329456

Review Article
Benign Prostatic Hyperplasia: A New Metabolic Disease of  the Aging Male and Its Correlation with Sexual Dysfunctions
Giovanni Corona,1 Linda Vignozzi,2 Giulia Rastrelli,2 Francesco Lotti,2
Sarah Cipriani,2 and Mario Maggi2
Endocrinology Unit, Medical Department, Azienda Usl, Maggiore-Bellaria Hospital, Bologna, Italy  Sexual Medicine Andrology Unit, Department of Experimental, Clinical and Biomedical Sciences, University of Florence,
Viale Pieraccini , Florence, Italy 
Correspondence should be addressed to Mario Maggi; [email protected]
Received October ; Accepted December ; Published February
Academic Editor: Antonio Aversa
Copyright © Giovanni Corona et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly  cited.
Metabolic syndrome (MetS) is a well-recognized cluster o cardiovascular (CV) risk actors including obesity, hypertension, dyslipidemia, and hyperglycaemia, closely associated with an increased risk o orthcoming cardiovascular disease and type diabetes mellitus. Emerging evidence indicates thatbenign prostate hyperplasia (BPH) and its related lower urinary tract symptoms (LUS) represent other clinical conditions requently observed in subjects with MetS. Several modiable actors involved in MetS determinism, such as inadequate diet, lack o physical exercise, and smoking and drinking behaviours are emerging as main contributors to the development o BPH. Te pathogenetic mechanisms underlying the connection between MetS and BPH have not been completely claried. MetS and its components, hypogonadism, and prostate inammation probably play an important role in inducing BPH/LUS. Although historically considered as a “normal” consequence o the aging process, BPH/LUS should now be aced proactively, as a preventable disorder o the elderly. ype o diet and level o physical activity are now considered important actors affecting prostate health in the aging male. However, whether physical exercise, weight loss, and modications o dietary habit can really alter the natural history o BPH/LUS remains to be determined. Further research is advisable to better clariy these points.
1. Introduction
ime is an absolute dimension which ranks events as past, present,and uture. Since biological agingis the accumulation and stratication o time-associated changes in a person, aging is an inevitable phenomenon, and, as such, it must be accepted. Because rejuvenation is impossible, the health- care intervention in aging should be ocused on ormatting this biological process as an acceptable lietime season and, thereore, as healthy as possible. We strongly believe that acting on modiable actors—such as going to the primary  care doctor routinely, a healthy diet, or smoking cessation— can reduce an individual’s absolute propensity to aging. In contrast, chronic morbidities—such as cardiovascular dis- eases (CVD), type diabetes mellitus (DM), osteoarthritis, and mental disabilities—are conditions that seniors ofen
ace as they age and that impair their enjoyment o this late lietime season. Low-grade inammation is supposed to represent the common determinant underlying almost all the aorementioned, age-related, and degenerative health conditions []. In act, almost years ago, ime magazine, on its cover, labeled inammation as “Te Secret Killer” or human health (http://content.time.com/time/magazine/ article/,,,.html). However, inammation per se is a benecial reaction o the body, and its innate immune system, to an injurious stimulus, recognized years ago in the pioneering work o Celsius.
Te concept o metabolic syndrome (MetS) was intro- duced almost years ago, but only recently it was recog- nized as a valid construct to cluster some common medi- cal disorders—such as visceral obesity, glucose intolerance, hypertension, and dyslipidemia—which increase the odds or
Hindawi Publishing Corporation International Journal of Endocrinology  Volume 2014, Article ID 329456, 14 pages http://dx.doi.org/10.1155/2014/329456
International Journal o Endocrinology  
CVD and DM []. Even in the case o MetS, chronic, low- grade inammation is considered, in concert with insulin resistance, the milestone o the syndrome. In the male, three other bothersome, age-related conditions were recently  proposed as new actors ofen associated with MetS [– ]. Tey are hypogonadism, erectile dysunction (ED), and benign prostate hyperplasia (BPH). Tese age-associated medical conditions have a relatively high socioeconomic bur- den and are generally not regarded as preventable ailments. In contrast, we strongly believe that their impact on male aging can be halted by liestyle changes or at least buffered by available medications. In this study we will overview  pathogenetic interconnections between BPH, inammation, MetS and hypogonadism, highlighting possible interventions to prevent their negative effect on men’s health. In act, several modiable actors, such as inadequate diet, lack o physical exercise, and smoking and drinking behaviors, are emerging as main contributors to the development o MetS and its related disorders, including BPH.
