Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia: From Research to Bedside 0128113979, 9780128113974

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Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia

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Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia From Research to Bedside

Edited by

Giuseppe Morgia Giorgio Ivan Russo

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2018 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-811397-4 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

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Contents

CONTRIBUTORS........................................................................................ xiii PREFACE ................................................................................................... xv CHAPTER 1

Epidemiology of LUTS and BPH ........................................... 1 Economic Impact of BPH and LUTS ................................................ 5 Risk Factors for BPH Development.................................................6 Age ............................................................................................... 6 Genetics ....................................................................................... 7 Sex Steroid Hormones ................................................................ 7 Metabolic Syndrome .................................................................... 7 Cardiovascular Disease............................................................... 8 Obesity ......................................................................................... 8 Diabetes and Alterations in Glucose Homeostasis .................... 8 Lipids............................................................................................ 9 Physical Activity ........................................................................... 9 Alcohol ......................................................................................... 9 Smoking ....................................................................................... 9 Inflammation.............................................................................. 10 Race ........................................................................................... 10 References...................................................................................... 10

CHAPTER 2

Pathologic Triggers Related to LUTS and BPH ................. 15 Introduction..................................................................................... 15 Etiology ........................................................................................... 16 Hyperplasia ..................................................................................... 16 Role of Inflammation...................................................................... 17 Prostatic Immune Cells and Inflammation ................................... 17 BPH and Prostatic Inflammation ................................................... 19 Clinical Evidence........................................................................ 19 Molecular Pathways .................................................................. 20 Hormonal Pathways .................................................................. 21

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Metabolic Syndrome, Inflammation, and BPH .............................. 22 Inflammation and BPH Progression ......................................... 23 Biomarkers of Prostatic Inflammation ..................................... 24 References...................................................................................... 25 Further Reading.............................................................................. 25

CHAPTER 3

The Relationship Between Inflammation and LUTS/BPH ........................................................................... 31 Introduction..................................................................................... 31 Pathophysiology.............................................................................. 32 The Immunochemical Pattern of BPH...................................... 32 The Inflammatory Pattern of BPH ............................................ 34 The Origin of Chronic Prostate Inflammation .......................... 34 The Role of Inflammatory Cytokines ........................................ 35 Chronic Inflammation and LUTS.................................................... 36 Prostate Inflammation and BPH Progression ............................... 38 Prostate Inflammation and LUTS Deterioration....................... 38 Prostate Inflammation and Acute Urinary Retention............... 39 Diagnostic Methods for Chronic Prostate Inflammation ..............41 The Role of Biomarkers ............................................................ 41 Concurrent Prostate Calcifications........................................... 43 Medical History of Chronic Urinary Tract Infections................ 44 Metabolic Syndrome—A More Recent Trend in the Etiology of LUTS/BPH. The Connection With Prostatic Inflammation ....44 Prostate Inflammation and Its Impact on LUTS Medication.........45 Conclusions .................................................................................... 46 References...................................................................................... 46 Further Reading.............................................................................. 50

CHAPTER 4

Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia and Erectile Dysfunction ................ 51 Anatomy and Physiology of Erectile Dysfunction .......................... 51 Epidemiology and Risk Factors of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia and Erectile Dysfunction ................................................................................. 53 Age ............................................................................................. 54 Sedentary Lifestyle and Lack of Exercise................................. 54 Cigarette Smoking ..................................................................... 55 Excessive Alcohol Intake........................................................... 55 Depression ................................................................................. 56 Hypertension and Cardiovascular Disease............................... 57 Hyperlipidemia........................................................................... 58

Contents

Type 2 Diabetes Mellitus ........................................................... 58 Obesity/Waist Circumference.................................................... 59 Hypogonadism ........................................................................... 59 Genetic Predisposition............................................................... 60 Pathophysiology of LUTS/BPH and ED .......................................... 61 Etiology and Clinical Aspects of LUTS/BPH and ED .....................62 Second-Line Evaluation............................................................. 68 Treatment of LUTS/BPH and ED.................................................... 72 Education and Lifestyle Modifications ...................................... 72 Phosphodiesterase Type 5 Inhibitors........................................ 72 Tadalafil ..................................................................................... 72 Other PDE5I Therapies (Not Approved by Current Guidelines for ED-LUTS/BPH)............................................... 76 Effects of Drugs Used for LUTS on Erectile Function ............. 80 Conclusive Remarks....................................................................... 81 References...................................................................................... 82

CHAPTER 5

Metabolic Syndrome and LUTS/BPH ................................. 89 Introduction..................................................................................... 89 Metabolic Syndrome: Definition and Prevalence ..........................90 MetS and BPH: Preclinical Evidences and Pathophysiology ........90 MetS and LUTS/BPE: The Role of Inflammation........................... 95 Prostate Size and Shape: The Influence of MetS ..........................96 The Correlation Between MetS and LUTS..................................... 97 Diet and Lifestyle in Men With MetS and LUTS Due to BPE ...... 101 Basis for Medical Treatment in Men With MetS and LUTS/BPE .....................................................................................102 The Impact of MetS on the Outcomes of BPH Surgery............... 104 Conclusions .................................................................................. 105 References.................................................................................... 106

CHAPTER 6

Diagnostic Work-up of LUTS/BPH: From Standard to New Perspectives ..........................................................113 Introduction................................................................................... 113 Diagnostic Workup of LUTS/BPH................................................. 115 Standard Diagnostic Tests ...................................................... 115 New Diagnostic Perspectives.................................................. 126 References.................................................................................... 130 Further Reading............................................................................ 133

CHAPTER 7

Phytotherapy in Benign Prostatic Hyperplasia .................135 Introduction................................................................................... 135 Serenoa Repens............................................................................ 139

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Mechanism of Action ............................................................... 139 Variability of Products and Extraction Techniques ................ 143 Clinical Studies ........................................................................ 146 Safety Profile ........................................................................... 151 Conclusion ............................................................................... 152 Pygenum Africanum ..................................................................... 152 Mechanism of Action ............................................................... 153 Clinical Studies ........................................................................ 155 Safety Profile ........................................................................... 155 Conclusion ............................................................................... 156 Urtica Dioica ................................................................................. 156 Mechanism of Action ............................................................... 156 Clinical Studies ........................................................................ 158 Safety Profile ........................................................................... 158 Conclusion ............................................................................... 159 Cucurbita Pepo ............................................................................. 159 Mechanism of Action ............................................................... 159 Clinical Studies ........................................................................ 160 Safety Profile ........................................................................... 161 Hypoxis Rooperi ............................................................................ 162 Mechanism of Action ............................................................... 162 Clinical Studies ........................................................................ 162 Safety Profile and Conclusion ................................................. 162 Rye Grass Pollen .......................................................................... 163 Mechanism of Action ............................................................... 163 Clinical Studies ........................................................................ 164 Safety Profile and Conclusion ................................................. 165 Conclusion .................................................................................... 165 References.................................................................................... 165

CHAPTER 8

Medical Aspects of the Treatment of LUTS/BPH: Alpha-Blockers ..................................................................177 Introduction................................................................................... 177 Pathophysiology and Mechanisms of Action of AlphaBlockers in BPH........................................................................ 178 Pathophysiology of LUTS/BPH/BPO: Reviewing AlphaAdrenoreceptors as a Valuable Therapeutic Target........... 178 Potential Action of Alpha-Blockers on BPO ........................... 178 Potential Effects of Alpha-Blockers on Storage Symptoms and Bladder Function ........................................ 179 Potential Effects of Alpha-Blockers on Nocturia ................... 179

Contents

Types of Alpha-Adrenergic Blockers: Family Members ............. 180 Efficacy.......................................................................................... 181 Global Efficacy on LUTS (IPSS), Quality of Life, and Placebo Effect ...................................................................... 181 Effects on BPO (Qmax, Urodynamics, and Postvoid Residuals)............................................................................. 182 Efficacy on the Long Term and Treatment Adherence .......... 183 Intermittent Treatment ........................................................... 183 Dose Adjustments ................................................................... 184 Safety and Tolerability.................................................................. 184 Clinical Use................................................................................... 185 General Indications/Single Therapy........................................ 185 Associations ............................................................................. 185 Conclusion .................................................................................... 185 References.................................................................................... 186

CHAPTER 9

Medical Aspects of the Treatment of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia: 5-Alpha Reductase Inhibitors............................................189 Mechanism of Action .................................................................... 189 Testosterone and Dihydrotestosterone .................................. 189 5-Alpha Reductase Enzyme Family ........................................ 189 Rationale for 5-Alpha Reductase Inhibition in BPH ............... 190 5-Alpha Reductase Inhibitors....................................................... 191 Finasteride ............................................................................... 191 Dutasteride .............................................................................. 191 5-ARI for the Treatment of BPH .................................................. 192 Indications for Treatment of BPH With 5-ARI ........................ 192 Clinical Effects of BPH Treatment With 5-ARI ....................... 193 Finasteride Versus Dutasteride for the Treatment of BPH ........ 194 Sexual Side Effects of 5-Alpha Reductase Inhibitor Use ............ 195 Combination Therapy With 5-ARI and Alpha-1 Adrenergic Receptor Blockers for the Treatment of BPH ......................... 196 5-ARI for Hematuria and Bleeding During Transurethral Resection of the Prostate in Men With BPH............................ 198 5-ARI for the Prevention and Treatment of Prostate Cancer..... 198 5-Alpha Reductase Inhibition for the Prevention of Prostate Cancer .................................................................................. 198 5-Alpha Reductase Inhibition for the Treatment of Prostate Cancer............................................................... 200 References.................................................................................... 201

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CHAPTER 10

Medical Aspects of the Treatment of LUTS/BPH: Antimuscarinic and β3-Agonists....................207 Keypoints ...................................................................................... 207 Introduction................................................................................... 207 Antimuscarinics ............................................................................ 208 Mechanism of Action ............................................................... 208 Efficacy..................................................................................... 209 Adverse Events ........................................................................ 210 β3-Agonists ................................................................................... 210 Mechanism of Action ............................................................... 211 Efficacy..................................................................................... 211 Adverse Events ........................................................................ 212 Conclusions .................................................................................. 213 References.................................................................................... 213

CHAPTER 11

Medical Aspects of the Treatment of LUTS/BPH: Combination Therapies......................................................217 Introduction................................................................................... 217 AB + 5ARI ....................................................................................... 217 Anticholinergic Agents and AB .................................................... 224 Tolterodine and AB.................................................................. 225 Solifenacin Succinate and AB ................................................. 227 Fesoterodine and AB ............................................................... 229 β3-Adrenoreceptor Agonist Mirabegron and AB ......................... 230 Phosphodiesterase-Type-5 Inhibitors and 5ARI or AB ............... 231 Plant Extracts/Phytotherapy and Other Agents .......................... 233 References.................................................................................... 234

CHAPTER 12

Surgical Management of LUTS/BPH: TURP vs. Open Prostatectomy....................................................................241 History of Surgical Treatment for Benign Prostatic Hyperplasia (BPH)..................................................................... 241 Pathophysiology of BPH ............................................................... 242 Epidemiology and Socioeconomic Burden of Surgical Treatment for BPH ................................................................... 242 Factors Affecting Choice of Surgery Type ................................... 243 Prostate Size............................................................................ 243 Surgeon Preference and Hospital Setting .............................. 243 Patient Age............................................................................... 244 Prostatectomy............................................................................... 244 Simple Prostatectomy ............................................................. 244 TUR of the Prostate................................................................. 246

Contents

Outcomes ...................................................................................... 247 Symptoms ................................................................................ 247 Physiological Measures........................................................... 248 Perioperative Outcomes .......................................................... 248 Retreatment Rate .................................................................... 249 Adverse Events ........................................................................ 250 Conclusion .................................................................................... 250 References.................................................................................... 250

CHAPTER 13

Surgical Treatment for LUTS/BPH: Laser Devices ..........257 Introduction................................................................................... 257 Lasers Typically Used for Vaporization .................................. 260 Lasers Typically Used for Resection/Enucleation.................. 260 Enucleation for BPO: Techniques and Results ........................... 261 Holmium Laser Enucleation of the Prostate.......................... 261 Thulium Laser Enucleation of the Prostate (ThuLEP) ........... 266 Greenlight Laser Enucleation of the Prostate (GreenLEP).... 270 Diode Laser Enucleation of the Prostate (DiLEP) .................. 273 Eraser Laser Enucleation of the Prostate (ELEP).................. 275 Laser Ablation for Benign Prostatic Enlargement: Techniques and Results ........................................................... 277 Holmium Laser Ablation of the Prostate................................ 277 Thulium Laser Vaporization of the Prostate (ThuVAP) .......... 278 Diode Laser Vaporization of the Prostate............................... 278 Greenlight: PVP ....................................................................... 279 References.................................................................................... 282

CHAPTER 14

Surgical Management of LUTS/BPH: New Mini-Invasive Techniques ..................................................289 Introduction................................................................................... 289 New Concepts and Objectives ...................................................... 289 Improvement Required With Surgical Ablative Techniques......290 Balancing Efficacy and Morbidity ............................................ 290 Pharmacological or Standard Surgical Treatment as Comparator .......................................................................... 292 A Validated Mini-Invasive Technique: UroLift Implants .............. 292 Technique................................................................................. 292 Evaluation ................................................................................ 293 Further Questions.................................................................... 294 An Experimental Mini-Invasive Technique: Prostatic Arteries Embolization ............................................................... 295 Procedure ................................................................................ 296

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Initial Prospective Cohorts ...................................................... 296 Comparative Randomized Trials ............................................. 298 Perspectives ............................................................................ 299 Botulinum NeuroToxin Type A (BoNT-A)................................ 299 Conclusions .................................................................................. 300 References.................................................................................... 300

INDEX ...................................................................................................... 305

Contributors

Maximilien Baron Charles Nicolle University Hospital, Rouen Cedex, France Michele Billia University of Eastern Piedmont, Novara, Italy Giovanni Burgio University of Catania, Catania, Italy Aldo E. Calogero University of Catania, Catania, Italy Jaime A. Cavallo Icahn School of Medicine at Mount Sinai, New York, NY, United States Christopher R. Chapple Royal Hallamshire Hospital, Sheffield, United Kingdom Sebastiano Cimino University of Catania, Catania, Italy Rosita A. Condorelli University of Catania, Catania, Italy Jean-Nicolas Cornu Charles Nicolle University Hospital, Rouen Cedex, France Nicolas B. Delongchamps Paris Descartes University, Paris, France Bob Djavan Rudolfinerhaus Foundation Hospital, Vienna, Austria Marco Franco University “Federico II”, Naples, Italy Mauro Gacci University of Florence, Florence, Italy Stavros Gravas University Hospital of Larissa, Larissa, Greece Christopher J. Hillary Royal Hallamshire Hospital, Sheffield, United Kingdom Steven A. Kaplan Icahn School of Medicine at Mount Sinai, New York, NY, United States Roberto La Rocca University “Federico II”, Naples, Italy Sandro La Vignera University of Catania, Catania, Italy Charalampos Mamoulakis University of Crete—Medical School, Heraklion, Crete, Greece Vincenzo Mirone University “Federico II”, Naples, Italy Francesco Montorsi Vita-Salute University San Raffaele, Milan, Italy Giuseppe Morgia University of Catania, Catania, Italy Matthias Oelke Maastricht University Medical Centre, Maastricht, The Netherlands Salvatore Privitera University of Catania, Catania, Italy Giorgio Ivan Russo University of Catania, Catania, Italy Giuseppe Saitta Vita-Salute University San Raffaele, Milan, Italy Matteo Salvi University of Florence, Florence, Italy Michael Samarinas University Hospital of Larissa, Larissa, Greece

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Arcangelo Sebastianelli University of Florence, Florence, Italy Nazareno Suardi Vita-Salute University San Raffaele, Milan, Italy Mojtaba Teimoori Rudolfinerhaus Foundation Hospital, Vienna, Austria Carlo Terrone University of Genoa, Genoa, Italy Daniele Urzı` University of Catania, Catania, Italy Luca Venturino University “Federico II”, Naples, Italy

Preface

Lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement (BPE) represent one of the most frequent diseases of the aging male. However, during the last decades, the knowledge, diagnosis, and treatment of LUTS/BPE have consistently changed. The multifactorial components of BPE thus determine the appearance of LUTS and its severity and progression of the disease over time. Besides the wellknown static elements, several new factors have been emerged over the years, like the role of metabolic syndrome and of chronic inflammation. The drug treatment also dramatically has been modified with more and more evidences about prevention and also arrest of the progression of the disease. Finally, the clinical history of the disease has been modified since we have switched from invasive intervention to mini-invasive treatment and prevention. Each chapter of this project has been produced by eminent author in this field, showing the best level of evidence, the best summary of scientific data, with a view to future perspectives. In this book we tried to illustrate each aspect of the disease, from a research point of view to a bedside prospective. We hope to fulfill all of your needs about this topic and to give you all available tools to manage LUTS/BPE. Giuseppe Morgia and Giorgio Ivan Russo

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CHAPTER 1

Epidemiology of LUTS and BPH Giorgio Ivan Russo, Daniele Urzı`, Sebastiano Cimino University of Catania, Catania, Italy

Lower urinary tract symptoms (LUTS) are very common in both sexes, especially in aged population and negatively affect health-related quality of life (QOL) of afflicted individuals. They are also associated with high-health care costs. The etiology is multifactorial. One of the most important causes of LUTS in men is benign prostatic hyperplasia (BPH). BPH is a histological diagnosis defined by the presence of abnormal proliferation of smooth muscle and epithelial cells in prostatic tissues that clinically translates into benign prostatic enlargement (BPE) or obstruction (BPO). Left untreated, serious complications can occur in men with BPH, including acute urinary retention (AUR), renal insufficiency and failure, urinary tract infection, and bladder stones. The prevalence of BPH is strongly related to age, ranging from 8% in men in their 50s to roughly 90% in men older than 80 years [1]. Although aging represents the strongest risk factor for this, chronic progressive disease, obesity, and metabolic syndrome (MS) have been recently shown to be associated with an increased risk of BPH. Not all men with histologic BPH develop LUTS that requires intervention. Several population-based studies evaluated the prevalence of LUTS using validated questionnaires. Particularly the International Prostate Symptoms Score (IPSS) questionnaire is a useful tool to stratify patients according to symptom severity of seven common LUTS. Indeed, patients can be classified in those with no or mild (IPSS
7), moderate (IPSS from 8 to 20), and greatersevere symptoms (IPSS 21). It is very difficult to compare different studies about LUTS, due to the varying disease definitions and assessment methods used (e.g., mail and telephone surveys, face to face interview). In addition, IPSS lacks questions on incontinence and pain that are reported in several subjects affected by LUTS. The impact of BPH on QOL can be significant and should not be underestimated. A self-administered questionnaire completed by 117 patients reported sleep, anxiety/worry over the condition, mobility, leisure, activities of daily living, and, to a larger extent, the effect on sexual activities as the most important concerns among patients with prostate symptoms (IPSS > 7) [2]. The impact of BPH-associated LUTS has also been studied in Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. https://doi.org/10.1016/B978-0-12-811397-4.00001-9 © 2018 Elsevier Inc. All rights reserved.

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a community-based population in the United Kingdom. A total of 1500 individuals aged 50 years or older were assessed for BPH symptoms and their impact on QOL using a self-administered survey. Moderate-to-severe LUTS was seen in 41% of the patients (as assessed by an IPSS of 8). Respondents experienced decrements in both QOL and health status as symptomatic severity increased, with most men experiencing problems with ability, self-care, activities of daily living, pain or discomfort, and anxiety or depression. Despite the high prevalence of LUTS reported in this survey, only 11% were aware of the pharmacologic or surgical interventions available to treat BPH; watchful waiting was the most common primary treatment (34%). The findings of this study underscore the need for better education about BPH and its treatments [3]. In a Japanese study, nocturia twice at night doubled the risk of fractures and mortality [4]. Its association with daytime fatigue, reduced work productivity, and reduced vitality is also recognized [5]. During past years, many authors studied the prevalence of seven symptoms by IPSS. These studies report many differences in prevalence, from 47% to 49%. In 1997 the International Continence Society (ICS) assessed the bothersomeness of LUTS in 1271 male patients presenting at urology clinics in 12 countries by administering a questionnaire. This study showed that voiding symptoms are more common (90%–94%) than storage symptoms (66%–71%), but that the latter are the most bothersome. It also established that a postmicturition symptom, terminal dribble, is the most common symptom of all (prevalence: 96%) [6]. Several studies confirmed a significant increase in prevalence with advancing age for both individuals LUTS and for the total LUTS reported by men. LUTS often appear in clusters. Overactive bladder (OAB) is a common symptom cluster. The ICS defines OAB as urinary urgency, with or without urinary incontinence, usually with frequency and nocturia [7]. Most studies investigated OAB and reported a general prevalence of 10%–25% in men [8,9]. The longest follow-up study of the prevalence of symptoms has shown a significant increase in LUTS over an 11-year period with a mean annual incidence of 3.7% for OAB and 0.8% for incontinence. The prevalence of OAB increases with age, especially in the sixth and seventh decade of life. A pooled analysis of 126 studies has shown an increase in urinary incontinence prevalence with age from 21% to 32% for elderly men. The prevalence of daily urinary incontinence in this analysis was reported at 9% [10]. Many publications focused specifically on the prevalence of urinary incontinence among community dwelling men; 11% of men over the age of 40 had experienced an incontinent episode during the prior year, and daily UI may be as high as 9% among men over the age of 60. The prevalence is near to 32% over 80 years [11]. An estimated 15 million men in the United States over the age of 30 years are affected by BPH/LUTS [12]. Large variations in existing prevalence rates are reported due to differences in BPH/LUTS definitions, assessment methods,

Epidemiology of LUTS and BPH

and geographic regions. BPH/LUTS prevalence estimates also vary by age [13–18]. Among men over the age of 50 years, 50%–75% experience BPH/ LUTS [19,20]. For the majority of these men, without treatment, voiding and storage symptoms will significantly worsen with increasing age and time. Among men over the age of 70 years, 80% on average are impacted by BPH/ LUTS. Prostate enlargement, peak flow rate, and LUTS have all been shown to be age-dependent conditions and are conditions that play a substantial role in BPH/LUTS development among aging men [21]. Urinary symptoms of urgency, nocturia, weak stream, intermittency, and incomplete emptying are the most strongly correlated with age, and prevalence estimates rise to as high as 88%–90% by 81 years of age or greater [22,23]. The BPH Registry and Patient Survey, a prospective observational disease registry documenting BPH/LUTS practices and patient outcomes among 6909 men in the United States, reported that 33% of men had mild LUTS; 52% of men had moderate LUTS, and 15% of men had severe LUTS. The average IPSS at baseline was 11.6 (range 0–35) [24]. In France 67% of men scored IPSS < 8, 13% scored IPSS < 19, and 1.2% scored IPSS > 19 [25]. Another study supported these results. Among only men aged 40–49 years, these prevalence estimates for mild, moderate, and severe symptoms were 89%, 9%, and 2%, respectively. This increased to 55% with mild, 37% with moderate, and 8% with severe LUTS among men over the age of 70 years [26]. Approximately 10% of men 50 cm3) are 3.5 times more likely to have age-adjusted moderate-to-severe LUTS than men without prostate enlargement. About incidence of BPH/LUTS four longitudinal cohort studies are very important: The Prostate Cancer Prevention Trial, The Olmstead County study, The Health Professionals Follow-up Study, and a database review in the Netherlands. The Prostate Cancer Prevention Trial included 5667 men over the age of 55 years and reported the incidence of BPH to be 34.4 cases per 1000 person-years [13]. The Olmstead County study, which identified men living in Olmstead County, Minnesota, review between 1987 and 1997, estimated the overall incidence of BPH to be 8.54 cases per 1000 men [17]. The Health Professionals Follow-up Study followed 9628 men with moderate-to-severe LUTS (IPSS < 14) and 2557 men with severe LUTS (IPSS < 20) from LUTS onset for an average of 12.7 years to assess LUTS incidence and progression rates. Incidence rates of moderate and severe LUTS were 41 and 19 cases per 1000 person-years, respectively [28]. Verhamme et al. [29] utilized a longitudinal observational database in the Netherlands to assess incidence rates of BPH/ LUTS among men over the age of 45 years who had at least 6 months of patient follow-up and reported the incidence of BPH/LUTS to be 15 cases per 1000

