Epidemiology and Pathogenesis of Benign Prostatic Hyperplasia - UpToDate

3/10/2018 Epidemiology and pathogenesis of benign prostatic hyperplasia - UpToDate
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Epidemiology and pathogenesis of benign prostatic hyperplasia
Authors: Glenn R Cunningham, MD, Dov Kadmon, MD
Section Editor: Michael P O'Leary, MD, MPH
Deputy Editor: Judith A Melin, MA, MD, FACP
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2018. | This topic last updated: Feb 27, 2018.
INTRODUCTION — Benign prostatic hyperplasia (BPH) is a common problem among older men and is
responsible for considerable disability. The large number of men with the symptoms of this disorder, the easy
access to diagnostic tests, and the availability of drug therapy make it appropriate for the primary care provider to
participate in the management of men with this disorder. To do so requires an appreciation for what is known
regarding the epidemiology and etiology of BPH, which will be reviewed here. The diagnosis and management of
this disorder are discussed elsewhere. (See "Clinical manifestations and diagnostic evaluation of benign prostatic
hyperplasia" and "Medical treatment of benign prostatic hyperplasia" and "Transurethral procedures for treating
benign prostatic hyperplasia".)
EPIDEMIOLOGY — The prostate on average weighs 20 grams in normal 21 to 30yearold men, and the weight
changes little thereafter unless the man develops benign prostatic hyperplasia (BPH) [1]. However, because of
the increased prevalence of BPH in older men, the mean prostate weight at autopsy increases after age 50 years
(figure 1).
Prevalence — The prevalence of histologically diagnosed BPH increases from 8 percent in men aged 31 to 40,
to 40 to 50 percent in men aged 51 to 60, to over 80 percent in men older than age 80 (figure 2). The Baltimore
Longitudinal Study of Aging compared the agespecific prevalence of pathologically defined BPH at autopsy with
the clinical prevalence based upon history and the results of digital rectal examination [2]. There was good
agreement between the clinical prevalence and autopsy incidence in men of all ages.
A major difficulty in comparing the prevalence of lower urinary tract symptoms (LUTS) among different groups
has been the lack of a common definition. The Olmsted County study found the prevalence of moderate or
severe LUTS for men in the fifth, sixth, seventh, and eighth decades of life to be 26, 33, 41, and 46 percent,
respectively [3]. In a communitybased group of 502 men aged 55 to 74 years without prostate cancer, the
prevalence of BPH and LUTS was 19 percent using the criteria of a prostate volume above 30 mL and a high
International Prostate Symptom Score (IPSS) [4]. However, the prevalence was only 4 percent if the criteria were
a prostate volume above 30 mL, a high IPSS, a maximal urinary flow rate below 10 mL/sec, and a postvoid
residual urine volume greater than 50 mL. (See "Lower urinary tract symptoms in men".)
Risk factors
● Race – Race has some influence on the risk for BPH severe enough to require surgery. While the age
adjusted relative risk (RR) of BPH necessitating surgery is similar in black and white men, black men less
than 65 years old may need treatment more often than white men [5]. In a study of 34,624 men, compared
with whites, Asians had a lower risk for nocturia (RR 0.7, 95% CI 0.50.9), physiciandiagnosed BPH (RR
https://www.uptodate.com/contents/epidemiology-and-pathogenesis-of-benign-prostatic-hyperplasia/print?search=hiperplasia%20prost%C3%A1tica%20benigna&so… 1/9
0.7, CI 0.20.5), and transurethral prostate surgery (RR 0.2, CI 0.10.6), while risks for blacks and whites
were similar [6]. In the American Male Health Professional Study, men of Asian ancestry were less likely (RR
0.4, 95% CI 0.20.8) to undergo surgery for BPH as compared with white men [7]. Black men had similar risk
to white men in this study. In a community sample of 2480 men in the United States, moderate to severe
LUTS were more common in blacks than in whites (41 versus 34 percent) [8], and blacks had greater total
and transitional zone prostate volume [9,10]. However, there is evidence that differences in risk of LUTS is
more related to socioeconomic factors such as income and insurance than to race [11].
