REVIEW ARTICLE
Chronic inflammation in the pathogenesis of benign
prostatic hyperplasia
B. Fibbi,* G. Penna, A. Morelli,* L. Adorini and M. Maggi*
*Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, and Intercept Pharmaceuticals, Corciano (Perugia), Italy
Introduction
Benign prostatic hyperplasia (BPH) is the most frequent
benign neoplasm in ageing men and one of the most
common chronic conditions in the male population, with
a histological prevalence at autopsy of 50% in men aged
50–60 years and of 90% over 80 years [McVary (2006)].
As most chronic diseases, BPH is progressive: it requires a
long period to evolve from earlier tissue alterations to
clinical onset with lower urinary tract symptoms (LUTS)
[Jacobsen et al. (1996); Roberts et al. (2000); Fitzpatrick
(2006)], and, if untreated, it often complicates with blad-
der dysfunction and hypertrophy possibly leading to acute
urinary retention (AUR) [McNeal (1990); Jacobsen et al.
(1997); Kolman et al. (1999); McConnell et al. (2003);
Roehrborn (2006); Roehrborn et al. (2008)].
Histologically, BPH can be defined as an enlargement
of transitional (or periurethral) prostatic zone associated
to a nodular, androgen-dependent, tissue remodelling that
involves both epithelium and fibromuscular stroma [Price
et al. (1990); Lee & Peehl (2004); Roehrborn (2008)].
Compared with the normal prostate tissue, hyperplastic
nodules are characterized by reduced epithelium-
to-stroma ratio, determined by an imbalance between
growth and death programmes of stromal cells [Ishigooka
et al. (1996); Claus et al. (1997); Lin et al. (2000)], lead-
ing to increased final stromal volume. Histological micr-
onodular alterations appear early in young men,
characterized by an immature mesenchyme displaying fea-
tures of embryonic mesenchyme, able to differentiate into
myofibroblasts and smooth muscle cells to generate a
‘‘reactive stroma’’ [Lee & Peehl (2004); Peehl & Sellers
(1997); Rumpold et al. (2002); Untergasser et al. (2005)].
These changes in stromal architecture and homeosta-
sis, and in the microenvironment of prostatic stromal-
epithelial cell interactions, induce subsequent epithelial
Keywords:
benign prostatic hyperplasia, chronic
inflammation, stromal cells, vitamin D
receptor agonists
Correspondence:
Mario Maggi, Andrology Unit, Department of
Clinical Physiopathology, University of
Florence, Viale G. Pieraccini, 6, 50139
Florence, Italy. E-mail: m.maggi@dfc.unifi.it.
Received 18 March 2009; revised 23 April
2009; accepted 24 April 2009
doi:10.1111/j.1365-2605.2009.00972.x
Summary
Benign prostatic hyperplasia (BPH) is a common disorder affecting 50–80% of
the aged male population. Androgens and age have been traditionally consid-
ered the main determinants of prostate enlargement, but in the last years a
potentially important role of chronic inflammation in BPH pathogenesis has
emerged. Bacterial and non-infectious chronic prostatitis could represent incit-
ing factors leading to tissue hyperproliferation, possibly via the recently dem-
onstrated antigen-presenting capacity of prostatic stromal cells, enabling them
to induce and sustain intraglandular immune responses. The prostate
growth-promoting chemokine IL-8 could represent a direct link between
chronic prostate inflammation and autocrine ⁄paracrine stromal cell prolifera-
tion, in agreement with its marked secretion induced in BPH stromal cells by a
combination of Th1 and Th17 cell-derived inflammatory cytokines. BPH stro-
mal cells express the vitamin D receptor (VDR), which is up-regulated by
exposure to inflammatory stimuli. The non-hypercalcaemic VDR agonist elo-
calcitol, shown to arrest BPH development by decreasing the intra-prostatic
androgen signalling without directly interfering with systemic androgen action,
exerts immunoregulatory and anti-inflammatory properties in different pros-
tatic pathology characterized by growth and inflammation. The mechanism of
action of VDR agonists supports an important role of chronic inflammation in
BPH pathogenesis and strengthens the concept of these agents as a therapeutic
option for pharmacological treatment of BPH.
international journal of andrology ISSN 0105-6263
ª 2009 The Authors
Journal compilation ª 2010 European Academy of Andrology • International Journal of Andrology 33 (2010), 475–488 475

rearrangements and BPH progression [McNeal (1990);
Donjacour & Cunha (1991); Bierhoff et al. (1997)].