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person-years of follow-up. The four studies with overall estimates mentioned previously also reported incidence rates by age and/or severity. The Prostate Cancer Prevention Trial reported that for every 1 year increase in patient age, the incidence of BPH increased by 4%. This corresponds to reports that an estimated 45% of urinary symptom-free men over the age of 45 will develop BPH/ LUTS before the age of 75. The Health Professionals Follow-up Study reported increases in both moderate and severe LUTS incidence rates with increasing patient age. Verhamme and colleagues reported the incidence of BPH to linearly increase by an average of 6.15 cases per 1000 man-years for every 5-year increase in age increment between 45 and 79 years of age. This increase was from 3 cases per 1000 man-years at age 45–49 to 38 cases per 1000 man-years at age 75–79 years. The EPIC survey was a population-based, cross-sectional, computer-assisted telephone survey conducted in five countries (Canada, Germany, Italy, Sweden, and the United Kingdom) [13]. A total of 19,165 men and women agreed to participate (33%) of the general population in the five countries. This study performed in 2005 established that the prevalence of LUTS is similar in the two genders: 62.5% of men and 66.6% of women. Storage symptoms were less common in men than in women (51.3% vs. 59.2%), whereas the opposite was true for voiding symptoms (25.7% in men vs. 19.5% in women). Nocturia was the common storage symptom, 48.6% of men and 54.5% of women reported one episode per night, and 20.9% of men and 24% of women reported two episodes per night. Terminal dribble, classified as a voiding symptom, was reported by 14.2% of men and 9.9% of women. The prevalence of the various symptoms was similar among countries, with a few exceptions, such as more common terminal dribble in both men and women in Italy. It found also that 11% of men and 13% of women in four European countries and in Canada reported OAB symptoms. Furthermore the prevalence of both urge urinary incontinence (UUI) and stress urinary incontinence (SUI) is higher in women compared with men (UUI: 13.1% vs. 4.5%; SUI 14.8% vs. 0.4%) [30]. Similar prevalence of LUTS in men and women also was reported in The Boston Area Community Health (BACH) Survey [18]. It studied a sample 5506 adults aged 30–79 from the city of Boston (2301 men, 3205 women, 1770 blacks, 1877 Hispanics, and 1859 whites) that assessed the prevalence of LUTS, defined as an American Urological Association symptom index (AUA-SI) >8 in adults of both genders. The study established that the overall prevalence of LUTS was 18.7% and did not differ by sex or race/ethnicity. The prevalence increased with age from 10.5% in the fourth decade up to 26.5% in the seventh decade. Age trends were similar by sex until age 60 but the course of the increase differed in the two genders; there was a notable increase in the seventh decade in men that was not seen in women. The mean storage score was worse in women, whereas the mean voiding score in men. About voiding and storage symptoms separately, the BACH survey shows that mean voiding scores are significantly higher

Economic Impact of BPH and LUTS

in men compared with women (1.53 and 1.28, respectively; P ¼ .04), whereas the mean storage score is higher among women compared with men (3.21 vs. 2.56; P < .001). Both mean voiding score and mean storage score increased with age (P < .001 for both). The EpiLUTS study [31] was a population-based, cross-sectional, Internet survey conducted in men and women >40 year of age in the United States, the United Kingdom, and Sweden. A total of 30,000 subjects took part in the survey: 20,000 in the United States (participation rate: 59.6%), 7500 in the United Kingdom (participation rate: 60.6%), and 2500 in Sweden (participation rate: 52.3%). The main objective of the survey was to establish the prevalence of LUTS and to explore the association of LUTS with comorbid conditions. The prevalence of LUTS was defined by two symptom frequency thresholds: “at least sometimes,” which resulted in a prevalence of 72.3% in men and of 76.3% in women, and “at least often,” which resulted in a prevalence of 47.9% in men and of 52.5% in women. Once again, storage symptoms were more common in women; for example, nocturia defined as one episode per night was reported by 75.8% women and 69.4% men, and nocturia defined as two or more episodes per night was reported by 33.7% of women and 28.5% of men. Urgency was reported by 35.7% of women and 22.4% of men. Once again, terminal dribble was common (45.5% in men and 38.3% in women). Postmicturition symptoms were quite common. Incomplete emptying occurred in 22.7% of men and 27.4% of women, and postmicturition incontinence occurred in 29.7% of men and 14.9% of women. Multiple associations with chronic comorbidities were found also in the EpiLUTS survey [32]. The triple combination of voiding, storage, and postmicturition symptoms was associated in both genders with arthritis, asthma, chronic anxiety, depression, heart disease, irritable bowel syndrome, neurologic conditions, recurrent urinary tract infection, and sleep disorders; in men, it was also associated with diabetes. It has been suggested that the association with heart disease, hypertension, and sexual disorders may be due to the presence of MS and that inflammation may be the common factor linking LUTS to diabetes, depression, arthritis, and prostatitis. The findings of the main epidemiologic studies show that the prevalence of LUTS does not differ by gender or race, but voiding symptoms are more common in men and storage symptoms are more common in women. Prevalence differs according to the definition used: 72.3% of men and 76.3% of women experience at least one symptom occasionally, but only 18.7% of adults have an AUA-SI score 109 cm) were at higher risk of being surgically treated for BPH as compared to not obese individuals. In this context, MS, diabetes, and hypertension might predispose patients to BPH and/or LUTS [58]. From a clinical point of view, these data clearly indicate that modification of lifestyle and physical activity may be of benefit to treat or prevent LUTS. There are some indications that both macronutrients and micronutrients may affect the risk of BPH, although the patterns are somewhat inconsistent. For macronutrients, increased total energy intake, energy-adjusted total intake, red meat, fat, milk, cereals, bread, poultry, and starch all potentially increase the risks of clinical BPH and BPH surgery, while vegetables fruits, polyunsaturated fatty acid, linoleic acid, and vitamin D potentially decrease the risk of BPH. About micronutrients vitamin E, Selenium, and carotene have been inversely associated with BPH [59,60].

Physical Activity Increased physical activity and exercise have been robustly and consistently linked to decreased risks of BPH surgery, clinical BPH, histological BPH, and LUTS [61,62]. A metaanalysis of 11 studies (43,083 patients) indicates that moderate to vigorous physical activity reduced the risk of BPH by as much as 25% relative to a sedentary lifestyle, with the magnitude of the protective effect increasing with higher levels of activity [63].

Alcohol Moderate alcohol intake has a protective function against BPH. A metaanalysis of 19 studies (120,091 patients) showed up to 35% decreased likelihood of BPH among who drank daily [64].

Smoking One review notes that while several studies support the existence of an inverse, protective effect of smoking on the risk of BPH, several others have reported either no or increased risk [65]. Thus, no definitive conclusions may be drawn at this time.

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Inflammation Many studies showed that inflammation is linked to the development of BPH and prostate cancer. In this sense, MS promotes systemic inflammation and oxidative stress and mediates the connection of both [66]. Oxidative stress, inflammatory mediators, and insulin growth pathway promote prostate growth in both conditions. Also infections such as gonorrhea, chlamydia, or trichomonas increase the risk of elevated prostate-specific antigene (PSA) and prostate enlargement. Inhibition of inflammation may potentially attenuate the BPH risk. In the Olmested County cohort, men who taken statin or nonsteroidal antiinflammatory drugs had significantly decreased risks of LUTS and BPH [67]. Instead other studies do not show similar results [68].

Race As concerning the influence of race on BPH severity, unfortunately there are no sufficient data about this association. Several studies showed an increase of prostate transition zone and total volume for US black men compared with white men. The PLCO study observed no differences in clinical BPH between black and white subjects. Some data suggested a decreased risk of clinical BPH in Asian compared with white men. BPH/LUTS prevalence estimates are infrequently reported by race/ethnicity. Many studies have primarily racially homogenous populations and are, therefore, unable to draw conclusions on racial or ethnic differences in disease prevalence. However, there are a few published articles of heterogeneous populations that are able to assess this difference, and these studies tend to indicate that the prevalence of BPH/LUTS may vary by race/ethnicity. The Prostate Cancer Prevention Trial reported the highest prevalence of BPH to be among Hispanic men, followed by black, white, and Asian men [13]. This mirrored the results of the California Men’s Health Study and the Research Program in Genes, Environment and Health, which reported the highest prevalence of LUTS among Hispanic men, followed by black, white, and Asian men [69]. Additionally, black men had an estimated moderate-to-severe LUTS prevalence of 39.6% in the Flint Men’s Health Study [70]. Other studies reported that Japanese, Chinese, and Indian men have significantly lower prostate volumes than Australian or American men, which could contribute to BPH/LUTS prevalence differences [71,72].

References [1] Rosen R, Altwein J, Boyle P, Kirby RS, Lukacs B, Meuleman E, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 2003;44(6):637–49. [2] Calais Da Silva F, Marquis P, Deschaseaux P, Gineste JL, Cauquil J, Patrick DL. Relative importance of sexuality and quality of life in patients with prostatic symptoms. Results of an international study. Eur Urol 1997;31(3):272–80.

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[61] Parsons JK. Modifiable risk factors for benign prostatic hyperplasia and lower urinary tract symptoms: new approaches to old problems. J Urol 2007;178(2):395–401. [62] Dal Maso L. Lifetime occupational and recreational physical activity and risk of benign prostatic hyperplasia. Int J Cancer 2006;118(10):2632–5. [63] Parsons JK, et al. Lipids, lipoproteins and the risk of benign prostatic hyperplasia in community-dwelling men. BJU Int 2008;101(3):313–8. [64] Parsons JK, et al. Alcohol consumption is associated with a decreased risk of benign prostatic hyperplasia. J Urol 2009;182(4):1463–8. [65] Parsons JK. Lifestyle factors, benign prostatic hyperplasia, and lower urinary tract symptoms. Curr Opin Urol 2011;21(1):1–4. [66] Furukawa S. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004;114(12):1752–61. [67] St Sauver JL, et al. Statin use and decreased risk of benign prostatic enlargement and lower urinary tract symptoms. BJU Int 2011;107(3):443–50. [68] Schenk JM. Indications for and use of nonsteroidal antiinflammatory drugs and the risk of incident, symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol 2012;176(2):156–63. [69] Van Den Eeden SK, Shan J, Jacobsen SJ, et al. Evaluating racial/ethnic disparities in lower urinary tract symptoms in men. J Urol 2012;187(1):185–9. [70] Wei JT, Schottenfeld D, Cooper K, et al. The naturalhistory of lower urinary tract symptoms in black American men: relationships with aging, prostate size, flow rate and bothersomeness. J Urol 2001;165(5):1521–5. [71] Jin B, Turner L, Zhou Z, et al. Ethnicity and migration as determinants of human prostate size. J Clin Endocrinol Metab 1999;84(10):3613–9. [72] Masumori N, Tsukamoto T, Kumamoto Y, et al. Japanese men have smaller prostate volumes but comparable urinary flow rates relative to American men: results of community based studies in 2 countries. J Urol 1996;155(4):1324–7.

CHAPTER 2

Pathologic Triggers Related to LUTS and BPH Vincenzo Mirone, Roberto La Rocca, Marco Franco, Luca Venturino University “Federico II”, Naples, Italy

INTRODUCTION Male LUTS in aging men are mainly caused by Benign prostatic hyperplasia (BPH) that is a pathologic process of prostatic growth in older men, which is strongly related to hormonal changes but cause-and-effect relationships have not been established. Nowadays we know that, androgens are a necessary but not the only causative aspect of BPH. LUTS were supposed to be held by the mass increase with a relative increase in urethral resistance, but this definition is overly simplistic, in fact male LUTS depend also on detrusor dysfunction or other conditions such as polyuria, sleep disorders, or any medical condition related to age. During the years, studies have identified that voiding symptoms have a limited relationship with pathophysiology, in fact LUTS can be related to any kind of urinary obstruction, such as a urethral stricture or impaired detrusor contractility. This has led to the recognition that, although LUTS may commonly be related to bladder outlet obstruction (BOO) as a result of benign prostatic obstruction, which is often associated with benign prostatic enlargement (BPE) resulting from the histologic condition of BPH, this is not invariably the case. For example, women also commonly present with voiding symptoms so failure to empty can be related to either an outlet obstruction or detrusor underactivity of the bladder, or combination of both. Postmicturition symptoms, such as postvoid dribbling, occur in both sexes, but most often in men, in whom these symptoms are highly common, are very troublesome, and cause significant interference with quality of life. Storage symptoms are currently largely encompassed by the term overactive bladder syndrome, which is defined as urgency, frequency, nocturia, and urge incontinence, and which is believed to be correlated with an underlying detrusor overactivity these symptoms tend to be more bothersome than voiding symptoms. Storage symptoms Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. https://doi.org/10.1016/B978-0-12-811397-4.00002-0 © 2018 Elsevier Inc. All rights reserved.

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in both sexes are commonly associated with urinary infections or, more rarely, with other conditions such as bladder stones, carcinoma, or carcinoma in situ in the bladder. After the age of 40 years, every man will develop histologic hyperplasia (i.e., BPH), but not all will have bothersome LUTS. The enlargement defined as BPE is not strictly related to LUTS and vice versa.

ETIOLOGY BPH depends on the increasing of number of epithelial and stromal cells in the periurethral area of the prostate and thus correctly referred to as hyperplasia and not hypertrophy, as is often found in the older literature. The precise molecular etiology of this hyperplastic process is uncertain. The observed increase in cell number may be due to epithelial and stromal proliferation or to impaired programmed cell death leading to cellular accumulation. Androgens, estrogens, stromal-epithelial interactions, growth factors, and neurotransmitters may play a role, either singly or in combination, in the etiology of the hyperplastic process.

HYPERPLASIA Hyperplasia is an increase in the amount of organic tissue that results from cell proliferation. It may lead to the gross enlargement of an organ. Microscopically, cells resemble normal cells but are increased in numbers. Hyperplasia is different from hypertrophy in that the adaptive cell change in hypertrophy is an increase in the size of cells, whereas hyperplasia involves an increase in the number of cells. An organ can enlarge not only by an increase in cell proliferation but also by a decrease in cell death. Although it is possible that the early phases of BPH are associated with a rapid proliferation of cells, the established disease appears to be maintained in the presence of an equal or reduced rate of cell replication. Increased expression of antiapoptotic pathway genes (e.g., BCL2) supports this hypothesis. Normally, androgens support cell proliferation and differentiation in the prostate having also inhibitory activity on cell death. At last also the neurologic activity has a role in cell death especially α-adrenergic innervation. The hyperplasia act by causing a total modification of the normal structure of the prostate tissue. In late 80s, a study proposed that BPH may be considered as stem cell disease. The observation of a new epithelial gland formation is normally seen only in fetal development and gives rise to the concept of embryonic reawakening of the stroma cell’s inductive potential. The precise molecular etiology of this hyperplastic process is uncertain. The proliferation causes the

Prostatic Immune Cells and Inflammation

formation of undifferentiated cells, in fact the secretion, which is a parameter of epithelial cell differentiation, decreases suggesting that the number of differentiated cells capable of secretory activity may be decreasing.

ROLE OF INFLAMMATION The development and progression of BPH depends also on prostate immune cells. Thus, prostatic inflammation should be considered a novel field of basic and clinical research in patients with BPH as well as a target for new treatment strategies. Also the identification of accurate biomarkers for prostatic inflammation is needed. Since 1937, different studies tried to clarify the influences between chronic inflammation and BPH and theorize that BPH could be an immune-mediated inflammatory disease. Several in vitro and in vivo studies showed alterations in the complex network of cytokines and growth factors that are implicated in the prostatic inflammatory process. This inflammatory process determines tissue damage and chronic healing leading to persistent stimulation of stromal and epithelial prostatic cells, potentially resulting in BPH. On these bases, it was theorized that antiinflammatory agents could be used as therapeutic option in the prevention and treatment of BPH-LUTS.

PROSTATIC IMMUNE CELLS AND INFLAMMATION The prostatic tissue is characterized by the presence of a complex intraglandular immune system that ensures the sterility of the genitourinary tract and the prevention of autoimmune reactions. This condition makes the prostate an immunocompetent organ. Within the prostate, >90% of immune cells are T-lymphocytes, in particular the CD8+ subtype, in both the epithelial and stromal compartments of the gland. The number of T-lymphocytes progressively increases during adult life, even in the absence of any prostatic disease, to develop the prostateassociated lymphoid tissue (PALT). A small number of other inflammatory cells (B-lymphocytes, macrophages, and mast cells) are also present. In periglandular areas the population of cytotoxic T-lymphocytes (CD8+) is the most present, in the stroma there are lymphoid aggregates composed of 50% B-lymphocytes surrounded by parafollicular-T-lymphocytes (mostly CD4+). Moreover, current data indicate that both prostatic epithelial and stromal cells express cytokine receptors being active actors of the immune response as antigen presenting cells (APCs). The epithelial cells widely express toll-like receptors and exhibit major histocompatibility complex class II (MHC II) molecules. Similarly, prostatic stromal cells express MHC II and co-stimulatory molecules (CD80, CD86, CD40, CD134L) on their membranes. Nowadays there were found several stimuli as triggers of different molecular pathways for the dysregulation of the prostatic immune

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system and the development of inflammation, which can be proven by biopsy samples and surgical specimens of prostatic tissue in patients with BPH. Many microorganisms as well as (1) viruses (human papilloma virus, herpes simplex virus type 2, and cytomegalovirus) (2) sexually transmitted organisms (including Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, and Treponema pallidum) (3) Gram-negative pathogens (Escherichia coli) have been recognized in the prostate and could trigger a proinflammatory reaction. Urinary reflux has also been correlated with prostatic inflammatory infiltrates by a chemical activity of molecules excreted within the urine. For example, crystalline uric acid can directly stimulate caspase-1-activating cryopyrin, an enzyme widely expressed by innate immune cells, primarily macrophages. The consequent inflammatory response could lead to the development of the corpora amylacea, which generate a glandular duct occlusion that further sustains the inflammatory process. Metabolic syndrome as well as it does with other organs can induce a prostate environment rich in proinflammatory cytokines, inflammatory mediators, and growth factors. Metabolic syndrome obviously determines a systemic alteration with hormonal alterations, insulin resistance, and increasing IFNγ release from lymphocytes that can all lead to organ and systemic inflammation. Furthermore it is considered that metabolic patients often have a high-fat diet with the presence of heterocyclic amines, which are derived from meats cooked at high temperatures, there is also this trigger to determine the inflammation in prostate. At least all these triggers of chronic inflammation cause chronic epithelial damage that deteriorate the barrier function of the epithelium influencing the activity of prostatic immune system, leading to the induction of autoimmune response with prostatic inflammatory infiltrates. Independently of the pathogenic noxae, the prostate undergoes an extensive alteration of the organization, localization, and composition of immune cells which can lead to the development of prostatic diseases including BPH and prostate cancer. Although it is not the subject of this chapter, it would be worth a small digression on the relationship between inflammation and prostate cancer. The most important trigger was found in the immunological response to different pathogenic noxae that might induce tissue injury and subsequent chronic and repetitive wound healing, which could be involved in BPH growth and progression, as well as in the prostate’s susceptibility to developing cancer. Despite their differences and the lack of a causative well-established relationship between these diseases, BPH and prostate cancer share several clinical features, including coexistence in the same prostatic zone in 20% of cases, hormone-dependent

BPH and Prostatic Inflammation

growth, and response to antiandrogen therapy. In addition, chronic inflammation, metabolic disruption, and variants in the genes involved in the inflammatory pathway and immune response might be common drivers for both diseases. These factors could increase the risk of uncontrolled stimulation of prostatic growth mechanisms, potentially leading to the development of BPH and cancer. Furthermore, proliferative inflammatory atrophy, which is considered to be a possible precursor to high-grade intraepithelial neoplasia and prostate cancer, arises in areas of the gland where cells are actively regenerating following tissue damage.

BPH AND PROSTATIC INFLAMMATION Clinical Evidence Data from the MTOPS (Medical Therapy of Prostate Symptoms) trial and REDUCE (Reduction by Dutasteride of prostate Cancer Events) trial population reported that chronic inflammatory infiltrates were found in  40% to 77.6% of samples from the patients undergoing prostatic biopsy in the study, in particular, in men with elevated serum PSA levels and larger prostate volumes. A statistically and clinically significant association among the degree of prostatic inflammation, prostate volume, and IPSS was found in 282 patients undergoing surgery for symptomatic or complicated BPH. Chronic prostatic inflammation in 79%, 48%, and 20% of patients with severe, intermediate, and no BPH, respectively, was reported. A further study assessed the prevalence of inflammation and BPH in prostate glands obtained during autopsy from 100 Asian and 320 Caucasian men. In >70% of autopsy specimens in both populations, chronic inflammation was found; patients with chronic inflammation were seven times more likely to have BPH than patients without inflammation (HR 6.84, 95% CI 4.05–11.78; P < .0001). These studies all examined the concomitant risk of BPE (evaluated by prostate volume) and LUTS. Although prostate inflammation has been identified as the cause of BPE, bladder and prostatic inflammation observed in obese patients or in patients with metabolic syndrome is related with storage symptoms independently from the effect of inflammatory infiltrates on prostate volume. These data are also confirmed in studies evaluating the effect of inflammation on LUTS in both sexes. In the Boston Area Community Health Survey was demonstrated that there is a relationship between levels of C-reactive protein (CRP), an inflammatory marker, and LUTS in both men and women. In men, log10(CRP) levels as a continuous variable were positively associated with urgency, urgency plus frequency, or urgency plus both frequency and nocturia. The adjusted ORs (95% CI) per log10(CRP) levels were respectively 1.90 (1.26–2.86) with urgency, 1.65 (1.06–2.58) with urgency plus frequency, and 1.92 (1.13–3.28) with urgency plus both frequency and nocturia. The association was more

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modest in women, the adjusted ORs (95% CI) per log10(CRP) levels were respectively 1.53 (1.07–2.18) with urgency, 1.51 (1.02–2.23) with urgency plus frequency, and 1.34 (0.85–2.12) with urgency plus both frequency and nocturia. Furthermore, in few studies was assessed the positive association between metabolic-syndrome-induced systemic inflammation and storage LUTS in female patients. From the results were identified higher levels of cytokines as well as MCP-1, CD40 ligand, IL-6, IL-8, and TNFα, in women with overactive bladder than in the control group. Another important evidence demonstrates that an altered sensitivity from the prostate dependent on chronic prostatic infiltrates can determine detrusor overactivity with associated storage symptoms independent of prostate volume. All this evidences suggests that the prostate and bladder could be considered as a single apparatus with a close interaction which is the basis of the pathogenesis of LUTS due to inflammation.

Molecular Pathways The study presented earlier defined the relationship between the activation and dysregulation of prostatic immune cells and the development of BPH-LUTS, but it is important to find the possible mechanisms behind this apparent causal relationship. A first milestone study identified the activation of T-helper1 (TH1) and T-helper2 (TH2) lymphocytes in prostate tissue, as well as the release of several cytokines and growth factors, that have been associated with the initiation and progression of BPH. In particular it was found that IL-17 is a very important cytokine in BPH development and progression. Its concentration is virtually insignificant in normal prostate, but it is amplified in BPH tissues, where it is mostly secreted by T-lymphocytes and prostate cells. IL-17 appears to trigger the release of TNFα, IFNc, IL-5, and IL-10 by BPH T-lymphocytes and upregulates expression of cyclooxygenase 2 (COX-2) in macrophages and epithelial cells. Remarkably in mouse models based on oxidative stress and aging that are frequently associated to BPH, IL-17 secretion is augmented. The TGFβ family also has an important role in BPH stromal proliferation and differentiation, as well as being a key factor for androgencontrolled prostatic growth. A total of 231 patients with BPH were analyzed for the expression of TGFβ receptor II protein (TGFBRII) in prostate. There was observed a positive association between TGFBRII and prostate volume. Data also suggest that bacterial infections and related prostatic inflammation could induce increased expression of androgen-responsive genes in the epithelium, and activate TGFβ1 cascade genes in the stroma. Moreover, macrophage infiltrates, as observed in inflamed prostate tissue, stimulate the secretion of TGFβ2 from epithelial cells. In BPH tissue is well known the epithelialmesenchymal transition (EMT) that is strongly supported by the activity of TGFβ2 and HIF-1α. EMT is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to

BPH and Prostatic Inflammation

become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. The following collaboration between the stromal cells and infiltrated macrophages increases CCL3 secretion, which endorses further proliferation of stromal cells. This mechanism could explain the altered stromal/epithelial ratio observed in BPH (from 2:1 in normal glands to 5:1 in BPH). IL-18 directly influences prostatic stromal cell proliferation and is produced by prostatic epithelial cell and by a complex of cytosolic proteins of the macrophages named the “inflammasome” that cleaves pro-IL-18 to the mature form and further increases its secretion from immune cells. IL-8 in BPH tissues is actively secreted by epithelial and stromal cells in response to the proinflammatory cytokines as IL-17, which are produced by prostate-infiltrating TH1 and TH17 cells. IL-8 induces stromal and epithelial overgrowth by directly stimulating the proliferation of senescent epithelial cells, the stromal acquisition of a myofibroblast reactive phenotype, and by indirectly promoting fibroblast growth factor 2 (FGF-2) secretion. Another important molecule is MCP-1, one of the most highly secreted proteins in large prostate glands. Stromal cells are the first producer of MCP-1; however, epithelial cells stimulated by IL-1b, IFNg, and IL-2 can produce high level of this protein. Both epithelial and stromal cells express the receptor of MCP-1 (CCR2), so it is activated a paracrine/autocrine pathway that stimulate the growth of epithelial cells. Another evidence is due to a not well-defined threshold of density of T-lymphocytes, CD8+ cytotoxic T cells start to kill the epithelial and stromal cells, leaving behind vacant spaces that are replaced by fibromuscular nodules. Local hypoxia is a further stimulus for the production of inflammatory mediators, producing a low level of reactive oxygen species (ROS) that can promote neoangiogenesis and fibroblast-tomyofibroblast transdifferentation. As a response to hypoxia, prostatic stromal cells upregulate the secretion of several growth factors, in particular, FGF-7, TGFβ, FGF-2, and IL-8, which contribute to prostatic growth. Increased activity of inflammatory cells in prostate tissue determines a stimulation of prostatic stromal and epithelial cell that respond to internal and external stimulation with uncontrolled proliferation that is preserved by autoimmune mechanisms. Subsequent inflammatory tissue damage and continuous cycles of wound healing could then eventually induce the development of BPH nodules.