One study applied the American Urological Association symptom score to 289 Japanese men ranging in age
from 40 to 79 years: the Japanese men had somewhat higher symptom scores than American men [12]. The
American men had an approximately 6 mL/decade increase in prostate size, as compared with 3 mL/decade
for the Japanese men. This correlates with the lower agespecific prevalence of BPH in Japan. However, an
autopsy study of men who lived in Beijing and Shanghai found that the frequency of BPH was similar to that
in Western countries, although prostate cancer was much less common [13]. There have been inconsistent
results across studies about the effects of various dietary components and supplements on the risk of
symptomatic BPH [1416].
● Family history of cancer – The relationship between cancer and BPH is unclear. One study found an
increased risk of BPH in men with a family history of bladder cancer, but risk of BPH was not associated with
a family history of prostate cancer [17].
● Hormone levels – Some reports have suggested a relationship between BPH and hormone levels. Higher
serum levels of testosterone and estradiol were associated with decreased risk of future development of
symptomatic BPH in the Prostate Cancer Prevention Trial [18]. There appears to be a weak inverse
relationship between autopsy findings of BPH and cirrhosis. Men with advanced cirrhosis have lower urinary
symptom scores, smaller prostate volumes, and higher ratios of serum estradiol to serum testosterone [19].
● Alcohol consumption – Alcohol consumption, particularly consumption of excessive amounts of alcohol
(three or more drinks per day), which can reduce androgen levels, may reduce the risk of BPH [20]. Alcohol
consumption was also associated with a decreased risk of LUTS in some [21], though not all, other studies
[22].
● Vasectomy – There is no relationship between vasectomy and BPH.
● Prostatitis – In a longitudinal, populationbased study, prostatitis was associated with an increased risk of
subsequent prostatism, enlarged prostate, and BPH [23]. However, in a study of prostate biopsies done for
any indication, inflammation of the peripheral zone of the prostate was not strongly associated with LUTS
[24].
● NSAIDs – An observational study found an inverse association between use of nonsteroidal
antiinflammatory drugs (NSAIDs) and risk of BPH [25]; this may be related to actual improvements in BPH
when men take NSAIDs [26].
● Obesity or metabolic syndrome – Obesity, elevated fasting glucose, and diabetes have been associated
with an increased risk of LUTS, whereas high adiponectin levels were associated with reduced risk of
symptomatic BPH [27,28]. In a crosssectional study using the United Kingdom Clinical Practice Research
Datalink, metabolic syndrome was diagnosed in 26.5 percent of men with clinical BPH and 20.9 percent of
matched controls [29]. Two metaanalyses found that men with the metabolic syndrome had higher prostate
growth rates and larger prostate volume than those without the metabolic syndrome [30,31]. An increased
waisthip ratio, an estimate of central obesity, has been associated with increased severity of prostate
inflammation; however, prostate size was not associated with proinflammatory cytokines [32]. Men with the
metabolic syndrome and nonalcoholic fatty liver disease are more likely to have severe prostatic
inflammation than men with only one metabolic alteration (75.8 versus 24.2 percent, p<0.01) [33].
● Other – In the Massachusetts Male Aging Study, increased risk of BPH was associated with higher free
prostatespecific antigen (PSA) levels, heart disease, and use of beta blockers [22]. The 2001 to 2008
National Health and Nutrition Examination Surveys (NHANES) also found cooccurrence of erectile
dysfunction and BPH in about 10 percent of men age 40 and older [34]. Sleeprelated problems may be
associated with LUTS [35].
The Massachusetts Male Aging Study found that a decreased risk of BPH was associated with cigarette
smoking (1 to 20 per day) and higher levels of physical activity [22]. Exercise was also associated with a
decreased risk of LUTS in other studies [21].
In the Massachusetts Male Aging Study, risk was not altered by total fat caloric intake, sexual activity, alcohol
intake, body mass index, waisthip ratio, waist circumference, diastolic blood pressure, diabetes, or serum
levels of androgens or estrogens [22]. However, in other studies, a higher diastolic blood pressure was
associated with increased incidence of LUTS [36,37]. NHANES failed to detect differences in LUTS/BPH
occurrence between men living in rural and urban areas [38].
