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

Abstract

Prostatitis causes substantial morbidity to men, through associated urinary symptoms, sexual dysfunction, and pelvic pain; however, 90% to 95% of cases have an unknown etiology. Inflammation is associated with the development of carcinoma, and, therefore, it is imperative to identify and study the causes of prostatitis to improve our understanding of this disease and its role in prostate cancer. As estrogens cause prostatic inflammation, here we characterize the murine prostatic phenotype induced by elevated endogenous estrogens due to aromatase overexpression (AROM؉). Early-life development of the AROM؉ prostate was normal; however, progressive changes culminated in chronic inflammation and pre-malignancy. The AROM؉ prostate was smaller at puberty compared with wild-type controls. Mast cell numbers were significantly increased at puberty and preceded chronic inflammation, which emerged by 40 weeks of age and was characterized by increased mast cell, macrophage, neutrophil, and T-lymphocyte numbers. The expression of key inflammatory mediators was also significantly altered, and premalignant prostatic intraepithelial neoplasia lesions emerged by 52 weeks of age. Taken together, these data link estrogens to prostatitis and premalignancy in the prostate, further implicating a role for estrogen in prostate cancer. These data also establish the AROM؉ mouse as a novel, non-bacterial model for the study of prostatitis. Prostatitis, an exceedingly common condition in the male population worldwide, has an incidence of ϳ9% and a prevalence of ϳ14%, and, unlike benign prostatic hyperplasia and prostate cancer (PCa), which are predominantly diseases of older men, prostatitis afflicts men of all ages. It is also the most common outpatient condition seen in men under 50 years of age and accounts for more clinical visits than either PCa and/or benign prostatic hyperplasia.1,2 At present our knowledge of prostatitis is lacking, with 90% to 95% of cases having an unknown etiology. This represents a significant problem, particularly as prostatitis has also been implicated in the development of PCa.3-5 Given the prevalence of prostatitis and this putative link to PCa, it is vitally important to identify the unknown causes of prostatitis.Several causes of prostatitis have been postulated, including hormonal variation or exposure, infection due to sexually transmitted disease, 6 dietary factors, and physical trauma from urine reflux. 7 However, of particular interest is an apparent link between estrogen and prostatic inflammation, 8 which has emerged mainly from the administration of pharmacological levels of exogenous estrogen to rodents.9 Additional data obtained from further rodent studies show that the prostate gland is particularly sensitive to estrogenic exposure during development in fetal and neonatal life; transient estrogen exposure before puberty results in inflammation later in life, well after the exposure has occurred.10,11 Several decades of research from various laboratories, including our own, has demonstrated that...

Serum Sex Steroids Depict a Nonlinear U-Shaped Association with High-Risk Prostate Cancer at Radical Prostatectomy

“…Moreover, although androgens and estrogens both play significant roles in the prostate, their specific balance seems to be even more critical in maintaining prostate health and tissue homeostasis in adulthood. Collectively, animal data have revealed that elevated T in the absence of estrogens may lead to the development of hypertrophy and hyperplasia of the prostate gland but not to malignancy (34). In contrast, high estrogen levels and low T have been shown to lead to the development of inflammation with aging and in premalignant lesions (34).…”

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

“…For instance, it has been observed that 72% of Lewis rat developed spontaneous prostatitis with advancing age compared to only 27% for Wistar rats while the administration of 17β-estradiol or castration promoted the incidence and severity of non-bacterial prostatitis to 100% in old adult Wistar rats [20] . The up-regulation of the systemic endogenous estrogens, including serum 17β-estradiol, concomitant with a decrease in the serum testosterone level by overexpressing aromatase (AROM) in FVB/N mice has also been observed to induce a chronic inflammation at 48 wk of age [28] . The inflammatory responses in AROM +/+ mice was also associated with an enhanced number of mast cells, macrophages, neutrophiles and T-lymphocytes and culminated to the formation of prostatic intraepithelial neoplasias (PINs) at 52 wk of age [28] .…”

“…The up-regulation of the systemic endogenous estrogens, including serum 17β-estradiol, concomitant with a decrease in the serum testosterone level by overexpressing aromatase (AROM) in FVB/N mice has also been observed to induce a chronic inflammation at 48 wk of age [28] . The inflammatory responses in AROM +/+ mice was also associated with an enhanced number of mast cells, macrophages, neutrophiles and T-lymphocytes and culminated to the formation of prostatic intraepithelial neoplasias (PINs) at 52 wk of age [28] . In this regard, a treatment of immortalized, nontransformed and androgen-responsive rat NRP-152 prostatic epithelial cell line with 17β-estradiol at concentrations 1-3 μmol/L for a period of 2-6 wk has also been observed to induce their capacity of forming colonies in soft agar and tumors in immunodeficient nude mice [29] .…”

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

“…Among the factors predisposing to PC development, there are intense oxidative stress, inflammatory atrophies and fibrosis associated with severe tissue injuries, hormonal deregulation, and, more particularly, advancing age (1,10,13,44,(79)(80)(81)(82)(83). Although the cellular origin for different PC subtypes remains not precisely established, a growing body of evidence suggests that the accumulation of distinct genetic and/or epigenetic alterations in prostatic stem/progenitor cells, and more particularly during chronological aging and intense tissue injuries, may result in their malignant transformation into highly tumorigenic PC stem/progenitor cells (5,13, (70).…”