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. 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.
KeywordsBPH, Triggers, Inflammation, Immunology, Pathways, Hormones, Testosterone
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.
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 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
Data from the MTOPS (Medical Therapy of Prostate Symptoms) trial and REDUCE (Reduction by Dutasteride of prostate Cancer Events) trial population reported that chronic inflammatory infiltrates were found in ~ 40% to 77.6% of samples from the patients undergoing prostatic biopsy in the study, in particular, in men with elevated serum PSA levels and larger prostate volumes. A statistically and clinically significant association among the degree of prostatic inflammation, prostate volume, and IPSS was found in 282 patients undergoing surgery for symptomatic or complicated BPH. Chronic prostatic inflammation in 79%, 48%, and 20% of patients with severe, intermediate, and no BPH, respectively, was reported. A further study assessed the prevalence of inflammation and BPH in prostate glands obtained during autopsy from 100 Asian and 320 Caucasian men. In > 70% of autopsy specimens in both populations, chronic inflammation was found; patients with chronic inflammation were seven times more likely to have BPH than patients without inflammation (HR 6.84, 95% CI 4.05–11.78; P < .0001). These studies all examined the concomitant risk of BPE (evaluated by prostate volume) and LUTS. Although prostate inflammation has been identified as the cause of BPE, bladder and prostatic inflammation observed in obese patients or in patients with metabolic syndrome is related with storage symptoms independently from the effect of inflammatory infiltrates on prostate volume. These data are also confirmed in studies evaluating the effect of inflammation on LUTS in both sexes. In the Boston Area Community Health Survey was demonstrated that there is a relationship between levels of C-reactive protein (CRP), an inflammatory marker, and LUTS in both men and women. In men, log10(CRP) levels as a continuous variable were positively associated with urgency, urgency plus frequency, or urgency plus both frequency and nocturia. The adjusted ORs (95% CI) per log10(CRP) levels were respectively 1.90 (1.26–2.86) with urgency, 1.65 (1.06–2.58) with urgency plus frequency, and 1.92 (1.13–3.28) with urgency plus both frequency and nocturia. The association was more modest in women, the adjusted ORs (95% CI) per log10(CRP) levels were respectively 1.53 (1.07–2.18) with urgency, 1.51 (1.02–2.23) with urgency plus frequency, and 1.34 (0.85–2.12) with urgency plus both frequency and nocturia. Furthermore, in few studies was assessed the positive association between metabolic-syndrome-induced systemic inflammation and storage LUTS in female patients. From the results were identified higher levels of cytokines as well as MCP-1, CD40 ligand, IL-6, IL-8, and TNFα, in women with overactive bladder than in the control group. Another important evidence demonstrates that an altered sensitivity from the prostate dependent on chronic prostatic infiltrates can determine detrusor overactivity with associated storage symptoms independent of prostate volume. All this evidences suggests that the prostate and bladder could be considered as a single apparatus with a close interaction which is the basis of the pathogenesis of LUTS due to inflammation.
The study presented earlier defined the relationship between the activation and dysregulation of prostatic immune cells and the development of BPH-LUTS, but it is important to find the possible mechanisms behind this apparent causal relationship. A first milestone study identified the activation of T-helper1 (TH1) and T-helper2 (TH2) lymphocytes in prostate tissue, as well as the release of several cytokines and growth factors, that have been associated with the initiation and progression of BPH. In particular it was found that IL-17 is a very important cytokine in BPH development and progression. Its concentration is virtually insignificant in normal prostate, but it is amplified in BPH tissues, where it is mostly secreted by T-lymphocytes and prostate cells. IL-17 appears to trigger the release of TNFα, IFNc, IL-5, and IL-10 by BPH T-lymphocytes and upregulates expression of cyclooxygenase 2 (COX-2) in macrophages and epithelial cells. Remarkably in mouse models based on oxidative stress and aging that are frequently associated to BPH, IL-17 secretion is augmented. The TGFβ family also has an important role in BPH stromal proliferation and differentiation, as well as being a key factor for androgen-controlled prostatic growth. A total of 231 patients with BPH were analyzed for the expression of TGFβ receptor II protein (TGFBRII) in prostate. There was observed a positive association between TGFBRII and prostate volume. Data also suggest that bacterial infections and related prostatic inflammation could induce increased expression of androgen-responsive genes in the epithelium, and activate TGFβ1 cascade genes in the stroma. Moreover, macrophage infiltrates, as observed in inflamed prostate tissue, stimulate the secretion of TGFβ2 from epithelial cells. In BPH tissue is well known the epithelial-mesenchymal transition (EMT) that is strongly supported by the activity of TGFβ2 and HIF-1α. EMT is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. The