Hormonal Pathways Proinflammatory cytokines can also regulate alterations in the metabolism of sex steroids and act synergistically with hormones to enhance the proliferative stimuli involved in BPH. Estrogen-metabolizing enzymes—such as aromatase, steroid sulphatase, and 17β-hydroxysteroid dehydrogenase 2 (HSD17β2)—are upregulated in a mouse

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model of prostatitis with a consequent increase in catechol estrogens within the prostate tissue [1]. Exposure to estrogens further induces inflammation and cell proliferation, suggesting synergism between hormonal modifications and inflammation. Current literature also supports a potential interaction between inflammation and the expression of the androgen receptor (AR) in both epithelial and stromal cells of hyperplastic infiltrates. Monti et al. [2] showed that the periurethral area of the transitional zone expresses the highest levels of androgens and AR compared with the other prostate areas, suggesting that it is involved in the initial BPH growth-promoting progressions. Interestingly a study analyzing 105 simple prostatectomy specimens highlighted a strong association between immune-mediated inflammation, prostate volume, and AR expression in BPH samples. The same study shows that the specimens of immune-mediated inflammation displayed a higher prostate volume and higher expression of AR than the specimens without immune-mediated inflammation. Izumi et al. [3] have provided a possible explanation: according to their findings, AR expression in epithelial cells attracts macrophages and the subsequent interaction between epithelial cells and macrophages increases the secretion of TGFβ-2 from epithelial cells. Equally, AR expression in stromal cells attracts macrophages and the interaction between stromal cells and infiltrated macrophages induces CCL3 secretion from both stromal cells and infiltrated macrophages. Proliferation of stromal cells is promoted by these interactions, further supporting also the development of BPH nodules. Androgens also directly influence the development of inflammatory infiltrates. Vignozzi et al. investigated whether AR activation could influence inflammatory responses induced by oxidized low-density lipoprotein (oxLDL) and the effect of dihydrotestosterone (DHT) on the secretion of IL-6 and IL-8 in human myofibroblast in BPH cultures. IL-6 and IL-8 are significantly inhibited by DHT treatment (30 nmol/L for 24 h); this effect was completely reversed by bicalutamide. The presented data suggest that the relationship between immune cells and androgens is complex. DHT—that is strongly expressed in the prostatic tissue—could have a direct protective effect on the human prostate, increasing the ability of prostate cells to react to metabolic insults; conversely, the presence of inflammatory cells within the prostate might also influence AR expression, which can strongly promote further enrollment of inflammatory cells and further stromal cell proliferation.

METABOLIC SYNDROME, INFLAMMATION, AND BPH Increasing evidences have shown a possible positive relationship between metabolic syndrome and its components and the development and progression of BPH-LUTS through mostly unknown molecular and pathophysiological pathways. Current literature has suggested that insulin resistance with secondary

Metabolic Syndrome, Inflammation, and BPH

hyperinsulinemia is involved in prostatic enlargement. Hyperinsulinemia increases sympathetic nervous system activity resulting in increasing in smooth muscle tone of the prostate and, consequently in LUTS independent of prostatic enlargement. Furthermore, the structural similarity between IGF-1 means that insulin can bind to the IGF-receptor, activating the pathways of serine/threonine kinases. Men with metabolic syndrome often present with low androgen and high-estrogen levels, a disorder which is also evident in men with LUTS/BPH. Murine models suggest that higher estrogen levels synergize with androgens resulting in an increase in total prostate weight. Different mechanisms behind the association between metabolic syndrome and LUTS/BPH have been proposed, including pelvic atherosclerosis. Changes in the cytokine setting might further explain the observed association between metabolic syndrome and BPH. A substantial increase in levels of IL-1β, IL-6, and TNFα have been observed in plasma and prostate samples from patients affected by metabolic syndrome. Gacci et al. [4] observed a positive association between prostatic volume and the number of metabolic syndrome components; in particular, dyslipidemia was strongly associated with an increased risk of prostatic volume >60 mL. Furthermore, prostatic inflammation grade and extension (evaluated together by the overall inflammatory score) seems to be strongly related to metabolic syndrome. A murine model was settled by Shankar et al. [5], they investigated changes in the cytokine cascade in rats fed with a high-fat diet and observed an uncontrolled immune response followed by increased cell proliferation mediated by increased expression of IL-6. Urologists should be prepared to carefully evaluate the association between metabolic syndrome and BPH to better understand if prostatic inflammation is the key candidate bridging this pathological relationship. The possibility of managing BPH and LUTS by treating and preventing metabolic syndrome is a fascinating option to be evaluated in the future.

Inflammation and BPH Progression Chronic prostatic inflammation could be considered an important risk factor of BPH progression. Several studies have shown a positive link between prostatic inflammatory infiltrates and an increased risk of acute urinary retention (AUR) in men with BPH/LUTS. Tuncel et al. [6] enrolled 92 patients undergoing BPH surgery, who were grouped according to their surgical indication. The authors reported a significantly higher rate of prostatic inflammation in different groups. The presence of prostatic inflammation has also been related with urinary retention at a younger age. Consistent with this evidence, data from the MTOPS trial confirmed that men with inflammation at prostate biopsy were at a higher risk of clinical progression, symptoms worsening, need for surgery

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at risk of urinary retention than those without inflammation. A further immunohistochemical analysis performed by Torkko et al. [7] on the same group of patients has underlined a positive association between prostate inflammation markers (CD45, CD4, and CD68) and the increased risk of clinical progression of BPH. Patients with prostatic tissue at prostate biopsy strongly positive for CD4 (3°tertile) had double the risk of progression when compared with patients with negative prostate samples. Otherwise, prostatic inflammation might also induce resistance to currently used BPH medical treatments, facilitating BPH progression. Kwon et al. [8] enrolled 82 patients receiving α-blocker therapy for BPH and observed that men with low-grade inflammatory infiltrates responded to treatment better than those without, an effect maintained up to 12 months after treatment initiation. In improvement in storage symptoms was no longer evident after 3 months of treatment in the setting of patients with high-grade prostatic inflammation. In this setting, 9.1% of patients eventually underwent surgery for AUR or symptom progression. The authors suggest that BPH progression might be more likely in patients with high-grade inflammatory infiltrates. The activity of 5-α reductase inhibitor (5-ARI) might be altered by the presence of prostatic inflammation. In particular, age and rising levels of inflammatory mediators, such as TNFα, nuclear factor-κB (NF-κB), and IL-6, can modify the activity of the enzyme DNA methyl-transferase 1, which regulates the expression of SRD5A2, the target of these medications. Moreover, in patients demanding for prostatic surgery, previous treatment with 5-ARIs was well associated with an increased expression of c-FOS, a gene involved in the proinflammatory response. Further studies also sustain the role of DHT as a modulator of prostatic inflammatory. Low levels of DHT possibly induce increased recruitment of T-lymphocytes promoted by epithelial cells, via upregulation of mRNA transcription. DHT could also inhibit the secretion of proinflammatory cytokines, chemokines, and growth factors involved in the NF-κB cascade. These preliminary findings suggest that 5-ARI treatment response is influenced by the presence of prostatic inflammation but at the same time it can modulate prostatic immune cell activity, although these data should be confirmed in large clinical trials.

Biomarkers of Prostatic Inflammation Considering the potential effect of inflammation on BPH/LUTS treatment, until now the only method to accurately diagnose and assess the grade and the extent of prostatic inflammatory infiltrates has been the use of tissue samples from prostate biopsy, radical or simple prostatectomy, or TURP. Exact definition of the anatomical location, grade, and extent of inflammation and glandular disruption is possible using tissues samples from TURP and/or

Further Reading

simple prostatectomy; however, these methods can only be used to assess prostatic inflammation and its effect on treatment outcomes in patients scheduled for BPH surgery, prostate biopsy, or radical prostatectomy and they cannot be adopted on a large scale in all men with BPH. Fujita and colleagues reported a positive correlation between prostate volume and white blood cell count in a cohort of 576 Japanese patients with BPH, and Menschikowski et al. reported an increase in serum levels of CRP and secreted group IIA phospholipase A2 in men with BPH compared with healthy men. All of these serum markers are highly nonspecific, as their serum concentrations can be affected by concomitant systemic inflammatory diseases. Thus, researchers have focused their attention principally on urinary and seminal-plasma biomarkers. In these categories, MCP-1 and ICOS seem to be the most promising biomarkers. High levels of MCP-1 in the expressed prostatic secretion have been correlated with increasing gland weight. ICOS is a cell-surface T-cell receptor, which is detected in high concentrations in urine, measurable by ELISA.

References [1] Mosli HA, et al. Local inflammation influences oestrogen metabolism in prostatic tissue. BJU Int 2012;110:274–82. [2] Monti S, et al. Androgen concentrations and their receptors in the periurethral region are higher than those of the subcapsular zone in benign prostatic hyperplasia (BPH). J Androl 1998;19:428–33. [3] Izumi K, Mizokami A, Lin WJ, Lai KP, Chang C. Androgen receptor roles in the development of benign prostate hyperplasia. Am J Pathol 2013;182:1942–9. [4] Gacci M, et al. Metabolic syndrome and lower urinary tract symptoms: the role of inflammation. Prostate Cancer Prostatic Dis 2013;16:101–6. [5] Shankar E, et al. High-fat diet activates proinflammatory response in the prostate through association of Stat-3 and NF-κB. Prostate 2012;72:233–43. [6] Tuncel A, et al. Do prostatic infarction, prostatic inflammation and prostate morphology play a role in acute urinary retention? Eur Urol 2005;48:277–84. [7] Torkko KC, et al. Prostate biopsy markers of inflammation are associated with risk of clinical progression of benign prostatic hyperplasia: findings from the MTOPS study. J Urol 2015;194:454–61. [8] Kwon YK, et al. The effect of intraprostatic chronic inflammation on benign prostatic hyperplasia treatment. Korean J Urol 2010;51:266–70.

Further Reading Kramer G, Mitteregger D, Marberger M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol 2007;51:1202–16. Robert G, Descazeaud A, Allory Y, Vacherot F, de la Taille A. Should we investigate prostatic inflammation for the management of benign prostatic hyperplasia? Eur Urol Suppl 2009;8:879–86.

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Sciarra A, et al. Inflammation and chronic prostatic diseases: evidence for a link? Eur Urol 2007;52:964–72. De Nunzio C, Albisinni S, Gacci M, Tubaro A. The role of inflammation in the progression of benign prostatic hyperplasia. Curr Bladder Dysfunct Rep 2013;8:142–9. Soler R, et al. Future direction in pharmacotherapy for non-neurogenic male lower urinary tract symptoms. Eur Urol 2013;64:610–21. Moore D. Inflammation of the prostate gland. J Urol 1937;38:173–82. Kramer G, et al. Increased expression of lymphocyte derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation. Prostate 2002;52:43–58. Kramer G, Marberger M. Could inflammation be a key component in the progression of benign prostatic hyperplasia? Curr Opin Urol 2006;16:25–9. Steiner GE, et al. Expression and function of proinflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate. Prostate 2003;56:171–82. Steiner GE, et al. Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue. Lab Invest 2003;83:1131–46. Nickel JC, et al. Examination of the relationship between symptoms of prostatitis and histological inflammation: baseline data from the REDUCE chemoprevention trial. J Urol 2007;178:896–900. Nickel JC, et al. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol 2008;54:1379–84. Roehrborn CG, et al. The impact of acute or chronic inflammation in baseline biopsy on the risk of clinical progression of BPH: results from the MTOPS study. J Urol 2005;173:346. Shortliffe LM, Werner N, Stamey TA. The detection of a local prostatic immunologic response to bacterial prostatitis. J Urol 1981;125:509–15. Vykhovanets EV, Resnick MI, Marengo SR. The healthy rat prostate contains high levels of natural killer-like cells and unique subsets of CD4+ helper- inducer T cells: implications for prostatitis. J Urol 2005;173:1004–10. Di Carlo E, Magnasco S, D’Antuono T, Tenaglia R, Sorrentino C. The prostate-associated lymphoid tissue (PALT) is linked to the expression of homing chemokines CXCL13 and CCL21. Prostate 2007;67:1070–80. Robert G, et al. Inflammation in benign prostatic hyperplasia: a 282 patients’ immunehistochemical analysis. Prostate 2009;69:1774–80. Penna G, et al. Human benign prostatic hyperplasia stromal cells as inducers and targets of chronic immuno-mediated inflammation. J Immunol 2009;182:4056–64. Fibbi B, Penna G, Morelli A, Adorini L, Maggi M. Chronic inflammation in the pathogenesis of benign prostatic hyperplasia. Int J Androl 2010;33:475–88. Kramer G, et al. Loss of CD38 correlates with simultaneous upregulation of human leukocyte antigen-DR in benign prostatic glands, but not in fetal or androgen-ablated glands, and is strongly related to gland atrophy. BJU Int 2003;91:409–16. Beadling C, Slifka MK. Regulation of innate and adaptive immune responses by the related cytokines IL-12, IL-23, and IL-27. Arch Immunol Ther Exp (Warsz) 2006;54:15–24. Sfanos KS, Isaacs WB, De Marzo AM. Infections and inflammation in prostate cancer. Am J Clin Exp Urol 2013;1:3–11. Elkahwaji JE. The role of inflammatory mediators in the development of prostatic hyperplasia and prostate cancer. Res Rep Urol 2012;31:1–10. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41.

Further Reading

Nakai Y, Nelson WG, De Marzo AM. The dietary charred meat carcinogen 2-amino-1-methyl 6-phenylimidazo[4,5-b]pyridine acts as both a tumor initiator and promoter in the rat ventral prostate. Cancer Res 2007;67:1378–84. De Marzo AM, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007;7:256–69. Bardan R, Dumache R, Dema A, Cumpanas A, Bucuras V. The role of prostatic inflammation biomarkers in the diagnosis of prostate diseases. Clin Biochem 2014;47:909–15. Chokkalingam AP, et al. Prostate carcinoma risk, subsequent to diagnosis of benign prostatic hyperplasia: a population-based cohort study in Sweden. Cancer 2003;98:1727–34. Ørsted DD, Bojesen SE. The link between benign prostatic hyperplasia and prostate cancer. Nat Rev Urol 2013;10:49–54. Ørsted DD, Bojesen SE, Nielsen SF, Nordestgaard BG. Association of clinical benign prostate hyperplasia with prostate cancer incidence and mortality revisited: a nationwide cohort study of 3,009,258 men. Eur Urol 2011;60:691–8. Vignozzi L, Maggi M. Intriguing data on inflammation and prostate cancer. Nat Rev Urol 2014;11:369–70. Roehrborn CG. Definition of at-risk patients: baseline variables. BJU Int 2006;97:7–11. Gandaglia G, et al. The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). BJU Int 2013;4:432–41. Zlotta AR, et al. Prevalence of inflammation and benign prostatic hyperplasia on autopsy in Asian and Caucasian men. Eur Urol 2014;66:619–22. He Q, et al. Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links. Prostate Cancer Prostatic Dis 2016;19:7–13. Kupelian V, et al. Association of overactive bladder and C-reactive protein levels. Results from the Boston Area Community Health (BACH) Survey. BJU Int 2012;110:401–7. De Nunzio C, et al. Metabolic syndrome and lower urinary tract symptoms in patients with benign prostatic enlargement: a possible link to storage symptoms. Urology 2014;84:1181–7. Konig JE, Senge T, Allhoff EP, Konig W. Analysis of the inflammatory network in benign prostate hyperplasia and prostate cancer. Prostate 2004;58:121–9. McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23–IL-17 immune pathway. Trends Immunol 2006;27:17–23. Wang W, Bergh A, Damber JE. Chronic inflammation in benign prostatic hyperplasia is associated with focal upregulation of cyclooxygenase-2, Bcl-2, and cell proliferation in the glandular epithelium. Prostate 2004;61:60–72. De Angulo A, Faris R, Daniel B, Jolly C, de Graffenried L. Age-related increase in IL’17 activates proinflammatory signaling in prostate cells. Prostate 2015;75:49–62. Descazeaud A, et al. Transforming growth factor β-receptor II protein expression in benign prostatic hyperplasia is associated with prostate volume and inflammation. BJU Int 2011;108: E23–8. Funahashi Y, et al. Upregulation of androgen responsive genes and transforming growth factor-β1 cascade genes in a rat model of non-bacterial prostatic inflammation. Prostate 2014;74:337–45. Funahashi Y, et al. Influence of E. coli-induced prostatic inflammation on expression of androgen responsive genes and transforming growth factor beta 1 cascade genes in rats. Prostate 2015;75:381–9. Kim HJ, et al. Pathogenic role of HIF-1α in prostate hyperplasia in the presence of chronic inflammation. Biochim Biophys Acta 2013;1832:183–94. Wang X, et al. Increased infiltrated macrophages in benign prostatic hyperplasia (BPH): role of stromal androgen receptor in macrophage-induced prostate stromal cell proliferation. J Biol Chem 2012;287:18376–85.

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Hamakawa T, et al. Interleukin-18 may lead to benign prostatic hyperplasia via thrombospondin-1 production in prostatic smooth muscle cells. Prostate 2014;74:590–601. Kashyap M, et al. Inflammasomes are important mediators of prostatic inflammation associated with BPH. J Inflamm (Lond) 2015;17:12–37. Castro P, Xia C, Gomez L, Lamb DJ, Ittmann M. Interleukin-8 expression is increased in senescent prostatic epithelial cells and promotes the development of benign prostatic hyperplasia. Prostate 2004;60:153–9. Schauer IG, Ressler SJ, Tuxhorn JA, Dang TD, Rowley DR. Elevated epithelial expression of interleukin-8 correlates with myofibroblast reactive stroma in benign prostatic hyperplasia. Urology 2008;72:205–13. Giri D, Ittmann M. Interleukin-8 is a paracrine inducer of fibroblast growth factor 2, a stromal and epithelial growth factor in benign prostatic hyperplasia. Am J Pathol 2000;157:249–55. Fujita K, et al. Monocyte chemotactic protein-1 (MCP-1/CCL2) is associated with prostatic growth dysregulation and benign prostatic hyperplasia. Prostate 2010;70:473–81. Wang L, Yang JR, Yang LY, Liu ZT. Chronic inflammation in benign prostatic hyperplasia: implications for therapy. Med Hypotheses 2008;70:1021–3. Briganti A, et al. Benign prostatic hyperplasia and its aetiologies. Eur Urol Suppl 2009;8:865–71. Nicholson TM, Sehgal PD, Drew SA, Huang W, Ricke WA. Sex steroid receptor expression and localization in benign prostatic hyperplasia varies with tissue compartment. Differentiation 2013;85:140–9. Wu ZL, Yuan Y, Geng H, Xia SJ. Influence of immune inflammation on androgen receptor expression in benign prostatic hyperplasia tissue. Asian J Androl 2012;14:316–9. Vignozzi L, et al. Fat boosts, while androgen receptor activation counteracts, BPH-associated prostate inflammation. Prostate 2013;73:789–800. Vignozzi L, Gacci M, Maggi M. Lower urinary tract symptoms, benign prostatic hyperplasia and metabolic syndrome. Nat Rev Urol 2016;13:108–19. Mishra VC, et al. Does intraprostatic inflammation have a role in the pathogenesis and progression of benign prostatic hyperplasia? BJU Int 2007;100:327–31. van Vuuren SP, Heyns CF, Zarrabi AD. Significance of histological prostatitis in patients with urinary retention and underlying benign prostatic hyperplasia or adenocarcinoma of the prostate. BJU Int 2012;109:1194–7. Lee HN, Kim TH, Lee SJ, Cho WY, Shim BS. Effects of prostatic inflammation on LUTS and alpha blocker treatment outcomes. Int Braz J Urol 2014;40:356–66. Ge R, et al. DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate. Am J Pathol 2015;185:870–82. Lin-Tsai O, et al. Surgical intervention for symptomatic benign prostatic hyperplasia is correlated with expression of the AP-1 transcription factor network. Prostate 2014;74:669–79. Fan Y, et al. Low intraprostatic DHT promotes the infiltration of CD8+ T cells in BPH tissues via modulation of CCL5 secretion. Mediat Inflamm 2014;2014.397815. Tsujimura A, et al. Histologic evaluation of human benign prostatic hyperplasia treated by dutasteride: a study by xenograft model with improved severe combined immunodeficient mice. Urology 2015;85:1–8. Meigs JB, Mohr B, Barry MJ, Collins MM, McKinlay JB. Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men. J Clin Epidemiol 2001;54:935–44. Sutcliffe S, et al. Non-steroidal anti-inflammatory drug use and the risk of benign prostatic hyperplasia related outcomes and nocturia in the prostate, lung, colorectal, and ovarian cancer screening trial. BJU Int 2012;110:1050–9.

Further Reading

Kang D, et al. Risk behaviours and benign prostatic hyperplasia. BJU Int 2004;93:1241–5. St Sauver JL, Jacobson DJ, McGree ME, Lieber MM, Jacobsen SJ. Protective association between nonsteroidal antiinflammatory drug use and measures of benign prostatic hyperplasia. Am J Epidemiol 2006;164:760–8. Altavilla D, et al. Effects of flavocoxid, a dual inhibitor of COX and 5 lipoxygenase enzymes, on benign prostatic hyperplasia. Br J Pharmacol 2012;167:95–108. Kahokehr A, Vather R, Nixon A, Hill AG. Non-steroidal anti-inflammatory drugs for lower urinary tract symptoms in benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. BJU Int 2013;111:304–11. Fourcade RO, Theret N, Taı¨eb C. Profile and management of patients treated for the first time for lower urinary tract symptoms/benign prostatic hyperplasia in four European countries. BJU Int 2008;101:1111–8.

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CHAPTER 3

The Relationship Between Inflammation and LUTS/BPH Michael Samarinas, Stavros Gravas University Hospital of Larissa, Larissa, Greece

INTRODUCTION Lower urinary tract symptoms (LUTS) are common in men over 45 years of age [1], and are divided into storage (urinary daytime frequency, nocturia, urinary urgency, incontinence), voiding (urinary hesitancy, slow stream, straining, splitting or spraying, intermittent stream, terminal dribbling), and postmicturition (feeling of incomplete emptying, postmicturition dribbling) symptoms [1,2]. In men, LUTS have been traditionally attributed to bladder outlet obstruction (BOO) as a result of benign prostatic obstruction (BPO), which is often associated with benign prostatic enlargement (BPE) resulting from the histologic condition of benign prostatic hyperplasia (BPH). The prostatic enlargement is age-related and seems to be androgen depended, while the whole process origins from a proliferation of epithelial and stromal benign cells. However, apart from those initial theories, other studies indicate a correlation of LUTS with other conditions responsible for voiding difficulties, such as decrease of detrusor activity or changes in the bladder neck and prostate smooth muscle. These conditions are not necessarily connected with the prostatic size [3]. However, BPO/BPE has the dominant role in the development of male LUTS. Additionally, more recent research focuses on the role of prostatic inflammation in the development of prostatic enlargement and consequently the severity of LUTS and the natural history of these symptoms. Several models and hypotheses have been suggested for the pathogenesis of this condition. Also, the relationship of the inflammation pattern with the progression of BPH is currently investigated through the molecular and metabolic pathways, which can be responsible for this connection. 31 Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. https://doi.org/10.1016/B978-0-12-811397-4.00003-2 © 2018 Elsevier Inc. All rights reserved.

