HYPERTROPHIE BÉNIGNE DE PROSTATE: UNE

PATHOLOGIE ENDOCRINO-

MÉTABOLIQUE ?

Béatrice CUZIN, GH E Herriot, Centre Lyonnais d’Urologie Bellecour Lyon, FRANCE

THE PREVALENCE OF HISTOLOGICAL BPH

INCREASES LINEARLY WITH AGE

0

10

20

30

40

50

60

70

80

90

100

20–29 30–39 40–49 50–59 60–69 70–79 80–89

Prevalence (%)

Pradhan 1975 Swyer 1944 Franks 1954

Moore 1943 Harbitz 1972 Holund 1980

Baron 1941 Fang-Liu 1991 Karube 1961

Campbell´s Urology,

8th Ed., Chapter 8

(2002)

DÉFINITIONS DU SM : NCEOP/ATP III, IDF 2005 ET IDF 2009

Alberti GK et coll. Circulation 2009;120:1640-45.

NCEP/ATPIII (2001)

IDF (2005) IDF/AHA/ NHLBI (2009)

3 des 5 critères suivants

tour de taille + 2 des 4 autres critères

3 des 5 critères suivants

Tour de taille élevé

> 102 cm/hommes > 88 cm/femmes

indispensable, avec seuils ethno-centrés ; origine européenne > 94 cm/hommes > 80 cm/femmes

seuils ethno-centrés, reprenant les seuils IDF 2005 pour les non-européens et laissant le choix entre seuils IDF et seuils NCEP/ATP III pour ceux d'origine européenne

TG élevés > 1,5 g/L ou traitement

> 1,5 g/L ou traitement > 1,5 g/L ou traitement

HDLc bas < 0,40 g/L/: hommes < 0,50 g/L: femmes

< 0,40 g/L/: hommes < 0,50 g/L: femmes

< 0,40 g/L: hommes < 0,50 g/L: femmes

PA élevées PAS > 130 mm Hg et/ou PAD >85 mm Hg ou traitement

PAS > 130 mm Hg et/ou PAD > 90 mm Hg ou traitement

PAS > 130 mm Hg et/ou PAD > 85 mm Hg ou traitement

Glycémie à jeun élevée

> 1,1 g/L ou traitement

> 1,0 g/L ou traitement > 1,0 g/L ou traitement

DÉFINITION OMS DU SM

Alberti GK et coll. Circulation 2009;120:1640-45.

OMS (1998) Diabète, troubles de la glycémie à jeun, tolérance abaissée au glucose ou insulinorésistance (HOMA) + 2 des autres critères

Rapport taille/hanche

> 0,90/hommes, > 0,85 femmes

TG élevés ou HDLc bas

TG > 1,5 g/L ou HDL < 0,35 g/L : hommes; < 0,39 g/L : femmes

Excrétion albumine urinaire

> 20 É g/min

PA > 140/90 mm Hg ou traitement

6

Figure 1: liens entre deux

conditions médicales

Figure 2: critères de Hill

Costabile RA, and Steers WD. How can we best characterize the relationship

between erectile dysfunction and benign prostatic hyperplasia? J Sex Med 2006;3:676–681.

Epidémiologie

Physiopathologie

Traitement/prévention

Il existe plusieurs hypothèses :

Altération de la voie de signalisation de NO/GMPc

PHYSIOPATHOLOGIE COMMUNE ENTRE

HBP/TUBA ET SYNDROME METABOLIQUE

12

13

Facteurs de risque de DE (diabète,

tabac, dyslipidémie, hypertension)