HISTOLOGY — Benign prostatic hyperplasia (BPH) develops primarily in the periurethral or transitional zone of
the prostate. The hyperplastic nodules are comprised primarily of stromal components and to a lesser degree
epithelial cells; stereologic measurements have revealed a fourfold increase in stroma and a twofold increase in
glandular components [39]. In one immunohistochemical study, stroma comprised 62 percent of the volume,
epithelium 15 percent, and glandular lumens 23 percent; the stromaltoepithelial ratio was 4.6 [40]. Some studies
have found inflammation to be a common finding in BPH tissue. Inflammation was assessed by cytological and
immunohistochemical parameters in 282 surgical specimens [41]. The investigators found a high correlation
between inflammation, International Prostate Symptom Score (IPSS), and prostate volume. A study of the
placebo arm of the Prostate Cancer Prevention Trial found that lowsoluble tumor necrosis factor receptor II and
elevated interleukin6 concentrations were associated with increased BPH risk [42].
PATHOGENESIS — Older age and the presence of functioning Leydig cells of the testes are essential for the
development of benign prostatic hyperplasia (BPH). Thus, BPH is very rare in hypogonadal men with onset
before age 40 years who are not treated with androgen. Studies have examined the molecular and cellular
changes associated with BPH [43]. It is likely that multiple factors are causally related to the development of BPH
[44].
The pathogenesis of BPH remains incompletely understood. Populationbased observational studies, disease
registries, biochemical, molecular and histochemical analyses of BPH tissue, in vitro studies of human tissue, and
clinical trials continue to contribute to our understanding of the pathogenesis of this common disorder.
Androgen — The necessity for androgen, in particular dihydrotestosterone (DHT), during prostate development
is best illustrated by observations in men with congenital deficiency of 5alphareductase activity (type 2), the
enzyme that converts testosterone to DHT in the prostate and other androgensensitive tissues [45]. Men with
this disorder have a rudimentary prostate throughout life despite normal serum testosterone concentrations and
normal androgen receptors (see "Steroid 5alphareductase 2 deficiency"). The importance of androgen in the
development of BPH is seen in androgen's ability to induce BPH in dogs [46,47], as well as the regression of
BPH in men when serum testosterone concentrations are lowered with medications. (See "Medical treatment of
benign prostatic hyperplasia".)
In general, the concentrations of DHT in prostatic tissue are not higher in men with BPH than in those without
BPH. Thus, excess intraprostatic conversion of testosterone to DHT is not responsible for the development of
BPH [48]. There may be, however, changes in androgen receptors in the prostate. These receptors are primarily
located in epithelial cells in normal prostatic tissue, as compared with a more heterogeneous distribution
(epithelial and stromal cells) in hyperplastic prostatic tissue [49]. A segment of DNA for the androgen receptor
(AR) encodes for a variable number of glutamine repeats. Results of one study suggest that risk of surgery for
BPH is increased with decreased CAG (trinucleotide cytosineadenineguanine) repeats [50]; however, analysis
of 416 BPH cases and 527 controls from the Prostate Cancer Prevention Trial failed to find an association
between CAG repeat length and BPH risk [51]. One study reported an increase in coactivators and another noted
a decrease in corepressors of the androgen receptor in BPH tissue [52,53]. Subsequent experiments suggest
that DHT stimulates response elements for a calciumactivated chloride channel to cause prostate enlargement
[54].
Serum testosterone or DHT concentrations do not appear to be higher in men in whom the prostate ultimately
becomes hyperplastic than in men in whom it does not. The Physicians' Health Study found similar serum
testosterone concentrations at the initial examination in 320 men who had BPH treated surgically up to nine years
later and 320 men who did not develop prostatic disease [55]. A nested casecontrol study of steroid
concentrations and risk of BPH found that the lowest quartiles of testosterone, estradiol, and
testosterone:17betadiolglucoronide ratio were associated with the highest risk of BPH [18].
In summary, the available evidence indicates that testosterone and DHT are necessary but not sufficient to cause
BPH.