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Although all connective bridges between LUTS/BPH and prostatic inflammation are not yet well understood, there is evidence for their etiological relationship and interaction. As a result, clinical studies have already evaluated and underlined the important role of inflammation diagnosis in the urological practice.

PATHOPHYSIOLOGY Chronic histological inflammation of the prostate is a common finding in the results of the histopathological examinations after a prostate biopsy or a transurethral or open prostatectomy [4,5]. However, the model of the suggestive pathophysiological way connecting the inflammation pattern with LUTS and BPH is multiparametric and sometimes not absolutely clear.

The Immunochemical Pattern of BPH The presence of activated T-cells in the hyperplastic prostate gland is known since the Theyer study at early 1990s [4]. Peripheral blood T-cells express VEGF, a potent epithelial mitogen, while they secrete other growth factors, like HB-EGF and bFGF/FGF-2 [5]. Therefore, the presence of T-cells in the prostate might have a potential role in the gland hyperplasia, affecting the local environment by producing stromal and epithelial factors, causing prostatic hyperplasia. The immunological pattern of the inflammatory process in the prostate was the study object for several studies. In their investigation, Di Siverio et al. [6] examined histologically 3942 patients’ biopsies, describing 43% cases with inflammation. Chronic type was the predominant (69% of them). Although the severity of the symptoms was characterized as mild in most of the cases, there has been a clear association with the age and prostate volume. In an older study, Irani and Robert [7,8] suggested a grading of prostatic inflammation, based on the hypothesis that the extension of the inflammatory cells could imply the whole histological grading of the inflammatory aggressiveness (Table 3.1). Prostate is normally populated by a small number of inflammatory cells (leukocytes) that increase with age, consisting of scattered stromal and epithelial T and B lymphocytes, macrophages, and mast cells [9]. The normal prostate gland is infiltrated around the periglandular area mainly by T lymphocytes and more particularly 70% CD8 cells. In the fibromuscular stroma, there are lymphoid aggregations, consisting of B lymphocytes, CD4 T lymphocytes over 50%, while CD8 cells are in a smaller ratio [10]. However, in the prostate of adult men, the infiltration pattern is usually described as different, mainly because of the inflammatory process been present. Steiner et al. [11] showed that the inflammatory infiltrates are mostly represented by CD3

Pathophysiology

Table 3.1 Histological Grading and Aggressiveness of Prostatic Inflammation by Irani et al. and Robert et al. [7,8] Irani’s Score Inflammation scale 0 1 2 3 Aggressiveness 0

No inflammatory cells Scattered inflammatory cell infiltrate Nonconfluent lymphoid nodules Large inflammatory areas with confluence of infiltrate No contact between inflammatory cells and glandular epithelium Contact between inflammatory cell infiltrate and glandular epithelium Clear but limited, that is less than 25% of the examined material, glandular epithelium disruption Glandular epithelium disruption on more than 25% of the examined material

1 2 3 Robert’s Score

Cytological Grading 0 Absent 1 Low 2 High Macrophage 0 Absent 1 Present Lymphocyte

Polynuclear

0 1

Absent Present

Atrophy

0 1

Absent Present

Destruction

0 1

Absent Present

Immunohestochemical Grading CD3 0 Absent 1 Low 2 High CD4 0 Absent 1 Low 2 High CD8 0 Absent 1 Low 2 High CD20 0 Absent 1 Low 2 High CD163 0 Absent 1 Low 2 High

T lymphocytes (70–80%), CD19 and CD20 B lymphocytes (10–15%), and macrophages (15%). There is, also, an interesting reverse of CD8 to CD4 T cells and finally the CD4 cells become prevalent in the inflammatory areas. Robert’s study [8] came to be even more confirmative, as the investigation on 282 patients with BPH proved the presence of T lymphocytes in the 80% of cases, associated with 52% of antigen-presenting cells, such as B lymphocytes, and 82% of macrophages.

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Another situation neighboring inflammation in the prostate is proliferative inflammatory atrophy, firstly described by De Marzo et al. [12]. In this condition, the epithelium becomes atrophic or hyperplastic due to atrophy, something that also occurs in association with the chronic inflammation. The main characteristic is the presence of inflammatory cells in both epithelial and stromal areas, as well as stromal atrophy with variable amount of fibrosis.

The Inflammatory Pattern of BPH The inflammatory pattern in BPH is based on the cytokine secretion from the inflammatory cells, hypoxia due to the increased oxygen demand by the cell proliferation, and eventually tissue damage. These cytokines are involved in the regulation of the immune response but may also interact with stromal and epithelial cells in the prostate [13]. BPH tissue is populated by T-B lymphocytes and macrophages, which are responsible for the release of IL-2, IFN-γ, and TGF-β. This may support the fibromuscular growth in BPH [14]. Moreover, some proinflammatory cytokines, such as IL-15 and IFN-γ in the stromal cells, IL-17 in the T-cells, and IL-8 in the epithelium, are upregulated in a BPH condition [13]. T cells concentration is gradually increased, due to the action of the proinflammatory cytokines and when they reach a certain threshold, the surrounding cells are killed and replaced by fibromuscular nodules [15–17]. The maintenance and progression of this immune inflammation process in the aging prostate is been regulated by the dendritic cells [18,19].

The Origin of Chronic Prostate Inflammation Although the correlation of LUTS and BPH is well described in several studies, their accurate pathophysiological connection is not yet absolutely clear. A variety of pathogens are implicated, including bacterial infections, urine reflux with chemical inflammation, dietary factors, hormones, autoimmune response [20,21], and a combination of these factors. Viruses, sexually transmitted organisms, and Gram-negative pathogens have been detected in the prostate and have been responsible for a chronic inflammatory situation leading to LUTS. Hence, chronic infections or colonization of human papilloma virus, human herpes simplex virus type 2, Neisseria gonorrhoea, Chlamydia trachomatis, Treponema pallidum, Trichomonas vaginalis, or even E. coli could imply a good connection between a chronic prostate inflammation and lower urinary tract symptoms [15,21,22]. Chemical irritation due to urine reflux may be another etiological factor contributing to the development of prostate inflammation [23]. In this case, the

Pathophysiology

pathway begins from the crystalline urine, which can be realized by dying cells, engaging caspase-1-activating NALP3, a multiprotein complex presented in leukocytes mostly in macrophages [24]. The next step is the stimulation for the production of cytokines and the incoming of more inflammatory cells. Corpora amylacea in the prostate is considered as another possible source of inflammation [25,26]. In fact, corpora amylacea are frequently found adjacent to the damaged epithelium inducing focal inflammatory infiltration. Prostate injury secondary to the earlier-mentioned etiologies can damage prostate epithelial cells and consequently provoke an immunological reaction, by releasing immunogenic antigens. This is based on the hypothesis that some prostatic proteins are not physiologically tolerated by the immune system and when they are released an autoimmune response is determined [4,9]. The interaction between gonadal sex hormones with the immune system is, also, well known and may be a key for the activation of lymphocytes in the prostate tissue. Estrogens are commonly considered proinflammatory hormones being involved in the susceptibility to inflammation by regulating the IFN-γ production in lymphocytes [27]. They, additionally, induce the accumulation of CD 4 (Th1 type) T cells, responding to the antigen, and moreover they stimulate the production of the Th2 antiinflammatory cytokines (IL-4, TGF-β). Those substances are usually present in the BPH nodules. Also, IL-4 and IL-3 are overexpressed in advanced BPH and they are known to increase the production of 3b-hydroxydehydrogenase/isomerize type1 (3b-HSD) by prostate epithelial cells, an essential catalyst in the metabolism of androgens [28]. The role of the diet factors, such as food wealthy in animal fat, has been investigated in animal models, showing variety of changes in the prostate tissue, with the role of mast cells and macrophage to be predominant inside the prostate [29,30]. The main hypothesis that all the above proposed mechanisms support is the development of a chronic epithelial injury in the prostate. Consequently, this may facilitate the growth of the inflammatory response, increasing the prostatic inflammatory infiltrates.

The Role of Inflammatory Cytokines The proinflammatory cytokines are released by the inflammatory cells and may, in parallel, induce cyclooxygenase-2 (COX-2) expression in BPH, which is associated with the increased cell proliferation [31,32]. There is evidence supporting that IL-17, an upregulator of COX-2, is overexpressed in patients with BPH, mainly produced by T-cells, while this process requires additional factors, as IL-23 [18,33]. The pathway including IL-17 and IL-23 interaction is involved in promoting the inflammation response in BPH.

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Penna et al. [20] showed in tissue samples of men with BPH that stromal cells have an antigenic action, stimulating CD4 T-cells to produce IFN-γ and IL-17. Afterward, the production of IL-8 and IL-6 is induced and finally fibroblast growth factor 2 (FGF-2) is produced. This may be a connection of the stromal cell autoimmune response and the prostate proliferation [34]. The possible role for TGF-β has also been investigated. TGF-β is an inflammatory cytokine regulating proliferation and differentiation in BPH. In the study of Descazeaud et al. [35], the role of TGF-b receptor II protein (TGFBRII) was evaluated in 231 patients with BPH. The results showed a significant correlation between TGFBRII with prostatic volume and inflammation. Certainly, the expression of this protein was more evident in cases with CD4 T cells within the prostate. Local hypoxia may also play a role in the prostate inflammation and furthermore in the development of BPH. Reactive oxygen species (ROS) seem to be released under hypoxia situations, leading to growth factor release, reaction with the epithelial and stromal cells, and finally gland enlargement [15]. The main growth factors involved in this condition is FGF-7, TGF-b, FGF-2, and IL-8 [32]. Taoka et al., in their investigations on hyperplastic prostatic tissues, proved significantly low levels of macrophage inhibitory cytokine-1 (MIC-1) in specimen with inflammation. This cytokine is expressed and/or increased in a normal prostate [36]. It is rather obvious that a clear cause and effect relationship between prostate inflammation and BPH is not yet well understood. T-cells activity in the inflammation pattern may stimulate the proliferation of stromal and epithelial cells. Additionally, tissue damage and chronic, repetitive wound healing result in the development of BPH nodules.

CHRONIC INFLAMMATION AND LUTS Several studies have investigated the potential association between chronic prostatic inflammation and the development of lower urinary tract symptoms (Table 3.2). In a subgroup of men in the Medical Therapy of Prostate Symptoms (MTOPS) trial with baseline biopsies, the presence of chronic inflammation was found in 40% of baseline biopsy and in particular, in men with higher prostate-specific antigen (PSA) values and larger prostate volumes [42]. Nickel et al. [37] analyzed data from 8224 men, 50–75 years old included in the REduction by DUtasteride of prostate Cancer Events (REDUCE), who had a negative prostate biopsy within 6 mo prior to enrolment. At baseline 15.4% of the patients had

Chronic Inflammation and LUTS

Table 3.2 Studies Evaluating the Correlation Between Chronic Prostate Inflammation and LUTS/BPH Progression Study

Population

Nickel et al. [37,42]

8224 patients from the REDUCE trial 282 patients treated with surgery BPH

Robert et al. [8]

Tuncel et al. [37] Roerhborn et al. [41] Mishra et al. [43] Torkko et al. [38] Nickel et al. [37] Kulac et al. [39]

92 patients operated with TURP 544 patients from the MTOPS study 374 operated with TURP 859 men from the MTOPS study 4109 men from the REDUCE study 357 patients from PCPT

Evaluation of LUTS IPSS IPSS, prostate volume AUR AUR AUR IPSS IPSS IPSS

Conclusion Chronic inflammation was associated with prostate volume and IPSS Chronic inflammation was associated with higher prostate volumes, IPSS, and a higher frequency of open prostatectomy AUR was higher in BPH patients with chronic inflammation Inflammation was associated with higher prostate volume and higher risk of AUR AUR was associated more with chronic inflammation, then with prostate volume Inflammation was correlated symptom progression and AUR Chronic inflammation was associated with higher IPSS and higher risk of AUR Progression for IPSS < 8 did not differ between cases with inflammation and controls

BPH, benign prostatic hyperplasia; LUTS, lower urinary tract symptoms; AUR, acute urinary retention; IPSS, international prostatic symptoms score; MTOPS, medical therapy of prostatic symptoms; REDUCE, reduction by dutasteride of prostate cancer events trial; PCPT, prostate cancer prevention trial; TURP, transurethral resection of the prostate.

acute inflammation, 77.6% had chronic inflammation, and 21.6% had no inflammation. Inside this selection, the 77.6% of the subjects presented with inflammation, either chronic or acute. The inflammation severity, for any subject, was assessed according to the pathology core findings with the following score: none (0), mild (1), moderate (2), or marked (3). Patients with chronic inflammation were found to have larger prostate volumes than those without relevant pathological findings (46.5 vs. 43.4 mL, respectively), resulting in a positive association between prostate volume and inflammation (P < .001). The severity of LUTS was evaluated using the International Prostate Symptoms Score (IPSS). Older men and those with more severe inflammation found to score higher IPSS (P < .001), while the chronic inflammation was statistically correlated with nocturia, frequency, urgency, and urge incontinence. Although these differences were statistical significant, their clinical significance seemed to be weak most probably due to the study inclusion criteria. Younger patients and patients with IPSS > 25 or those with IPSS > 20 under a-blocker treatment had been excluded. Robert et al. [8] moved one step further and evaluated prostatic inflammation by using cytological and immunohistochemical parameters. The study

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included 282 patients who were treated with surgery for complicated and/or symptomatic BPH. The evaluation of symptoms was based on the IPSS, while the inflammation grade was defined with the contribution of cytological and immuonohistochemical parameters. Cytological parameters were lymphocytes, macrophages, and polynuclear leukocyte infiltrates, and three glandular aspect modifications: glandular atrophy, glandular destruction, and tissue fibrosis, while immunohistochemistry markers included CD3, CD4, and CD8 decorating T-lymphocytes, CD20 decorating B-lymphocytes, and CD163 decorating macrophages. The median values of inflammation scores were used as thresholds to differentiate low- from high-grade inflammation patients. Patients with high-grade inflammation had higher IPSS score (21 vs. 12, respectively) and higher prostate volume (77 cc vs. 62 cc, respectively) than patients with low grade inflammation. In addition, patients with highgrade inflammation were also more likely to be operated by open prostatectomy (62% vs. 43%) probably as a result of their larger prostate volume. Finally, more patients with high-grade inflammation had a history of transrectal ultrasound (TRUS) guided biopsies than those with low-grade inflammation (37.6% vs. 23.9%, respectively). This may represent a possible limitation of the study since TRUS biopsies are known to be responsible for a bacteriological contamination of the prostatic gland that may result in a local immune response. Despite the described limitations of these studies, they provide evidence to the hypothesis that prostate inflammation could contribute to the development and worsening of LUTS.

PROSTATE INFLAMMATION AND BPH PROGRESSION Chronic prostate inflammation could represent a reasonable hypothesis for the progression in the natural history of BPH. Progression of BPH usually is characterized by the deterioration of symptoms over time and/or the occurrence of acute urinary retention (AUR).

Prostate Inflammation and LUTS Deterioration In order to assess the impact of prostatic inflammation on symptoms worsening, we need prospective studies. The most important studies include the MTOPS and the REDUCE trials. Data from the MTOPS study was recently published. The inflammation score was based on CD45, CD4, CD8, and CD68 cell markers at the transition zone biopsies from 859 men in the MTOPS biopsy substudy [38]. Symptom progression was defined as a four-point or greater increase in the AUA symptom score (AUASS) from baseline. CD4 showed the highest risk. After median follow-up of 5 years, men with moderate or severe inflammation at prostate biopsy had

Prostate Inflammation and BPH Progression

significantly higher risk of symptom progression compared with men without inflammation at biopsy (CD4, HR 1.86, P ¼ .01). In the longitudinal evaluation of REDUCE with a median follow-up of 41.4 months, a total of 2659 men with LUTS were included in the analysis of BPH/LUTS progression. A post hoc analysis evaluating the severity of baseline chronic inflammation showed a weak association of moderate/marked inflammation with the development and/or progression of BPH/LUTS on multivariable analyses [37]. On the other hand, Kulac et al. [39] evaluated patients with proven inflammation in the peripheral zone at prostate biopsy. The analyzed population was participated in the placebo arm of the Prostate Cancer Prevention Trial (PCPT). Results from this nested case-control analysis could not establish a strong association between inflammation in these prostate biopsy tissues and LUTS incidence or progression. Interestingly, percentage of tissue area with inflammation was higher in cases with progression from low LUTS than their controls, especially when restricting to men with at least one biopsy core with inflammation (cases 10.1%, controls 4.6%, P ¼ .06). Certainly, for patients with an IPPS < 8, the progression of LUTS did not differ between the group of cases with inflammation and the control group. Plausible limitations of the analysis included the case-control nature of the study, the assessment of inflammation in only three randomly selected biopsies in the peripheral zone, the fact that biopsies were performed at the end of the study and not at baseline and inclusion criteria of the trial.

Prostate Inflammation and Acute Urinary Retention One of the most unfavorable outcomes related to BPH progression is the acute urinary retention (AUR). Several studies have evaluated the possible role of prostate inflammation in the development of AUR (Table 3.2). Tuncel et al. [40] studied 98 patients, 43–88 years old, who were treated either with transurethral or open prostatectomy. Patients were allocated into two groups; the first group included patients with AUR and the second one those with LUTS. There was no significant statistical difference in prostate volume between the two groups. The histological examination showed that the inflammation in the prostate gland was destructive not only for the epithelial, but also for the stromal cells. Prostatic inflammation was significantly higher in the AUR group (54.7%) compared with the LUTS group (28.9%) and it was the only contributory factor on AUR. Indeed AUR risk was 3.03 times higher in the patients with prostatic inflammation. The MTOPS study was the first double-blind placebo-controlled study assessing the impact of medical therapies on the risk of BPH progression in men with moderate to severe LUTS. The mean follow-up was 4.5 years and the primary

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outcome was the risk of overall clinical progression. Subanalyses of the MTOPS trial provide important evidence on the role of chronic inflammation. Roehrborn et al. reported an association between inflammation and higher risk of AUR (P ¼ 0003) in a subgroup of 544 patients who had a prostate biopsy with inflammation. Torkko et al. revisited MTOPS and analyzed data from 859 men included in a biopsy substudy [38]. It was demonstrated that men with moderate or severe inflammation in the transitional zone of the prostate were more likely to develop AUR compared with men with a prostate biopsy negative for inflammation. Interestingly inflammation was more strongly associated with progression defined by acute urinary retention or incontinence (HR ranging from 2.39 to 3.08) than an AUASS increase. Furthermore, a higher risk of progression was found in patients who reported use of nonsteroidal antiinflammatory drugs or steroids at baseline. Nickel et al. [42] longitudinally evaluated the REDUCE patients randomized to placebo. AUR developed in 262 of the 4109 men included in study and in 221of the 2659 men with a history of BPH/LUTS at baseline during a median follow-up of 48.4 months. Chronic inflammation at baseline was associated with a shorter time to the risk of AUR in the entire placebo group and in subjects with baseline clinical BPH/LUTS. It was reported that chronic inflammation at baseline was associated with a clinically meaningful increased risk of AUR (HRs of 1.6 and 1.8 at the multivariable and univariable analysis, respectively). Although this analysis is the largest and longest available longitudinal study, it has the limitation that represents a post-hoc analysis of a cancer prevention trial with the exclusion of men with severe BPH due to the entry criteria. Mishra et al. [43] also investigated the association of LUTS and AUR with prostate inflammation. They evaluated 374 patients with complete data who underwent transurethral resection of the prostate and were classified according to the indication for surgery (either AUR or LUTS). Acute and/or chronic inflammation was found in 70% of men with AUR, and in 45% of patients with LUTS. These results are in line with other studies, confirming the statistically significant relationship between inflammation and AUR (P < 0.001). The main limitations of the study were its retrospective nature and presence of catheter that could be responsible for the higher incidence of inflammation in the AUR group. However, although the presence of a catheter as a categorical variable was highly associated with inflammation, when analyzed as a continuous variable, a longer catheterization time was not associated with a higher incidence of inflammation. These studies support the hypothesis that prostate inflammation is associated with the presence of higher symptoms scores, larger prostates, and may induce BPH progress in terms of more severe LUTS and AUR (Table 3.2).

Diagnostic Methods for Chronic Prostate Inflammation

DIAGNOSTIC METHODS FOR CHRONIC PROSTATE INFLAMMATION For the time being, the only accurate method for the diagnosis of chronic prostate inflammation is the prostate biopsy. Obviously, prostate biopsy cannot be offered to all patients with LUTS due to BPH. Hence, some indirect clinical parameters could be used in order to support the presence of inflammation. Such parameters could be the estimation of LUTS severity using IPSS score, the poor response to medical treatment, history of urinary tract infections (UTIs), and a large prostate gland [22]. The severity and type symptoms of the lower urinary tract could be a useful tool to identify a possible inflammatory condition inside the prostate as indicated by the studies [9,35]. In Nickel’s study [37], which is a reanalysis on REDUCE population, and in Robert’s [8] study this association has been well established showing that storage symptoms (including frequency, nocturia, urgency, precipitancy, urge incontinence) and higher IPSS are more likely in men with chronic prostatic inflammation. Other laboratory parameters include calcifications in the prostate, and biomarkers in urine, serum, and seminal plasma. These parameters are analyzed in more details later. In fact, only a creative combination of these parameters could lead to a well-based suspicion that a prostate inflammation is underneath LUTS.

The Role of Biomarkers Biomarkers may be the most interesting and investigation worthy parameter, for a less-invasive way of diagnosis of prostate inflammation. Several biomarkers have been evaluated. Bardan et al. [44] reviewed all the available biomarkers including white blood cells (WBC), interleukin 1a, interleukin 1β, interleukin 2, interleukin 4, interleukin 6, interleukin 8, interleukin 13, interleukin 15, interleukin 17, interleukin 18, interleukin 23, interferon gamma interferon gamma (IFN-γ), transforming growth factor alpha, transforming growth factor beta, fibroblast growth factor 2, C-reactive protein, soluble tumor necrosis factor receptor II, secreted group IIA phospholipase A2, monocyte chemotactic protein 1, serum malondialdehide, inducible T-cell co-stimulator (ICOS) and cytotoxic T lymphocyte associated antigen 4 (CTLA4), intercellular adhesion molecule-1 and CD40 ligand (CD40L), and isoprostane 8. The most promising biomarkers include: Interleukin 8 (IL-8) attracts and activates the neutrophils, basophils, and T-cells, and has a proangiogenic action. Penna et al. evaluated seminal plasma levels of eight cytokines and nine chemokines in 83 men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and BPH. It was concluded that

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IL-8 seminal plasma levels were the most reliable and predictive marker to diagnose prostatic inflammation [45] while in addition IL-8 was expressed in situ by epithelial and stromal prostate cells. The IL-8 levels were also correlated with symptom scores and serum PSA values, increasing its value as a biomarker for prostate inflammation [45]. Liu et al. [46] assessed prostate inflammation in 44 patients, who underwent surgery for BPH. Seminal plasma levels of IL-8 in patients with chronic inflammation and BPH were found higher than those in patients with BPH only. The sensitivity and specificity of IL-8 in seminal plasma detecting BPH with chronic inflammation from the simple BPH were 85.7% and 91.3%, respectively. Higher IL-8 levels have been also reported in the expressed prostatic secretions of subjects with BPH, bacterial prostatitis, and chronic prostatitis/chronic pelvic pain syndrome [47]. In another study, high levels of IL-8 in the seminal plasma were associated with clinical and ultrasonographic signs of prostatic inflammation in BPH patients, including intraprostatic calcifications, nonhomogenous structure of the prostate, and high arterial blood flow [48]. Consequently, this IL-8 might be a useful marker for the diagnosis of prostate inflammation in patients with BPH. ICOS is a cell-surface T-cell receptor which is detected in high concentrations in urine and has important role in cell signaling, immune response, and cell proliferation, constituting potential urinary biomarkers for inflammation of the prostate. Robert et al. [49] collected tissue and urine samples from 90 patients after BPH surgery. In this study, expression of 96 genes was compared with the histological prostatic inflammation score based on the density and the confluence of lymphoid nodules. In fact, four of them had been evaluated in the complete sample: CCR7, CD40LG, CTLA4, and ICOS. It was found that maximum flow rate and post void residual were significantly associated with high urine levels of ICOS. Thus, the levels of this protein could be used for the diagnosis of prostate inflammation. High serum C-reactive protein (CRP) levels were correlated with an increased risk of BPH in the Prostate Cancer Prevention Trial (PCPT). This finding was independent of any confounder, including body mass index (BMI), smoking status, or age. However, the high concentrations of serum CRP were not in direct correlation with the severity of LUTS in patients with BPH [50]. Recently two studies investigated the association between serum CRP level in men with LUTS/BPH. In 4256 Korean healthy men, CRP was independently correlated with storage symptoms after adjustment for age, BMI, and prostate volume, indicating that subclinical inflammation might play a role in the pathophysiology of storage symptoms [51]. The serum CRP levels were also associated with the storage predominant LUTS in 853 men with LUTS/BPH, suggesting the presence of chronic inflammation in those men [52].

