Obesity, Neural Influences, LUTS/BPH and PDE5 Inhibitors

Transcription

1 Obesity, Neural Influences, LUTS/BPH and PDE5 Inhibitors Kevin T. McVary, MD-FACS Professor of Urology Feinberg School of Medicine Northwestern University Chicago, Illinois

2 Obesity Trends* Among U.S. Adults BRFSS, 1990, 1998, 2007 (*BMI 30, or about 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

3 LUTS/BPH Epidemiology Kristal: J Urol Examined predictors of LUTS Age, Baseline LUTS, Hip-waist ratio, ethnicity Giovannucci et al, ,892 men (HPFU Study) Abdominal obesity as a risk factor for TURP and LUTS Meigs (NERI) 2001, Physical activity reduced BPH/LUTS Glynn: American Journal of Epidemiology Examined predictors of BPH BMI as the only predictor of BPH/TURP

4 Relationship of Obesity with BPH/LUTS? Does waist circumference/waist-to-hip ratio make a difference in surgery risk? Increased risk specific to abdominal obesity Waist circ. (> 102 cm) more likely to have LUTS (OR = 1.48, 95% CI: 0.87, 2.54) Dahle et al J Urol, 2002

5 Association between markers of the metabolic syndrome and LUTS in the NHANES III Rohrmann S et al. Int J Obes, 2005 Men (n = 2,372) >60y >2 components of the metabolic syndrome: increased odds of LUTS (OR = 1.80; 95% CI ) Noted a strong association with lifestyle linked diseases: elevated HgBA1C diabetes mellitus hypertension

6 Metabolic Syndrome Correlates with Level of LUTS in BACH Survey Prevalence of MetS increases with >AUA-SI (2-7) Effect stabilizes with AUA-SI >8 Overall trend test p-value = Kupelian et al. 2009

7 Risk Factors for BPH Risk Factor Male gender and aging 1,2 Positive family history 2 Smoking 2 Obesity 2 High physical activity 1 Sexual activity 1,2 Alcohol 2 Heart disease 1 Effect on BPH Increases risk Increases risk Indeterminate effect Increases risk Protective effect Indeterminate effect Protective effect Increases risk 1.Meigs JB et al. J Clin Epidemiol. 2001;54: Boyle P et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication

8 Physical Activity and BPH Platz EA et al. Arch Int Med 1998

9 Where does this variable epidemiological data leave us? Bias: Case-control studies: clinic/hospitalized Largely cross sectional studies Evolving Treatment: Switch from surgery to med Rx Evolving Definition: LUTS, BPH, enlargement

10 Influence of Modifiable Risks on LUTS/BPH The relationship between LUTS and objective measures of BPH is lacking Extrinsic/systemic factors Anatomic/physiologic derangements LUTS

11 LUTS/BPH and Modifiable Risks Pathophysiolic Mechanisms Low grade inflammation Hormonal basis Sympathetic Hyperactivity Direct effect of hyperinsulinemia Osmotic diuresis/glucosuria

12 LUTS/BPH and Metabolic Syndrome Low Grade inflammation Central Obesity-BMI Insulin Resistance (receptor interference) Increase CRP IL-6 WBC Hyperinsulinemia Prostatic epithelial cell proliferation Increase IGF Reduced Apoptosis BPH LUTS Kasturi S, Russell S, McVary KT. Curr Urol Rep. 2006

13 C-Reactive protein (CRP) Level Correlates with Level of LUTS in BACH Survey Men Women Prevalence (%) <1 mg/l 1-3 mg/l >3 mg/l <1 mg/l 1-3 mg/l >3 mg/l <1 mg/l 1-3 mg/l >3 mg/l <1 mg/l 1-3 mg/l >3 mg/l <1 mg/l 1-3 mg/l >3 mg/l <1 mg/l 1-3 mg/l >3 mg/l <1 mg/l 1-3 mg/l >3 mg/l <1 mg/l 1-3 mg/l >3 mg/l AUA-SI 8 Incomplete Emptying Intermittency Weak Stream Straining Frequency Urgency Nocturia N= 3,757 (1,898 men, 1,854 women) Significant association between CRP and LUTS among both sexes. Nocturia and straining: men Incomplete emptying and weak stream women. The dose-response relationship between increased CRP Kupelian et al. 2009

14 Comparative Effects of Diet on Ventral Prostate Growth Standard Chow Western diet : 45% energy as animal fat (lard) 35% as refined carbohydrate 60% lard, 20% refined CHO diet Marked Influence: body weight, ventral prostate and [ 3 H]NE turnover rates Group (n) Chow (21) 60% lard diet (21) P Body wt (g) ± ± Prostate wt (mg) ± ± bwt adj d * Prostate NE (ng) 452 ± ± Prostate NETR (ng NE/hr) 19.9 ± ± 2.5 <0.05 IBAT NETR (ng NE/hr) 59.4 ± ± 14.1 NS * Prostate weight was not significantly related to body weight.

