Clinical Section / Mini-Review

Gerontology 2019;65:458–464 Received: December 12, 2018

Accepted: December 18, 2018
DOI: 10.1159/000496289 Published online: April 3, 2019

Pathophysiology of Benign Prostatic

Hyperplasia and Benign Prostatic
Enlargement: A Mini-Review
Stephan Madersbacher a, b Natalie Sampson c Zoran Culig c
     

a Department of Urology, Kaiser Franz Josef Hospital, Vienna, Austria; b Sigmund Freud Private University, Vienna,
   

Austria; c Department of Urology, Medical University of Innsbruck, Innsbruck, Austria

 

Keywords Introduction
Benign prostatic hyperplasia · Benign prostatic
enlargement · Pathophysiology · Androgens · Metabolic Benign prostatic hyperplasia (BPH) belongs to the
syndrome · Management most frequent diseases in ageing men. In the 4th decade
of life, BPH is demonstrable in 30–40% of men, and its
prevalence increases almost linearly to 70–80% in those
Abstract older than 80 years. BPH, however, is a purely histological
Benign prostatic hyperplasia (BPH), benign prostatic enlarge- definition and must be distinguished from benign pros-
ment (BPE) and lower urinary tract symptoms (LUTS) belong to tatic enlargement (BPE), which describes an enlarged
the most frequent diseases in ageing men. Beyond the 6th de- prostate, and lower urinary tract symptoms (LUTS),
cade of life, more than 30% of men suffer from moderate to which usually lead to medical consultation [1]. LUTS can
severe LUTS requiring intervention. The pathophysiology of be separated into storage symptoms (urgency, frequency,
BPH/BPE is still incompletely understood. The dominant role nocturia and urge urinary incontinence), voiding symp-
of the androgen system and the androgen receptor is well de- toms (reduced flow and feeling of incomplete emptying)
fined. Androgen receptors are expressed in BPH tissue in which and post-void dribbling. LUTS are best quantified by val-
they are activated by the potent androgen dihydrotestoster- idated questionnaires, such as the International Prostate
one. Synthesis of dihydrotestosterone is under control of the Symptom Score (IPSS) or the American Urological As-
5α-reductase enzyme, activity of which is antagonized by fin- sociation (AUA) symptom score [1]. LUTS in elderly
asteride and dutasteride. More recently, the impact of pros- men are dominantly caused by urodynamic changes of
tatic inflammation and metabolic parameters particularly for the lower urinary tract, such as benign prostatic obstruc-
the development of BPE and LUTS has increasingly been rec- tion and detrusor overactivity or underactivity [2].
ognized. A better understanding of the pathophysiology is a In parallel to BPH, also BPE, LUTS and abnormal uro-
prerequisite for the development of novel, more effective dynamic patterns increase with age. The prevalence of
medical treatment options. © 2019 S. Karger AG, Basel moderate/severe LUTS (IPSS > 7) is around 20% in the