2. BPH/LUTS and Hypogonadism
Androgens play an essential role in the development and growth o the entire male genital tract and in particular o the prostate, stimulating  differentiation  and   proliferation o both the epithelial and the stromal compartments o  the gland. Androgens acts through activation o androgen receptor (AR), which is expressed in both prostatic stromal and epithelial cells.
.. Androgens and Prostate Differentiation.  Te differentiat- ing and growth-promoting actions o androgens are exerted starting in early embryonic lie and still persist in adulthood and senescence. In etal lie, the AR-induced differentiation and branching morphogenesis was deeply explored by the Cunha laboratory, which demonstrated the role o androgens in mesenchyme cell-induced prostatic development [,  ]. Cunha et al. [,   ] ound that androgens could stimu- late prostatic epithelial development and growth interacting with AR within the stromal tissue, under the inuence o  specic growth actors. Tis concept was originally based on tissue recombinant experiments, composed o wild-type stromal cells and AR-decient epithelium rom the testicular eminization mouse. During prostatic development, several growth actors, termed andromedins (IGF-, EGF, and sev- eral FGF-related proteins), have been proposed to be the paracrine mediators o these androgen-induced, stromal- mediated, generation o prostatic epithelial buds, and subse- quent ductal elongation and branching morphogenesis []. In the adult prostate, AR expression drives basal epithelial cells o the glands into differentiation to generate intermediate cells and into terminal differentiated luminal cells [ ]. As a caveat o these prodifferentiating actions o androgens, recent studies indicate that hypogonadism is associated with a more aggressive phenotype o prostate cancer [].
.. Androgens and Prostate Growth.  Besides differentiation, another biological action o androgens in the prostate is to
promote growth [], which is essentially orchestrated in three distinct waves. Te rst growth wave is completed at birth, when the average weight o the prostate is about . grams. Prostatic development at this stage is a clear unction o androgen signaling and is dependent on the unction o  the etal testis. Afer a quiescent phase, at puberty—under the inuence o increasing testosterone—the second wave starts: the prostate size reaches approximately grams at early puberty andalmost doublethat around the age o twenty  []. Tereafer, the size o the prostate remains constant until midlate adulthood. At that time, in contrast to the pubertal growth phase which involves the entire gland, ofen there is a third selective growth phase, involving one o the three anatomically distinct prostate zones, the periurethral one, and which gives rise to BPH. BPH is a condition extremely  prevalent in male adulthood and senescence, affecting % o men in the fh decade to almost % in men older than years[]. BPH is essentially a histological diagnosis, char- acterized by hyperprolieration o the stromal and, to a lesser extent, o the epithelial compartment o the prostate, which can be clinically maniested as benign prostate enlargement (BPE), in almost hal o the cases, or, less ofen, as benign prostate obstruction (BPO). Te latter two clinical entities are characterized by progressive development o symptoms (lower urinary tract symptoms, LUS), that are derived rom prostate enlargement to the point where urination becomes difficult (BPE) or impaired (BPO), due to mechanical pres- sure on the bladder and urethra. Approximately % o men in their s and % o men in their s have clinically  signicant LUS. However, not all men with BPH develop LUS. In addition, not all men with LUS have BPH as the underlying cause, because they are not disease-specic, being ofen multiactorial.