Estrogen — The most compelling evidence for a role of estrogen in the pathogenesis of BPH is that induction of
the disorder in dogs is potentiated by the addition of estrogen [46,47]. This relationship has been partially
explained by estrogen induction of androgen receptors. In addition, the finding of an increase in the ratio of
estrogen to androgen in the serum in older men suggests a possible role for estrogen in the maintenance, but not
necessarily the causation, of BPH. The agerelated increase in the serum estrogenandrogen ratio is associated
with an increase in the estrogenandrogen ratio in prostatic tissue, especially in the stroma [56]. The prostate also
contains the enzymes needed to convert dehydroepiandrosterone (DHEA) and testosterone to estradiol [57].
The results of other studies relating estrogen with BPH are conflicting [55,5861]. The following observations, for
example, are compatible with a role for estrogen:
● Estrogen receptor alpha has been observed to promote epithelialtomesenchymal transition, which is
thought to be involved in the pathogenesis of BPH [62].
● Estrogensignaling pathways have been associated with prostate volume and the pathophysiology of BPH
[63].
● A study of 86 men between 52 and 82 years of age and a family history of prostatic cancer, transition zone
and total prostate volume correlated with serum estrone concentrations [58]. There was no correlation with
serum total or free testosterone or estradiol concentrations.
● In 64 men aged 42 to 71 years with small prostate cancers who underwent radical prostatectomy, the volume
of hyperplastic prostatic tissue (excluding the tumor) correlated with the serum free testosterone, estradiol,
and estriol concentrations [60].
● The Physicians' Health Study demonstrated a strong trend for increasing risk of BPH across quintiles for
serum estradiol concentrations and a weak inverse trend for serum estrone concentrations in the 320 men
who developed BPH necessitating surgery up to nine years later [55].
On the other hand, there are also findings arguing against an important role for estrogen:
● Prostatic stromal cells contain estrogen receptors, and the concentrations are lower in hyperplastic than in
normal prostatic tissue [64]. The concentrations of progesterone receptors in the two types of tissue are
similar.
● Treatment of men with BPH with atamestane, an aromatase inhibitor, reduced serum estrogen
concentrations but did not relieve symptoms, increase the urine flow rate, or reduce prostatic size [61].
However, mepartricin, an antifungal agent that also reduces serum estrogen concentrations, has been
reported to improve symptoms and peak flow rates without changing prostate volume or serum prostate
specific antigen (PSA) concentrations [65].
Dysregulation of stromal growth factors — Since BPH is primarily a disease of the stroma, the stroma might
have intrinsic properties that enable it to proliferate and also to induce hyperplasia of the epithelium. In the
presence of androgen, mesenchymal tissue derived from the urogenital sinus can induce differentiation of
prostate epithelium [66]. By contrast, stroma lacking functional androgen receptors cannot induce differentiation
of normal epithelium. These observations emphasize the importance of the stroma in development of the
prostate.
It has been suggested that BPH occurs because prostatic tissue reverts to an embryoniclike state in which it is
more sensitive to various growth factors. Tissue concentrations of several growth factors are increased in
hyperplastic prostatic tissue as compared with normal prostatic tissue. The most consistent increases are in
several fibroblast growth factors, insulinlike growth factor (IGF)II, and transforming growth factorbeta and the
mRNAs for these substances [6671]. In vitro, epidermal growth factor, transforming growth factoralpha, several
fibroblast growth factors, and IGFI and II stimulate and transforming growth factorbeta inhibits prostatic
epithelial cell growth. Most of these factors stimulate stromal cell growth. A nested case control study found that
serum IGF binding protein3 (IGFBP3) was inversely associated with BPH risk among men with severe
symptoms, while the IGF1:IGFBP3 ratio was positively associated with BPH risk [72]. T lymphocytes and
macrophages appear to play an important role in the induction of cell proliferation [73].
Inflammation — Inflammatory infiltrates are present in up to 70 percent of the prostates of patients with BPH
[74]. The cause for the inflammation has not been identified with certainty; possible etiologies include obesity,
autoimmune processes, and chronic infections.