During foetal and adult life, prostate development and
trophism are regulated both directly and indirectly by
androgens [Roehrborn (2008)]. Testosterone and its
metabolite dihydrotestosterone (DHT), locally generated
by the enzymatic activity of 5a-reductase type II, promote
prostate cells growth and differentiation by two different
mechanisms: the ligation of the androgen receptor (AR),
expressed by epithelial and stromal cells, and the induc-
tion of stromal synthesis of growth factors, that act on
epithelial and stromal compartments in a paracrine and
an autocrine manner respectively [Lee & Peehl (2004);
Roehrborn (2008)]. Among these intrinsic factors, a cru-
cial role in embryological differentiation and prostatic
branching is exerted by fibroblast growth factors (FGFs),
transforming growth factor b (TGFb) and insulin-like
growth factors (IGFs), which are all markedly increased
in hyperplastic glands. In particular, they have been
proved to reawaken prostatic developmental programmes
normally repressed in adult life [Lee & Peehl (2004);
Roehrborn (2008); Mori et al. (1990), Barni et al. (1994);
De Bellis et al. (1998); Planz et al. (1999); Ropiquet et al.
(1999); Crescioli et al. (2000); Eaton (2003)]. The most
represented FGFs in prostate are FGF-2 and FGF-7 (or
keratinocyte growth factor, KGF). FGF-2 is actively syn-
thesized by stromal and epithelial prostate cells, which
express also its specific receptor FGFR1 [Sherwood et al.
(1992); Deshmukh et al. (1997); Story et al. (1989); Boget
et al. (2001)]. It acts as an autocrine inducer of stromal
proliferation, able to maintain mesenchymal homeostasis
in normal prostate and to promote the structural remod-
elling typical of BPH at the earliest stages [Mori et al.
(1990); Janssen et al. (2000)]. It has been also proposed
that an oestrogenic stimulation of the prostate secondary
to the age-related decline of testosterone to oestrogens
ratio may lead to reactivation of tissue growth, with a
preferential proliferation of prostate stromal cell [see
Prins & Korach (2008) for review].
The highest incidence of BPH in the elderly men,
whose levels of circulating testosterone progressively
decrease by ageing, suggests that the local production of
these mitogens is regulated by other mechanisms besides
sexual hormones. A major player in the pathogenesis of
prostate overgrowth appears to be glandular inflammation
[Kramer et al. (2002, 2007); Sciarra et al. (2007)], joining
the static (mechanical urethral obstruction by prostatic
adenoma) and dynamic (detrusor hypertrophy and blad-
der neck smooth muscle failure) components in LUTS
development [Nickel (1994)]. The aim of this review was
to overview the cell types and molecular mediators
involved in immuno-mediated inflammatory reactions
that characterize BPH onset and clinical progression. The
use of vitamin D receptor (VDR) agonists in the modula-
tion of intraprostatic inflammatory processes, extensively
analysed by our groups, highlight new therapeutic per-
spectives potentially able to target multiple pathogenetic
components in BPH.
Chronic inflammation and BPH
The association between BPH and intraprostatic inflam-
mation was first proposed based on the histological coex-
istence of hyperplastic nodules and chronic inflammatory
infiltrates in a high proportion of BPH tissues [Nickel
(1994); Odunjo & Elebute (1971); Kohnen & Drach
(1979); Theyer et al. (1992); Bedalov et al. (1994); Steiner
et al. (1994); Nickel et al. (1999); Di Silverio et al. (2003);
Nickel et al. (2007); Sciarra et al. (2008)]. Accordingly,
symptoms suggestive of prostatitis and LUTS frequently
overlap in BPH patients [Nickel (2006)]. The importance
of inflammatory reactions in the pathogenesis and evolu-
tion of BPH symptoms was also confirmed by the dem-
onstration of a positive correlation between a history of
young-onset prostatitis and later development of LUTS
[Sutcliffe et al. (2005)]. On the other hand, an inverse
correlation between the daily use of non-steroidal anti-
inflammatory drugs and the clinical condition worsening
has been detected [St Sauver et al. (2006)]. In addition,
several epidemiological studies evidenced that acute or
chronic inflammation contributes to the clinical progres-
sion of BPH-related symptoms. Results from the MTOPS
trial indicate that inflamed glands have larger volumes
than non-infiltrated ones, and predispose patients to a
higher risk of unfavourable outcomes, such as AUR
[McConnell et al. (2003)]. Similarly, in a subgroup of
randomly-selected patients from the REDUCE trial the
association between inflammation and severity of BPH
symptoms has been described [Nickel et al. (2007)].
The intraprostatic immune system
The prostate, long considered an immunoprivileged organ
[Whitmore & Gittes (1977)], is an immunocompetent
site, thanks to the presence of an intraglandular immune
system that takes part in the maintenance of reproductive
tract sterility and in the prevention of autoimmune reac-
tions towards intraprostatic and sperm antigens [Short-
liffe et al. (1981); Vykhovanets et al. (2005)]. In the
normal prostate, infiltrating leucocytes are localized
within the interstitium around epithelial ducts and
between epithelial cells and consist of mast cells, T lym-
phocytes (with a prevalence of CD8+ cytotoxic cells on
CD4+ helper cells), macrophages and B lymphocytes
[Theyer et al. (1992); Steiner et al. (1994)]. T lympho-
cytes populate the gland about the 12th week of foetal
BPH and inflammation B. Fibbi et al.
476
ª 2009 The Authors
Journal compilation ª 2010 European Academy of Andrology • International Journal of Andrology 33 (2010), 475–488