Although an increased androgen signaling is clearly  implicated in the rst two waves o prostate growth, its role in the third phase, BPH, is a matter o debate. In act, a clear dose-response relationship between circulating androgen levels and BPH has never been demonstrated [ , ]. In addition, during male senescence, androgens tend to decrease and not to increase [ ]. Several recent studies indicate that a low testosterone (), more than a high , might have a detrimental effect on prostate biology. In act, LUS can even be lessened by androgen supplementation in hypogonadal men [–]. Recent data indicate that not only  low testosterone but also high estradiol can avor BPH/LUS progression. It is important to note that circulating is actively metabolized to estrogens and part o hormonal activity depends upon its binding to the estrogen receptors (ERs), that are present in both the prostate and bladder []. In addition, the enzyme Paromatase which converts androgens to estrogens [] is highly expressed not only in at tissue but also in the urogenital tract [ ]. Evidence o an increased estrogen/androgen ratio was originally provided by  Marmorston et al. almost hal a century ago [] reporting that the estrogen/androgen ratio in -hour urinary collec- tions was elevated in men with BPH, as compared to normal controls. Several studies have observed a correlation between plasma estradiol (E
2 ) levels and prostate volume or
other eatures o BPH [–], while others have not [].
 
   t  o    t  a
   t  o    t  a
   P   r  o   s   t  a   t  e
   t  r  a   n   s   i   t   i  o   n   a
    l    z   o   n   e   v   o
    l  u   m   e
(b)
F : Association between insulin levels and prostate total or transitional zone volume. Association between insulin levels and prostate total (a) or transitional zone (b) volume. Insulin levels are reported as quartiles. All data are adjusted or age and total testosterone. Data are derived rom a series o subjects seeking medical care or coupler inertility at our unit. Te number o subjects with available parameters is reported in the inset. Note that the statistical analyses have been perormed using insulin levels as a continuous variable, even i grouped in quartiles or graphical purposes.
In two longitudinal, population-based cohort studies it was recently shown that a higher baseline E
2  was associated
with a worse orthcoming maximal ow rate and urinary  symptoms [, ].
3. BPH/LUTS and Metabolic Syndrome
Te historical view that BPH-related LUS are merely gener- ated by the compression o the urethra through the volumet- ric increased transitional prostatehas been heavily challenged in the last ew years []. In act, nowadays, BPH/LUS are not only viewed as a mere hydraulic problem, to be solved by a surgical intervention, but as a metabolic problem, to be solved with a multidisciplinary approach, which includes also the endocrinologist. Several recent studies have provided convincing evidence o a possible role o MetS, and/or its individual components, in the development o BPH, prostate growth, and worsening o LUS [].
.. Hyperinsulinemia, Glucose Intolerance/DM, and BPH. Possible links between BPH and DM were noted, in a retrospective study, as ar back as [ ]. Since that time, hyperinsulinaemia/glucose intolerance (the key component o MetS) and even DM have been considered as potential risk actors or BPH/LUS based on several studies [ , ]. In a population-based cohort oArican-American men aged – years, BPH patients reporting a diabetes history have a -old increase in the risk o moderate-severe LUS [ ]. In diabetic individuals, a similar odds ratio or having LUS was reported in the second Nord-rondelag Health Study  []. In a stepwise regression analysis, Nandeesha et al. [ ] ound that insulin levels were an independent predictor o  prostate volume in symptomatic BPH patients aged over
sixty. Interestingly, a similar conclusion was drawn by us in a sample o young subjects undergoing transrectal sonography or couple inertility and not complaining o  LUS[]. We ound an association between prostate volume and insulin levels, which was retained afer adjusting or totaltestosterone, other metabolic actors, and blood pressure []. All thesendings indicate that insulin is an independent risk actor or BPH, most probably stimulating prostate growth acting on IGF receptors [].  Figure   shows the relationship between increasing insulin levels (represented as quartiles) and prostate total and transitional zone volume, as detected by transrectal sonography, in the sample o  subjects consulting or couple inertility, collected as previ- ously described []. Te highest quartile o insulin levels is associated with a clear increase in prostate size.
.. Obesity and BPH.   In worldwide conducted studies, obesity—and in particular visceral obesity—was ound to be ofen comorbid with BPH [–]. Although there were also some negative reports [,  ], a recent meta-analysis, including a total o studies, reported a positive association between BMI and LUS associated with BPH (odds ratio (OR)= .%)[]. In population-based case-control studies, a marginal positive association was observed between risk  o BPH and increased BMI. []. Te impact o obesity  on prostate size is apparent even in early adulthood, as demonstrated by a sonographic study conducted in young men seeking medical care or couple inertility [].
