Inflammation and epithelial alterations in rat prostate: impact of the androgen to oestrogen ratio

Abstract

Chronic non-bacterial prostatitis may offer new insights into the pathogenesis of human benign prostatic hyperplasia and prostate cancer and the strategies for their treatment and prevention. The potential significance of androgen replacement therapy in terms of the reversal of oestradiol (E(2))-induced inflammatory reaction was studied in the dorsolateral prostate (DLP) of the Noble rat. Castrated Noble rats were treated with E(2) and different doses of androgens [dihydrotestosterone (DHT) and testosterone (T)] to achieve an elevated concentration of E(2) and a wide range of the androgen-to-oestradiol ratios in serum. After the 3-week treatment, inflammatory changes in the DLP were classified and counted. Oestrogen receptor alpha (ER alpha), progesterone receptor (PR), fos-related antigen-2 (Fra2), Ki-67 and P63 were immunocytochemically stained. T, E(2) and prolactin concentrations in serum were measured and the relative weights of the seminal vesicles and pituitary glands and microscopic structures of the DLP and seminal vesicle ducts were determined. Hypoandrogenic doses of DHT (judged on the basis of seminal vesicle weight gain), dose-dependently increased the number of perivascular and stromal inflammatory infiltrates. T and DHT were anti-inflammatory at the doses which normalized or over stimulated the growth of the seminal vesicles. As signs of anti-oestrogenicity, androgens dose-dependently decreased the number and distribution of the ER alpha and PR-positive cells at proinflammatory concentrations. Anti-inflammatory concentrations were needed to reduce the expression of Fra2, E(2)-increased prolactin concentration in serum and pituitary weight. The androgen concentrations required to prevent proinflammatory and epithelial responses to E(2) in the presence of elevated E(2) concentrations may subject the accessory sex glands to more intense androgenic stimulation than is normal for the male. The androgen-resistant endpoints of oestrogen action (body weight reduction and hyperplasia of seminal vesicle ducts) further indicate limitations in the possible preventive effects of androgen-replacement therapy.

Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit

“…An anti-inflammatory effect of testosterone in castration-induced prostate inflammation was previously reported (Robinette 1988, Tangbanluekal & Robinette 1993, Quintar et al 2006, Yatkin et al 2009). Androgens therefore act as endogenous inhibitors of immune responses, even in the prostate, as already reported for other autoimmune processes (Ansar Ahmed et al 1986, Fox 1992, Harbuz et al 1995, Fijak et al 2011.…”

Anti-inflammatory therapies in TRAMP mice: delay in PCa progression

“…Boehm et al (1997) demonstrated that the acute inflammation in induced prostatitis increased the proliferative process of epithelial and stromal cells. Other studies verified inflammatory cell occurrence in the prostate of elderly animals due to changes in aging process, highlighting the hormonal imbalance as a determining factor in triggering prostatic inflammation, particularly, when the estrogen level is higher than the testosterone level (Yatkin et al 2009, Montico et al 2011. In addition, the interaction between an inflammatory process and sexual hormones led to favorable conditions for androgen-and estrogen-activating lymphocytes, which are essential for the immune response in the prostatic tissue (Djavan et al 2009).…”

“…It is well known that the COX2 overexpression, resulting from inflammatory process, increases the angiogenic factor production and the carcinogenic potential of cells by means of pro-carcinogenesis oxidation to carcinogens, thus promoting cellular growth and decreasing the apoptosis (Kirschenbaum et al 2001, Hamid et al 2011, Vendramini-Costa & Carvalho 2012. High levels of COX2 related to proliferative lesions associated to inflammation suggest a risk factor for CaP development (Yatkin et al 2009). According to Narayanan et al (2006) celecoxib administration, added to the diet for 16 weeks, resulted in a reduced PIN and adenocarcinoma 23:4 incidence in the TRAMP mice model, due to an increase of apoptotic index and simultaneous pro-inflammatory mediator inhibition, such as NFκB p65 and COX2.…”

Development of animal models underlining mechanistic connections between prostate inflammation and cancer

“…The oncogenic effect of 17β-estradiol on NRP-152 cells was accompanied by an increase of expression levels of estrogen receptor-α (ER-α) and PC stem cell-like markers (integrins α2β1, CD44, CD133, ABCG2 and CXCR4) but a decrease of ER-β and androgen receptor (AR) expression levels [29] . Moreover, it has been reported that the androgen replacement therapy with 4-dihydrotestosterone (4-DHT) or testosterone may prevent the 17β-estradiolinduced inflammatory reaction and proliferative epithelial response in the rat prostate of castrated Noble rats in a dose-dependent manner [30] . Altogether, these data suggest that the hormone imbalance, including the decrease of serum testosterone level in men with advancing age, which may promote the development of different prostate disorders, inflammation and pre-neoplastic lesions could be attenuated by a treatment aiming to increase the androgen-to-17β-estradiol ratio in serum.…”