Diagnostic Methods for Chronic Prostate Inflammation

Some well-known inflammation associated factors such as monocytes or macrophages have, also, been studied for their potential role in the prostate. Fujita et al. [53] found that increased monocyte chemotactic protein-1 (MCP-1) levels in prostatic secretions are associated with the size of prostate gland, as well as with the expression of the macrophage marker CD-68. This probably implies a relationship of MCP-1 and macrophages with the development of prostatic inflammation. Certainly, MCP-1 levels can be easily detected with ELISA and this protein could be a potential optimal marker for the diagnosis of chronic inflammation and treatment of BPH. Indeed, hexanic lipidosterolic extract of Serenoa repens inhibits MCP-1 expression by prostate cells, blocking the key steps of the inflammatory process. This hypothesis has been totally evidenced by Latil et al. in their in vitro study [54].

Concurrent Prostate Calcifications Patients with BPH usually present with co-existing prostate calcification and this finding increases with the age [55], indicating a possible role in the pathogenesis of BPH. However, it is not so rare even in men younger than 50 years old, who reported LUTS [56]. A plausible hypothesis is that in young patients’ alterations in the prostatic fluid caused by infections or inflammatory diseases might result in prostatic calcifications, which may obstruct intraprostatic ducts and further induce the inflammatory process. Therefore the presence of calcifications may be the result of previous infections leading to a chronic inflammatory process, with higher risk of BPH development. The easy and noninvasive use of TRUS for the detection of prostatic classifications could designate them as a useful marker for the diagnosis of prostatic inflammation. Shoskes et al. [55] evaluated the significance of prostate calcifications, detected with TRUS, in 47 patients, suffering from chronic pelvic pain. Symptoms were independent from the presence of calcifications, patients with calcification were similar in age and had a similar prostate size compared with men without calcifications. On the contrary patients with calcifications had symptoms longer and were more likely to have bacteria in the prostatic fluid. Therefore, prostatic calcifications may be associated with chronic prostate inflammation. In another study [57], 101 patients with prostatic stones were assessed according to the size of prostatic calculi. Small, multiple calcifications were compared with larger, coarser stones. It was found that LUTS severity and chronic prostatitis/chronic pelvic pain syndrome were associated with larger stones. On the contrary, Kim et al. [58] could not confirm the earlier-mentioned findings. This study investigated the relationship between chronic prostatic inflammation and prostatic calculi, and clinical parameters of BPH in 225 patients undergoing TURP for BPH. The inflammation pattern had been graded from 0 to 3. Prostate volume and IPSS were increased following the inflammation

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grade. However, prostatic calculi had no significant association with chronic inflammation at histological specimens and clinical parameters of BPH. Despite the fact that the calcifications in the prostate seem to have a potential role in the beginning of the inflammatory steps in the gland, the exact pathophysiological pathway needs to be more investigated.

Medical History of Chronic Urinary Tract Infections Urinary tract infections (UTIs) may be another cause for tissue damage through the inflammation pathway in the prostate gland. The development of acute or chronic prostatitis may stimulate the onset and progress of LUTS. The relationship of gonorrheal infection in men younger than 30 years old with the presence of LUTS later is well evidenced [59]. A systematic review analyzed data of 10,617 men and showed that men with a history of prostatitis had substantially increased risk of developing LUTS due to BPH [60]. In another study, Nickel et al. [61] examined the records of 5597 men from the REDUCE population. The Chronic Prostatitis Symptoms Index (CPSI) was used to assess prostatitis-like symptoms. Patients, usually, reported pain and burning sensation, hesitant urination, urgency, pain of the penis and testicles, or even painful ejaculations. Cases of acute prostatitis were excluded. The distribution of inflammation status was similar for those with and without chronic prostatitis-like symptoms. Significant correlations were found between average chronic inflammation, and total Chronic Prostatitis Symptom Index score and subscores for urinary symptoms and quality of life but the clinical significance of these correlations was small. Therefore, the clinical association of CPSI and chronic inflammation was not clearly confirmed. In the animal model of Lee et al. [62], bacterial uropathogenic E. coli-1677 induced prostatic inflammation and the effect of prostatic inflammation on voiding behavior in adult mice was examined. Mice with prostatic inflammation showed significantly increased voiding frequency and decreased volume per void, compared to those without inflammation.

METABOLIC SYNDROME—A MORE RECENT TREND IN THE ETIOLOGY OF LUTS/BPH. THE CONNECTION WITH PROSTATIC INFLAMMATION The association of metabolic syndrome with BPH has been recently widely investigated. It has been showed that components of MetS such as type 2 diabetes (T2DM), hypertension, hyperinsulinemia, and dyslipidemia directly correlate with proinflammatory state, oxidative stress, and profibrosis [63–65]. Additionally, metabolic syndrome is related with increased levels of

Prostate Inflammation and Its Impact on LUTS Medication

C-reactive protein, IL-1b, IL-6, IL-8, and TNF-a, mirroring to a general inflammatory status [66]. Inflamed adipose tissue may explain this inflammatory sequence, as obesity induces adipose cell enlargement and chemokine release, leading to macrophage infiltration of adipose tissue [67]. Studies and experiments in animal models have shown that high fat diet intake increases the expression of IL-6 in the prostate, followed by the activation of some other factors, like Stat-3 and NF-κB/p65, also related to prostatic inflammation [68,69]. A clinical study suggests that centralized obesity advances prostate tissue inflammation increasing LUTS severity [70]. Several biomarkers have been investigated, including serum IL-6, IL-1β, IL-8, and TNF-α, as well as urinary prostaglandin E2 metabolite (PGE-M), F2-isoprostane (F2iP), and F2-isoprostane metabolite (F2iP-M) levels. All those parameters were correlated with the changes in patients’ body by measurement of the waist-hip ratio (WHR), a factor that can co-estimate their body fat, weight, and the height. The results showed that prostate size was not associated with proinflammatory cytokines, PGE-M, F2iP, F2iP-M, prostate tissue inflammation scores, or immune cell infiltration. In contrast, the severity of prostate tissue inflammation was significantly associated with LUTS. Finally, men with a greater WHR were significantly more likely to have severe prostate tissue inflammation (P ¼ 0.02) and a high WHR was significantly associated with more severe LUTS (P ¼ 0.03) for those participants with prostate inflammation. Hence, a possible connection of metabolic syndrome and prostatic inflammation could be supported. In fact, macrophages and cytokines infiltration related to obesity and metabolic syndrome may contribute to the development of an inflammatory pattern in the prostate for patients with BPH. Thus, those patients could be considered as of higher risk for developing prostate inflammation due to their metabolic disorders. However, the correlation of metabolic syndrome with BPH and chronic inflammatory prostatic disease may need the use of more clinical parameters to be well established [71,72].

PROSTATE INFLAMMATION AND ITS IMPACT ON LUTS MEDICATION Nowadays, the burning question is whether treatment of prostate inflammation could be the new target for the medical treatment of LUTS. The driving forces behind this question are the relationship between prostate inflammation and BPH, the cases of patients with LUTS/BPH or acute urinary retention which are refractory to drugs, and the potential negative role of inflammation on the efficacy of the conventional medical therapies. This hypothesis was supported by the Kwon’s study [73], which included 82 patients with BPH with a prostate biopsy. According to the biopsy results, patients were allocated in two groups;

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with low and high inflammation grades respectively. All patients were receiving medical therapy for BPH, having a follow-up for 1 year. During this period, IPSS, voiding storage, and quality of life scores were evaluated. Interestingly, patients with low grade of prostate inflammation responded better to medical treatment, while the 9.1% of patients with high grade of inflammation required surgery for insufficient clinical response to the treatment or even for progress to urinary retention. These primary results could trigger more research about the role of prostate inflammation on the medical treatment outcome, especially on patients with large prostate volume and consequently high inflammatory pattern.

CONCLUSIONS There has been an emerging body of literature suggesting that inflammation might play an important role in the pathogenesis and progression of BPH. Metabolic, immunological, or combined mechanisms could be responsible for this relationship. Men with LUTS/BPH and chronic prostatic inflammation should be considered at increased risk of symptom progression and acute urinary retention during the follow-up. Therefore patients with inflammation could be the target of novel therapies to treat more effectively LUTS. Drugs aiming at controlling inflammatory environment could also be used as a preventive agent in prostate disease development. Nowadays, prostate biopsy remains the only way for the diagnosis of the inflammatory status. The optimal diagnostic biomarker has not yet been established and the development of an easy, noninvasive, and sensitive way to detect and grade inflammation should be the objective of future studies.

References [1] Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003;61(1):37–49. [2] Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 2013;64(1):118–40. https://doi.org/10.1016/j.eururo.2013.03.004. [3] Nickel JC, Downey J, Young I, Boag S. Asymptomatic inflammation and/or infection in benign prostatic hyperplasia. BJU Int 1999;84:976–81. [4] Robert G, Descazeaud A, Allory Y, et al. Should we investigate prostatic inflammation for the management of benign prostatic hyperplasia? Eur Urol Suppl 2009;8:879–86. [5] Schatteman PHF, Hoekx L, Wyndaele JJ, et al. Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis: correlation with total serum PSA and PSA density. Eur Urol 2000;37:404–12.

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[6] Di Silverio F, Gentile V, De Matteis A, et al. Distribution of inflammation, pre-malignant lesions, incidental carcinoma in histologically confirmed benign prostatic hyperplasia: a retrospective analysis. Eur Urol 2003;43:164–75. [7] Irani J, Levillain P, Goujon JM, et al. Inflammation in benign prostatic hyperplasia: correlation with prostate specific antigen value. J Urol 1997;157:1301–3. [8] Robert G, Descazeaud A, Nicolaiew N, et al. Inflammation in benign prostatic hyperplasia: a 282 patients’ immunohistochemical analysis. Prostate 2009;69:1774–80. [9] De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007;7:256–69. [10] Di Carlo E, Magnasco S, D’Antuono T, et al. The prostate-associated lymphoid tissue (PALT) is linked to the expression of homing chemokines CXCL13 and CCL21. Prostate 2007;67:1070–80. [11] Steiner GE, Stix U, Handisurya A, et al. Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue. Lab Investig 2003;83:1131–46. [12] De Marzo AM, Marchi VL, Epstein JI, et al. Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol 1999;155:1985–92. [13] Briganti A, Capitanio U, Suardi N, et al. Benign prostatic hyperplasia and its aetiologies. Eur Urol Suppl 2009;8:865–71. [14] Kramer G, Steiner GE, et al. Increased expression of lymphocyte-derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation. Prostate 2002;52(1):43–58. [15] Kramer G, Marberger M. Could inflammation be a key component in the progression of benign prostatic hyperplasia? Curr Opin Urol 2006;16:25–9. [16] Nickel JC. Inflammation and benign prostatic hyperplasia. Urol Clin North Am 2008;35:109–15. [17] Handisurya A, Steiner GE, Stix U, et al. Differential expression of interleukin-15, a proinflammatory cytokine and T-cell growth factor, and its receptor in human prostate. Prostate 2001;49:251–62. [18] Kramer G, Mitteregger D, et al. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol 2007;51(5):1202–16. [19] Ja ¨hnisch H, Fussel S, Kiessling A, et al. Dendritic cell-based immunotherapy for prostate cancer. Clin Dev Immunol 2010;2010:493–517. [20] Penna G, Fibbi B, Amuchastegui S, et al. Human benign prostatic hyperplasia stromal cells as inducers and targets of chronic immuno-mediated inflammation. J Immunol 2009;182:4056–64. [21] Penna G, Fibbi B, Maggi M, et al. Prostate autoimmunity: from experimental models to clinical counterparts. Expert Rev Clin Immunol 2009;5:577–86. [22] Gandaglia G, Briganti A, Gontero P, et al. The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). BJU Int 2013;112 (4):432–41. [23] Sciarra A, Di Silverio F, Salciccia S, et al. Inflammation and chronic prostatic diseases: evidence for a link? Eur Urol 2007;52:964–72. [24] Martinon F, Petrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41. [25] Sciarra A, Mariotti G, Salciccia S, et al. Prostate growth and inflammation. J Steroid Biochem Mol Biol 2008;108:254–60.

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[26] Drachenberg CB, Papadimitriou JC. Prostatic corpora amylacea and crystalloids: similarities and differences on ultrastructural and histochemical studies. J Submicrosc Cytol Pathol 1996;28:141–50. [27] Djavan B, Eckersberger E, Espinosa G, et al. Complex mechanisms in prostatic inflammatory response. Eur Urol Suppl 2009;8:872–8. [28] Gingras S, Moriggl R, Groner B, et al. Induction of 3beta-hydroxysteroid dehydrogenase/ delta5-delta4 isomerase type 1 gene transcription in human breast cancer cell lines and in normal mammary epithelial cells by interleukin-4 and interleukin-13. Mol Endocrinol 1999;13:66–81. [29] Borowsky AD, Dingley KH, Ubick E, et al. Inflammation and atrophy precede prostatic neoplasia in a PhIP-induced rat model. Neoplasia 2006;8:708–15. [30] Narayanan NK, Nargi D, Horton L, et al. Inflammatory processes of prostate tissue microenvironment drive rat prostate carcinogenesis: preventive effects of celecoxib. Prostate 2009;69:133–41. [31] Wang W, Bergh A, et al. Chronic inflammation in benign prostate hyperplasia is associated with focal upregulation of cyclooxygenase-2, Bcl-2, and cell proliferation in the glandular epithelium. Prostate 2004;61(1):60–72. [32] Wang L, Yang JR, Yang LY, et al. Chronic inflammation in benign prostatic hyperplasia: implications for therapy. Med Hypotheses 2008;70:1021–3. [33] Steiner GE, Newman ME, Paikl D, et al. Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate. Prostate 2003;56:171–82. [34] Castro P, Xia C, et al. Interleukin-8 expression is increased in senescent prostatic epithelial cells and promotes the development of benign prostatic hyperplasia. Prostate 2004;60 (2):153–9. [35] Descazeaud A, Weinbreck N, Robert G, et al. Transforming growth factor beta-receptor II protein expression in benign prostatic hyperplasia is associated with prostate volume and inflammation. BJU Int 2011;108(2 Pt 2):E23–8. [36] Taoka R, Tsukuda F, et al. Association of prostatic inflammation with down-regulation of macrophage inhibitory cytokine-1 gene in symptomatic benign prostatic hyperplasia. J Urol 2004;171(6 Pt. 1):2330–5. [37] Nickel JC, Roehrborn CG, O’Leary MP, et al. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol 2008;54:1379–84. [38] Torkko KC, Wilson RS, Smith EE, et al. Prostate biopsy markers of inflammation are associated with risk of clinical progression of benign prostatic hyperplasia: findings from the MTOPS study. J Urol 2015;194(2):454–61. [39] Kulac I, Gumuskaya B, Drake CG, et al. Peripheral zone inflammation is not strongly associated with lower urinary tract symptom incidence and progression in the placebo arm of the prostate cancer prevention trial. Prostate 2016;76(15):1399–408. [40] Tuncel A, Uzun B, Eruyar T, et al. Do prostatic infarction, prostatic inflammation and prostate morphology play a role in acute urinary retention? Eur Urol 2005;48:277–84. [41] Roehrborn CG, Kaplan SA, Noble WD, et al. The impact of acute or chronic inflammation in baseline biopsy on the risk of clinical progression of BPH. Results from the MTOPS study. In: AUA Meeting; 2005. Abstract 1277. [42] Nickel JC, Roehrborn CG, Castro-Santamaria R, et al. Chronic prostate inflammation is associated with severity and progression of benign prostatic hyperplasia, lower urinary tract symptoms and risk of acute urinary retention. J Urol 2016;196(5):1493–8.

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[43] Mishra VC, Allen DJ, Nicolaou C, et al. Does intraprostatic inflammation have a role in the pathogenesis and progression of benign prostatic hyperplasia? BJU Int 2007;100:327–31. [44] Bardan R, Dumache R, Dema A, et al. The role of prostatic inflammation biomarkers in the diagnosis of prostate diseases. Clin Biochem 2014;47(10–11):909–15. [45] Penna G, Mondaini N, Amuchastegui S, et al. Seminal plasma cytokines and chemokines in prostate inflammation: interleukin 8 as a predictive biomarker in chronic prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia. Eur Urol 2007;51:524–33. [46] Liu L, Li Q, Han P, et al. Evaluation of interleukin-8 in expressed prostatic secretion as a reliable biomarker of inflammation in benign prostatic hyperplasia. Urology 2009;74:340–4. [47] Hochreiter WW, Nadler RB, Koch AE, et al. Evaluation of the cytokines interleukin 8 and epithelial neutrophil activating peptide 78 as indicators of inflammation in prostatic secretions. Urology 2000;56(6):1025–9. [48] Lotti F, Corona G, Mancini M, et al. Ultrasonographic and clinical correlates of seminal plasma interleukin-8 levels in patients attending an andrology clinic for infertility. Int J Androl 2011;34:600–13. [49] Robert G, Smit F, Hessels D, et al. Biomarkers for the diagnosis of prostatic inflammation in benign prostatic hyperplasia. Prostate 2011;71:1701–9. [50] Schenk JM, Kristal AR, Neuhouser ML, et al. Biomarkers of systemic inflammation and risk of incident, symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol 2010;171:571–82. [51] Kim JH, Doo SW, Yang WJ, et al. Association between high-sensitivity C-reactive protein and lower urinary tract symptoms in healthy Korean populations. Urology 2015;86(1):139–44. [52] Hung S-F, Chung S-D, Kuo H-C. Increased serum C-reactive protein level is associated with increased storage lower urinary tract symptoms in men with benign prostatic hyperplasia. PLoS ONE 2014;9:e85588. [53] Fujita K, Ewing CM, Getzenberg RH, et al. Monocyte chemotactic protein-1 (MCP-1/CCL2) is associated with prostatic growth dysregulation and benign prostatic hyperplasia. Prostate 2010;70:473–81. [54] Latil A, Libon C, Templier M, et al. Hexanic lipidosterolic extract of Serenoa repens inhibits the expression of two key inflammatory mediators, MCP-1/CCL2 and VCAM-1, in vitro. BJU Int 2012;110:E301–7. [55] Shoskes DA, Lee CT, Murphy D, et al. Incidence and significance of prostatic stones in men with chronic prostatitis/chronic pelvic pain syndrome. Urology 2007;70:235–8. [56] Bock E, Calugi V, Stolfi V, et al. Calcifications of the prostate: a transrectal echographic study. Radiol Med 1989;77:501–3. [57] Geramoutsos I, Gyftopoulos K, Perimenis P, et al. Clinical correlation of prostatic lithiasis with chronic pelvic pain syndromes in young adults. Eur Urol 2004;45:333–8. [58] Kim SH, Jung KI, Koh JS, et al. Lower urinary tract symptoms in benign prostatic hyperplasia patients: orchestrated by chronic prostatic inflammation and prostatic calculi? Urol Int 2013;90:144–9. [59] Sutcliffe S, Giovannucci E, De Marzo AM, et al. Sexually transmitted infections, prostatitis, ejaculation frequency, and the odds of lower urinary tract symptoms. Am J Epidemiol 2005;162(9):898–906. [60] Krieger JN, Lee SWH, Jeon J, et al. Epidemiology of prostatitis. Int J Antimicrob Agents 2008;31:85–90. [61] Nickel JC, Roehrborn CG, O’Leary MP, et al. Examination of the relationship between symptoms of prostatitis and histological inflammation: baseline data from the REDUCE chemoprevention trial. J Urol 2007;178:896–901.

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[62] Lee S, Yang G, Bushman W. Prostatic inflammation induces urinary frequency in adult mice. PLoS ONE 2015;10(2):e0116827. [63] Abdollah F, Briganti A, Suardi N, et al. Metabolic syndrome and benign prostatic hyperplasia: evidence of a potential relationship, hypothesized etiology, and prevention. Korean J Urol 2011;52:507–16. [64] Devaraj S, Singh U, Jialal I. Human C-reactive protein and the metabolic syndrome. Curr Opin Lipidol 2009;20(3):182. [65] Fagerberg B, Behre CJ, Wikstrand J, et al. C-reactive protein and tumor necrosis factor-alpha in relation to insulin-mediated glucose uptake, smoking and atherosclerosis. Scand J Clin Lab Investig 2008;68(7):534–41. [66] Fibbi B, Penna G, Morelli A, et al. Chronic inflammation in the pathogenesis of benign prostatic hyperplasia. Int J Androl 2010;33(3):475–88. [67] Kalyani RR, Dobs AS. Androgen deficiency, diabetes, and the metabolic syndrome in men. Current opinion in endocrinology. Diabetes Obes 2007;14(3):226–34. [68] Shankar E, Vykhovanets EV, Vykhovanets OV, et al. High-fat diet activates pro-inflammatory response in the prostate through association of Stat-3 and NF-κB. Prostate 2012;72 (3):233–43. [69] Vykhovanets EV, Shankar E, Vykhovanets OV, et al. High-fat diet increases NF-κB signaling in the prostate of reporter mice. Prostate 2011;71(2):147–56. [70] Fowke JH, Koyama T, Fadare O, et al. Does inflammation mediate the obesity and BPH relationship? An epidemiologic analysis of body composition and inflammatory markers in blood, urine, and prostate tissue, and the relationship with prostate enlargement and lower urinary tract symptoms. PLoS ONE 2016;11(6):e0156918. [71] Vignozzi L, Gacci M, Maggi M. Lower urinary tract symptoms, benign prostatic hyperplasia and metabolic syndrome. Nat Rev Urol 2016;13(2):108–19. [72] De Nunzio C, Aronson W, Freedland SJ, et al. The correlation between metabolic syndrome and prostatic diseases. Eur Urol 2012;61(3):560–70. [73] Kwon YK, Choe MS, Seo KW, et al. The effect of intraprostatic chronic inflammation on benign prostatic hyperplasia treatment. Korean J Urol 2010;51:266–70.

Further Reading Theyer G, Kramer G, et al. Phenotypic characterization of infiltrating leukocytes in benign prostatic hyperplasia. Lab Investig 1992;66(1):96–107. Blotnik S, et al. T lymphocytes synthesize and export heparin-binding epidermal growth factor–like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: differential production and release by CD4+ and CD8+ T cells. Proc Natl Acad Sci USA 1994;91:2890–4.