 
Overall population Men with MetS Men without MetS
Study    MetS criteria Age (years) Number o pts   IPSS total
score Prostate
  IPSS total score
Prostate  volume (cc)
Ozden et al., []
  NCEP AP III –      
content in the prostate o BPH subjects and reported that its concentration was twice that in a normal prostate. Later on, Nandeesha et al. [] reported that circulating total and HDL cholesterol were associated, in a positive and negative manner, respectively, with prostate enlargement in a series o  symptomatic BPH cases and controls. However, other studies did not conrm the association [–]. In the Ran- cho Bernardo cohort study, Parsons et al. [] ound a -old increased risk o BPH among diabetic men with elevated low  density lipoprotein (LDL) cholesterol, but not in the overall cohort. Tis observation suggests that dyslipidemia per se is not sufficient enough to concur with BPH determinism, but the presence o other metabolic derangements, like DM, avors the process, because o an unavorable total and LDL cholesterol particle size and density [].
.. Hypertension and BPH.  An association between BPH, hypertension, and DM was originally reported in a retro- spective study years ago []. Later on, hypertension was associated with increased odds o surgery or BPH in the Physician’s Health Study [] and with a higher prevalence o LUS in other studies [–]. However, because both hypertension and BPH prevalence increase as a unction o aging, the relationship between the two conditions was underlooked.
.. Metabolic Syndrome and BPH.  From all the previ- ous considerations (see Sections  .–.) it can be derived that each individual actor o MetS has been associated in some study with BPH/LUS prevalence or progression, although several authors noted that their clustering, more than their individual presence, underlies the link. In ,
Hammarsten et al. [] elaborated this concept investigating the relationship between prostate volume and individual MetS components in men with BPH, demonstrating that DM, hypertension, obesity, high insulin, and low HDL- cholesterol levels were all risk actors or the development o BPH. Tereafer, only ew additional studies, based on the concept o the MetS construct, have investigated the association between MetS and BPH/LUS; results are sum- marized in  able   [,   –]. All the studies ound an association between the presence o MetS, even i dened with different criteria, and prostate volume, whereas the relationship between MetS and LUS is more controversial (see able ). However, changing denition o MetS has little impact on its long-term metabolic and CV consequences [, ]. In the study o Gacci et al. [], reduced HDL-cholesterol and increased triglyceride levels were noted to be the main determinants o MetS-related prostate alterations.
A recently published epidemiological survey o the Boston area (BACH) conrmed an association between MetS and LUS; however, when subjects were stratied by age, the association was conrmed only in the youngest individuals [].
 
International Journal o Endocrinology
evidence suggest that, beginning at a young age, MetS and in particular high waist circumerence and reduced HDL cholesterol play an important role in prostate overgrowth. Interestingly, no association between MetS severity and prostate-related symptoms was observed, using either IPSS or the National Institutes o Health Chronic Prostatitis Symptom Index (NIH-CPSI) [], which is a brie sel- reported questionnaire or screening prostatitis symptoms [].
4. BPH/LUTS and Inflammation
.. Epidemiological Evidence.   In the last decade, cross- sectional and longitudinal observation o several large cohorts have nally conrmed that chronic inammation is a crucial component o BPH pathogenesis. An examination o baseline prostate biopsies in a subgroup o , patients, ollowed or more than years in the Medical Terapies o  Prostate Symptoms (MOPS) study to assess BPH-disease progression, ound that men in the placebo arm with inam- mation were signicantly more likely to experience BPH worsening and at higher risk o acute urinary retention (AUR) or BPH-related surgery than those without []. Tis was conrmed in the subgroup analysis o , men in the Reduction by Dutasteride o Prostate Cancer Events (REDUCE) trial indicating that histologic inammation was present in more than % men and that the severity o  LUS and the intensity o inammation were related [ ]. Another study retrospectively reviewed all histopathological examinations o , patients with BPH and showed that %o patients hadhistologic inammation and% o them had chronic inammation. In addition, inammation in the prostate increased signicantly with the increase in prostate  volume and age []. Finally, the data rom the placebo arm ( men) o the Prostate Cancer Prevention rial (PCP) demonstrated that circulating levels o inammatory  markers, including elevated CRP and interleukin- (IL-), were associated with risk o incident, symptomatic BPH [].