TUBA

• Prolifération musculaire

lisse

• Modification structurelle

de la prostate

• Obstruction cervicale

Diminution de NOS/NO

au niveau de la prostate

et de la vessie

• Contraction

musculaire lisse

• Augmentation de la

résistance uréthrale

Réduction de la Nitric Oxide Synthase (NOS) et de la production de NO au niveau pelvien en présence

d’un syndrome métabolique

La baisse de NOS/NO au niveau du pénis est responsable de DE

La baisse de NOS/NO au niveau de la prostate et de la vessie augmente le tonus des cellules

musculaires lisses du col vésical et de l’urètre et stimule potentiellement la prolifération des

cellules musculaires lisses prostatiques ayant pour conséquence une augmentation de

l’obstruction

VOIE DE NO/GMPC : RATIONNEL

McVary. Eur Urol 2005;47:838-45

McVary. BJU Int 2006;97(Suppl.2):23-8

Il existe plusieurs hypothèses…..

Altération de la voie de signalisation de NO/GMPc

Hyperactivité du système nerveux sympathique

PHYSIOPATHOLOGIE COMMUNE ENTRE

HBP/TUBA ET SYNDROME METABOLIQUE

14

15

HBP

Augmentation du tonus

sympathique

TUBA

DE

Inactivité

physique

Age ObésitéHyperinsulinémie

HYPERACTIVITÉ DU SYSTÈME NERVEUX

SYMPATHIQUE

Les composants du syndrome métabolique (telle qu’obésité ethyperinsulinémie) induisent une hyperactivité du systèmesympathique, responsable d’une HBP, de troubles mictionnels etd’une DE

McVary. BJU Int 2006;97(Suppl. 2):23-8

Il existe plusieurs hypothèses…..

Altération de la voie de signalisation de NO/GMPc

Hyperactivité du système nerveux sympathique

Athérosclérose pelvienne

PHYSIOPATHOLOGIE COMMUNE ENTRE

HBP/TUBA ET DYSFONCTION ÉRECTILE

16

17

Réduction du flux

artériel vésical

• Augmentation de la contraction

musculaire lisse

• Diminution de compliance

vésicale

• Obstruction

TUBA

Ischémie/hypoxie

vésicale chronique

• Prolifération musculaire

lisse vésicale

• Modification structurelle de

la prostate

• Fibrose du col vésical

• Obstruction sous vésicale

• Augmentation de la

pression intravésicale

Athérosclérose

entrainant une

insuffisance artérielle

ATHÉROSCLÉROSE DES ORGANES PELVIENS :

RATIONNEL

Le syndrome métabolique a un impact sur le flux artériel pelvien entraînant

potentiellement une modification structurelle de la vessie, une fibrose

prostatique et des TUBA

Diminution de la vascularisation pénienne entrainant une diminution des

cellules musculaires lisses caverneuses et une DE

McVary. Eur Urol 2005; 47: 838-45

ROLE DE LA TESTOSTÉRONE

HBP ET ACTIVITÉ PHYSIQUE

Platz et al chez 30,634 hommes qui participaient à l’enquête HPFS ont observé que que ceux qui avaient

une activité physique avaient un risque plus faible d’HBP(OR: 0.75; 95% CI: 0.64-0.90; p＜0.001), de

chirugie pour HBP (OR: 0.76; 95% CI: 0.64-0.90; p＜0.001), et d’HBP symptomatique (OR: 0.75; 95% CI:

0.64-0.87; p 0.001) Platz EA, Kawachi I, Rimm EB, Colditz GA, Stampfer MJ, Willett WC, et al. Physical activity and benign

prostatic hyperplasia. Arch Intern Med 1998;158:2349-56.

Dans la cohorte du Massachusetts , les hommes rapportant les plus haut niveaux d’activité physiques

avaient 50% de chance en moins d’avoir des symptômes urinaires en lien avec l’HBP.Meigs JB, Mohr B, Barry MJ, Collins MM, McKinlay JB. Risk factors for clinicalbenign prostatic hyperplasia in a

community-based population of healthy agingmen. J Clin Epidemiol. 2001 Sep;54(9):935-44.