CHAPTER 4

Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia and Erectile Dysfunction Aldo E. Calogero, Giovanni Burgio, Rosita A. Condorelli, Sandro La Vignera University of Catania, Catania, Italy

ANATOMY AND PHYSIOLOGY OF ERECTILE DYSFUNCTION The central erectile structures are bilateral corpora cavernosa, seen as dorsolaterally placed low-reflectivity bodies on ultrasound, surrounded by the thick fibrous tunica albuginea. The corpora cavernosa are formed by multiple sinusoids composed of endothelium and smooth muscle. These sinusoids are capable of substantial volume expansion. The ventrally located corpus spongiosum is enclosed by a thinner layer of tunica albuginea and surrounds the penile urethra. The corpus spongiosum is anatomically independent of the cavernosa. The three corpora are enclosed by the more superficial Buck’s fascia. The penile arterial supply displays slight variation in its anatomy. The penis is usually supplied by branches of the internal pudendal artery, which continue as the penile artery. The bulbar artery supplies the proximal shaft and is the first branch of the penile artery, which then divides into the dorsal and cavernosal arteries. The cavernosal artery enters and supplies the corpora cavernosal via several helicine arteries, which in turn flow into the sinusoids via multiple arterioles. The intercavernous septum is perforated, allowing for communication of blood (and injected pharmacological agents) across the midline. Emissary veins pierce the tunica albuginea to drain into the deep dorsal vein, via the spongiosal, circumflex, and cavernosal veins [1] (Fig. 4.1). The penile erectile tissue, specifically the cavernous smooth musculature and the smooth muscles of the arteriolar and arterial walls, plays a key role in the sequence of events that brings to erection. In the flaccid state, smooth muscles are tonically contracted, letting a small amount of arterial flow for nutritional purposes. The blood partial pressure of oxygen (pO2) is about 35 mmHg. The flaccid penis is in a mild state of contraction, as shown by a Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. https://doi.org/10.1016/B978-0-12-811397-4.00004-4 © 2018 Elsevier Inc. All rights reserved.

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Intercavernous septum Superficial dorsal vein Deep dorsal vein

Superficial lateral vein

Corpora cavernosa

Sinusoids

Cavernosal artery Dorsal artery Penile urethra Corpus spongiosum

FIG. 4.1 Penile anatomy.

further shrinkage following exposure to cold temperatures or after phenylephrine intracavernous injection. Sexual stimulation triggers the release of neurotransmitters from the cavernous nerve terminals. This results in relaxation of these smooth muscles and the following chain of events: 1. Dilatation of the arterioles and arteries resulting in an increased blood flow in both diastolic and systolic phases; 2. Trapping of the incoming blood by the expanding sinusoids; 3. Compression of the subtunical venular plexuses between the tunica albuginea and the peripheral sinusoids. This results in a decreasing venous outflow; 4. Stretching of the tunica to its maximal capacity, which occludes the emissary veins between the inner circular and the outer longitudinal layers and further decrease of the venous outflow; 5. A pO2 of about 90 mmHg and an intracavernous pressure of about 100 mm/Hg raise the penis from the dependent position to the erect state (the full-erection phase); 6. A further pressure increase (to several hundred mm/Hg) with contraction of the ischiocavernosus muscles (rigid-erection phase). Three phases of detumescence have been distinguished in animal studies. The first entails a transient intracorporeal pressure increase, indicating the beginning of smooth muscle contraction against a closed venous system. The second phase shows a slow pressure decrease, suggesting a slow reopening of the venous channels with resumption of the basal level of arterial flow. The third

Epidemiology and Risk Factors of LUTS/BPH and Erectile Dysfunction

phase shows a fast pressure decrease with fully restored venous outflow capacity. Erection thus involves sinusoidal relaxation, arterial dilatation, and venous compression. This process is dependent upon the parasympathetic nervous system, which induces smooth muscle relaxation allowing arterial pressure blood into the corpus cavernosum by nitric oxide (NO) action [2]. NO is generated by three nitric oxide synthase (NOS) enzyme isoforms: neuronal, endothelial, and inducible. The neuronal isoform appears to be the primary mediator of physiologic erection [3]. Neuronal NO induces erections while shear stress also propagates the erectile response via endothelial NO. Regardless of the source, NO modulates smooth muscle cyclic GMP to induce relaxation in a paracrine fashion. Vascular relaxation in turn allows arterial blood to fill the corpora that, by distention, creates a venous seal to maintain erection.

EPIDEMIOLOGY AND RISK FACTORS OF LOWER URINARY TRACT SYMPTOMS/BENIGN PROSTATIC HYPERPLASIA AND ERECTILE DYSFUNCTION The term erectile dysfunction (ED) is widely mentioned nowadays within both the medical professional and lay public communities, and many understand its basic meaning and reference to sexual dysfunction. However, its clinical implications are far more extensive and very likely less well understood. The clinical condition, commonly referred to as ED, is accurately defined as the inability to attain and maintain a satisfactory erection of the penis to permit sexual intercourse sufficiently [4]. Therefore, this definition is effective to establish sexual dysfunction boundary among an array of sexual disorders. It is fair also to comprehend the term as a descriptive symptom, in acknowledgment that it portrays erection difficulty or inability without specific attribution to a medical disease. However, this sexual dysfunction is indisputably associated with underlying adverse health conditions and risk factors, and clinical evaluation is used to establish the apparent clinical association. Current biomedical advances in sexual medicine affirm its real pathophysiologic basis and support its strong links with clinical health and disease. Moreover, beyond its multiple associations with health comorbidities, ED appears also to carry long-term health risks and adversely influence survival. Men who recognize a defect in their ability to achieve an erection might not immediately recognize that ED is the problem. The quality of man’s erections deteriorates gradually over time. Consequently, men may be uncertain whether their erectile difficulties are permanent or temporary [5] and may wait to see if ED resolves on its own [6]. The most frequent reasons for such passiveness are

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the belief that lack of complete erection was part of a normal aging, sexual inactivity caused by widowhood, lack of perception of ED as a medical disorder, ashamed to talk with a physician about sexuality. Moreover, the stigma or embarrassment of having ED may lead to denial of the problem. For these issues, the incidence of ED is often undervalued. This problem is further increased by a bad clinical practice, in which specialists or general practitioners do not investigate sexual habits while managing other conditions. Many men with risk factors associated with ED have ED, including those who had moderate or severe dysfunction; however, the awareness of these men of having ED is often low [7]. Considering the impact that ED has on quality of life and that it may often respond to treatment, ED should be suspected and assessed in men with risk factors, such as cardiovascular disease or presence of cardiovascular risk factors, diabetes mellitus (DM), and lower urinary tract symptoms (LUTS), regardless of their apparent level of awareness of ED [7]. BPH causes LUTS and approximately 70% of men with LUTS/BPH have coexisting ED [8]. This prevalence ranges from about 35% to 95% and increases with LUTS severity [9]. Often patients referring to clinician for LUTS/BPH are found to have ED and vice versa. The prevalence of coexisting LUTS and ED increases with age; the severity of one disease often correlates with the other, with most men who sought treatment for either LUTS or ED having both conditions [10]. LUTS/BPH and ED share similar risk factors, suggesting that the pathophysiology of LUTS and its underlying mechanisms may be similar to those of ED. The main potential risk factors for LUTS/BPH and ED are discussed as follows.

Age Nowadays, sexual activity has been reconsidered for aging men and the concept of sex is different from the past. Sexual activity is more common among older men than before, being an important component of quality of life for aging men [11]. The majority of men between the ages of 50 and 75 years report that they are sexually active, but many are bothered by sexual problems, including ED. Because of LUTS/BPH treatment-related sexual side effects and the known strong association between LUTS/BPH and ED, the effects of LUTS/BPH medical therapies on sexual function are an important consideration when selecting the most appropriate LUTS/BPH treatment and when monitoring men on LUTS/BPH treatment.

Sedentary Lifestyle and Lack of Exercise Many evidence support the central role of exercise in ameliorating both LUTS/ BPH and ED. No daily walking is associated with more progressive LUTS than to stable or remitting LUTS [12], and physical exercise at a level that can decrease low-grade clinical inflammation has been recognized as central factors

Epidemiology and Risk Factors of LUTS/BPH and Erectile Dysfunction

influencing both vascular NO production and erectile function. Moreover, this lifestyle habit may have a role in reducing the burden of sexual dysfunction [13]. It can be stated that moderate physical activity can have significant effects in improving erectile function as well as on serum testosterone levels. Therefore as an independent risk factor, there may be a role for lifestyle measures to prevent progression or even enhance the regression of the earliest manifestations of ED, as well as to help stabilization or remission of LUTS/BPH.

Cigarette Smoking The past three decades have led to a compendium of evidence being compiled into the development of a relationship between cigarette smoking and ED. A positive dose-response relationship suggests that increased quantity and duration of smoking correlate with a higher risk of ED (dose-dependent and cumulative effect). The risk of ED is higher for smokers and exsmokers than nonsmokers, but this risk is higher for smokers than exsmokers. It is possible that smoking cessation can lead to recovery of erectile function, but only if limited lifetime smoking exposure exists [14]. Studies have shown that the increased risk of ED associated with smoking becomes statistically significant only after 20 pack-years or more (20 cigarettes/day for 1 year). The physiopathological mechanism that leads to ED involves decreased penile neuronal NOS expression, decreased endothelial integrity, and diminished smooth muscle content. Smoking has also been shown to impair endothelial NOS-mediated vascular dilation in young men. In addition, to the vascular damage associated with tobacco smoking, some data suggests that it may lower testosterone levels [15–17]. This effect may also explain the reported relationship between smoking and LUTS/BPH. Indeed, heavy smoking (defined as
50 pack-years) was found to increase the risk of LUTS exacerbation and can affect storage and voiding symptoms. Subjects who smoked
50 pack-years in a lifetime had greater probability of severe deterioration of storage symptoms. Nicotine may increase sympathetic nervous system activity and could contribute to storage symptoms by increasing the tone of the bladder smooth muscle [18,19]. Furthermore, smoking could cause hormonal and nutrient imbalances affecting the bladder as well as collagen synthesis [20]. It also affects bladder wall strength and detrusor instability [21]. Therefore it is mandatory to ask for smoking cessation in the combined phenotype LUTS/BPH-ED to increase chances of controlling both diseases.

Excessive Alcohol Intake The role of alcohol in development of LUTS/BPH-ED is more difficult to establish, compared to other risk factors. The moderate consumption of alcohol may

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exert a protective effect on ED in the general population [22,23], but some studies have not confirmed this protective role. Population-based studies showed that low-alcohol consumption was predictor of ED [24], and, among drinkers, the odds were lowest for consumption between 1 and 20 standard drinks per week [25]. In general, the overall findings are suggestive of alcohol consumption of a moderate quantity conferring the highest protection [26]. The beneficial effects of alcohol on erectile function may be due, in part, to long-term benefits of alcohol on high-density lipoprotein cholesterol and other variables that increase the bioavailability of NO. Data on the association between LUTS/BPH and alcohol consumption is conflicting. While some studies have shown that alcohol consumption is associated with a decreased risk of BPH, others have not. Moreover, some studies have reported an association between alcohol and LUTS but not BPH. Light drinking (less than one per day) may increase the likelihood of LUTS, whereas moderate-to-heavy drinking has shown no associations with LUTS. Urgency symptoms may be the exception, as they more likely occur among all alcohol drinkers. A review of studies concluded that daily drinking might increase the likelihood of LUTS, while decrease the risk of BPH [27]. Indeed, one out of the two prospective studies examining LUTS found that daily drinking increased the risk of moderate-to-severe LUTS over a 4-year follow-up [28], whereas the other showed that heavier drinking decreased the risk of high-moderateto-severe LUTS or medically treated BPH over 7 years [29]. It is plausible that light alcohol intake increases LUTS by a diuretic effect or increasing sympathetic nervous system activity, while moderately high alcohol intake decreases the risk of BPH and concurrent higher-severity LUTS by altering androgen levels [30,31]. More data is needed to establish how to advice patients with LUTS/ BPH-ED regarding alcohol intake, but light alcohol consumption has not strong evidence to be denied.

Depression The Massachusetts Male Aging Study (MMAS) showed that ED was associated with depressive symptoms after controlling for potential aging and para-aging confounders [32]. ED is also associated with untreated and treated depressive symptoms. The association between ED and depression may be disorienting in clinical practice. Indeed, depression can be the consequence of or trigger for ED, as moderate or severe depressive mood or antidepressant drug use may cause ED and ED independently may cause or exacerbate depressive mood [33,34]. This kind of bidirectional relationship has also been discovered for depression and LUTS/BPH: depression can be not only developing from the pathological condition of LUTS/BPH, but also be triggered or exacerbated by systemic inflammation, which is also associated with LUTS/BPH [35,36].

Epidemiology and Risk Factors of LUTS/BPH and Erectile Dysfunction

Hypertension and Cardiovascular Disease Most men with hypothetic vasculogenic ED present at least one traditional cardiovascular risk factor [37]. These evidences allowed the consideration of ED as a clinical manifestation of a functional (lack of vasodilation) or structural abnormality in penile circulation as component of a systemic vasculopathy. It is well known that ED may predict 5 years before the development of a major coronary event in 11% of ED cases; this, in terms of preventive medicine, means that ED could be considered equivalent to the coronary disease [38]. The association between cardiovascular health and ED has not always been so clear in past years. One of the first studies to ask about sexual function among patients with hypertension was the classic TOMHS (The Treatment of Mild Hypertension Study) [39] and its results contributed to the false belief that ED was rare in this population since they found only 12.2% of men referring any degree of sexual dysfunction at inclusion. TOMHS excluded subjects with comorbidities, such as DM or hyperlipidemia, older and moderate or severe hypertension. At the end of TOMHS, ED was more frequent among those patents using more antihypertensive drugs or with systolic blood pressure over 140 mmHg. Other trials also refuse the high prevalence of ED among patients with hypertension [40] probably due to the characteristics of the sample and the method to diagnose ED. Another issue relates to antihypertensive drugs and ED development, is an usual popular belief to blame medical therapy for hypertension as the main reason of ED, especially when there is a temporal coincidence between symptom initiation and the use of antihypertensive drugs, in particular when including the “old” diuretics and ß-blockers [39]. In almost all trials where this topic was studied, ED was not the primary objective and was assessed by patient reports instead of questionnaire evaluation or measurement of penile rigidity. Therefore there is a lack of definitive evidence even with ß-blocker and diuretics. Recently, a systematic analysis of trials concluded that only thiazide diuretics and ß-blockers, not including nebivolol, might influence erectile function. ACE inhibitors, angiotensin receptor blockers, and calcium channel antagonists were reported to have no relevant or even a positive effect on erectile function [41]. Hypertension worsens also LUTS/BPH and may decrease the efficacy of α1blockers, especially for the increased frequency and severity of storage symptoms [42]. Moreover, men with hypertension are more likely to have a higher IPSS and large prostate volume than men without hypertension. This finding implicates a pathophysiological association between hypertension and LUTS, and the need to manage comorbid symptoms simultaneously [43]. It is likely that hypertension plays a role in physiopathological mechanisms common to ED and LUTS/BPH, and focus on this modifiable risk factor is mandatory in clinical approach.

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Hyperlipidemia Epidemiologic data has confirmed that hyperlipidemia is a strong independent risk factor for the development of ED via endothelial damage and inflammation. Statins are first-line medical therapy for hyperlipidemia and protect the vascular endothelium. In fact, statins have been shown to improve endothelial function prior to altering lipid levels. Various metaanalyses have supported the conclusion that statins improve erectile function [44]. Prostate synthesizes cholesterol at a level similar to the liver and accumulates it in a deposit within the gland in an age-dependent manner. More than 70 years ago, Swyer analyzed the cholesterol content in the prostate of BPH subjects and reported that its concentration was twice that in a normal prostate [45]. Studies on the effect of dyslipidemia on prostate are heterogeneous, showing positive and negative association for circulating total and HDL-cholesterol, respectively, with prostate enlargement [46]. However, other studies did not confirm the association. Many observations suggest that dyslipidemia per se is not sufficient to determine a LUTS/BPH phenotype, but the presence of other metabolic derangements, such as type 2 DM, favors the process, because of an unfavorable total and LDL-cholesterol particle size and density [47].

Type 2 Diabetes Mellitus Diabetic patients have a well-known increased risk of developing ED, with prevalence ranging from 35% to 90%. In addition, patients with DM tend to develop ED 10–15 years earlier than the ED patients without DM. They appear to present with more severe ED and suffer a greater diminishment in healthrelated quality of life components than the general population. ED secondary to DM is more resistant to medical management with phosphodiesterase 5 inhibitors (PDE5i). Moreover, poor glycemic control in patients with type II DM contributes significantly to the development and severity of ED. Reactive oxygen species generated because of hyperglycemia impacts erectile function in multiple pathways. The chronic complications of macrovascular changes, microvascular changes, neuropathy, and endothelial dysfunction increase the odds that a diabetic man will develop ED. Furthermore, many patients with type 2 DM ultimately experience the negative impact of metabolic syndrome (MetS) on erectile function [44]. The links between LUTS/BPH and glucose metabolism diseases were known since 1966 [48]. Hyperinsulinemia/glucose intolerance and type 2 DM have been considered as potential risk factors for BPH/LUTS based on several studies. Strong evidence correlates insulin levels and prostate volume, being the first an independent predictor of the second in symptomatic BPH patients aged over sixty [46], and this association remains significant after adjusting for total

Epidemiology and Risk Factors of LUTS/BPH and Erectile Dysfunction

testosterone, other metabolic factors, and blood pressure [49]. These findings indicate that insulin is an independent risk factor for BPH, most probably stimulating prostate growth acting on IGF receptors. More studies are needed to establish a relation between glycemic controls and control/worsening of LUTS/BPH.

Obesity/Waist Circumference It is not easy to identify the sole contribution of obesity to the development of ED, as it is often coexistent with DM and hypertension. Nevertheless, data do suggest that it has an independent contribution to ED, being an independent predictor of ED. Weight loss in obese men is also associated with a regain of normal erectile function [44]. In worldwide conducted studies, obesity—and in particular visceral obesity—is often comorbid with BPH. A recent metaanalysis, including 19 studies, reported a positive association between BMI and LUTS associated with BPH. Obesity can have a role even in early adulthood in determining a LUTS/BPH phenotype, as shown by a sonographic study conducted in 222 young men seeking medical care for couple infertility [47,50].

Hypogonadism Testosterone is essential for erectile function. Literature has proven the necessity of androgens to maintain sufficient intracavernosal pressures and smooth muscle function to obtain an erection. The literature showing the role of testosterone replacement therapy (TRT) on erectile function is heterogeneous, and sometimes conflicting, showing positive correlation with erectile function or no improvement. It may be that the improvement in erectile function after TRT is transient, or that poor control of other modifiable risk factors for ED may have played a role against TRT. The recently published multicenter randomized double-blind placebo-controlled Testosterone Trial study provides solid evidence that TRT has a positive impact on overall sexual function in men 65 years of age or older. This trial consisted of three separate studies: The Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The sexual function trial showed that sexual activity and sexual desire were increased. Men in the TRT group reported significantly increased international index of erectile function (IIEF) score with a mean improvement of 2.64 points. This provides sound evidence that treating hypogonadism can improve erectile function [44]. The role of androgens in determining LUTS/BPH and the physiopathological ways that may lead to it are still a matter of debate. Although an increased androgen signaling is clearly implicated in the first two waves of prostate growth (the first one at birth, the second one at puberty—under the influence of increasing testosterone levels), its role in the third phase (starting

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at mid-late adulthood and involving selectively the periurethral zone) is not completely clear yet. In fact, 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 one, might have a detrimental effect on prostate biology. In fact, LUTS can even be lessened by androgen supplementation in hypogonadal men [51]. Recent data indicate that not only low testosterone but also high estradiol can favor BPH/LUTS progression. It is important to note that circulating testosterone is actively metabolized to estrogens and part of testosterone hormonal activity depends upon its binding to the estrogen receptors (ERs) that are present in both the prostate and bladder. In addition, the enzyme P450 aromatase that converts androgens to estrogens is highly expressed not only in fat tissue but also in the urogenital tract. Marmorston and colleagues showed an increased estrogen/androgen ratio almost half a century ago [52] reporting that the estrogen/androgen ratio in 24-hour urinary collections was elevated in men with BPH, as compared to normal controls. Many studies have reported a correlation between plasma 17β-estradiol levels and prostate volume or other features of LUTS/BPH, while others have not. The fear of clinicians to start a TRT on hypogonadal men with LUTS/BPH must be redefined based on this upcoming evidence [51]. It is necessary to establish ways to determine which patients with LUTS/BPH, and even combined phenotype LUTS/BPH-ED, may benefit from TRT and in which terms; for this purpose, more studies are needed [47].

Genetic Predisposition The underlying genetic mechanisms linked to LUTS/BPH are not fully known. Animal models have shown changes, often aging related, in genes related to nervous control, vascularization of lower urinary tract, and smooth muscles, but these models have shown discrepancies between in vitro and in vivo studies. More can be added if these two models could be studied in the same animal [53]. In addition, a correlation has been shown between inflammatory genes and LUTS/BPH. Genes involved in physiology of erectile function, as well as development of ED, also involve control of NOS genes encoding various types of neurotrophic factors, and K+ channel genes; these have been proposed as targets for gene-based therapy when other treatments fail [54]. Full comprehension of aberrant signaling pathways common to LUTS/BPH and ED could lead to a form of personalized medicine based on gene therapy [55]. Protective factors include increased physical activity, increased vegetable consumption, moderate alcohol intake [56–58].

Pathophysiology of LUTS/BPH and ED

PATHOPHYSIOLOGY OF LUTS/BPH AND ED Two main pathways in LUTS lead to the development of symptoms in men: benign prostatic obstruction (BPO) and benign prostatic enlargement (BPE). In addition to this setting, detrusor overactivity/overactive bladder (OAB) can occur in both men and women. This dichotomy associates with voiding symptoms and/or storage symptoms. Voiding symptoms are associated with BPO, which is linked to BPE because of BPH. Storage symptoms are more complex and do not appear to be BPH related or BPE related because they manifest in men and women; more likely, these symptoms are associated with involuntary detrusor contractions or detrusor overactivity (DO) [59,60]. Involuntary detrusor contraction during the storage phase of the voiding cycle [61] seems to lead to OAB symptoms. Storage LUTS may be associated with bladder dysfunction due to changes or alterations in afferent nerves or in interstitial cells within the bladder rather than BPE [57,62]. Four pathophysiological pathways might lead to increased risk of LUTS development. These include reduced nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling, chronic inflammation/steroid hormone imbalance/increased RhoA-Rho-kinase activity, autonomic hyperactivity, and pelvic atherosclerosis [58,63–65]. These factors can lead to reduced function of nerves and endothelium, alterations in smooth muscle tone, arterial insufficiency, reduced blood flow and hypoxia-related tissue damage, increased smooth muscle cell proliferation in the prostate, and bladder hypertrophy/ noncompliance [58]. The vascular system of the low urinary tract is regulated by smooth muscle cell relaxation, which responds to PDE5 inhibition. LUTS/BPH may develop from decreased oxygenation of lower urinary tract tissue, which might ensue with the above-mentioned risk factors. Atherosclerosis contributes also with remodeling of smooth muscle structure and function in the pelvic vasculature to its development [66,67] in penis [68], prostate [69], and bladder [67]. This results in chronic ischemia of the low urinary tract often associated with LUTS/BPH [70]. Moreover, three nerve systems are involved in physiopathology of LUTS/BPH: the pudendal, pelvic, and hypogastric nerves. The voiding process involves stimulation of the detrusor and inhibition of the parasympathetic innervation of the urethra and bladder neck hypogastric nerves, plus recruitment of motor neurons to the urethral sphincter [71]. The storage process involves inhibition of the parasympathetic innervation of the detrusor muscle with urethral sphincter contraction via sympathetic innervation of the hypogastric nerves and recruitment of the pudendal nerves. Storage symptoms may be the result of bladder dysfunction due to changes or alterations in afferent nerves or in interstitial cells [11].

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Ageing

Hypertension

Hyperlipidemia

Diabetes mellitus

Endothelial and nitrergic dysfunction in microcirculation

Microvascular dysfunction and decreased blood flow Endothelial dysfunction

Altered smooth muscle function

Tissue and nerve hypoxia

Urothelial dysfunction

Smooth muscle cell hyperplasia

Nitrergic dysfunction

Autonomic/sensory nerve dysfunction

FIG. 4.2 Pathophysiologic pathways leading to LUTS/BPH-ED.

Similar mechanisms have been studied in pathophysiology of ED and are strongly linked to this condition. The NO-cGMP pathway is important in smooth muscle relaxation and erection of the penis. Activation of the RhoA/ ROCK signaling pathway decreases smooth muscle relaxation tone in corpora cavernosa. Increased sympathetic nervous system activity might affect smooth muscle and vascular tone via α1-adrenergic receptors in the penis. Finally, atherosclerosis can result in decreased perfusion/ischemia of penile arteries [63,64,72]. All of these pathophysiological mechanisms are thought to contribute to the development of either ED or LUTS/BPH [63] and can explain a link between these conditions (Fig. 4.2).