.. Physiopathology.  Within the prostate, several classes o  immunocompetent cells (lymphocytes, macrophages, and granulocytes) are physiologically resident and termedhuman prostate-associated lymphoid tissue (PAL). Activation o the intraglandular immune system PAL is the usual response to inectious agents. However, we believe that this initial acute inammation could be succeeded by chronic inam- mation that persisted i avored by hormonal and metabolic derangements or by exposure to other environmental and dietary actors []. Activated PAL recruits and stimulates the prolieration o other immunocompetent cells leading to an upregulation o several proinammatory chemokines and cytokines []. Prostatic stromal cells—acting as targets o  bacterial or viral toll-like receptor (LR) agonists and, later on, as antigen-presenting cells (APC)—play a crucial role in theinduction o inammatory responses. Tey in act activate CD+ lymphocytes and avor their differentiation to the effector subsets T andT []. In addition,LR activation leads to the production o proinammatory cytokines (IL-)
and chemokines (IL- and CXCL) capable o recruiting CXCR- and CXCR-positive leukocytes and CD+ neu- trophils and urther promoting prostate cell hyperplasia, through the direct action o IL- or the release o other intraprostatic growth actors, like basic FGF [–]. Stromal BPH cells are able to secrete IL-, CXCL-, and IL-not only  in response to specic proinammatory stimuli (i.e.,NF or the LR agonist lipopolysaccharide), but also to metabolic insults and, in particular, to oxidized LDL and insulin. Tis suggests the hypothesis that lipids can induce and sustain an inammatory response in human prostatic cells [, ].
.. Clinical Evidence.  In line with this preclinical evidence, in a multicentre study on consecutive men treated with simple prostatectomy, we demonstrated that the presence o  MetS—and in particular o some o its components, such as dyslipidemia—is associated with a more severe intrapro- static inammation [,  ]. In particular, histopathologi- cal examination o BPH specimens demonstrated that the inammatory score (IS), as well as the positivity or the pan leukocyte marker CD, signicantly increased as a unction o MetS components [–]. Among MetS components, reduced HDL cholesterol and elevated triglycerides were signicantly associated with elevated IS and CD positivity. Fats could have, thereore, a detrimental effect on prostate cells, boosting prostate inammation, a key actor in the development and progression o BPH/LUS. In the previ- ously mentioned cohort o young, inertile subjects [], we noted a signicant, stepwise correlation between the number o MetS components and seminal IL-, which has been proposed as a surrogate marker o prostate inammation [–]. In addition, in the same population, a higher MetS severity was associated with sonographic eatures o  prostate inammation, including texture nonhomogeneity, major calcication size, and elevated arterial peak systolic  velocity. Abdominal adiposity and dyslipidemia were the main determinants, among MetS actors, o sonographic alterations and increased seminal IL- [].
 
400,00
300,00
200,00
100,00
0
1000,00
800,00
600,00
400,00
200,00
0
   R    N    A
   R    N    A
  m    R    N    A
Number of MetS factors
0 1 2 >3
n = 41, P < 0.05
  m    R    N    A
F : Gene expression o sex steroid receptors (upper panel) and inammatory markers (middle and lower panels) in prostate o rabbits eda regular diet (RD) or a high at diet (HFD), according to metabolic syndrome (MetSseverity). MetS severity wascategorized as previously  described [], according to the number o actors present (abscissa). Ordinate axis indicates level o mRNA expression in arbitrary unit, as derived rom quantitative R-PCR analysis o the indicated prostate samples. Level o signicance was derived rom Kruskall-Wallis analysis o the data.