De même dans la troisième enquête « National Health And Nutrition Examination Survey », réalisée chez

2797 hommes, ceux qui n’avaient aucune activité physique liée aux loisirs avaient deux fois plus de

chance d’avoir des troubles urinaires du bas appareil que ceux qui avaient une activité Rohrmann S, Crespo CJ, Weber JR, Smit E, Giovannucci E, Platz EA. Association of cigarette smoking, alcohol consumption

and physical activity with lowerurinary tract symptoms in older American men: findings from the third National Health And

Nutrition Examination Survey. BJU Int. 2005 Jul;96(1):77-82.

HBP ET ACTIVITÉ PHYSIQUE

Dal Maso et al ont rapportés chez des hommes à forte activité physique professionnelle (fermier,

bâtiment) un risque plus bas de développer une HBP que les hommes avec des ativités sédentaires. Dal Maso L, Zucchetto A, Tavani A, Montella M, Ramazzotti V, Polesel J, et al. Lifetime occupational and

recreational physical activity and risk of benign prostatic hyperplasia. Int J Cancer

2006;118:2632-5.

De même une meta-analyse qui a inclus les résultats de 8 études avec un effectif total de 35,675

patients a confirmé que l’activité physique reduisait le risque de ces the risk d’HBP/TUBA.Parsons JK, Kashefi C. Physical activity, benign prostatic hyperplasia, andlower urinary tract symptoms.

Eur Urol. 2008 Jun;53(6):1228-35.

Ces résultats sont confirmés par une étude récente, de type transversale, qui précise que cette activité

physique est d’autant plus efficace qu’il existe des troubles irritatifs, toutefois, il n’existe pas de

changement dans la taille de la prostate.Fowke JH, Phillips S, Koyama T, Byerly S, Concepcion R, Motley SS, Clark PE.Association between physical

activity, lower urinary tract symptoms (LUTS) andprostate volume. BJU Int. 2012 Jun 22. doi: 10.1111/j

1464-410X.2012.11287.x.

ANDROGEN DEPRIVATION INDUCES BLADDER HISTOLOGICAL

ABNORMALITIES AND DYSFUNCTION VIA TGF-Β IN ORCHIECTOMIZED MATURE

RATS

Symptomatic late-onset hypogonadism, one of the most common elder diseases, is defined as a syndrome associated with a deficiency in serum testosterone. Recent studies have indicated thatandrogen deficiency in men is also associated with lower urinary tract symptoms and bladderdysfunction. To determine the pathologic consequences of androgen deprivation in bladder histologyand function, wead dressed the underlying mechanism. Male rats were divided in to 4 groups:emasculated rats (EMR), emasculated rats treated with testosterone, emasculated rats treated with anti- transforming growth factor-β (TGF-β) neutralizing antibody, and sham surgery rats. TGF-β is a common profibrotic factor that mediates the pathologic process of fibrosis in multiple organs. Two months later,urodynamic evaluations were employed to determine the bladder function in vivo. And then rats were sacrificed, and the bladder tissues were collected.Histological studies wereemployed to determine the degree of bladder fibrosis.Real time PCR was used to evaluate the mRNAlevel of pro-collagen I, a fibroticmarker. We demonstrate here that androgen deficiency inducesbladder fibrosis and decreases the bladder maximal volume and compliance. Androgen replacement treatment completely prevented the histological and functional abnormalities induced by androgendeficiency. Subsequently, we identified that androgendeprivation induced the induction of TGF-β mRNA level. Importantly, treatmentwith anti-TGF-β antibody abolished androgen deprivation-inducedbladder fibrosis and dysfunction.

Our study reveals an essential role of TGF-β in the pathogenesis of androgen deprivation-inducedbladder fibrosis and dysfunction and offers apotential target for prevention and treatment of bladderdysfunction associatedwith androgen deficiency.

Tohoku J Exp Med. 2012;226(2):121-

8..Zhang Y, Chen J, Hu L, Chen Z.

