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Abstract
Keywords:
Benign prostatic hyperplasia
Pathogenesis
Inflammation
Context: Benign prostatic hyperplasia (BPH) is a well-known condition characterised by prostate growth accompanied by lower urinary tract symptoms. Several
mechanisms seem to be involved in the development and progression of BPH.
Objective: To review the most important ndings regarding the key mechanisms
involved in the pathophysiology of BPH.
Evidence acquisition: During the 2009 annual meeting of the European Association
of Urology in Stockholm, Sweden, a satellite symposium was held on BPH and its
treatment. This paper is based on one of the presentations at the symposium. A
structured, comprehensive literature review was performed using data retrieved
from recent review articles, original articles, and abstracts.
Evidence synthesis: Several mechanisms seem to be implicated in the pathophysiology of BPH. These represent age-related tissue modications, hormonal alterations, and metabolic syndrome as well as inammation. Although androgens do not
cause BPH, the development of BPH requires the presence of androgens. Moreover,
several studies support the association between noninsulin-dependent diabetes
mellitus, hypertension, obesity, and low high-density lipoprotein cholesterol and
the development of BPH. Finally, recent increasing evidence seems to support the
idea that BPH consists of an inammatory-based disorder. Inammation would be
initiated by an unknown stimulus that would create a proinammatory milieu
within the gland. This theory is conrmed by several basic research and clinical
studies that showed a statistically signicant association between inammation and
BPH severity and progression.
Conclusions: Although the pathogenesis of BPH is not yet fully understood, several
mechanisms seem to be involved in the development and progression of the disease.
These mainly include systemic and local hormonal and vascular alterations as well as
prostatic inammation that would stimulate cellular proliferation. Inammation
would be initiated by an unknown stimulus that would create a proinammatory
environment within the prostate. Therefore, from the recent clinical and basic
research studies, a novel approach in the clinical management of BPH might focus
on the inammatory process involved in the development and progression of the
disease.
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* Corresponding author. University Vita-Salute San Raffaele, Via Olgettina 60, 20132, Milan, Italy.
Tel. +39 02 2643 7286; Fax: +39 02 2643 7298.
E-mail address: briganti.alberto@hsr.it (A. Briganti).
1569-9056/$ see front matter # 2009 Published by Elsevier B.V. on behalf of European Association of Urology.
doi:10.1016/j.eursup.2009.11.002
866
1.
Introduction
Benign prostatic hyperplasia (BPH) is a progressive condition characterised by prostate enlargement accompanied by
lower urinary tract symptoms (LUTS) [1,2]. Benign prostatic
hyperplasia arises in the periurethral and transition zones
of the prostatic gland and represents an inescapable
phenomenon for the ageing male population [3]. Although
BPH is uncommon before age 40, roughly 50% of men
develop BPH-related symptoms at 50 yr of age. The
incidence of BPH increases by 10% per decade and reaches
80% at approximately 80 yr of age [4,5]. An estimated 75% of
men >50 yr of age have symptoms arising from BPH, and
2030% of men reaching 80 yr of age require surgical
intervention for the management of BPH [1,2]. Despite the
high impact of BPH on public health, however, the
pathogenesis of BPH is still largely unresolved. Indeed,
although multiple theories have been proposed, the
aetiology of BPH still remains uncertain in some aspects.
Several mechanisms seem to be involved in the development and progression of BPH. Although ageing represents
the central mechanism implicated, recent novel findings
also highlighted the key role of hormonal alterations,
metabolic syndrome, and inflammation [3,612] (Fig. 1).
The current paper reviews the most important findings
regarding the key mechanisms involved in the pathophysiology of BPH.
2.
Evidence acquisition
During the 2009 annual meeting of the European Association of Urology in Stockholm, Sweden, a satellite symposium was held on BPH and its treatment. This paper is based
on one of the presentations at the symposium. A structured,
comprehensive literature review was performed. Separate
Evidence synthesis
3.1.