the MetS prostate to changing sex steroids. We, in act, ound that administration to HFD rabbits reverted the majority  o MetS-induced prostate alterations []. Tis nding is in line with the observation that, in human BPH stromal cells, the selective AR agonist DH was able to blunt NF , LPS, or CD(+) cell-induced secretion o inammatory/growth actors, including IL-, IL-, and bFGF, by blocking NF- B nuclear translocation []. A protective effect o DH was also ound on oxLDL- or insulin-induced IL- secretion []. Interestingly, DH was also able to prevent NF- induced LOX- (the receptor or oxLDL) mRNA expression. Tis strongly indicates a potential benecial effect o AR  signaling on diet-induced prostate inammation. In contrast,
tamoxien dosing to HFD rabbits urther exacerbated MetS- induced prostate alterations, most probably by stimulating GPER/GPR, as demonstrated by experiments with selec- tive ligands orthese receptorsand by genetic ablation o their expression [].
 
Overall population
Study Age (years) Duration (weeks) Drugs Dosage (mg) Placebo number o pts PDE number o pts
McVary et al., [] Sildenal ( weeks);
McVary et al., []∗ . adalal ( weeks);
Stie et al., [] . Vardenal
Roehrborn et al, []∗ . adalal .; ; ;
Porst et al., []∗ . adalal .; ; ;
amimi et al., []∗ . UK- ; ; ,
Porst et al., [] . adalal
Egerdie et al., []∗ . adalal .;
Oelke et al., [] . adalal
Brock et al., [] . adalal
Dmochwski et al., [] . adalal
Yokoyama et al., []∗ . adalal .; ∗Te effect derived rom a ponderated mean at end point on International Prostate Symptom Score and maximum urinary ow rate were analyzed.
among those genes specically involved in brosis and myobroblast activation. Interestingly, HFD-induced PDE overexpression was counteracted by dosing. Consistent with this effect, a negative correlation between prostate PDE mRNA expression and plasma testosterone/estradiol ratio was identied. However, a direct role o hypogonadism in HFD-induced PDE upregulation was ruled out by the obser-  vation that hypogonadotropic hypogonadal rabbits (GnRH analog-treated group), characterized by a reduced plasma testosterone/estradiol ratio, showed prostatic PDE mRNA expression similar to that o the RD group, which was not modied by treatment []. Hence, we can hypothesize that HFD-related derangements, rather than hypogonadism per se, may be related to the PDE overexpression in the prostate.
5. Possible Intervention in MetS-Associated BPH/LUTS
Current therapy or BPH/LUS is largely based on the use o  
1 -adrenergic receptor blockers, which relax pro-
static smooth muscle, and  5-   reductase inhibitors, which reduce prostatic volume. Accordingly, current EAU guide- lines attributed level o evidence o b and a to  
1 -blockers
and 5- reductase inhibitors, respectively, or the treatmento  men with moderate-to-severe LUS []. Recently, the pos- sible use oPDE inhibitors was also recognized as a valuable treatment o the condition, with a level o evidence o b []. However, the same guidelines also suggest the useulness o  liestyle modications, without better explanation except or avoidance or moderation o caffeine or alcohol intake that may have a diuretic andirritant effect,thereby increasing uid output and enhancing requency, urgency, and nocturia [].
.. Lifestyle Modication.  Current evidence, suggesting a close relationship among BPH/LUS, MetS, hypogonadism, and inammation, indicates that the impact o liestyle modication should be more careully analyzed. Prospective data o the Health Proessionals Follow-up Study (HPFS), on
more than , men without LUS at baseline, recently  showed that men with higher total and abdominal adiposity  or who gainedweight at ollow-up were more likelyto develop LUS or experience progressive LUS []. Previous meta- analyses have clearly demonstrated that liestyle modica- tions, such as weight loss and increased consumption o ruit and vegetables, can reduce the incidence o obesity-related morbidities including hypogonadism [], type diabetes [], coronary artery disease [], and stroke []. Quite unexpectedly, studies on efficacy o liestyle modications on BPH/LUS outcome are still lacking.
