Altered Structure and Function of Reproductive Organs in Transgenic Male Mice Overexpressing Human Aromatase*

Abstract

Aromatization of androgens is a key step in estrogen production, and it regulates the delicate balance between estrogens and androgens in the gonads and sex steroid target tissues. In the present study, we generated transgenic mice (AROM(+)) bearing the human ubiquitin C promoter/human P450 aromatase fusion gene. AROM(+) male mice are characterized by an imbalance in sex hormone metabolism, resulting in elevated serum E(2) concentrations, combined with significantly reduced testosterone and FSH levels, and elevated levels of PRL and corticosterone. AROM(+) males present a multitude of severe structural and functional alterations in the reproductive organs, such as cryptorchidism associated with Leydig cell hyperplasia, dysmorphic seminiferous tubules, and disrupted spermatogenesis. The males also have small or rudimentary accessory sex glands with abnormal morphology; a prominent prostatic utricle with squamous epithelial metaplasia, and edema in the ejaculatory ducts and vas deferens. In addition, the abdominal muscle wall is thin, and the adrenal glands are enlarged, with cortical hyperplasia. Some of the abnormalities, such as undescended testes and undeveloped prostate, resemble those observed in animals exposed perinatally to high levels of exogenous estrogen, indicating that the elevated aromatase activity results in excessive estrogen exposure during early phases of development. Some of the disorders in the reproductive organs, furthermore, can be explained by the fact that AROM(+) males are hypoandrogenic, and have elevated levels of serum PRL and corticosterone. Thus, the AROM(+) mouse model provides a novel tool to investigate the consequences of a prolonged increase in conversion of androgens to estrogens which results in complex hormonal disturbances altering the structure and function of various male reproductive organs.

Fetal but not adult Leydig cells are susceptible to adenoma formation in response to persistently high hCG level: a study on hCG overexpressing transgenic mice

“…Also, estrogens have been shown to cause LC adenomas by increasing LH or LHR levels in certain mouse strains (Huseby, 1980;Navickis et al, 1981). Our recent study of male TG mice overexpressing P450 aromatase (AROM þ ) demonstrated development of LC hyperplasia in the presence of normal circulating LH and low testicular T (Li et al, 2001). However, it is possible that the high prolactin levels in these mice have enhanced LC response to LH, because prolactin in rodents is able to upregulate testicular Lhcgr expression (Huhtaniemi et al, 1985b).…”

Estrogen regulation of testicular function

“…In contrast to the lack of E2, overexpression of the aromatase gene and enhanced E2 production in mice induced cryptorchidism or undescended testis, spermatogenic arrest, Leydig cell hyperplasia, and decreased serum FSH and testosterone levels. Disruption of spermatogenesis was associated with decreased FSH levels while increased exposures to E2 induce Leydig cell hyperplasia [58]. Progressive degeneration of testicular tissue, dilation of the seminiferous tubules, and sexual behavioral problems are typical findings in αERKO mice [5].…”

Relationship between urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites and reproductive hormones in polyvinyl chloride production workers

“…Other studies13 46 57 also showed that DEHP exposure induced the aromatase stimulation proliferative capacity of Leydig cell-precursor proliferation and resulted in Leydig-cell hyperplasia during the pubertal period in rats. Studies on the T-treated rat model,58 aromatase knockout mice59 and aromatase-overexpressing mice60 61 suggest that an imbalance between androgens and oestrogens, and a shift in the E 2 :T ratio might be associated with a risk of prostate cancer. In humans, however, there is not enough evidence of an association between circulating oestrogen levels and the risk of prostate cancer; a clear relationship is uncertain and warrants further investigation 62.…”