following collaboration between the stromal cells and infiltrated macrophages increases CCL3 secretion, which endorses further proliferation of stromal cells. This mechanism could explain the altered stromal/epithelial ratio observed in BPH (from 2:1 in normal glands to 5:1 in BPH). IL-18 directly influences prostatic stromal cell proliferation and is produced by prostatic epithelial cell and by a complex of cytosolic proteins of the macrophages named the “inflammasome” that cleaves pro-IL-18 to the mature form and further increases its secretion from immune cells. IL-8 in BPH tissues is actively secreted by epithelial and stromal cells in response to the proinflammatory cytokines as IL-17, which are produced by prostate-infiltrating TH1 and TH17 cells. IL-8 induces stromal and epithelial overgrowth by directly stimulating the proliferation of senescent epithelial cells, the stromal acquisition of a myofibroblast reactive phenotype, and by indirectly promoting fibroblast growth factor 2 (FGF-2) secretion. Another important molecule is MCP-1, one of the most highly secreted proteins in large prostate glands. Stromal cells are the first producer of MCP-1; however, epithelial cells stimulated by IL-1b, IFNg, and IL-2 can produce high level of this protein. Both epithelial and stromal cells express the receptor of MCP-1 (CCR2), so it is activated a paracrine/autocrine pathway that stimulate the growth of epithelial cells. Another evidence is due to a not well-defined threshold of density of T-lymphocytes, CD8 + cytotoxic T cells start to kill the epithelial and stromal cells, leaving behind vacant spaces that are replaced by fibromuscular nodules. Local hypoxia is a further stimulus for the production of inflammatory mediators, producing a low level of reactive oxygen species (ROS) that can promote neoangiogenesis and fibroblast-to-myofibroblast transdifferentation. As a response to hypoxia, prostatic stromal cells upregulate the secretion of several growth factors, in particular, FGF-7, TGFβ, FGF-2, and IL-8, which contribute to prostatic growth.
Increased activity of inflammatory cells in prostate tissue determines a stimulation of prostatic stromal and epithelial cell that respond to internal and external stimulation with uncontrolled proliferation that is preserved by autoimmune mechanisms. Subsequent inflammatory tissue damage and continuous cycles of wound healing could then eventually induce the development of BPH nodules.
Proinflammatory cytokines can also regulate alterations in the metabolism of sex steroids and act synergistically with hormones to enhance the proliferative stimuli involved in BPH.
Estrogen-metabolizing enzymes—such as aromatase, steroid sulphatase, and 17β-hydroxysteroid dehydrogenase 2 (HSD17β2)—are upregulated in a mouse model of prostatitis with a consequent increase in catechol estrogens within the prostate tissue [ ]. Exposure to estrogens further induces inflammation and cell proliferation, suggesting synergism between hormonal modifications and inflammation. Current literature also supports a potential interaction between inflammation and the expression of the androgen receptor (AR) in both epithelial and stromal cells of hyperplastic infiltrates. Monti et al. [ ] showed that the periurethral area of the transitional zone expresses the highest levels of androgens and AR compared with the other prostate areas, suggesting that it is involved in the initial BPH growth-promoting progressions. Interestingly a study analyzing 105 simple prostatectomy specimens highlighted a strong association between immune-mediated inflammation, prostate volume, and AR expression in BPH samples. The same study shows that the specimens of immune-mediated inflammation displayed a higher prostate volume and higher expression of AR than the specimens without immune-mediated inflammation. Izumi et al. [ ] have provided a possible explanation: according to their findings, AR expression in epithelial cells attracts macrophages and the subsequent interaction between epithelial cells and macrophages increases the secretion of TGFβ-2 from epithelial cells. Equally, AR expression in stromal cells attracts macrophages and the interaction between stromal cells and infiltrated macrophages induces CCL3 secretion from both stromal cells and infiltrated macrophages. Proliferation of stromal cells is promoted by these interactions, further supporting also the development of BPH nodules.
Androgens also directly influence the development of inflammatory infiltrates. Vignozzi et al. investigated whether AR activation could influence inflammatory responses induced by oxidized low-density lipoprotein (oxLDL) and the effect of dihydrotestosterone (DHT) on the secretion of IL-6 and IL-8 in human myofibroblast in BPH cultures. IL-6 and IL-8 are significantly inhibited by DHT treatment (30 nmol/L for 24 h); this effect was completely reversed by bicalutamide. The presented data suggest that the relationship between immune cells and androgens is complex. DHT—that is strongly expressed in the prostatic tissue—could have a direct protective effect on the human prostate, increasing the ability of prostate cells to react to metabolic insults; conversely, the presence of inflammatory cells within the prostate might also influence AR expression, which can strongly promote further enrollment of inflammatory cells and further stromal cell proliferation.