TESTOSTERONE AND FARNESOID X RECEPTOR AGONIST INT-747

COUNTERACT HIGH FATDIET-INDUCED BLADDER ALTERATIONS IN A RABBIT

MODEL OF METABOLIC SYNDROME

In the male, metabolic syndrome (MetS) is associated to an increased risk of benign prostatic hyperplasia (BPH) and lower

urinary tract symptoms (LUTS). A recently established rabbit model of high fat diet (HFD) induced MetS showed

hypogonadism and the presence of prostate gland alterations, Including inflammation, hypoxia and fibrosis. The present

study investigated whether HFD-induced MetS might also alter bladder structure and function. Testosterone and the

farnesoid X receptor (FXR) agonist INT-747, were evaluated for possible effects on HFD bladder. MetS rabbits develop

bladder alterations, Including fibrosis (reduced muscle/fiber ratio), hypoxia [2-fold increase as compared to regular diet

(RD) group], low-grade inflammation (increased leukocyte infiltration and inflammatory markers) and RhoA

ROCK hyperactivity. Bladder strips from HFD rabbits, pre-contracted with carbachol, showed an overactive response to the

selective ROCK inhibitor Y-27632. All these HFD-induced bladder alterations were partially blunted by testosterone and

almost completely reverted by INT-747. Both treatments prevented some MetS features (glucose intolerance and visceral

fat increase), thus suggesting that their effects on bladder could be ascribed to an improvement of the metabolic and/or

hypogonadal state. However, a pathogenetic role for hypogonadism has been ruled out as GnRH analog-induced

hypogonadal rabbits, fed a regular diet, did not show any detectable bladder alterations. In addition, INT-747 did not revert

the MetS-induced hypogonadal state. FXR mRNA was highly expressed in rabbit bladder and positively associated with

visceral fat increase. A direct effect of INT-747 on bladder smooth muscle was further suggested by inhibition of RhoA

ROCK-mediated activity by in vitro experiments on isolated cells. In conclusion, HFD related MetS features are associated

to marked effects in counteracting MetS-related RhoA/ROCK overactivity, thus opening novel therapeutic opportunities for

this drug.

Morelli A, Comeglio P, Filippi S, Sarchielli E, Cellai I, Vignozzi L,Yehiely-Cohen

R, Maneschi E, Gacci M, Carini M, Adorini L, Vannelli GB, Maggi M. J Steroid

Biochem Mol Biol. 2012 Oct;132(1-2):80-92.

MECHANISM OF ACTION OF PHOSPHODIESTERASE TYPE 5 INHIBITION IN

METABOLICSYNDROME-ASSOCIATED PROSTATE ALTERATIONS: AN

EXPERIMENTAL STUDY IN THE RABBIT.

BACKGROUND: Phosphodiesterase type 5 (PDE5) inhibitors improve benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS), often associated with metabolic syndrome (MetS). This study investigated the effects of PDE5inhibition in the prostate of rabbits fed a high fat diet (HFD) for 12 weeks.HFD-rabbits develop the most important features of human MetS (glucoseintolerance, dyslipidemia, increased abdominal adiposity, and hypertension),along with hypogonadism and LUT abnormalities (prostate and bladder inflammation/tissue remodeling). METHODS: Gene expression was evaluated by quantitative RT-PCR. Prostate morphological changes and oxygenation were evaluated by immuno histochemistry. RESULTS: HFD prostates showed increased PDE5expression, suggesting a peculiar sensitivity of prostate to the action of PDE5inhibitors during MetS. Accordingly, prostate PDE5 mRNA was negatively associated to plasma testosterone/estradiol ratio, whose reduction characterizes MetS, and positively with the expression in prostate of several genes exploring pathogenetic processes for BPH/LUTS, such as inflammation, leukocyte infiltration, and fibrosis/myofibroblast activation. Most of these genes wasup-regulated by HFD, and significantly reduced by PDE5 inhibition, through either chronic (12 weeks) or, at a lower extent, acute (1-week) tadalafil dosing.Tadalafil was also able to reduce blood pressure and visceral fat in HFD rabbits,without changing any other MetS parameter. Interestingly, 1-week tadalafil administration to HFD rabbits, significantly blunted prostate inflammation(increased CD45 immunopositivity), fibrosis (reduced muscle/fiber ratio) and hypo-oxygenation, thus suggesting a potential curative effect of PDE5 inhibition on MetS-related prostate alterations. CONCLUSIONS: Our data provide the experimental evidences to support the multiple potentiality of PDE5 inhibitors as a useful therapeutic tool in LUTS.