ETIOLOGY AND CLINICAL ASPECTS OF LUTS/BPH AND ED This chapter will not widely report the standard definition of LUTS/BPH (please consult other chapters of the book). The European Association of Urology (EAU) and the American Urological Association (AUA) [73] guidelines define LUTS as storage (irritative) symptoms (daytime urinary frequency, urgency, and nocturia), voiding (obstructive) symptoms (straining, weak stream, intermittent stream, and incomplete emptying), or postmicturition symptoms (postmicturition dribbling) that affect the lower urinary tract [73,74]. The clinical diagnosis of LUTS/BPH is a multistep process used to eliminate prostate cancer, identify risk factors, and obtain physiological measures.

Etiology and Clinical Aspects of LUTS/BPH and ED

Symptoms of LUTS/BPH are generally assessed using the International Prostate Symptom Score (IPSS) or AUA Prostate Symptom Index (AUA-SI), serum prostate specific antigen (PSA) levels, urinalysis, a transrectal ultrasound of the prostate, the measurement of the maximal urinary flow rate (Qmax) assessed by uroflowmetry, and the measurement of postvoid residual volume assessed by postvoid bladder ultrasound. The definition of LUTS/BPH used in clinical studies and in the literature varies widely. Men with LUTS/BPH have generally been identified: • histologically by having BPH; • with symptom severity assessed by total IPSS as being either mild (0–7), moderate (8–19), or severe (20–35); • with increased prostate size (BPE—defined as prostate volume
20 mL [58]. Since patients with prostate volume
30 mL have 3.5 times greater risk of having moderate-to-severe symptoms, 3 times greater risk of acute urinary retention, and a significantly greater risk of requiring BPH-related surgery [75,76], we suggest to start the treatment when prostate volume is found
25 mL); • and with a Qmax of 4–15 mL/s, which is indicative of BPO. The large overlap of men with both LUTS and ED has shown the strong link between the two conditions, being age a known predictor of the combined phenotype and LUTS/BPH severity an even better predictor, thus establishing an independent link between LUTS/BPH and ED [65]. According to the underlying causes, ED can be classified as (Table 4.1): • psychogenic • organic; this one further divided in nonendocrine and endocrine In the past, ED was considered, in most cases, to be a purely psychogenic, but current evidence shows that more than 80% of cases have an organic etiology. The two milestone epidemiological studies (MMAS and EMAS) have studied this condition in men aged 40–80 years. However, the prevalence of ED in younger men is increasing even due to social awareness and overcoming taboo issues. In this context, a recent naturalistic study has demonstrated that one out of four men seeking medical help for ED is 2 cm; search for signs of chronic cardiopulmonary diseases), distribution of body hair and androgenization grade. Evaluation of penis prostate and testes is mandatory to establish related volumes: according to patient’s age, small testes and/or small prostate volume might imply hypogonadism. It is important to ask for eventual muscular force decrement, as well as a decrease in beard and body hair growth. Assessment of the

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peripheral vascular system is also important to determine the characteristics of the pulse, to ascertain the presence of an arterial bruit (a vascular sound that is associated with turbulent blood flow). Increased pulse rate (tachycardia) might suggest hyperthyroidism, whereas reduced pulse rate (bradycardia) might be evident in men with heart block (arrhythmia), hypothyroidism, or in those who use certain drugs (fe.g., β-blockers). Diminished or absent pulses in the various arteries examined could be indicative of impaired blood flow caused by atherosclerosis. The evaluation of the penis in the flaccid state might show the presence of Peyronie’s disease (involving palpable fibrous plaques), phimosis (congenital narrowing of the opening of the foreskin), or frenulum breve (whereby the tissue under the glans penis that connects to the foreskin is too short and restricts the movement of the foreskin), which can all contribute to ED. Measurement of blood pressure, waist circumference, and body mass index should also performed [93]. A few biochemical and hormonal parameters are of value in patients with ED (hormonal parameters include essentially total testosterone LH, prolactin, SHBG to assess free testosterone). However, levels of cholesterol, triglycerides, fasting glucose, and glycosylated hemoglobin (HbA1c) are important determinants of cardiovascular and metabolic risk stratification. Total testosterone and SHBG for the evaluation of calculated free testosterone are sufficient parameters to rule out hypogonadism. Prolactin and thyroid hormone evaluation are limited to a subset of patients. In the eventuality of abnormal biochemical or hormonal values, a second-line evaluation is necessary. If the fasting plasma glucose level is 100–126 mg/dL, or HbA1c is >5.7%, an oral glucose tolerance test can be used to exclude overt type 1 and type 2 diabetes mellitus. The Princeton III Consensus Panel has established criteria for performing further cardiovascular evaluation (Table 4.3).

Second-Line Evaluation Ultrasound examination is a second-line test that can be used to examine penile structure and vasculature with penile Doppler ultrasonography, allowing for the examination of the cavernosal and dorsal penile arteries. The ultrasound scan can be performed during flaccidity (static) or following drug-stimulated erection (dynamic). Drugs commonly used to stimulate erection comprehend PgE1 derivatives, such as alprostadil, which, injected through a fine needle into the corpora cavernosa, cause smooth muscle relaxation, vasodilatation, and increased blood inflow, leading to erection in physiological conditions. An adequate response to a trial of these agents confirms adequate arterial supply and veno-occlusive mechanism and precludes the need for further investigation. Penile Doppler ultrasonography is used in those patients in whom arterial or venous insufficiency is suspected. Furthermore, penile Doppler sonography

Etiology and Clinical Aspects of LUTS/BPH and ED

Table 4.3 Princeton III Consensus Recommendations for Risk Stratification and Cardiovascular Evaluation for Sexual Activity Profile

Description

Low

• Fewer than three risk factors for coronary artery diseasea (excluding sex) • Controlled hypertension • Class I or II stable anginab • Successful coronary revascularization • History of uncomplicated myocardial infarction • Mild valvular disease, congestive heart failure without left ventricular dysfunction and/or New York Heart Association class I heart failure • At least three risk factors for coronary artery diseasea (excluding sex) • Class I or II stable anginab • Recent myocardial infarction (within 2–6 weeks) • Left ventricular dysfunction and/or New York Heart Association class II congestive heart failure • Noncardiac sequela from atherosclerotic disease (stroke and/ or peripheral vascular disease) • Unstable or refractory angina • Uncontrolled hypertension • New York Heart Association class III–IV congestive heart failure • Recent myocardial infarction (within 2 weeks) • High-risk arrhythmias • Severe cardiomyopathy • Moderate-to-severe vascular disease

Intermediate

High

Sexual Activity and PDE5 Inhibitor Use • Cleared to resume sexual activity • Cleared to take PDE5 inhibitors

• Cardiac evaluation necessary prior to resuming sexual activity • No contraindication to PDE5 inhibitor use

• Sexual activity delayed until cardiac condition stabilized

a Major cardiovascular risk factors include age, male gender, hypertension, type 1 and type 2 diabetes mellitus, smoking, dyslipidemia, a sedentary lifestyle, and a family history of premature cardiovascular disease. b

Defined by the Canadian Cardiovascular Society (Reference: Campeau L. Grading of angina pectoria. Circulation 1976;54:522–523).

may be used to study the penile anatomy in patients with posttraumatic/ postsurgical abnormalities where curative/reconstructive surgery is being considered. At ultrasound, the corpora cavernosa appear as longitudinally orientated vascular beds of mixed echogenicity, with the tunica albuginea visualized as a thin echogenic envelope, usually 2 mm thick. In the absence of cavernosal fibrosis, the interface between the tunica and the underlying cavernosal tissue is quite distinct. The spongiosum is visualized on the ventral surface and is of slightly higher reflectivity than the cavernosa. The cavernosal arteries can be found within the corpora cavernosa at ultrasound as parallel hyperechoic lines. Variants in arterial anatomy exist in up to 20%, but they are not relevant to clinical practice. After intracavernosal injection of alprostadil, Doppler scan shows

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a change overtime of the spectral Doppler waves in a velocity/time curve to evaluate the cavernosal arteries both anatomically and functionally. A quiet, private, and comfortable environment is essential for a good outcome of the test. Many patients will be anxious, and a detailed explanation of the procedure is of paramount importance. Informed consent should be obtained, especially with regard to the low risk of priapism following intracavernosal injection; this accounts for about 0.01% of the procedures, and is defined as prolonged and painful response of the penis to drug-stimulated erection (longer than 4 hours), which requires urgent treatment. With patient positioned supine on the bed, an initial injection of alprostadil is done at the basis of left and/or right corpora cavernosa, with an angle of about 30 degrees and perpendicular to longitudinal axis of the penis. Before injection, eventual abstinence from antiplatelet drugs, if possible, is advised. If the patient is pharmacologically naive, a small dose (5 mg of alprostadil) is initially given. If there has been a poor response to PDE5i agents previously, then up to the full dose (20 mg) may be given. Utilizing a high frequency linear probe, and once tumescence starts; a longitudinal scan enables visualization of the cavernosal artery at its root. A velocity gradient exists within the artery from the base to the tip, and reproducible and accurate measurements are best obtained at the penile base toward the peno-scrotal junction. Two-three minutes after injection, the cavernosal arteries should become more visible, and spectral measurement and image acquisition should begin at this stage. In addition, the quality of the erection should be assessed both objectively (by the operator) and subjectively (by the patient) and recorded. If the quality of the erection is insufficient, repeated injection can be made. Repeated Doppler measurements should occur at 5-min intervals until the maximal peak systolic velocity (PSV) and end-diastolic velocity (EDV) are judged to have been reached. The PSV cutoff is >35 cm/s and EDV is usually normal if negative or close to 0 cm/s, usually 35 cm/s) and decreasing end-diastolic velocity (EDV, cutoff 12 at the enrollment were randomized to either 10 mg vardenafil or a matched placebo tablet twice daily for 8 weeks. The mean IPSS at baseline was 16.8 and the Qmax was 15.9 mL/s in both groups. The treatment phase with vardenafil was associated with a significant improvement in the IPSS compared to placebo (5.9 vs 3.6, respectively, P < .001). The group treated with vardenafil had a significant advantage for obstructive and irritative subscores (P < .008 and 21

IPSS = 0–7

Phytotherapy

IIEF-5 < 21

IPSS > 7

α-Blockers

IPSS > 7

IPSS = 0–7

Tadalafil 5 mg daily

IPSS score showing a greater severity than IIEF5 score

IPSS score showing a lower severity than IIEF5 score

α-Blockers

Tadalafil 5 mg daily

FIG. 4.5 Flowchart of a practical andrological evaluation of a patient with benign prostatic hyperplasia to decide first drug-therapeutic approach.

significantly higher risk of ED and libido loss compared to monotherapy. The combined treatment showed a similar risk of altering libido compared to 5α-ARI monotherapy [116]. A schematic practical approach to the patient with LUTS/BPH and ED to establish the therapeutic approach is reported in Fig. 4.5.

CONCLUSIVE REMARKS This chapter summarizes years of challenging research on ED, a condition that has an important social and cultural relevance. Preclinical and clinical research progress has led to new therapeutic approaches to ED in patients with different comorbidities and particularly in those with LUTS/BPH. These goals were possible only by combined work of specialists and researchers of different and intertwined medical disciplines. A correct diagnosis is essential to choose ideal candidates for the best pharmacological treatment when both LUTS/BPH and ED are present, considering that, they share similar risk factors and pathophysiological aspects. Currently, tadalafil (5 mg/day) is the best choice; other PDE5i are not included among options, despite the growing evidence of therapeutic effects. Different regimens of tadalafil may be prescribed based on patient needs, severity of LUTS/BPH-ED profile, and clinical experience. An integrated approach is necessary to choose for a combined therapy with PDE5i and α-blockers following urological and cardiac counseling in terms of outcomes and adverse effects.

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The future of patients with LUTS/BPH-ED will comprehend new molecules and recent studies have paved the road toward new frontiers, not clarified yet, such as gene therapy or stem cell therapy [117]. Combined efforts of physicians and researchers will enrich available therapeutic options with new variable approaches, with the aim of avoiding surgical solutions, often marked by adverse effect or nondeployable.

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CHAPTER 5

Metabolic Syndrome and LUTS/BPH Mauro Gacci, Arcangelo Sebastianelli, Matteo Salvi University of Florence, Florence, Italy

INTRODUCTION Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are highly prevalent in the adult male [1]. Traditionally, male LUTS were thought to be merely caused to benign prostatic enlargement (BPE). However, a simplistic causal relationship linking prostatic overgrowth, bladder outlet obstruction and LUTS, has been challenged, based on the lack of a strict correlation between BPE and LUTS [2]. Emerging data indicate nowadays that a spectrum of age-related disorders, such as type 2 diabetes (T2DM), cardiovascular (CV) disease, hypogonadism, or a combination of these conditions such as metabolic syndrome (MetS), have a heretofore unrecognized, negative impact on LUTS. Several MetS components have been closely associated with BPH and LUTS, suggesting that MetS has very heterogeneous clinical ramifications [3–6]. Although the exact nature of the association between MetS and LUTS/BPH are still not completely understood [7], finding that men with metabolic alterations show a faster-developing BPH or are more frequently candidate to BPH surgery [8] support the hypothesis that metabolic and pathological alterations characterizing MetS can also predispose to the development and progression of BPH/LUTS. Chronic inflammation has been proposed as a possible mechanism at the crossroad between these two entities. Hence, visceral adipose tissue secretes various bioactive substances that can induce inflammatory response and have proinflammatory effects: the progressive development of inflammation in men with MetS can explain the emerging link between MetS, BPE, and LUTS [9]. 89 Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. https://doi.org/10.1016/B978-0-12-811397-4.00005-6 © 2018 Elsevier Inc. All rights reserved.

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MetS can broadly be considered a systemic inflammatory state and a chronic inflammation-driven tissue remodeling and overgrowth is recognized to play a causative role in BPH/LUTS [10].

METABOLIC SYNDROME: DEFINITION AND PREVALENCE MetS is a complex disorder with a high socioeconomic cost and it is considered worldwide epidemic. According to the 2003–12 National Health and Nutrition Examination Survey (NHANES) data, more than 50 million people are affected by MetS in US, involving approximately 33% of the US adult population, with significantly higher prevalence in women compared with men (35.6% vs. 30.3%) [11]. The increasing of MetS prevalence was seen with increasing age. Prevalence of the MetS was 18.3% among those aged 20–39 years and increased to 46.7% among those aged 60 years or older. In the last decades, several definitions of MetS have been proposed and updated a number of times (Fig. 5.1). However, MetS always describes the combination of metabolic and cardiological abnormalities, including central obesity, hypertension, dyslipidemia, insulin resistance with compensatory hyperinsulinemia, and glucose intolerance. Currently, the most commonly used definitions are focused on abdominal obesity measured by waist circumference: the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III) and the International Diabetes Federation (IDF). Otherwise, the European Group for the Study of Insulin Resistance (EGIR) and the World Health Organisation (WHO) definitions principally focus on insulin resistance [12].

METS AND BPH: PRECLINICAL EVIDENCES AND PATHOPHYSIOLOGY In 1998 for the first time Hammarsten et al. revealed an association between MetS features and BPH. Men with fast-growing BPH had a higher prevalence of NIDDM and treated hypertension. These patients were also taller and more obese as measured by body weight, BMI, waist measurement, hip measurement, and WHR. Moreover, they had elevated fasting plasma insulin levels and lower HDL cholesterol level than men with slow-growing BPH. The annual BPH growth rate correlated positively with diastolic blood pressure, BMI, and four other expressions of obesity and fasting plasma insulin level, and negatively with the HDL cholesterol level. In conclusion, the data suggested that NIDDM, hypertension, tallness, obesity, high insulin, and low-HDL cholesterol levels constitute a risk factor for the development of BPH.

WHO (1998)

EGIR (1999)

AACE (2003)

IDF (2005)

Ncep ATP III (2005 Revision)

Required component

IR(IGT, IFG, T2DM or additional evidence of lR)

Hiperinsulinemia (plasma insulin > 75 percentile)

IR (IGT or IFG)

CO (WC)

None

Criteria

Required component and ≥ 2/5 below

Required component and ≥ 2/4 below

Required component and any below based on clinical judgment

Required component and ≥ 2/4 below

≥ 3/5 below

Obesity

WHR > 0.9 (M) WHR > 0.85 (F) BMI > 30

WC ≥ 94cm (M) WC ≥ 80cm (F)

BMI ≥ 25

-

WC ≥ 102cm (M) WC ≥ 88cm (F)

+

+

+

Fasting Glucose ≥ 100

TG ≥ 150 or HDL-C < 35 (M) HDL-C < 39 (F)

TG ≥ 150 or HDL-C < 39

TG ≥150 and HDL-C < 40 (M) HDL-C < 50 (F)

TG ≥150 or Rx

TG ≥150 or Rx

HDL-C < 40 (M) HDL-C < 50 (F) or Rx

HDL-C < 40 (M) HDL-C < 50 (F) or Rx

>140/90

>140/90 or Rx

>140/(S), >85(D) or Rx

>130 (S), >85 (D) or Rx

Hyperglycemia (mg/dL)

Dyslipidemia (mg/dL)

Hypertension (mm/Hg)

Other criteria

Microalbuminuria

>130/85

Fasting Glucose ≥ 100 or Rx

Other features of IR

FIG. 5.1 Definitions of Metabolic Syndrome according to different criteria over time. IR, insuline resistance; IGT, impaired glucose tolerance; CO, central obesity; WC, waist circumference. Adapted from Carona et al. J sex med. 2007.

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Furthermore, a growing body of evidence has documented a strong and independent association between BPH/LUTS and obesity/MetS [13–15]. Relationship between MetS and LUTS has been investigated also in animal models including a mouse model of type 2 diabetes mellitus/obesity (diabesity). In particular these mice with a neuron-specific conditional Shp2 deletion developed obesity and diabetes and the associated pathophysiological complications that resemble those encountered in humans, including hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin and leptin resistance, vasculitis, diabetic nephropathy, urinary bladder infections, prostatitis, gastric paresis, and impaired spermatogenesis. In males was evident florid bacterial infection of the urinary bladder, prostate, seminal vesicles, and adipose tissue surrounding the vas deferens demonstrating an association of prostate inflammation to bladder dysfunction [16]. Since these evidences, hyperglycemia, insulin resistance, hypogonadism, and low-grade chronic inflammation have been proposed as crosslink between MetS and LUTS/BPH [17–20]. Although the association among the aforementioned conditions and MetS is generally accepted, all the pathways involved in the pathogenetic mechanism are still not completely clarified. In particular, chronic inflammation has been proposed to play a causative role in BPH/LUTS, rather than merely occurring in response to prostate and bladder tissue remodeling. An autoimmune dysregulation and an immune response toward a Th1/Th17 cytokine profile might lead to the development of chronic immune-mediated tissue destruction and fibromyomatosus remodeling, as observed in the initial phase of BPH development. Moreover, hypogonadism resulted in an important determinant in developing LUTS/BPH in MetS subject. Recent data suggested that low testosterone in males might be considered an additional MetS component [17,18,21]. Although testosterone supplementation in MetS significantly improves metabolic parameters like fasting glucose, glucose tolerance, waist circumference, triglycerides, and HDL cholesterol [22], warnings for the potential prostatic side effects strongly limit a widespread clinical use. These concerns are based on the concept that androgens are essential for prostate growth, which potentially can worsen LUTS. However, some prospective [23] and cross-sectional studies [24,25] have demonstrated an inverse association between serum testosterone levels and LUTS or BPH. Consistent with these observations, testosterone replacement therapy has been proposed to treat LUTS in hypogonadal men with both BPH [26,27] and MetS [28]. To better understand the link between MetS and LUTS/BPH, an animal model of MetS-like syndrome was obtained by feeding rabbits with a high fat diet (HFD) for 12 weeks [29]. HFD rabbits recapitulate most of the components of MetS described in humans, including altered glucose tolerance, dyslipidemia, increased abdominal adiposity, and hypertension. Compared to standard

MetS and BPH: Preclinical Evidences and Pathophysiology

rabbits, HFD rabbits showed hypogonadotropic hypogonadism, erectile dysfunction, and LUT abnormalities, consisting of a prostatitis-like syndrome and bladder alterations and also developed decreased seminal vesicles and testis weight. In these models chronic treatment with testosterone for 12 weeks restored plasma testosterone levels, prevented HFD-induced seminal vesicles hypotrophy, and completely normalized fasting glucose levels, glucose tolerance, and VAT accumulation. Immunohistochemical analysis demonstrated an important development of HFD-induced prostate fibrosis, hypoxia, and inflammation. Interestingly in this study testosterone supplementation normalizes all the aforementioned HFD-induced prostatic alterations, including inflammation, hypoxia, and fibrosis, thus suggesting that hypogonadism-related inflammation could be a potential mechanism in linking MetS and LUTS/BPH. An antiinflammatory effect of testosterone in castration-induced prostate inflammation was previously reported [30–33]. Androgens therefore act as endogenous inhibitors of immune responses, even in the prostate, as already reported for other autoimmune processes [34,35]. Although these data showing that testosterone supplementation reduces the expression of proinflammatory cytokines are consistent with previous studies [35–37], the detailed mechanisms of testosterone-mediated immunomodulation are still unknown. Moreover, obesity itself induces adipose cell enlargement and chemokine release, leading to macrophage infiltration of adipose tissue [38,39]. Rising evidences suggest the ability of IL-8 to stimulate prostatic growth, and a significant and stepwise correlation between various MetS components and seminal IL-8 (sIL-8) has been proposed as a surrogate marker of prostate inflammation [40–42]. IL-8 is a proinflammatory chemokine secreted by several cell types that contributes to inflammation by acting in concert with IL-1β and IL-6. Of all kinds of cytokines and chemokines, sIL-8 seems to be the most reliable and predictive surrogate marker of prostatitis. Higher IL-8 levels have been reported in the expressed prostatic secretions of subjects with BPH, bacterial prostatitis, and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). IL-8 has been shown to be actively involved in BPH-associated chronic inflammation and mediates epithelial and stromal cell proliferation. In clinical BPH-prostate tissue studies, epithelial and stromal cells were analyzed to secrete IL-8 actively in response to various stimuli, including the proinflammatory cytokines interferon (IFN) γ and IL-17, which are produced by prostate-infiltrating Th1 and Th17 cells, respectively. As underlined by Penna et al. [43], human stromal prostatic cells actively contribute to the organ-specific inflammatory process by acting as targets of bacterial or viral toll-like receptors agonists and as antigen-presenting cells capable of activating antigen-specific CD4 + T cells. In BPH, toll-like receptor activation

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leads to the production of proinflammatory cytokines (IL-6) and chemokines (IL-8 and CXCL10) capable of recruiting CXCR1 and CXCR2-positive leukocytes and CD15 + neutrophils. Moreover, another important component of MetS, insulin resistance caused by obesity results in a proinflammatory state. Tissue inflammation results in tissue fibrosis, which is supposed to represent an inflammation-initiated, aberrant wound-healing process characterized by myofibroblast accumulation, collagen deposition, extracellular matrix (ECM) remodeling, and increased tissue stiffness. A few studies have investigated possible associations between MetSinduced inflammation and overactive bladder or urinary incontinence (UI). Some investigators have studied the role of urinary cytokines in patients with OAB [44,45] (Fig. 5.2).

FIG. 5.2 Pathophysiology of MetS and its potential biologic mechanisms for lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH). Adapted from De Nunzio Eur Urol 2012.

MetS and LUTS/BPE: The Role of Inflammation

METS AND LUTS/BPE: THE ROLE OF INFLAMMATION Several recent epidemiological and histopathological studies suggest that MetS plays a significant role in BPH/LUTS development and progression. However, most of these studies did not find a univocal causal relationship between these two clinical entities. Even if visceral obesity and insulin resistance can be considered the focal pathophysiological alterations characterizing MetS, several other factors, such as sex-steroid imbalance and a proinflammatory state, could also be involved in its pathogenesis and clinical manifestation. Indeed, chronic low-grade inflammation has been recognized as a crucial pathogenic mechanism underlying the pathophysiology of MetS [46]. Similarly, several recent studies have clearly indicated that prostate chronic inflammation is not only a common finding in BPH [47,48] but has also plays a primary role in triggering prostatic cells overgrowth [10]. In particular, MetS could induce or maintain an inflammatory state within the prostate that could even be exacerbated by a relative hyperestrogenism [49] or by androgen deficiency [29–50]. Hence, a chronic inflammatory insult could be considered the most probable candidate link between MetS and BPE/LUTS (Fig. 5.3). The diagnosis of BPH is based on histological findings of proliferating stromal and epithelial cells within the prostatic transition zone. Even if the precise etiology of BPE is still unclear, a number of epidemiological evidence have led to the hypothesis that an inflammatory process represents the key driver for both the development and the progression of BPH [6,47,51,52].

