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REVIEW

URRENT
C
OPINION

Correlation between benign prostatic hyperplasia


and inflammation
Yakup Bostanci a, Amir Kazzazi a, Shabnam Momtahen b, Juliana Laze a, and
Bob Djavan a

Purpose of review
This review aims to evaluate the available evidence on the role of prostatic inflammation in the
pathogenesis and progression of benign prostatic hyperplasia (BPH).
Recent findings
Although there is still no evidence of a causal relation, accumulating evidence suggests that inflammation
may contribute to the development of BPH and lower urinary tract symptoms (LUTS). Inflammatory infiltrates
are frequently observed in prostate tissue specimens from men with BPH and the presence or degree of
inflammation has been found to be correlated with prostate volume and weight. The inflammatory injury
may contribute to cytokine production by inflammatory cells driving local growth factor production and
angiogenesis in the prostatic tissue. This proinflammatory microenvironment is closely related to BPH
stromal hyperproliferation and tissue remodeling with a local hypoxia induced by increased oxygen
demands by proliferating cells which supports chronic inflammation as a source of oxidative stress leading
to tissue injury in infiltrating area.
Summary
Although the pathogenesis of BPH is not yet fully understood and several mechanisms seem to be involved
in the development and progression, recent studies strongly suggest that BPH is an immune inflammatory
disease. The T-cell activity and associated autoimmune reaction seem to induce epithelial and stromal cell
proliferation. Further understanding of the role of inflammation in BPH and clinical detection of this
inflammation will expand the understanding of BPH pathogenesis and its histologic and clinical
progression, allow risk stratification for patients presenting with BPH-related LUTS, and suggest novel
treatment strategies.
Keywords
benign prostate hyperplasia, cytokines, immune response, inflammation, lower urinary tract symptoms,
pathogenesis

INTRODUCTION
Benign prostatic hyperplasia (BPH) is a prevalent
and chronic progressive disease that may be correctly defined as prostate gland enlargement secondary to hyperproliferation of stromal and glandular
cells, with predominance of mesenchymal cells [1].
Aging and the presence of androgens are necessary
for the development of BPH, but the pathogenesis
of BPH is still largely unresolved [23]. Several
parameters including inflammatory mediators,
hormones, dietary factors, inflammatory genes,
and oxidative stress have been considered to play
a role for the development of BPH, but there is no
consensus as to which is the primary one. To date,
these multifactorial and chronic conditions have
been studied to prevent BPH progression.

In the last few years, a potentially important role


of inflammation in BPH development and progression has emerged [45], and recent clinical trials
have suggested a relationship between prostatic
inflammations and lower urinary tract symptoms

Department of Urology, New York University School of Medicine, NYU


and bDepartment of Pathology and Laboratory Medicine, NewYorkPresbyterian Hospital/Weill Cornell Medical Center, New York, New
York, USA
Correspondence to Shabnam Momtahen, MD, Department of Pathology
and Laboratory Medicine, NewYork-Presbyterian Hospital/Weill Cornell
Medical Center, New York, New York, USA. Tel: +1 201 282 4973; fax:
+1 201 282 4973; e-mail: momtahen_sh@yahoo.com
Curr Opin Urol 2013, 23:510
DOI:10.1097/MOU.0b013e32835abd4a

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Benign prostatic hyperplasia

KEY POINTS
 Although the pathogenesis of BPH is not yet fully
understood and several mechanisms seem to be
involved in the development and progression, recent
studies strongly suggest that BPH is an immune
inflammatory disease.
 The T-cell activity and associated autoimmune reaction
seem to induce epithelial and stromal cell proliferation.
 Understanding of the role of inflammation in BPH and
clinical detection of this inflammation will expand the
understanding of BPH pathogenesis and its histologic
and clinical progression.

(LUTS) related to BPH [67]. Today, even though it


is not yet known exactly when and why chronic
inflammation occurs, it has been hypothesized that
BPH is an immune-mediated inflammatory disease
and inflammation may directly contribute to prostate growth [810].