© 2019 S. Karger AG, Basel Stephan Madersbacher, MD, FEBU

Department of Urology, Kaiser Franz Josef Hospital
Kundratstrasse 3
E-Mail karger@karger.com
AT–1100 Vienna (Austria)
www.karger.com/ger E-Mail stephan.madersbacher @ wienkav.at
5th, 30% in the 6th and 40% in the 8th decade of life. In a binding domains of the receptor. Importantly, alterations
prevalence study based on 2,096 men living in Austria, it in AR expression comparable to those observed in cancer
was calculated that currently approximately 350,000 men tissue have not been observed in benign disorders. Thus,
older than 40 years living in Austria (total population 8.7 there are no reports in the literature on AR gene amplifi-
million) have moderate to severe LUTS [3]. Due to demo- cations, mutations or enhanced interaction with coacti-
graphic changes, this figure will rise substantially to ap- vators in BPH. Differences in the number of polymorphic
proximately 500,000 in the next 2 decades, emphasising CAG repeats in the N-terminal region of the AR structure
also its socioeconomic relevance [3]. have been reported in the literature; however, there is no
Despite its high prevalence and socioeconomic im- consensus in the scientific community on the clinical rel-
pact, the pathophysiology of BPH is only incompletely evance of these polymorphisms in the pathogenesis of
understood. It is, for example, still largely unknown why BPH/LUTS. It is established that receptors with a lower
some men develop a 40-g prostate and others a 200-g number of CAG repeats have a higher transcriptional ac-
prostate. Herein, we review several pathophysiological tivity. Shorter CAG repeats in BPH patients in Finland
(with emphasis on the androgen pathway) and the most were less common, contrary to expectations [5]. It seems
relevant clinical aspects of BPH and BPE. The pathomech- that this issue is more relevant to understanding racial
anisms leading to LUTS are much more complex than differences in prostate cancer rather than BPH.
just BPH/BPE and involve several urodynamic patterns In order to understand the basis for therapeutic inter-
(e.g., detrusor overactivity/underactivity), changes with- ference in BPH, it is important to emphasize that
in the urothelium and bladder ultrastructure, receptor 5α-reductase is responsible for the synthesis of a more
status of the anticholinergic system, pelvic ischaemia and potent androgen, DHT. Therefore, inhibitory approaches
many more [4]. This extensive field is not covered in this in BPH primarily target 5α-reductase. BPH tissue con-
review, and the interested reader is referred to the respec- tains oestrogen receptor α in stroma and oestrogen recep-
tive literature [4]. tor β in epithelium. Epigenetic alterations that lead to
changes in oestrogen receptor β expression have been de-
scribed in primary and metastatic cancer tissue. Thus,
Androgen Pathway one could conclude that there are no alterations in the
expression of steroid receptors that considerably affect
The prostate, like other sex-accessory tissues, is stimu- benign hyperplastic tissue. However, since the more po-
lated in its growth, maintenance and secretory function by tent androgen DHT is generated in hyperplastic tissue,
the continued presence of certain hormones and growth the use of anti-hormonal agents, which suppress func-
factors. Foremost among these is testosterone. Serum tes- tional activity of the AR, on the basis of pre-clinical find-
tosterone is under the control of the hypothalamic (LHRH)- ings will be further discussed.
pituitary (LH/FSH)-testicular (testosterone) hormone In this context, it is interesting to mention that the neu-
axis. Testosterone originating from the testis (95%) and ad- ropeptide serotonin (5-HT) down-regulates AR, thus pre-
renal gland (5%) is the major serum androgen stimulating venting prostate branching [6]. The experiments with dif-
prostate growth. The average testosterone concentration in ferent 5-HT agonists yielded similar results regarding the
the plasma is approximately 600 ng/mL. Serum testoster- androgen signalling pathway. 5-HT, which is a constituent
one levels remain fairly constant between 25 and 60 years of neuroendocrine cells, is down-regulated in benign pros-
of age, yet decline gradually thereafter. Although testoster- tate tissue. It is a general opinion that neuroendocrine cells
one is the primary plasma androgen, it appears to function contribute to the progression of prostate cancer, whereas in
as a prohormone in that the most active form of the andro- BPH, they could have a different effect. Another compound
gen in the prostate is dihydrotestosterone (DHT) (Fig. 1). which attenuates the effects of testosterone on BPH tissue
Hormonal regulation of BPH is dependent on the presence is vanillic acid [7]. It was demonstrated that treatment with
of androgen and oestrogen receptors. In addition, activity vanillic acid, which is also known as an anti-inflammatory
of the enzyme 5α-reductase plays an important role in the agent, leads to reduction of prostate weight and induction
BPH pathogenesis. of epithelial thickness. Vanillic acids was shown to inhibit
Androgen receptors (AR) are widely expressed in be- AR, oestrogen receptor α and steroid receptor coactivator
nign epithelium and adjacent stroma. The action of AR 1. The authors have also performed in vitro experiments
in prostate tissue is enhanced by coactivators which may which largely confirmed the in vivo data. BPH medical
interact with N-terminal, DNA-binding and/or ligand- treatment with the 5α-reductase type II inhibitor finasteride

Benign Prostatic Hyperplasia Gerontology 2019;65:458–464 459

DOI: 10.1159/000496289
 Color version available online
Fig. 1. Hormonal regulation of BPH. The
potent androgen DHT is synthesized from
testosterone, and the process is under con-
trol of 5α-reductase. DHT regulates ex-
pression of growth-promoting and pro-
differentiation genes in benign prostate
cancer, in part in coordination with the
IGF pathway. The effects of DHT could be
antagonized by finasteride and dutasteride
and the effects of IGF by metformin. AR,
androgen receptor; BPH, benign prostatic
hyperplasia; DHT, dihydrotestosterone;
IGF, insulin-like growth factor.