Ageing is the most significant risk factor for the development of BPH and the occurrence of LUTS [3,1012]. Several
studies have demonstrated a relationship between age and
markers of BPH progression [1316]. For instance, in the
population-based Olmsted County study, moderate to
severe urinary symptoms were recorded in 13% of men
4049 yr of age versus 28% in subjects >70 yr [16]. Recently,
Loeb et al performed pelvic magnetic resonance imaging in
278 men without prostate cancer, and prostate volume
measurements were assessed over time. The authors
reported a median rate of prostatic volume change of
0.6 ml per year of age, corresponding to a median growth
rate of 2.5% per year [17].
In ageing males, a significant tissue-remodelling process
takes place within the prostate, especially in the transition
zone (TZ). Interference in the delicate balance of interacting
growth factor signalling pathways occurs, and stromal
epithelial interactions generate an increase in prostate
volume. Specifically, the most significant modifications take
place in the basal cells, which change their intracellular
metabolism and become enlarged and hypertrophic. The
development of BPH is also accompanied by the occurrence
of corpora amylacea and prostatic calculi. These elements
typically contain phosphate salts of calcium, magnesium,
potassium, calcium carbonate, or calcium oxalate [18].
Subsequently, the altered secretions of luminal cells and the
presence of corpora amylacea and prostatic calculi lead to
further calcification, and clogged ducts become visible [19].
All of this tissue remodelling leads to alterations of highly
specialised cell types responsible for tissue homeostasis and
function.
Because cell growth is a consequence of either increased
cell proliferation or decreased cell death, apoptotic activity
was also suggested as a key cofactor in BPH development
and progression. Although some authors reported similar
levels of apoptosis in the epithelium of BPH relative to
normal epithelium, other more recent reports have
indicated that abnormal regulation of apoptosis may
be associated with BPH [68]. Kiprianou et al examined
the relative expression of two proteins involved in the
regulation of prostate apoptosis: transforming growth
factor (TGF)b1 and Bcl-2, a potent apoptosis suppressor
[7]. Analysis of the incidence of apoptosis in situ, using the
867
3.2.
3.3.
Hormonal alterations
Metabolic syndrome
868
Inflammation
Table 1 Most significant evidence-based data supporting the role of inflammation in the pathophysiology of benign prostatic hyperplasia
Study
Kohnen et al [54]
Kramer et al [53]
Kramer and Marberger [58]
Theyer et al [59]
Steiner et al [60]
Steiner et al [68]
Kakehi et al [63]
Handisurya et al [67]
Royuela et al [69]
Giri and Ittmann [70]
Evidence
High inammatory inltrate prevalence in BPH specimens
Chronic inammation supporting the process of bromuscular growth in BPH
Inammation associated with signicantly larger prostates, higher PSA levels,
and greater risk of acute urinary retention
BPH tissue containing a disseminated inltration of T lymphocytes, B
lymphocytes, and macrophages
Inammation mediators chronically activated in BPH
Upregulation of IL-17 in inltrating T cells
Downregulation of the gene for MIC-1 in BPH
Upregulation of IL-15 in stromal cells
Upregulation of IFN-g in basal and stromal cells
Upregulation of IL-8 in epithelial cells
BPH = benign prostatic hyperplasia; IFN = interferon; IL = interleukin; MIC-1 = macrophage inhibitory cytokine-1; PSA = prostate-specic antigen.
Conclusions
869
putative autoantigen, the influence of infiltrating inflammatory cells on the stroma/epithelial cross-talk, and a new
classification of BPH quantifying local and systemic
inflammatory/immune response in relation to clinical
relevance. On the basis of all the available data, the control
of inflammation in the clinical management of BPH patients
appears to be of fundamental importance. New treatments
for BPH investigating these specific inflammatory pathways
will be key in the near future.
Conflicts of interest
The authors have nothing to disclose.
Funding support
None.
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