INFLAMMATION AND PROSTATE


Acute and chronic prostate inflammation is a common finding in histologic prostate specimens
obtained from aging men which reported in
4398% of specimens [1112]. Studies on the
pathogenesis of BPH have provided an evidencebased thesis that strongly suggests a role of
inflammation in the propagation of histologic
BPH [9,1314]. However, it has been more difficult
to determine whether the inflammation arose as
a normal biologic part of the aging process or
whether inflammation actually contributes to prostatic enlargement and development of LUTS [15].
Investigators have suggested that BPH might
have an autoimmune component, whereby antigenic stimuli may result in the development of a
chronic inflammatory response within the prostate
that leads to tissue rebuilding and stromal growth in
the prostate [8,16]. The inflammation-induced
damage of the prostatic tissue represents a chronic
process of wound healing which activates hyperproliferative programs resulting in BPH nodules
[17]. Inflammatory processes may contribute to prostatic enlargement directly through stimulation of
prostate growth, or, alternatively, through decreasing prostatic apoptosis.
All baseline biopsies from the Medical Therapy of
Prostatic Symptoms (MTOPS) study were examined
for the presence of inflammation and 2.6% of the
men had acute inflammation, while 43% had chronic
inflammation, in prostatic biopsy specimens at baseline. Men with acute or chronic inflammation (ACI)
had larger prostate volumes (41.1 vs. 36.8 ml;
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P 0.0002) and a greater risk of acute urinary retention (AUR) due to BPH than those without ACI (2.4 vs.
0.6%; P 0.011). Furthermore, there was a trend for
increased overall clinical progression in men with
ACI compared with those without ACI, although this
was not statistically significant. From these data, it
was hypothesized that the presence of histologic
inflammation may be a predictor of progression of
BPH and need for invasive therapy [18].
In another prospective study of autopsy specimens obtained from 93 men who had histologic
evidence of BPH, chronic inflammation was found
in 75% of prostates examined compared with 55%
of prostates not affected by BPH [19]. Di Silverio
et al. [11] showed that 69% of inflammation was
also chronic inflammation, inflammation in the
prostate increased significantly with the increase
in prostate volume and age.
Although the presence of inflammatory infiltrates in human prostates is a well described situation, the origin of inflammation in the prostate
remains a subject of debate and is likely to be multifactorial [20]. Different pathogens are described,
including bacterial infections, urine reflux with
chemical inflammation, dietary factors, hormones,
autoimmune response [2123], and a combination
of these factors. As proposed by De Marzo et al. [21],
all of these mechanisms of chronic epithelial injury
may be responsible for a decreased barrier function
and facilitate the growth of infectious agents, with a
chain reaction that further sustains and stimulates
the inflammatory response and increases the
prostatic inflammatory infiltrates.

INFLAMMATION AND CLINICAL BENIGN


PROSTATIC HYPERPLASIA
Clinical evidence reports that chronic inflammation
represents a key condition leading to prostate
enlargement and to an increased symptoms score
as well as a major risk of complications [8]. Furthermore, when inflammation is clinically supposed
and then proven histologically, it may be taken into
account in the management and treatment of BPH
[24].
Prostatic inflammation is correlated with symptomatic progression, risk for urinary retention, and
need for surgery [25]. In cross-sectional studies,
patients referred to urology clinics with AUR were
more likely to have evidence of inflammation in
prostatic specimens compared to men referred for
benign prostatic obstruction [2627]. Intraprostatic
inflammation was also present in 70% of men
requiring transurethral prostatic resection for AUR
compared to 45% of men requiring resection to treat
LUTS [28]. Additionally, Roehrborn et al. [18] found
that MTOPS participants with acute inflammation
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Benign prostatic hyperplasia and inflammation Bostanci et al.

