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Increased Endogenous Estrogen Synthesis Leads to the Sequential Induction of Prostatic Inflammation (Prostatitis) and Prostatic Pre-Malignancy
Stuart J. Ellem,* Hong Wang,* Matti Poutanen,† and Gail P. Risbridger*
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 ∼9% and a prevalence of ∼14%, 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.3,4,5 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 this action is mediated by the estrogen receptor (ER) α subtype and involves a cascade of events that permanently and irreversibly alter gene expression patterns in the gland.12 These data indicate that exposure to estrogen causes prostatic inflammation and directly links estrogen and prostatitis.
Studies have shown that chronic inflammation predisposes individuals to various types of cancer; indeed, underlying infection and inflammatory responses have been linked to 15% to 20% of all human cancers.5,13,14 This is also believed to be true for the prostate, and there is an emerging and growing body of evidence implicating inflammation in the etiology of PCa similar to other organs such as the liver and stomach.3,4,5 Epidemiological evidence also indicates that men with a history of prostatitis have an increased risk for PCa.15 Additionally, lesions characterized by proliferating epithelial cells and activated inflammatory cells (proliferative inflammatory atrophy) are frequently observed in juxtaposition to premalignant prostatic lesions (prostatic intraepithelial neoplasia; PIN) and PCa.
To study the effects of estrogen on the prostate, previous studies have typically relied on the addition of exogenous estrogens at either low or pharmacological doses. This, however, introduces a number of complicating factors. Low dose effects can be difficult to discern, while pharmacological doses may not mimic normal physiological responses. In addition, this methodology also precludes the ability to examine the effects of estrogen and the progression of disease throughout development and adult life. Consequently, the development of new experimental animal models of prostatitis is essential to determine whether inflammation is linked to development of PCa. This need was highlighted and stressed in the report from the Bar Harbor Consensus meeting.16 Although two models of prostatitis have recently been developed, they are of limited utility: one is bacterial17 while the other is rat-based and requires the administration of exogenous hormones.18 As a result, both of these models preclude the ability to cross-breed with other types of genetically manipulated mice to delineate and study specific mechanisms. Consequently the imperative remains to develop new mouse models for the study of prostatitis.
The aromatase overexpressing (AROM+) transgenic mouse provides a novel model to examine the effect of altered aromatase activity, and therefore estrogen levels and action, in the prostate within physiological hormonal environment. Estrogen levels in these mice are significantly elevated and are associated with a concomitant decrease in androgens. It has been previously reported that the prostates of these mice are rudimentary due to the suppression of androgens.19
In this study, we show for the first time that the AROM+ mouse develops chronic prostatitis by 40 weeks of age. This inflammation is characterized by an elevation in mast cell numbers from puberty and ultimately leads to chronic inflammation and the development of PIN lesions. This demonstrates a continuum, with estrogen-inducing inflammation, which subsequently results in the onset of pre-malignancy.
===============================================================
The article goes on longer, click URL to read the whole thing.
.
Stuart J. Ellem,* Hong Wang,* Matti Poutanen,† and Gail P. Risbridger*
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 ∼9% and a prevalence of ∼14%, 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.3,4,5 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 this action is mediated by the estrogen receptor (ER) α subtype and involves a cascade of events that permanently and irreversibly alter gene expression patterns in the gland.12 These data indicate that exposure to estrogen causes prostatic inflammation and directly links estrogen and prostatitis.
Studies have shown that chronic inflammation predisposes individuals to various types of cancer; indeed, underlying infection and inflammatory responses have been linked to 15% to 20% of all human cancers.5,13,14 This is also believed to be true for the prostate, and there is an emerging and growing body of evidence implicating inflammation in the etiology of PCa similar to other organs such as the liver and stomach.3,4,5 Epidemiological evidence also indicates that men with a history of prostatitis have an increased risk for PCa.15 Additionally, lesions characterized by proliferating epithelial cells and activated inflammatory cells (proliferative inflammatory atrophy) are frequently observed in juxtaposition to premalignant prostatic lesions (prostatic intraepithelial neoplasia; PIN) and PCa.
To study the effects of estrogen on the prostate, previous studies have typically relied on the addition of exogenous estrogens at either low or pharmacological doses. This, however, introduces a number of complicating factors. Low dose effects can be difficult to discern, while pharmacological doses may not mimic normal physiological responses. In addition, this methodology also precludes the ability to examine the effects of estrogen and the progression of disease throughout development and adult life. Consequently, the development of new experimental animal models of prostatitis is essential to determine whether inflammation is linked to development of PCa. This need was highlighted and stressed in the report from the Bar Harbor Consensus meeting.16 Although two models of prostatitis have recently been developed, they are of limited utility: one is bacterial17 while the other is rat-based and requires the administration of exogenous hormones.18 As a result, both of these models preclude the ability to cross-breed with other types of genetically manipulated mice to delineate and study specific mechanisms. Consequently the imperative remains to develop new mouse models for the study of prostatitis.
The aromatase overexpressing (AROM+) transgenic mouse provides a novel model to examine the effect of altered aromatase activity, and therefore estrogen levels and action, in the prostate within physiological hormonal environment. Estrogen levels in these mice are significantly elevated and are associated with a concomitant decrease in androgens. It has been previously reported that the prostates of these mice are rudimentary due to the suppression of androgens.19
In this study, we show for the first time that the AROM+ mouse develops chronic prostatitis by 40 weeks of age. This inflammation is characterized by an elevation in mast cell numbers from puberty and ultimately leads to chronic inflammation and the development of PIN lesions. This demonstrates a continuum, with estrogen-inducing inflammation, which subsequently results in the onset of pre-malignancy.
===============================================================
The article goes on longer, click URL to read the whole thing.
.