15 Nerve Perturbations

16 Histological Effects of Denervation Reduction in luminal staining Decrease in cell height Increase in intracellular vacuoles Apical epithelial cells with reduction in number/height of microvilli Decrease in the height of supranuclear and apical regions of epithelial cells, Reduction in number of secretory vesicles in the apical region Wang et al 1991

17 Nerve Perturbation Affects Prostate Growth McVary KT, et al. Biol Reprod.1994;51:

18 Fluorogold tracing: analysis of retrograde transport to cell bodies in the DRG and peripheral ganglia g g y Prostate DRG Labeling % Cells Staining Left Right Mean?SEM (n = 8) 0 T10 T11 T12 T13 L1 L2 L3 L4 L5 L6 S1 S2 Spinal Cord Segment Spinal Cord Segment McVary et al. 1998

19 Gene Expression Protein Content Localization

20 Spontaneous BPH in Aging SHR A and B: normotensive WKY control A C C and D: SHR B D Golomb et al., J Androl 21: 58, 2000

21 Adrenergic Induction of Ventral Prostate Hyperplasia in Mice A Saline, 26 d A B Phenylephrine, 26 d C C Phenylephrine + α-ar antagonist, 26 d B Marinese et al, Prostate 54:230, 2003

22 Detrusor Dysfunction in Spontaneously Hypertensive Rats (SHR) SHR have increased voiding frequency and detrusor overactivity Persson et al, Am J Physiol 275:R1366, 1998

23 Increased LUTS With Increased Autonomic Activity McVary KT et al., Autonomic Nervous System Overactivity in Men With LUTS Secondary to BPH. Journal of Urology 2005.

24 Autonomic Hyperactivity and LUTS Obesity-HWR-BMI Hyperinsulinemia Caloric Intake Age Increased Sympathetic Tone Physical Inactivity Erectile Dysfunction BPH Voiding Dysfunction BPH Growth McVary KT et al., Autonomic Nervous System Overactivity in Men with LUTS Secondary to BPH. Journal of Urology 2005.

25 Increased ED With Increased Autonomic Activity McVary KT et al., Autonomic Nervous System Overactivity in Men With ED.

26 Does the concept of a modifiable risk carry any weight? Central obesity related pathophysiology Insulin, IGF, leptin, inflammatory markers Physical Activity Caloric intake/diet type Systemic vs. pelvic autonomic tone Prostate proliferation (BPH) vs. bothersomeness of symptoms (LUTS)? Not mutually exclusive!

27 Effect of Diet and Exercise on Growth of Prostate Epithelial Cells Barnard Kobayashi Aronson. Prostate Cancer Prostate Diseases weeks of Pritikin Diet in obese vs. Trim cohort (1-28 y)

28 Obesity with LUTS Intervention Rather than Prevention? Physical Activity Caloric Input Measure LUTS Physical Activity Obesity with LUTS Caloric Input Measure LUTS

29 PDE-5 Inhibitors and LUTS

30 Prevalence of Histologic BPH Increases With Age Prevalence (%) Pradhan (1975) Moore (1943) Baron (1941) Swyer (1944) Harbitz (1972) Fang-Liu (1991) Franks (1954) Holund (1980) Karube (1961) Age (yr) Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:

31 Major Risk Factors for ED: Aging Feldman HA, et al. J Urol. 1994;151:54-61.

32 MSAM-7: Erectile Function Declines With Increasing Severity of LUTS Independent of Age Average Erectile Function Score (IIEF)* y y y Average score on a scale from 1-30 (6 questions) measured by IIEF Per question: 1 = Negative to 5 = Positive Base: Men sexually active/sexual intercourse during past 4 weeks, *as measured by IIEF. Rosen R, et al. Eur Urol. 2003;44: LUTS None Mild Moderate Severe

33 P < 0.05 P < 0.05 P < 0.05 P < 0.05 P < 0.05 Sexual Function Domains Versus AUA-SI P < 0.05 P < 0.05 P < 0.05 P < 0.05 Sexual Function Domains Versus TRUS Volume McVary KT et al. J Urol 169: 2003

34 Biological Evidence for Causal Relationship Between BPH, LUTS, and ED NOS/NO theory LUTS and autonomic hyperactivity - metabolic syndrome Alternate pathway: ET-1/Rho kinase Pelvic atherosclerosis

35 Sustained NO Reduces Smooth Muscle Tension Tension (g/cm 2 ) Human Prostate P <.005 Canine Prostate Reduced human prostatic smooth muscle tension with SNP Reduced canine prostatic smooth muscle tension with SNP NO, nitric oxide; SNP, sodium nitroprusside. Takeda M, et al. Urology.1995;45:

36 Reduced enos Staining in Transition Zone Reduced intensity of enos staining in TZ -BPH tissue compared to the more robust abundance of enos protein in epithelial layers from control tissue IHC generally used for location not quantitative Quantification (Western) absent! Podlasek CA, Zelner DJ, McKenna KE and McVary KT: Journal of Urology 169: No. 4, 285, Abstract #1108, 2003

37 Cyclic Nucleotide PDE Isoenzymes of the Human Prostate Pmol cnmp Hydrolized/mL/min PDE-5 PDE-1 (?) PDE-4 Most PDEs present in prostate tissue PDE-5 and PDE-4 most abundant in prostate transition zone camp cgmp camp + Ca/CaM camp + 5 µm cgmp Fraction No. Uckert S et al. J Urol. 2001;166:2484.