in their biopsy specimens were slightly more likely


to develop worsening LUTS compared to those
without acute inflammation. Taken together, these
studies suggest that inflammatory processes may
contribute to the development and exacerbation
of BPH and LUTS.
The Reduction by Dutasteride of Prostate Cancer
Event (REDUCE) trial [6,7] confirmed these data.
Among 8224 men enrolled in the REDUCE trial,
chronic histologic inflammation was found in
greater than 78% of men. Chronic inflammation
was more common than acute inflammation (78 vs.
15%, respectively). Statistically significant but clinically small increases in IPSS symptoms were noted
in men with inflammation compared with those
without. Similarly, statistically significant correlations were found between average chronic inflammation score and the IPSS variables. However, the
magnitude of these correlations was small, indicating very weak associations which demonstrate that
inflammation in BPH may be important.
The data from the placebo arm of the PCPT
demonstrated that when controlled for age and race,
high C-reactive protein and interleukin-6 (IL-6) concentrations and low sTNF-RII concentrations may
increase the risk of BPH [29 ]. The authors suggested
that systemic inflammation or lower levels of
soluble receptors that bind inflammatory cytokines
may increase BPH risk.
In a cohort study of 282 patients with and without BPH, Robert et al. [30] observed chronic prostatic
inflammation in 79, 48, and 20% of severe, intermediate, and no BPH patients, respectively. A significant association among the degree of prostatic
inflammation, prostate volume, and urinary symptoms was also confirmed; mean prostate volume was
62 ml with low-grade inflammation and 77 ml in
high-grade inflammation (P 0.002). Similarly, the
mean IPSS score was 12 and 21 in low-grade and highgrade inflammation (P 0.02), respectively.
Although a number of potential markers
(C-reactive protein, IL-8, and markers of oxidative
stress) have been evaluated, these markers are generally nonspecific for prostate or BPH [31]. However, it
opens the search for biomarkers that could be used
to stratify patients as to the risk of developing BPH
or related BPH adverse outcomes, or to monitor
symptoms and response to medical therapy for BPH.
&

CYTOKINES AND ROLE OF


INFLAMMATION IN THE PATHOGENESIS
OF HISTOLOGIC BENIGN PROSTATIC
HYPERPLASIA
Chronic inflammation can be considered the third
component of BPH pathogenesis, taking part with

the androgen receptor signaling in the induction of


the tissue remodeling typical of the advanced stages
of the disease. Prostatic inflammation observed in
BPH may cause cytokine release from inflammatory
cells and a condition of relative hypoxia resulting
from the increasing oxygen demand of proliferating
cells that may end up in tissue injury [32]. Cytokines
and growth factors released from inflammatory cells
may not just interact with immune effectors but
also with stromal and epithelial cells of the prostate
[33]. Inflammatory mediators may contribute to
prostatic epithelial and stromal cell growth both
directly, through induction of growth via cytokines
that stimulate the production of prostatic growth
factors, and indirectly through decreases in prostate
cell death via downregulation of prostate cell
apoptosis [34].
In the last years, specific inflammatory mediator
pathways have been studied in detail to elucidate
the potential role of these pathways in BPH pathogenesis. A large number of inflammatory cells and
proinflammatory cytokines may be involved in
the proliferation of the prostate. Kramer et al. [35]
first investigated the effect of lymphocyte-derived
growth factors on prostatic stromal cell growth.
They confirmed that BPH tissue contains infiltrates
of T lymphocytes, B lymphocytes, and macrophages
that are chronically activated and responsible for
the release of cytokines mostly IL-2, IFN-g, and
TGF-b that may support fibromuscular growth in
BPH. Furthermore, an upregulation of different
proinflammatory cytokines has been reported in
BPH tissue particularly IL-15 in stromal cells,
IL-17 in infiltrating T cells, IFN-g in basal and
stromal cells, and IL-8 in epithelial cells [32].
Proinflammatory cytokines released from
adjacent inflammatory cells were shown to induce
the expression of cyclooxygenase-2 (COX-2) in epithelial cells, which then elevated the proliferation
rate of cells in the prostate. In 79% of patients with
BPH, IL-17 produced by activated T-cells was
increased and this overexpression of IL-17 could
play a role in increasing COX 2 expression [9,36].
In a report by Penna et al. [23], human prostate
stromal cells were shown to act as antigen-presenting cells, activating alloantigen-specific CD4 T cells
to produce IFN-g and IL-17. It appears that prostate
stromal cells may induce and maintain an autoimmune response [37].
Local hypoxia can play a role as one of the
inflammatory mediators by inducing lower levels
of reactive oxygen species (ROS), which can
promote transdifferentiation of fibroblasts to myofibroblast and neovascularization [38]. As a response
to hypoxia, prostatic stromal cells upregulate the
secretion of several growth factors that can

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Benign prostatic hyperplasia

determine prostatic growth. In particular, increased


secretion of vascular endothelial growth factors,
fibroblast growth factors, FGF-7, TGF-b, FGF-2,
and IL-8 was observed under the hypoxic condition
in vitro [36].
The possible role of TGF-b has also been extensively evaluated [8,39 ,40]. TGF-b, an inflammatory
cytokine, has been shown to regulate stromal proliferation and differentiation in BPH, and it is a key
factor for androgen control of prostatic growth.
Descazeaud et al. [39 ] investigated the transforming growth factor b-receptor II (TGFBRII) protein
expression in BPH patients. They observed a significant association between TGFBRII stromal staining
and prostatic volume; BPH inflammation was also
associated with TGFBRII staining.
&&