is a standard clinical procedure so that there is no need to terone-induced BPH in rats [11]. Metformin antagonized
discuss the experimental basis and early studies in this field the effects of testosterone on the up-regulation of oestrogen
in detail. However, it should be mentioned that investiga- receptor α and the down-regulation of oestrogen receptor
tions on the oncogenes Bcl-2 and Bcl-xl in BPH tissue after β in an animal model. Although metformin did not cause
finasteride treatment have been carried out [8]. No effect of any effect on 5α-reductase, it decreases mRNA for insulin-
finasteride was reported, thus suggesting that 5α-reductase like growth factor (IGF)-I and its receptor. Consequently,
inhibition does not parallel inhibition of these 2 members metformin acted as a pro-apoptotic factor through inhibi-
of the Bcl family. Interestingly, it has been proposed that the tion of the Akt pathway. IGFs regulate cell proliferation and
presence of the oncogene c-Jun in prostate fibroblasts is re- apoptosis through a complex system which depends on the
quired for the in vitro growth of BPH-1 cells. Finasteride expression of receptors and binding proteins. Expression of
inhibitory effects on cellular proliferation were observed in both IGFs is increased in human BPH tissue [12]. Interest-
the presence of c-Jun [9]. Consistent with previous pre- ingly, higher levels of IGF binding protein-3 were measured
clinical studies with finasteride, a therapeutic basis for the in the stromal compartment of the prostate [13]. Impor-
use of the 5α-reductase inhibitor dutasteride in benign and tantly, this binding protein potentiated stromal remodel-
malignant prostate disorders has been established [10]. ling by transforming growth factor (TGF)-β by a mecha-
Concomitant use of dutasteride and testosterone led to nism that is independent of IGF. On the basis of these find-
growth inhibition of BPH-1 cells. ings, it could be concluded that the IGF axis is a valid target
There are several options to interfere with androgen-in- for novel therapy approaches for BPH.
duced growth of BPH cells when different nutrition ingre- Hormonal regulation of BPH could be antagonized by
dients or compounds that regulate cellular metabolism are chemopreventive agents. The term “chemopreventive” is
used. For example, the widely used anti-diabetic agent met- in most cases used in connection with cancer prevention;
formin, which is known for its anti-proliferative and pro- however, the in vitro and in vivo effects of these com-
apoptotic properties, was demonstrated to attenuate testos- pounds on benign tissue are of considerable interest. In

460 Gerontology 2019;65:458–464 Madersbacher/Sampson/Culig

DOI: 10.1159/000496289
 Color version available online
Metabolic
syndrome

Insulin Hormone Pelvic

Inflammation
resistance changes atherosclerosis

Sympathetic Bladder and

nervous system Increased estradiol
prostatic Cytokine release
activation Lower testosterone
ischaemia

Increase in
prostate smooth
Fig. 2. The potential role of the metabolic muscle tone
syndrome in the pathophysiology of BPE/
LUTS. BPE, benign prostatic enlargement; LUTS/BPH/BPE
BPH, benign prostatic hyperplasia; LUTS,
lower urinary tract symptoms.