BPH is more common in obese patients and obesity is associated with increased inflammatory cytokines. Dietary
fats have been implicated, and lipopolysaccharides can induce prostatic inflammation in experimental animals. It
has been hypothesized that macrophages secrete cytokines that stimulate stromal and epithelial hyperplasia.
Investigators have found increased concentrations of hypoxiainducible factor (HIF)1 alpha, which can be
secreted by epithelial cells and is known to be induced by proinflammatory cytokines and to be involved in
testosteronemediated hyperplasia [75]. HIF1 alpha enhances epithelialmesenchymal transition in experimental
models. These investigators proposed that developing agents that block the effects of HIF1 alpha could provide
a new approach to treatment of BPH. If inflammation is a causal mechanism for BPH, it also could provide an
explanation for improvement with nonsteroidal antiinflammatory drugs (NSAIDs) [26]. There is also some
evidence that phosphodiesterase5 inhibitors decrease fibroblast to myofibroblast transdifferentiation, which
could be a mechanism by which they decrease symptoms [76].
Inflammation could be caused by an autoimmune process or in response to chronic infection. Investigators have
failed to associate BPH with any of 17 singlenucleotide polymorphisms in genes involved in obesity [77]. The
lymphotoxinbetareceptor (LTbetaR) gene has been reported to be involved in autoimmune disease and
inflammatory disorders. Korean investigators found nucleotide polymorphisms located in the promoter and coding
regions of LTbetaR in BPH tissue, and an allele was significantly associated with BPH [78]. Heat shock protein
(HSP) 27 also is known as a mediator in immune responses. Expression of HSP27 is reported to increase with
increasing inflammation in BPH tissue [79].
Investigators have sought to identify chronic infections that might cause prostatitis. One possibility is Escherichia
coli. It is postulated that phospholipase D, which is attached to the outer membrane of E. coli, stimulates the
production of lysophosphatidic acid (LPA), and LPA stimulates other factors that cause inflammation [80]. Zinc,
which is known to affect some prostate processes, can enhance LPA stimulation in BPH smooth muscle cells
[81]. Infection with trichomonads also has been shown to induce migration and activation of mast cells, which can
induce proliferation of prostate stromal cells [82].
Another approach to understanding inflammation in BPH tissue has been to measure heme oxygenase (HO). HO
has been found to be inversely related to metaflammation in the prostate [83].
Decreased cell death — The average lifespan of stromal cells exceeds 30 years, while the average lifespan of
epithelial cells exceeds two years. These observations are consistent with the infrequency with which mitoses or
apoptotic bodies are seen in hyperplastic prostatic tissue and indicate that decreased cell death may be a major
contributor to prostatic hyperplasia and enlargement [84]. Increased immunoreactivity for interleukin2 and its
receptors and bcl2 expression are consistent with a lower apoptotic rate in BPH [85,86]. These observations
also attest to the difficulty in causing regression of established BPH in the absence of increasing cell death.
Furthermore, androgen deprivation does not alter bcl2 expression, which has been found to be increased in
hyperplastic tissue [87].
Increased stem cells — An increase in stem cells that reside in the basal epithelial compartment is
hypothesized to cause BPH [88]. Studies in animal models have found that in rats, the size of the prostate is
defined by the absolute number of potential stem cells and their subsequent recruitment and maturation [89,90].
In mice, experimental induction of prostate inflammation, which results in prostate stem cell expansion [91].
However, the relevance of these observations in animal models to prostatic growth in humans is not known.
Genetic susceptibility — A role for genetic factors is suggested by studies of familial tendencies towards BPH
and by genetic studies. Familial BPH is characterized by larger prostate size and diagnosis at an earlier age than
sporadic BPH [92]. Twin studies suggest that heritability is a more important determinant of lower urinary tract
symptoms (LUTS) than age, transition zone volume or total prostate volume [93]. BPH may have an autosomal
dominant mode of inheritance for some men [94].
Various studies have shown familial tendencies. In one study, men with three or more affected family members
had large prostate glands, abovenormal serum androgen concentrations, and a normal response to 5alpha
reductase inhibition [92]. In a survey of men in Olmsted County, Minnesota, 21 percent of 2119 men between 40
and 70 years of age had a family history of an enlarged prostate [95]. The odds ratio of a man with a positive
family history of BPH having moderate to severe LUTS was 1.3 (95% CI, 1.11.7).