&&

PROSTATIC INFLAMMATION AS A
TARGET FOR PREVENTION AND
TREATMENT
Prostatic inflammation has been considered a
possible target for BPH prevention and treatment,
and so far, different anti-inflammatory agents have
been tested in vitro and in vivo for the management
of BPH [4145]. Unfortunately, there are few good
data available to assess the clinical response of antiinflammatory therapy in BPH. Several drugs may
reduce prostate volume by acting at various points
in the inflammatory pathway, possibly through
direct action on the antiapoptotic protein bcl-2,
indirectly through the COX-2 pathway, or through
as yet unidentified mechanisms.
Epidemiological studies showed an inverse correlation between the daily use of NSAIDs and the
onset of moderate-to-severe urinary symptoms, low
maximum urinary flow rate, increased prostate volume, and elevated PSA levels [46]. Sutcliffe et al. [47]
found a positive association between a history of
young-onset prostatitis and later development of
LUTS; another study suggested that elevated circulating C-reactive protein concentration might be an
indicator of ACI in symptomatic BPH [48]. Sutcliffe
et al. [49 ] found no association for NSAIDs use with
the risk of BPH and LUTS. Prostate, Lung, Colorectal,
and Ovarian (PLCO) cancer screening trial observed
a weak positive association between regular NSAID
use and prevalent BPH and LUTS [50], whereas
Olmsted County Study observed a strong inverse
association between daily NSAID use and incident
BPH and LUTS [46].
Minnery and Getzenberg [51] showed that doxazosin, as well as ibuprofen, significantly decreased
cell viability and induced apoptosis in BPH prostate
cell lines. In addition, it decreased the expression of
JM-27, a protein particularly expressed in the
&&

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prostate that appears to be highly upregulated in


symptomatic BPH.
Di Silverio et al. [44] hypothesized that the
association of rofecoxib with finasteride induced a
more rapid improvement in clinical results until the
effect of finasteride becomes predominant and they
found that, although there was not a significant
difference between symptom improvement at
24 weeks, there was a statistically significant
advantage of the combination therapy compared
with finasteride alone in a short-term interval.
Phytotherapy has become one of the most popular treatment modalities for BPH. One of the
primary mechanisms of why these herbal agents
work is the anti-inflammatory effects of the various
herbal preparations [33,45,5255]. Vela Navarrete
et al. [45] found that patients taking a common
phytotherapy for BPH had fewer inflammatory infiltrates in resected prostate specimens, suggesting
that this agent may have anti-inflammatory properties.
BXL-628, a potent vitamin D receptor agonist,
was able to inhibit prostatic growth and control
prostatic inflammation by reducing intraprostatic
cell infiltrates (CD4, CD8, macrophages, and B
cells) and decreasing IFN-g and IL-17 secretion in
in-vitro BPH cell cultures and in an in-vivo experimental model of autoimmune prostatitis [33,43]. At
the very least, the potential of anti-inflammatory
agents in preventing the progression of BPH merits
close examination [28].

CONCLUSION
Although we do not completely understand the
pathways of prostatic inflammation, accumulating
evidence suggests that inflammatory processes
affecting both the prostate and the bladder may
play essential roles in the development and maintenance of prostate growth and LUTS. In all prostatic
diseases, immunologic processes and inflammation
either have a role in pathogenesis or are discussed as
potential triggers of disease progression. T-cell
activity in inflammatory infiltrates may result in
the stimulation of stromal and epithelial cell proliferation that is sustained by autoimmune mechanism. Tissue damage and the subsequent chronic
process of repetitive wound healing induced by
inflammation end up in the development of BPH
nodules. There is not yet proof that targeting prostate inflammation with a pharmacologic agent
results in a lower incidence and progression or
regression of BPH. Further research is required to
better understand the role of prostatic inflammation
in the initiation, development, and progression
of BPH.
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Benign prostatic hyperplasia and inflammation Bostanci et al.

Acknowledgements
None.
Conflicts of interest
Disclaimers: All authors have read and approved the
final draft. There is no financial or commercial interest
on this article. This work has not already been published
and has not been submitted simultaneously to any other
journal.

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