case of BPH, it would be more appropriate to use the term Age-Related Tissue Remodelling
“dietary compounds.” They include polyphenols, flavo-
noids and isoflavonoids. They are contained in fruits, broc- Aging and androgens are the 2 established risk factors
coli, and green tea. Pomegranate fruit extract, which has for the development of BPH/BPE [17]. In addition, local
anti-inflammatory and anti-oxidative properties, reduced para- and luminocrine pleiotrope mechanisms/factors are
testosterone increase in prostate weight and prevented implicated in the prostatic tissue remodelling process as
hormonally induced histological changes [14]. Similarly, exemplified in a review by Untergasser et al. [18]. Prostate
ginseng, which is used in traditional Korean herbal medi- tissue remodelling in the transition zone is characterized
cine, was evaluated as a potential drug in multiple diseases by (1) hypertrophic basal cells; (2) altered secretions of lu-
and was suggested for use in the experimental therapy of minal cells leading to calcification, clogged ducts and in-
BPH [15]. Its effect is in part based on the inhibition of ad- flammation; (3) lymphocytic infiltration with production
renergic receptors in BPH. Although the role of the envi- of proinflammatory cytokines; (4) increased radical oxy-
ronmental endocrine disruptor bisphenol needs to be in- gen species production that damages epithelial and stromal
vestigated in more detail in appropriate BPH models, the cells; (5) increased basic fibroblast and TGF-β production
evidence that it up-regulates aromatase should be taken leading to stromal proliferation, transdifferentiation and
into consideration with regard to BPH pathogenesis. Bis­ extracellular matrix production; (6) altered autonomous
phenol is nearly ubiquitously present in the environment, innervation that decreases relaxation and leads to a high
including plastics and food containers. In addition to oes- adrenergic tonus; and (7) altered neuroendocrine cell func-
trogen receptor ligands, the ability of selective oestrogen tion and release of neuroendocrine peptides [18].
receptor modulators in the inhibition of BPH has been de-
scribed in the literature (reviewed by [16]).
In summary, therapeutic options in BPE/LUTS could be Inflammation
based on the antagonism between androgenic and oestro-
genic hormones. Hormonal regulation also includes sev- The observation of chronic inflammation coexisting
eral peptide hormones, and the regulatory system based on with BPH histologic changes in pathologic specimens led
IGFs seems to be the most important one. Antagonism of to the suspicion that inflammation plays a role in the de-
this system in combination with 5α-reductase inhibitors velopment of BPH/BPH and also LUTS (Fig. 2). Local in-
may be a valuable option in future BPH treatment. flammation may be triggered by viral or bacterial infection,

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DOI: 10.1159/000496289
which would lead to the secretion of cytokines, chemokines above) as a required permissive element and age. The role
and growth factors involved in the inflammatory response of testosterone/DHT is further substantiated by the ab-
with consequent growth of epithelial and stromal prostatic sence of an enlarged prostate (and also of prostate cancer)
cells [4]. It has been hypothesized that the inflammatory in men with a genetic defect of the 5α-reductase type II
response is perpetuated by the release of prostatic self-an- and those castrated around the age of puberty (eunuchs).
tigens following tissue damage, which would sensitize the Numerous epidemiological studies have attempted to
immune system and start autoimmune responses (Fig. 2) identify correlates and risk factors for BPE/LUTS, such as
[4]. Important factors in this process are the prostatic stro- religion, socioeconomic factors, sexual activity, vasecto-
mal cells, which activate CD4+ lymphocytes and proin- my, cigarette smoking and alcohol. These studies failed to
flammatory cytokines and chemokines, such as stromal- demonstrate a consistent association with BPE/LUTS [1,
derived interleukin-8 (Fig. 2) [19]. 23].
Prostatic inflammation was associated with overall There is evidence of familial aggregation of male LUTS,
clinical progression and an increased risk of urinary re- although more recent studies suggest only a modest asso-
tention and the need for surgery [20]. Furthermore, a ciation. In the Olmsted County study, for instance, having
positive association between high plasma C-reactive pro- either a father or a brother with a history of diagnosed BPE
tein levels and the odds of reporting moderate to severe was associated with an odds ratio of 1.5 for moderate to
LUTS was reported as well. severe LUTS at baseline, and such risks seem to be cumula-
tive, with 2 or more affected relatives conferring a greater
risk [24]. Twin studies provide estimates of heritability that
Metabolic Factors are less confounded by environmental or lifestyle factors
that may be shared within families. Several twin studies
Results from multiple pre-clinical and clinical studies have confirmed a heritability of BPH/BPE/LUTS in the
indicate that several age-related metabolic aberrations range of 50–70%, suggesting a similar heritability as for
(metabolic syndrome, obesity, dyslipidaemia and diabetes) many complex diseases [25]. A recent meta-analysis aimed
are important determinants in both the development and to identify candidate polymorphisms/genes for BPH/
the progression of BPH/LUTS (Fig. 2) [21]. Metabolic syn- LUTS and yielded only a few putative genetic risk variants
drome and its related comorbidities, such as sex steroid reliably replicated across populations. This review includ-
alterations and low-grade inflammation, have been related ed also the most frequently cited genetic variant in this con-
to BPH/LUTS development and progression (Fig. 2). In the text, the number of CAG repeats within the AR [26]. The
Baltimore Longitudinal Study of Aging cohort, each 1 kg/ authors observed consistent evidence of a reduced risk of
m2 increase in body mass index (BMI) corresponds to a LUTS associated only with the common rs731236 variant
0.4-mL increase in prostate volume. Obese (BMI >35 kg/ of the vitamin D receptor gene [26].
m2) participants had a 3.5-fold increased risk of prostate The high prevalence of the disease and its socioeconom-
enlargement compared to non-obese (BMI <25 kg/m2) ic impact raises the issue of disease prevention. Long-term
participants [22]. Most established aspects of the metabol- studies with the 5α-reductase inhibitors finasteride and
ic syndrome are linked to BPH/BPE. The presence of met- dutasteride suggest that both drugs reduce the risk of acute
abolic syndrome is associated with a higher annual BPE urinary retention and the need for surgery [1]. However, for
growth rate, increased sympathetic activity and LUTS [4, the indication “prevention” in men with no or only mild
2]. The underlying pathophysiologic mechanisms involved LUTS, both drugs are not licensed mainly because the risk
in the association of metabolic factors with BPH/BPE/ (costs/side effects)/benefit ratio remains unclear. Whether
LUTS are not completely understood, but systemic inflam- promoting a healthier lifestyle (metabolic syndrome) can
mation, pelvic ischaemia and increased sympathetic activ- alter a man’s propensity to develop BPH/LUTS remains to
ity may play a role (Fig. 2) [4, 21]. be clarified in large-scale, long-term controlled trials.