In , Suzuki et al. [] rst reported that men with high energy intakes and particularly with high consumption oprotein andpolyunsaturated atty acid were at a greater risk  odeveloping BPH. Data rom the placebo arm in the Prostate Cancer Prevention rial (PCP), which enrolled , men aged over years, conrmed that high consumption o red meat and a high at diet increased the risk o BPH [ ]. In addition, the same authors reported that high consumption o vegetables reduced risk o BPH []. Similarly, data rom HPFS study have demonstrated that consumption o ruits and vegetables rich in  -carotene lutein or vitamin C was inversely related to BPH []. As reported above, oxidative damage and inammation are thought to be associated with development o BPH. High consumption o unsaturated atty acids might contribute to lipid peroxidation o the cell membrane exacerbating the inammation and impairing 5- reductase activity []. Conversely, high intake o ruits and  vegetables was ound to be associated with less oxidative stress, as measured by malondialdehyde concentration []. Te effect o diet on BPH/LUS is also supported by the lower incidence o prostate related problems in some Asian countries usinga predominantly plat-baseddiet,as compared with Western countries, using a provokingly animal-based diet [].
 
Brock et al., 2013 § § Dmochowski etal.,  2010
Yokoyama et al., 2013 Overall
Source −8 −6 −4 −2 0 2
Placebo PDE5i
IPSS score mean differences
−3,90 −2,50 −2,20 −1,81 −2,20 −4,09 −1,30 −1,42 −2,10 −1,90 −2,20 −4,20 −3,65 −2,39
−5,28 −3,89 −5,12 −3,46 −3,73 −5,65 −2,52 −2,26 −3,34 −3,42 −3,24 −6,66 −6,19 −2,93
0,00 0,00 0,14 0,03 0,00 0,00 0,04 0,00 0,00 0,01 0,00 0,00 0,00 0,00
P valueDiff. in means
LL, 95% CI
−2,52 −1,11 0,72 −0,15 −0,67 −2,53 −0,08 −0,58 −0,86 −0,38 −1,16 −1,74 −1,11 −1,85
UL, 95% CI
Qmax mean differences P valueDiff. in
means LL, 95%
CI UL, 95%
CI
(b)
F : Weighted differences (with % condence interval (CI)) o International Prostate Symptom Score (IPSS; (a)) and maximum ow rate (
max ; (b)), or the studies on phosphodiesterase type inhibitors (PDE-Is) versus placebo. § no erectile dysunction; §§ erectile
dysunction.
enrolled,male patients, intensity o exercise was related to reduction o risk oprostate enlargement. Compared to the sedentary group, the risk or BPH or LUS was signicantly  reduced with OR = ., ., and . or men engaging in light, moderate, and heavy physical activity, respectively [].
In conclusion, type o diet and level o physical activity  are emerging as other important actors affecting prostate health in the aging male, most probably reducing risk actors such as MetS, hypogonadism, and inammation. However, whether physical exercise, weight loss, and modications o  dietary habit can really alter the natural history oBPH/LUS remains to be determined. Further research is advisable to better clariy these points.
.. PDE Inhibitors and BPH/LUS.  Emerging evidence suggests that PDEi might reduce moderate-to-severe (stor- age and voiding) LUS in men with or without ED []. Accordingly, tadalal (mg once daily) has been approved by the US Food and Drug Administration (FDA) and by  the European Medical Agency (EMA) and licensed or
the treatment o male LUS in Europe. By meta-analyzing the available evidence we previously reported that PDEi alone, as compared with placebo, is able to improve LUS symptoms, as detected by the decrease o IPSS score [ ]. In addition, the association oPDEi and-adrenergic blockers improved both IPSS score and maximum urinary ow rate (
max ) at the end point, as compared with    blockers alone
[]. Since our last analysis, otherve double-blind, placebo- controlled, randomized clinical trials (RC) comparing the effect o PDEi versus placebo on BPH/LUS, have been published (see able ). Hence, so ar, RCs [–] have specically evaluated the effect o PDEi alone in patients with BPH/LUS. Overall, the studies enrolled patients, with a mean ollow-up o . weeks (able ). Similar to previous analysis [], we now report that PDEi treatment was associated with a signicant improvement o LUS, as detected by the reduction o total IPSS score ( Figure (a)). In addition, present meta-analysis also originally shows that PDEi users report a small, but signicant, improve- ment in  
max  (Figure (b)). Hence, the current analysis, in
 
International Journal o Endocrinology
a larger cohort o subjects, urther indicates a role oPDEi in improving LUS in patients with BPH. In addition, it shows ortherst timea possible role oPDEi in improving urinary  outow in the same category o subjects.
