Elevated Androgens and Prolactin in Aromatase-Deficient Mice Cause Enlargement, But Not Malignancy, of the Prostate Gland

Abstract

Although androgens are the main steroids controlling the growth of the mammalian prostate, increasing evidence demonstrates that estrogens also regulate prostate development and growth. This study describes the effects of estrogen deficiency using aromatase knockout mice (ArKO) with targeted disruption of the cyp19 gene. Serum and tissue testosterone and 5alpha-dihydrotestosterone as well as serum PRL levels are significantly (P < 0.05) elevated in mature male ArKO mice. Histological, stereological, and immunohistochemical studies demonstrated enlargement of the ventral, anterior, and dorsolateral lobes of the prostate in young and older ArKO mice. Hyperplasia of the epithelial, interstitial, and luminal compartments was identified and associated with up-regulation of androgen receptors. There was no evidence of malignancy as the animals aged (up to 56 weeks). The changes observed in the prostates of ArKO mice were unaffected by maintaining mice on regular or soy-free diets. It is concluded in ArKO mice that, despite the long-term elevation of androgens and PRL, the absence of estrogen in these animals does not result in induction of malignancy in the prostate gland.

Oestrogens and prostate cancer.

“…Serum testosterone levels were increased up to eightfold in the ArKO mice and dihydrotestosterone (DHT) levels were also elevated. In the prostate tissue itself the hormone profiles were different: DHT rather than testosterone levels were significantly elevated and were accompanied by an up-regulation in androgen receptor immunoexpression (McPherson et al 2001). As well, serum prolactin was elevated in these mice and may contribute to the emergence of the prostatic phenotype since overexpression of prolactin causes prostatic enlargement (Wennbo et al 1997).…”

“…In the absence of oestrogen there is a lifelong elevation of androgens in male ArKO mice, benign prostatic hyperplasia (BPH; Fig. 2B) develops in maturity (McPherson et al 2001). Serum testosterone levels were increased up to eightfold in the ArKO mice and dihydrotestosterone (DHT) levels were also elevated.…”

Increased Endogenous Estrogen Synthesis Leads to the Sequential Induction of Prostatic Inflammation (Prostatitis) and Prostatic Pre-Malignancy

“…21,22 Briefly, following fixation the prostate tissues or recombinants were processed and embedded in paraffin wax and serially sectioned at 5 m for histological and/or stereological analysis. After dewaxing, the sections were rehydrated antigen retrieval (0.01 M/L citrate buffer at pH 6.0 or 0.05 M/L Tris/0.01% EDTA at pH 9.0) was performed.…”

“…Uniform systematic random sampling was then used to quantitate the number of positive cells on toluidine blue or immunohistochemical stained sections, as previously described. [21][22][23] In brief, the sections were examined under ϫ40 magnification; they were mapped to define tissue boundaries and were sampled at predetermined intervals along the x-and y-axes using a single point grid-counting frame. Positive cells were then scored and totaled for each respective gland, the final number being expressed as the number of positive cells per unit area.…”

Elevated level of inhibin-α subunit is pro-tumourigenic and pro-metastatic and associated with extracapsular spread in advanced prostate cancer

“…Lymph node volumes were determined using stereological analysis as previously described (McPherson et al, 2001). The lymph nodes were serially sectioned at 5 mm thickness and using a random sampling scheme, every 20th section was chosen for analysis.…”