38 Immunolocalization of PDE-5 in Human Bladder PDE-5 Immunolabeling Control Filippi S et al. Endocrinology. 2007;148:1019.

39 Concentration of Rodent PDE-5 mrna in Multiple Organs PDE-5/β2-Microglobulin mrna (a.u.) n=6 n=5 n=5 n=4 n=5 * n=10 n=6 * P<0.01 vs rat corpus cavernosum Filippi S et al. Endocrinology. 2007;148:1019.

40 Efficacy of PDE-5 Inhibitors on Rodent Urinary Tract Tissue Bladder Strip Contraction Prostate Strip Contraction Urethral Strip Contraction Tinel, H, et al. BJU 2006;98:

41 Sildenafil for LUTS/BPH ED Trial Sildenafil 100 mg Sildenafil 50 mg Screening Randomization Baseline SV1 SV2 Placebo 0 weeks 2 weeks 12 weeks No Placebo Run-in SV, study visit McVary KT et al. J Urol March 2007

42 Sildenafil Improves LUTS: IPSS 0 Total Irritative Voiding LS Mean (±SE) Change * * * Placebo (n=162) Sildenafil (n=179) *P< vs placebo McVary KT et al. J Urol. 2007;177:1071.

43 Tadalafil for LUTS/BPH - IPSS Score Mean Change Clinically meaningful Improvement* Tadalafil compared to placebo: Tadalafil 2.5mg P<.05 at Weeks 4, 8, and 12. Tadalafil 5, 10, and 20 mg P<.001 for Weeks 4, 8, and 12. ANCOVA analysis. *Barry et al

44 44 IPSS Changes Stratified by ED History n= No ED History ED History and Sexually Active Pbo-adj. LS Mean change * -2.7* -2.1 Pbo-adj. LS Mean change * -2.5* -2.6* Change from baseline ED history at Visit 1 - Sexual activity with female partner at Visit 2 No ED history irrespective of sexual activity * p<.05 compared to placebo (ANCOVA analysis)

45 BPH Impact Index Mean Change from Baseline to Endpoint after 4, 8, and 12 Weeks 45 Clinically meaningful Improvement* Tadalafil compared to placebo: tadalafil 5 mg P<.05 at Weeks 4 and 12; P<.001 at Week 8. Tadalafil 10 mg P<.001 at Weeks 4 and 8; P<.05 at Week 12. Tadalafil 20 mg P<.001 at Weeks 4 and 8; P<.05 at Week 12. ANCOVA analysis. *Barry et al. 1995; AUA Guideline on Management of BPH 2006.

46 46 Qmax (ml/s) Treatment group (n) Time Point Mean Change Placeboadjusted LS mean P-value Placebo (198) Tad 2.5 mg (201) Tad 5 mg (202) Tad 10 mg (201) Tad 20 mg (190) Baseline Endpoint Baseline Endpoint Baseline Endpoint Baseline Endpoint Baseline Endpoint Ancova analyses

47 Urodynamic Effects of Once Daily Tadalafil in Men With LUTS/BPH: RCT Dmochowski et al J Urol UDS remained largely unchanged during the study No statistically significant or clinically adverse Difference between tadalafil and PL: Pdet@Qmax : mean difference: 2.2 cm H 2 O, p = 0.33 Qmax, BOOI, bladder capacity (all measures p 0.13).

48 How can NO/NOS hypothesis be valid if urinary flow rates are unchanged? 1. Wrong organ? 2. Bladder compliance/boo change offset? 3. Central effect? 4. Bladder/prostate perfusion change?

49 Obesity Effects Response to Treatment McVary KT et al Urology Sep;72(3): Obese (>30 BMI) had the greatest improvement in IPSS total and storage and voiding subscores compared with baseline This group also had the largest placebo response among the groups

50 Prostate, Penis and PDE-5: Prostate, bladder and penis share regulatory and functional pathways Relationship between ED and LUTS remains significant after controlling for risk factors LUTS is an independent risk factor for erectile dysfunction In vitro and preclinical evidence show that NO-cGMP pathway mediates bladder, urethral, and prostate SM relaxation PDE5 is abundant in these tissues, suggesting that a PDE5i may offer a novel approach to relieving LUTS

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