Introduction

Male LUTS in aging men are mainly caused by Benign prostatic hyperplasia (BPH) that is a pathologic process of prostatic growth in older men, which is strongly related to hormonal changes but cause-and-effect relationships have not been established. Nowadays we know that, androgens are a necessary but not the only causative aspect of BPH. LUTS were supposed to be held by the mass increase with a relative increase in urethral resistance, but this definition is overly simplistic, in fact male LUTS depend also on detrusor dysfunction or other conditions such as polyuria, sleep disorders, or any medical condition related to age. During the years, studies have identified that voiding symptoms have a limited relationship with pathophysiology, in fact LUTS can be related to any kind of urinary obstruction, such as a urethral stricture or impaired detrusor contractility. This has led to the recognition that, although LUTS may commonly be related to bladder outlet obstruction (BOO) as a result of benign prostatic obstruction, which is often associated with benign prostatic enlargement (BPE) resulting from the histologic condition of BPH, this is not invariably the case. For example, women also commonly present with voiding symptoms so failure to empty can be related to either an outlet obstruction or detrusor underactivity of the bladder, or combination of both. Postmicturition symptoms, such as postvoid dribbling, occur in both sexes, but most often in men, in whom these symptoms are highly common, are very troublesome, and cause significant interference with quality of life. Storage symptoms are currently largely encompassed by the term overactive bladder syndrome, which is defined as urgency, frequency, nocturia, and urge incontinence, and which is believed to be correlated with an underlying detrusor overactivity these symptoms tend to be more bothersome than voiding symptoms. Storage symptoms in both sexes are commonly associated with urinary infections or, more rarely, with other conditions such as bladder stones, carcinoma, or carcinoma in situ in the bladder.

After the age of 40 years, every man will develop histologic hyperplasia (i.e., BPH), but not all will have bothersome LUTS. The enlargement defined as BPE is not strictly related to LUTS and vice versa.

Etiology

BPH depends on the increasing of number of epithelial and stromal cells in the periurethral area of the prostate and thus correctly referred to as hyperplasia and not hypertrophy, as is often found in the older literature. The precise molecular etiology of this hyperplastic process is uncertain. The observed increase in cell number may be due to epithelial and stromal proliferation or to impaired programmed cell death leading to cellular accumulation. Androgens, estrogens, stromal-epithelial interactions, growth factors, and neurotransmitters may play a role, either singly or in combination, in the etiology of the hyperplastic process.

Hyperplasia

Hyperplasia is an increase in the amount of organic tissue that results from cell proliferation. It may lead to the gross enlargement of an organ. Microscopically, cells resemble normal cells but are increased in numbers. Hyperplasia is different from hypertrophy in that the adaptive cell change in hypertrophy is an increase in the size of cells, whereas hyperplasia involves an increase in the number of cells. An organ can enlarge not only by an increase in cell proliferation but also by a decrease in cell death. Although it is possible that the early phases of BPH are associated with a rapid proliferation of cells, the established disease appears to be maintained in the presence of an equal or reduced rate of cell replication. Increased expression of antiapoptotic pathway genes (e.g., BCL2 ) supports this hypothesis. Normally, androgens support cell proliferation and differentiation in the prostate having also inhibitory activity on cell death. At last also the neurologic activity has a role in cell death especially α-adrenergic innervation.

The hyperplasia act by causing a total modification of the normal structure of the prostate tissue. In late 80s, a study proposed that BPH may be considered as stem cell disease. The observation of a new epithelial gland formation is normally seen only in fetal development and gives rise to the concept of embryonic reawakening of the stroma cell’s inductive potential. The precise molecular etiology of this hyperplastic process is uncertain. The proliferation causes the formation of undifferentiated cells, in fact the secretion, which is a parameter of epithelial cell differentiation, decreases suggesting that the number of differentiated cells capable of secretory activity may be decreasing.

Role of Inflammation

The development and progression of BPH depends also on prostate immune cells. Thus, prostatic inflammation should be considered a novel field of basic and clinical research in patients with BPH as well as a target for new treatment strategies. Also the identification of accurate biomarkers for prostatic inflammation is needed. Since 1937, different studies tried to clarify the influences between chronic inflammation and BPH and theorize that BPH could be an immune-mediated inflammatory disease. Several in vitro and in vivo studies showed alterations in the complex network of cytokines and growth factors that are implicated in the prostatic inflammatory process. This inflammatory process determines tissue damage and chronic healing leading to persistent stimulation of stromal and epithelial prostatic cells, potentially resulting in BPH. On these bases, it was theorized that antiinflammatory agents could be used as therapeutic option in the prevention and treatment of BPH-LUTS.