Despite the aorementioned clinical evidence, the mech- anism o action (MOA) o this class o medication in BPH/LUS is still a matter odebate. Several dedicated recent reviews are available on this topic [, –]. Preclinical studies demonstrated that prostate, bladder, and urethra, as well as their relative blood vessels, all represent potential targets o PDEi [, ]. Experimental evidence suggested that chronic blockade oPDE could impact several pathways involved in LUS generation [, , –], including a reduced nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) and an increased RhoA/Rho-kinase signalling [ – ]. In addition, PDEi can also reduce chronic pelvic hypoxia and its related unctional and morphologic changes in the bladder and prostate, by increasing blood perusion [,  ]. A possible direct effect or PDEi in modulating autonomic nervous system overactivity and bladder/prostate afferent nerve activity was also suggested [ ]. However, in the last ew years, some experimental and clinical data have offered a new MOA or PDEi in BPH/LUS, reducing MetS- associated prostateinammation. In the previously described rabbit model o MetS-associated prostate alterations we ound that tadalal dosing was able to reduce inamma- tion and leukocyte inltration (CD scoring), along with brosis/myobroblast activation []. In a retrospective pilot study on a BPH population ( = 60), previously enrolled in a double-blind, placebo-controlled, clinical study on the effi- cacy o daily vardenal (mg) added to tamsulosin (.mg) [], we evaluated prostatic CD score in those undergoing simple prostatectomy or persistent/recurrent severe urinary  symptoms. Patient cohort was categorized according to the presence o MetS. In those without MetS, CD positivity  was low and unaffected by vardenal dosing. In those with MetS, increased CD positivity was signicantly blunted by chronic vardenal treatment []. It is interesting to note that even in this small cohort the MetS actor most closely associated with CD positivity was dyslipidemia. Interestingly, in isolated human BPH stromal cells both tadalal and vardenal decreased NF-induced expression o genes related to inammation (COX-, IL-, Il-, IP-, and MCP-) and tissue remodelling (SMA, bFGF). Similar results were obtained when NF-induced secretion o IL- and CXCR- was considered. Both vardenal and tadalal were able to blunt IL- secretion induced also by metabolic stimuli, such as oxLDL, AGE, and IGF-. Te effect was apparently due to the ability o these PDEi to stimulate PKG activity because it was mimicked by a nonhydrolysable cGMP analog and blocked by a PKG antagonist. Finally, both PDEi signicantly reduced the ability o NF  to increase the expression o oxLDL receptor, LOX- [].
6. Conclusions
People are living longer and, in some parts o the world, healthier lives. In, almostmillion people worldwide
Healthy  prostate
Bladder
dysfunction
Aging
F : Graphical representation o a proposed multiactorial pathogenesis o benign prostatic hyperplasia/low urinary tract symptoms (BPH/LUS). Symptomatic or asymptomatic prostate inammation (very common in young individuals), in the presence o permissive actors such as metabolic syndrome (MetS), and in particular dyslipidemia, or an altered sex steroid milieu, can progress through prostate enlargement (BPE). Te latter can or cannot be associated with LUS, in particular in the presence o  bladder dysunction. Recent data indicates that MetS itsel can also avour bladder alteration.
 
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that the adverse CV effects o having MetS on coronary  heart disease could be substantially reduced or nullied by  increasing physical activity. Several epidemiological studies support this view also or BPH/LUS; intervention studies are urgently needed.
Conflict of Interests
Te authors declare that there is no conict o interests regarding the publication o this paper.
 Acknowledgment
Te authors would like to thank DavideFrancomano, Depart- ment o Experimental Medicine, Sapienza University o  Rome, Rome, Italy, or his helpul clinical collaboration and or his critical reading o the paper.
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