Prostate. 2012 Sep 19. doi: 10.1002/pros.22584. Morelli

A, Comeglio P, Filippi S, Sarchielli E, Vignozzi L, Maneschi

E, Cellai I,Gacci M, Lenzi A, Vannelli GB, Maggi M.

TESTOSTERONE PROTECTS FROM METABOLIC SYNDROME-ASSOCIATED

PROSTATE INFLAMMATION:AN EXPERIMENTAL STUDY IN RABBIT

Metabolic syndrome (MetS) and benign prostatic hyperplasia (BPH)/lower urinarytract symptoms (LUTS)

are often associated. One of their common denominators is hypogonadism. However, testosterone

supplementation is limited by concerns for potential prostatic side effects. The objective was to determine

whetherMetS-associated prostate alterations are prevented by testosterone supplementation. We used a

previously described animal model of MetS, obtained byfeeding male rabbits a high-fat diet (HFD) for 12

weeks. Subsets of HFD rabbitswere treated with testosterone or with the farnesoid X receptor agonist

INT-747. Rabbits fed a standard diet were used as controls. HFD-animals develop hypogonadism and all

the MetS features: hyperglycemia, glucose intolerance,dyslipidemia, hypertension, and visceral obesity. In

addition, HFD-animals show a prostate inflammation. Immunohistochemical analysis demonstrated that

HFD-induced prostate fibrosis, hypoxia, and inflammation. The mRNA expression of several

pro inflammatory (IL8, IL6, IL1β, and TNFα), T lymphocyte (CD4, CD8, Tbet, Gata3, and ROR γt),

macrophage (TLR2, TLR4, and STAMP2), neutrophil (lactoferrin),inflammation (COX2 and RAGE), and

fibrosis/myofibroblast activation (TGFβ, SM22α,αSMA, RhoA, and ROCK1/ROCK2) markers was

significantly increased in HFD prostate.Testosterone, as well as INT-747, treatment prevented some MetS

features,although only testosterone normalized all the HFD-induced prostate alterations.Interestingly, the

ratio between testosterone and estradiol plasma level retains a significant, negative, association with all

the fibrosis and the majority ofinflammatory markers analyzed. These data highlight that testosterone

protects rabbit prostate from MetS-induced prostatic hypoxia, fibrosis, and inflammation, which can play a

role toward the development/progression of BPH/LUTS.

J Endocrinol. 2012 Jan;212(1):71-84.Vignozzi L, Morelli A, Sarchielli E,

Comeglio P, Filippi S, Cellai I, Maneschi E,Serni S, Gacci M, Carini M,

Piccinni MP, Saad F, Adorini L, Vannelli GB, Maggi M

27

études épidémiologiques critères

de Hill, HBP/SM

Facteurs de risque communs HBP/SM: sédentarité

+/- Odds ratios:inf à 2

+/-Seules la moitié des études montrent une association

Non

?

?

Lien avec la taille de la prostate, les symptômes ?

?

Exercice physique/HBP

CONCLUSION

Il existe une association entre l’HBP/LUTS et le

syndrome métabolique.

Sur le plan physiopathologique plusieurs hypothèses

sont possibles.

L’activité physique améliore l’HBP/LUTS

La testostérone a un rôle mitigé

D’autres études sont nécessaires dans tous les

domaines: cliniques, expérimentales.