Prostatic Immune Cells and Inflammation

The prostatic tissue is characterized by the presence of a complex intraglandular immune system that ensures the sterility of the genitourinary tract and the prevention of autoimmune reactions. This condition makes the prostate an immunocompetent organ. Within the prostate, > 90% of immune cells are T-lymphocytes, in particular the CD8 + subtype, in both the epithelial and stromal compartments of the gland. The number of T-lymphocytes progressively increases during adult life, even in the absence of any prostatic disease, to develop the prostate-associated lymphoid tissue (PALT). A small number of other inflammatory cells (B-lymphocytes, macrophages, and mast cells) are also present. In periglandular areas the population of cytotoxic T-lymphocytes (CD8 +) is the most present, in the stroma there are lymphoid aggregates composed of 50% B-lymphocytes surrounded by parafollicular-T-lymphocytes (mostly CD4 +). Moreover, current data indicate that both prostatic epithelial and stromal cells express cytokine receptors being active actors of the immune response as antigen presenting cells (APCs). The epithelial cells widely express toll-like receptors and exhibit major histocompatibility complex class II (MHC II) molecules. Similarly, prostatic stromal cells express MHC II and co-stimulatory molecules (CD80, CD86, CD40, CD134L) on their membranes. Nowadays there were found several stimuli as triggers of different molecular pathways for the dysregulation of the prostatic immune system and the development of inflammation, which can be proven by biopsy samples and surgical specimens of prostatic tissue in patients with BPH.

Many microorganisms as well as (1) viruses (human papilloma virus, herpes simplex virus type 2, and cytomegalovirus) (2) sexually transmitted organisms (including Neisseria gonorrhoeae , Chlamydia trachomatis , Trichomonas vaginalis , and Treponema pallidum ) (3) Gram-negative pathogens ( Escherichia coli ) have been recognized in the prostate and could trigger a proinflammatory reaction.

Urinary reflux has also been correlated with prostatic inflammatory infiltrates by a chemical activity of molecules excreted within the urine. For example, crystalline uric acid can directly stimulate caspase-1-activating cryopyrin, an enzyme widely expressed by innate immune cells, primarily macrophages. The consequent inflammatory response could lead to the development of the corpora amylacea, which generate a glandular duct occlusion that further sustains the inflammatory process.

Metabolic syndrome as well as it does with other organs can induce a prostate environment rich in proinflammatory cytokines, inflammatory mediators, and growth factors. Metabolic syndrome obviously determines a systemic alteration with hormonal alterations, insulin resistance, and increasing IFNγ release from lymphocytes that can all lead to organ and systemic inflammation. Furthermore it is considered that metabolic patients often have a high-fat diet with the presence of heterocyclic amines, which are derived from meats cooked at high temperatures, there is also this trigger to determine the inflammation in prostate.

At least all these triggers of chronic inflammation cause chronic epithelial damage that deteriorate the barrier function of the epithelium influencing the activity of prostatic immune system, leading to the induction of autoimmune response with prostatic inflammatory infiltrates.

Independently of the pathogenic noxae, the prostate undergoes an extensive alteration of the organization, localization, and composition of immune cells which can lead to the development of prostatic diseases including BPH and prostate cancer.

Although it is not the subject of this chapter, it would be worth a small digression on the relationship between inflammation and prostate cancer. The most important trigger was found in the immunological response to different pathogenic noxae that might induce tissue injury and subsequent chronic and repetitive wound healing, which could be involved in BPH growth and progression, as well as in the prostate’s susceptibility to developing cancer. Despite their differences and the lack of a causative well-established relationship between these diseases, BPH and prostate cancer share several clinical features, including coexistence in the same prostatic zone in 20% of cases, hormone-dependent growth, and response to antiandrogen therapy. In addition, chronic inflammation, metabolic disruption, and variants in the genes involved in the inflammatory pathway and immune response might be common drivers for both diseases. These factors could increase the risk of uncontrolled stimulation of prostatic growth mechanisms, potentially leading to the development of BPH and cancer. Furthermore, proliferative inflammatory atrophy, which is considered to be a possible precursor to high-grade intraepithelial neoplasia and prostate cancer, arises in areas of the gland where cells are actively regenerating following tissue damage.

BPH and Prostatic Inflammation