The possible role of genetic factors was evaluated in several studies. A genomewide association study (GWAS)
of men from three independent populations indicated that genetic variants of GATA3 may play a role in the
inherited susceptibility and etiology of BPH/LUTS [96]. A 2014 systematic review and metaanalysis of genes that
may cause urinary symptoms in men only found a variant of the vitamin D receptor that was consistently
protective across different populations [97]. In a casecontrol study of men under 64 years of age who had
undergone prostatectomy for BPH and in whom more than 37 grams of tissue was resected, the firstdegree
relatives of these men had a fourfold increased risk of developing BPH that required surgical therapy as
compared with the relatives of normal men [98]. Segregation analysis suggested an autosomal dominant mode of
disease transmission (with an estimated penetrance of 0.89) and an allele frequency of 3.4 percent in the
population. Hereditary BPH could account for 9 percent of all cases requiring surgery and for more than 50
percent in men under 60 years of age. One study evaluated genes expressed in prostates that were <60 mL and
compared them with glands >60 mL in men undergoing surgery [99]. Analyses of microarrays revealed 227
genes that were differentially expressed between the two groups. This included growth factor genes, cell cycle
genes, apoptosis genes, inflammation genes and androgenregulated genes.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
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Here are the patient education articles that are relevant to this topic. We encourage you to print or email these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Benign prostatic hyperplasia (enlarged prostate) (The Basics)")
● Beyond the Basics topic (see "Patient education: Benign prostatic hyperplasia (BPH) (Beyond the Basics)")
SUMMARY
● The prevalence of histologically diagnosed benign prostatic hyperplasia (BPH) increases from 8 percent in
men aged 31 to 40, to 40 to 50 percent in men aged 51 to 60, to over 80 percent in men older than age 80.
(See 'Prevalence' above.)
● Black men are more likely than white men to have larger prostate volume and more moderate to severe
lower urinary tract symptoms (LUTS). Asian men are less likely than white and black men to have BPH.
Increased risk of BPH was associated with higher free prostatespecific antigen (free PSA) levels, heart
disease, use of beta blockers, and lack of physical exercise. (See 'Risk factors' above.)
● BPH develops primarily in the periurethral or transitional zone of the prostate, with a fourfold increase in
stromal tissue and a twofold increase in glandular components. (See 'Histology' above.)
● Although testosterone, dihydrotestosterone (DHT), and estrogen may be involved in the development of
BPH, these hormones alone are not sufficient to cause BPH. (See 'Androgen' above and 'Estrogen' above.)
● It has been suggested that BPH occurs because prostatic tissue reverts to an embryoniclike state in which it
is unusually sensitive to various growth factors. (See 'Dysregulation of stromal growth factors' above.)
● Twin studies suggest that heritability is a more important determinant of LUTS than age, transition zone
volume, or total prostate volume. (See 'Genetic susceptibility' above.)
● The pathogenesis of BPH remains incompletely understood. Populationbased observational studies,
disease registries, in vitro studies of human tissue, and clinical trials continue to contribute to our
understanding of the pathogenesis of this common disorder. (See 'Pathogenesis' above.)
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Topic 6890 Version 24.0
GRAPHICS
Agerelated increase in prostate weight
Average prostatic weights (mean ± standard error of the mean in gray) are
presented for 10year intervals. The prostate glands were obtained at autopsy
from 925 samples collected from five separate studies.
Data from Berry, SJ, Coffey, DS, Walsh, PC, et al, J Urol 1984; 132:474.
Graphic 71296 Version 1.0
Prevalence of benign prostatic hyperplasia pathology
with age
Ageassociated increase in pathologic evidence of benign prostatic hyperplasia
in 1075 men at autopsy. The percentage with benign prostatic hyperplasia was
determined during 10year intervals from five different studies; the mean values
are shown.
Data from Berry, SJ, Coffey, DS, Walsh, PC, et al. The development of human benign
prostatic hyperplasia with age. J Urol 1984;132:474.
Graphic 55614 Version 1.0

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