Risk Factors and Disease Prevention Clinical Perspective

For decades there have been 2 accepted, well-estab- The development of LUTS is a multifactorial process
lished risk factors for the development of BPH/BPH: the with BPH/BPE and urodynamic changes being important
presence of functioning testes at the time of puberty (see co-factors. Another relevant aspect is the response of the

462 Gerontology 2019;65:458–464 Madersbacher/Sampson/Culig

DOI: 10.1159/000496289
urinary bladder to benign prostatic obstruction, i.e., the For more than 50 years, the standard surgical proce-
development of detrusor overactivity or detrusor hypo-/ dure has been transurethral resection of the prostate with
acontractility. The most frequent urodynamic pattern in excellent long-term data unsurpassed by alternative tech-
elderly men with LUTS is detrusor overactivity (60%), niques [1]. Open prostatectomy (which was the surgical
while benign prostatic obstruction is only present in 30– standard for patients with prostates exceeding 80–100
40% [3]. Other important mediators are inflammation, mL) is increasingly forced back by various enucleation
atherosclerosis, urothelial dysfunction, α- and anti-mus- techniques resulting in similar functional outcomes yet
carinic receptor status, etc. [4]. considerably lower morbidity, such as risk of bleeding,
The standard of care is defined by evidence-based duration of catheterisation and hospitalisation [1]. As
guidelines, such as those of the European Association of outlined in BPH/LUTS guidelines, the surgical approach
Urology (EAU) [1]. Management of men with LUTS due should be individualized based on surgical risk (anaesthe-
to BPH/BPE is driven by symptom status, objective pa- siologic, bleeding), prostate volume and patient prefer-
rameters (post-void residual volume and uroflowme- ences (preservation of sexual function).
try), risk of disease progression and the presence of
BPH-related complications, such as recurrent urinary
retention, bladder stones or hydronephrosis/decline in Statement of Ethics
renal function [1].
The authors have no ethical conflicts to disclose.
It is beyond the scope of this article to describe the
various treatment options in more detail, and the reader
is referred to, for example, the above-mentioned EAU
Disclosure Statement
guidelines; yet, a few principles are briefly presented [1].
All guidelines suggest a risk-adapted, individualized ap- The authors have no conflicts of interest to declare.
proach (AUA guidelines [1]). In men with mild symp-
toms (IPSS <8), no complications and low risk of disease
progression, a conservative, watchful waiting approach is Funding Sources
recommended. In those with moderate/severe symptoms
and no complications, medical therapy is indicated [1]. There are no funding sources.
The following drugs are currently in use, either alone or
in various combinations: plant extracts (low level of evi-
dence), α-blockers (level I evidence, moderate effect on Author Contributions
LUTS, uroflowmetry and post-void residual volume, no
All authors contributed equally to this manuscript.
effect on prostate volume and disease progression),
5α-reductase inhibitors (level I evidence, moderate effect
on LUTS/uroflowmetry/post-void residual volume, 20–
30% reduction of prostate volume and effect on disease
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DOI: 10.1159/000496289