alteri ng the structure and function of various male reproductive organs.