Hormone unbalancing Aging

(Low Testosterone, high oestrogen)

Lifestyle (Diet Physical activity)

Pelvic inflammation

Reduced nerves function

Altered muscle activity

Abnormal proliferation

Vascular insufficiency

Fibrosis

BPE LUTS

FIG. 5.3 Role of inflammation in the development of LUTS/BPE in MetS patients.

MetS

95

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Several clinical studies evaluated the role of prostatic inflammation on BPE development and progression. Indeed, intraprostatic inflammation within BPH tissue detected in baseline prostate biopsy samples predicted not only BPH progression, but also an increased risk of acute urinary retention or BPH-related surgery in a subgroup of 1197 men with BPH in the placebo arm of the Medical Therapies of Prostate Symptoms study [53]. Likewise, the degree of histological chronic inflammation was weakly but significantly associated with the severity of LUTS in a subgroup analysis of the Reduction by Dutasteride of Prostate Cancer Events trial [54]. Accordingly, in a population of obstructed men requiring a surgical procedure, only the presence of a severe inflammatory pattern, leading to the disruption of the normal glandular arrangement, was determinant for the worsening of LUTS [55]. Moreover, data from a multicenter study in men surgically treated for BPH showed that specimens of patients with MetS presented a more severe intraprostatic inflammation in histopathological assessment in comparison with patients with BPH without MetS [56], in addition to an increased prostate volume [10]. Thus, it has been recently postulated that MetS promotes a direct inflammatory effects within the prostate [6]. In a study enrolling young male partners of infertile couples [57], IL-8 levels in seminal plasma (a well-defined surrogate marker of prostate inflammation) [43] and a number of ultrasonographic features of prostatitis showed a stepwise positive association with the number of MetS components. Moreover, central obesity and dyslipidemia were significantly associated with markers of prostate inflammation. These findings indicate that metabolic derangements have detrimental effects already early in human life, even in asymptomatic or paucisymptomatic individuals.

PROSTATE SIZE AND SHAPE: THE INFLUENCE OF METS Since 1998, different studies have associated single MetS parameters to BPH, but only few studies based on the concept of the MetS construct have been published. This correlation was found both in western and eastern population studies. More recently in a prospective study on over 370 consecutive patients [58] undergone surgery for BPH, the number of MetS parameters and MetS itself was associated with higher calculated prostate volume. In this trial the authors evaluated a possible correlation between different MetS features to specific prostate diameters: AP diameter was mainly correlated with HDL cholesterol, CC diameter with triglycerides, and LL diameter with systolic blood pressure. However, at the binary regression, only low-HDL cholesterol was the main determinant for the enlargement of all diameters and consequently of the whole PV.

The Correlation Between MetS and LUTS

In a recent metaanalysis [5], 8 studies were included for a total of 5403 patients, of which 1426 (26.4%) had MetS defined according to current classification and prostate volume difference between patients with MetS versus patients without MetS was evaluated: the combination of results of trials showed that patients with MetS have significantly higher total prostate volume versus those without MetS (+ 1.8 mL, P < 0.001) (Fig. 5.4). Differences in prostate volume between patients with or without MetS were confirmed even when only studies based on NCEP-ATPIII criteria were considered (+1.73 mL, P < 0.002); in particular, transitional prostate volume was 3.67 mL higher in MetS patients. Metaregression analysis showed that waist circumference and, again, lowHDL cholesterol level was the strongest factor related to increasing prostate volume. The role of dyslipidemia is not surprising since lipids (oxidized low-density lipoprotein, LDL) increase in vitro the secretion of growth (VEGF, b-FGF) and proinflammatory factors (interleukin 6 [IL-6], IL-8, and IL-7) by human stromal BPH cells in culture; Nandeesha et al. [59] reported that HDL cholesterol was lower and total and LDL cholesterol higher in patients with symptomatic BPH than in controls. However, other studies did not confirm the association between dyslipidemia and BPE [60]. In the Rancho Bernardo cohort study, Parsons et al. [61] found a fourfold increased risk of BPH among diabetic men with LDL cholesterol in the highest tertile, but not in the overall cohort. This observation suggests that dyslipidemia itself is not strong enough to induce prostate enlargement, but the concomitant presence of other metabolic derangements, such as diabetes or those concurring with the MetS construct, favors the process. Advanced age was a further determinant in transitional and total prostate volume enlargement: indeed in elderly men with a larger prostate, the occurrence of MetS could represent a major contributing factor in BPE progression as evident in some longitudinal studies like Baltimore Longitudinal Study of Aging. In a study on over 600 men, age (OR, 2.45) and waist circumference (OR, 1.45) were significantly correlated with prostate volume [62]. MetS and in particular dyslipidemia and central obesity are specifically associated with a greater overall (and transitional) increase of prostate volume; this aspect together with the derangements caused by inflammatory functional alterations seems to be crucial in MetS and LUTS/BPH association.

THE CORRELATION BETWEEN METS AND LUTS The evidence on the association between MetS and LUTS mainly derived from epidemiological studies in populations from US and Asian with conflicting results. The Boston Area Community Health (BACH) survey [63] used the Adult

97

A Source

–4

–2

Prostate volume mean difference, mL 0 2 4 6 8 10

12

14

Diff. in mean

LL, 95% CI

UL, 95% CI

P

Jeong et al. 2011 [51]

0.90

0.28

1.52

0.00

Yim et al. 2011 [52]

0.60

–0.37

1.57

0.22

Byun et al. 2012 [54]

4.90

3.29

6.51

0.00

Park et al. 2013 [55]

1.00

0.16

1.84

0.02

Overall mean prostate volume < 30 mL

1.66

0.38

2.94

0.01

Ozden et al. 2007 [49]

5.40

–0.36

11.16

0.07

Park et al. 2008 [50]

1.30

–2.99

5.59

0.55

Yang et al. 2012 [53]

1.60

–0.58

3.78

0.15

Gacci et al. 2013 [19]

5.00

–2.09

12.09

0.17

Overall mean prostate volume > 30 mL

2.13

0.34

3.91

0.02

Overall

1.80

0.74

2.87

0.00

Favours no MetS

Favours MetS

FIG. 5.4 MetS and Prostate volume: weighted differences (with 95% CIs) of total prostate volume mean differences (mL) between patients with or without MetS. Adapted from Gacci M. et al., BJU Int 2015.

The Correlation Between MetS and LUTS

Treatment Panel III Report criteria created by the National Education Program (NCEP-ATPIII) to define MetS and the American Urologic Association symptom index (AUA-SI) to quantify LUTS. The authors reported a trend of increasing prevalence of MetS with increasing AUA-SI scores. In particular, the prevalence of MetS was increased by 40% in men with mild to severe symptoms (AUA-SI 2-35 vs. AUA-SI 0-1). Moreover, increased prevalence of MetS was observed even with mild symptoms, primarily for incomplete emptying, intermittency, and nocturia. Interestingly, a statistically significant association was observed only between MetS and voiding symptom score of 5 or greater, but not storage symptom score of 4 or greater. Similarly, the NHANES III found that those men who fulfilled MetS criteria had a significantly increased risk of LUTS compared with controls [64]. Conversely, a negative correlation between MetS and LUTS has been described in some Eastern Asia studies [65–67]. MetS was not directly associated with LUTS [66] in a study from Japan: in particular, MetS was significantly inversely correlated with storage symptoms in middle-aged men (aged 50–64 years). Moreover, a South Korean study [65] including 33,841 men aged
30 years showed a negative association between MetS and LUTS. Similarly, lower total and voiding IPSS scores were found in Taiwanese men with MetS compared with controls [67]. A 2015 systematic review and metaanalysis of studies with a US Preventive Services Task Force level of evidence II-2 found no significant relationship between total IPSS or its storage or voiding subscores and MetS [5]. This finding was confirmed in another 2015 metaanalysis, specifically designed to evaluate MetS and LUTS relationships. The researchers did not find a significant difference regarding total IPSS or its voiding or storage subscores between men with and without MetS. In addition, the presence of MetS was not significantly associated with the risk of having moderate-severe LUTS (OR 1.13) [68]. By contrast, some of the components of MetS, such as hypertriglyceridemia, elevated fasting glucose and/or T2DM (CI 1.15–2.73), were significantly associated with increased risk of LUTS. Further studies specifically designed to evaluate the association between MetS and LUTS have been recently published describing the positive correlation between MetS and LUTS. A population-based European study demonstrated a strong positive association between MetS (defined by NCEP-ATPIII criteria) and LUTS severity. The presence of MetS was correlated not only with total IPSS score, but also with voiding and storage subscores, as well as each single question of the IPSS questionnaire [69]. Moreover, higher IPSS scores were also positively associated with each component of MetS, and an increased risk of LUTS treatment was associated with severity of MetS. Indeed, the presence of two components was associated with a 51% increased risk of being treated for LUTS, rising to nearly 250% when all five components were present. In particular,

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Metabolic Syndrome and LUTS/BPH

25

10

20

8

IPSS IRRITATIVE

C HA PT E R 5 :

IPSS TOTAL

100

15 10 5 0 PRE WC < 102 cm

POST WC ≥ 102 cm

6 4 2 0 PRE WC < 102 cm

POST WC ≥ 102 cm

FIG. 5.5 Pre- and postoperative International Prostatic Symptoms Score (IPSS)—total and irritative IPSS—according to waist circumference (WC) with a cut-off of 102 cm. Adapted from Gacci M. et al., BJU Int 2015.

men with a waist circumference
102 cm were 39% (OR 1.39) and 40% (OR 1.40) more likely to report a voiding IPSS subscore
5 and a storage IPSS subscore
4, respectively (Fig. 5.5). Accordingly, MetS (defined by NCEP-ATPIII criteria) was the only independent parameter associated with a risk of IPSS storage subscores
4 upon multivariate analysis in a single-center Italian cohort study in 431 men with BPE-related LUTS [70]. A comparable correlation between the number of MetS components and the severity of urinary symptoms has been also reported in a prospective crosssectional study on male aged 50-59 years who had participated in a health examination at the hospital [71]: the authors demonstrated that the number of men with LUTS (IPSS >7), enlarged prostate volume (total prostate volume
30 mL), and/or reduced urinary flow rate (Qmax < 15 mL/s) significantly increased with the increasing number of metabolic abnormalities. The conflicting results on the relationship between MetS and LUTS could be explained by the heterogeneity of the studied populations. If most of the US or European population-based studies demonstrate a positive association between MetS and LUTS, Asian studies often show opposite results. These findings indicate that ethnicity could represent a central issue for the association of MetS and LUTS. Moreover, these differences could be related with the multiple separate definitions of MetS and its components related to different ethnicities too. Furthermore, most of the studies evaluated LUTS using the IPSS. However, the IPSS measures the subjective perception of LUTS, which can be associated with other variables, such as race or ethnic background, age, overall health, and socioeconomic status, as well as quality of life (QoL). By contrast, the strong evidence that MetS is associated with increased prostate size, most of the transition zone, supports a role for metabolic derangements in the development and progression of BPE.

Diet and Lifestyle in Men With MetS and LUTS Due to BPE

Moreover nowadays it is clear that the correlation between MetS and its components to cardiovascular events and, recently, a metaanalysis has revealed the association between major adverse cardiac events and LUTS in the male population [72], suggesting an holistic approach in considering the cardiovascular, metabolic, urinary, and prostatic morbidities of aging men.

DIET AND LIFESTYLE IN MEN WITH METS AND LUTS DUE TO BPE Since the established relationships between MetS, low testosterone, inflammation, BPH, and LUTS, lifestyle and diet changes, which represent the first line of treatment for MetS, might be helpful in preventing the development of BPH/LUTS or delay its progression. Indeed even in the most important urological association guidelines, behavioral and dietary modifications have become essential: in particular reduction of fluid intake at specific times, moderation of intake of caffeine or alcohol, treatment of constipation, weight loss or physical activity. All five components of MetS have been shown to improve with lifestyle and diet modification, in particular by increasing physical activity. It seems that the occurrence of LUTS as well could be reduced by high levels of physical activity. Indeed, men reporting high levels of physical activity were 50% less likely to report LUTS secondary to BPH than those reporting low physical activity [73]. The role of physical activity in preventing LUTS has been confirmed by a metaanalysis including eight studies covering 35,675 men with BPH or LUTS [74] and a large study which enrolled 106,435 men [75]. Men who engaged in light, moderate, and heavy physical activity had a significantly decreased risk of LUTS or BPH in comparison with the sedentary group, moreover the risk of severe LUTS decreased with increasing physical activity. The modification of lifestyle with the introduction of physical activity seems to be beneficial also in obese sedentary men. It has been proved that already moderate-intensity exercise of short duration (40 mL) and/ or elevated PSA concentration (>1.4–1.6 ng/mL), treatment with 5 alpha reductase inhibitors (5-ARIs), alone or in combination with αlpha1-blockers, should be considered as first-line treatment [87]. As reported by the PLESS study, histologic features, such as chronic inflammation, basal cell hyperplasia, and transitional cell metaplasia, were not different between men treated with 5-ARIs and placebo groups. In particular, the overall incidence on chronic inflammation was similar between those men treated with or without finasteride (16% vs. 19%, respectively) [88]. However, 5-ARIs can induce a regression of prostatic glandular tissue, the precise area where intraprostatic inflammation is located, that can lead to a regression of overall prostatic inflammation [89]. On the other hand, it has been suggested that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes, and vascular disease [90]. In that scenario the new role of phosphodiesterase type 5 inhibitor (PDE5-Is) in LUTS treatment appears of great interest. in vitro treatment with tadalafil or vardenafil on human BPH reduced IL-8 secretion induced by either TNFa

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or metabolic factors, including oxidized low-density lipoprotein (oxLDL). Moreover, treatment with tadalafil or vardenafil significantly suppressed oxLDL receptor (LOX-1) expression, potentially reducing chronic inflammation in the prostate and bladder [91]. Even if the exact mechanism of PDE5Is on LUTS remains unclear, several RCTs have demonstrated that PDE5Is reduce IPSS, storage and voiding LUTS, and improve QoL [92], alone or in combination with αlpha1-blockers [93] or 5-ARIs [94]. Although clinical trials of several selective oral PDE5Is have been conducted in men with LUTS, currently only tadalafil (5 mg once daily) has been licensed for the treatment of male LUTS. Interestingly, in a recent study in an animal model of MetS tadalafil reduced visceral fat accumulation (VAT), induced the expression of UCP1 (brown-fat marker) in visceral fat, improved insulin sensitivity in preadipocytes (PAD) isolated from VAT, and promoted PAD differentiation toward a metabolically healthy phenotype [95]. Even if clinical studies specifically addressing this point are needed, these beneficial effects of tadalafil on visceral adipose tissue add a new facet into the pleiotropic actions of PDE5 inhibitors in MetS-related disorders.

THE IMPACT OF METS ON THE OUTCOMES OF BPH SURGERY Endoscopic (TURP) or open (OP) simple prostatectomy are the surgical standard procedures for men with moderate-to-severe LUTS secondary of BPE [87]. A recent prospective trial evaluated the impact of MetS and its components on the outcomes of transurethral resection of the prostate (TURP) in 50 patients with and 50 without MetS [96]. The authors reported a significantly better IPSS and Qmax improvement in the group without MetS, versus those with MetS: 6 months postoperatively, IPSS was found to be 11.2  0.87 versus 12.9  0.88 and Qmax 18.2  0.81 versus 13.9  1.12. In addition, there was a statistically significant improvement in terms of QoL in both groups after TURP, but when the groups were compared, patients without MetS presented a more remarkable improvement of their QoL, as compared to those with MetS (P ¼ 0.034). Interestingly, after multivariate analyses, among MetS factors, abdominal obesity retained a significant and negative correlation with QoL (evaluated by IPSS, question 8) (OR ¼ 7.286; 95% CI, 0.727–73.059, P ¼ 0.043). Even if the authors did not report subanalyses on storage and voiding score, the detrimental effect of central obesity on QoL could be due to persistent storage symptoms. In a recent pooled data analysis, McVary et al. demonstrated that changes in storage symptoms can improve urinary bother and related QoL, more than changes in voiding symptoms [97]. In particular, storage symptoms had a

Conclusions

two-fold greater effect on voiding ones (0.61; P < 0.0001) versus voiding symptoms on storage ones (0.28; P < 0.0001). Direct effect of storage on bother was two-fold greater than voiding (0.64 storage, 0.29 voiding; each P < 0.0001). Bother directly impacted QoL by the largest magnitude (0.83), mainly driven by storage LUTS (P < 0.0001). In a recent multicenter prospective study on 378 men treated with surgery (OP or TURP) for large BPE, a waist circumference of
102 cm was associated with a higher risk of an incomplete recovery of both total IPSS (OR 0.343, P ¼ 0.001) and storage IPSS (OR 0.208, P < 0.001), as compared with men with a WC of 300 mL) Bladder stones/diverticula Hydronephrosis Renal insufficiency

History, urine analysis History, urine analysis History, PVR urine measurement (ultrasound) History, PVR urine measurement (ultrasound) Bladder ultrasound Serum creatinine measurement, renal ultrasound Serum-creatinine level/clearance measurement

progression risk, treatment planning, and prediction of treatment outcome [1,2]. After baseline investigations, the physician should be able to determine if and how the patient should be treated.

DIAGNOSTIC WORKUP OF LUTS/BPH Standard Diagnostic Tests History The assessment of the medical history of patients has been always considered very important [3–5]. According to the EAU Guidelines on Nonneurogenic Male LUTS [1,2], a complete medical history must always be taken from men with LUTS (Level of Evidence (LE) 4; Grade of Recommendation (GR) A; Fig. 6.2). It aims to identify potential LUTS causes, relevant comorbidities, current medication, lifestyle habits, and emotional or psychological factors. Symptoms and available therapeutic options should be discussed from the patient’s perspective, and the patient should be reassured that presence of LUTS is not indicative of a higher prostate cancer (PCa) prevalence compared to asymptomatic men [6,7]. The urological history should be supplemented by a self-completed validated symptom questionnaire that objectifies and quantifies LUTS; a voiding diary especially if patients with nocturia and/or storage symptoms are assessed; and a validated symptom questionnaire such as the International Index for Erectile Function (IIEF) assessing sexual function [1,2].

Symptom Questionnaires A validated symptom questionnaire should always be used [3–5]. According to the EAU Guidelines on Non-neurogenic Male LUTS [1,2], a validated symptom score questionnaire (incl. the evaluation of quality of life (QoL)) should be used for the routine assessment of male LUTS in all patients at baseline and for re-evaluation during and/or after treatment to objectively quantify treatment effects (LE 3; GR B; Fig. 6.2). Despite the fact that symptom

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Diagnostic Work-up of LUTS/BPH: From Standard to New Perspectives

History (+ sexual function) Symptom score questionnaire Physical examination Urinalysis PSA (if diagnosis of Pca will change the management— discuss with patient) • Measurement of PVR • • • • •

No

Bothersome symptoms ?

Yes

Significant PVR • • • •

Abnormal DRE Suspicion of neurological disease High PSA Hematuria, nitrites, pyuria, glucose

Evaluate according to relevant guidelines or clinical standard

• US of kidneys ± renal function assessment

Medical treatment according to treatment algorithm

• FVC with predominant storage LUTS/nocturia

• US assessment of prostate • Uroflowmetry

Benign conditions of bladder and/or prostate with baseline values Plan treatment

• Endoscopy (if test alters the choice of surgical modality)

• Pressure flow studies (see text for specific indications)

Treat underlying condition (if any, otherwise return to initial assessment)

Surgical treatment according to treatment algorithm

FIG. 6.2 Recommended algorithm for the assessment of men aged 40 years or older with LUTS/BPH; EAU Guidelines on the Assessment of Male LUTS. Modified according to Gratzke C, Bachmann A, Descazeaud A, et al. EAU guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 2015;67:1099–1109; Gravas SBT, Bachmann A, Drake M, Gacci M, Gratzke C, Madersbacher S, et al. Guidelines Associates: Karavitakis M, Malde S, Seakales V, Umbach R. EAU guidelines on management of non-neurogenic male lower urinary tract symptoms (LUTS), incl. benign prostatic obstruction (BPO); 2016.

score questionnaires are not age-, gender-, or disease-specific [8], many are available for routine use and able to qualify/quantify LUTS, identify predominance of voiding or storage LUTS, and sensitively detect changes during treatment [9–15]. The most widely used questionnaire worldwide is the International Prostate Symptom Score (IPSS) questionnaire (Fig. 6.3). It is a validated 8-item tool consisting of seven symptom questions and one question for QoL assessment; symptom questions and the QoL question are evaluated separately. The IPSS-questionnaire produces reliable, consistent, and stable results [10]. It should be noted once more that the IPSS-questionnaire is also not age-, gender-, or disease-specific and thus can only be used to evaluate LUTS independent of the underlying disease. The IPSS questionnaire has the disadvantage that questions concerning urinary incontinence or postmicturition symptoms are missing and only global QoL can be measured—instead of the assessment of bother caused by each individual symptom [1,2].

Diagnostic Workup of LUTS/BPH

International Prostate Symptom Score (I-PSS) Patient name:

Date of birth:

Date completed

In the Past Month:

Not at All

Less than 1 in 5 Times

Less than Half the Time

About Half the Time

More than Half the Time

Almost Always

1. Incomplete emptying How often have you had the sensation of not emptying your bladder?

0

1

2

3

4

5

2. Frequency How often have you had to urinate less than every two hours?

0

1

2

3

4

5

0

1

2

3

4

5

4. Urgency How often have you found it difficult to postpone urination?

0

1

2

3

4

5

5. Weak stream How often have you had a weak urinary stream?

0

1

2

3

4

5

6. Straining How often have you had to strain to start urination?

0

1

2

3

4

5

None

1 Time

2 Times

3 Times

4 Times

5 Times

0

1

2

3

4

5

Your Score

3. Intermittency How often have you found you stopped and started again several times when you urinated?

7. Nocturia How many times did you typically get up at night to urinate? Total I-PSS Score

Score:

1–7: Mild

Quality of Life due to Urinary Symptoms If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?

8–19: Moderate

20–35: Severe

Delighted

Pleased

Mostly satisfied

Mixed

0

1

2

3

Mostly Unhappy Dissatisfied

4

5

Terrible

6

FIG. 6.3 International Prostate Symptom Score (IPSS) questionnaire to evaluate lower urinary tract symptoms and quantify symptomatology for baseline assessment or follow-up [10]. Patients should complete the questionnaire alone and indicate how frequently the individual symptoms appear during a 24 h period during the last 4 weeks. The results of the seven symptom questions (IPSS questions 1–7) have to be added to quantify symptomatology (IPSS 0 ¼ no symptoms; IPSS 1–7 ¼ mild symptoms; IPSS 8–19 ¼ moderate symptoms; IPSS 20–35 ¼ severe symptoms). The eighth IPSS question quantifies symptom bother as a proxy parameter for quality of life.

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Symptom questions of the IPSS questionnaire can be divided into storage symptoms (IPSS questions 2, 4, and 7) and voiding symptoms (IPSS questions 1, 3, 5, and 6). For each question, the patient can choose between six answers (score 0–5) and indicate how frequently this symptom has appeared on average during a 24 h period during the last 4 weeks. Total IPSS can range between 0 and 35 points, thereby documenting a span between no symptoms (score 0) and maximum amount of symptoms (score 35). Scores between 1 and 7 points indicate “mild,” between 8 and 19 points “moderate,” and between 20 and 35 points “severe” symptom severity. Medical or surgical treatment should be considered in men with “moderate to severe” LUTS (symptom scores >7). The 8th IPSS question evaluates how the patient would feel if LUTS remained for the rest of his life; the patient has seven answers to express symptom bother (scores 0–6), thereby documenting a span between excellent (answer 0) and very poor QoL (answer 6). Storage symptoms are usually associated with greater bother than voiding symptoms. Greater bother (answers 3–6) implies a need for treatment. During treatment, including watchful waiting and conservative treatment, a decrease of at least 3 points in the symptom questions (score of questions 1–7) can be realized by the patient as symptom relief and is usually associated with improvement of QoL and symptom bother (question 8).

Frequency Volume Charts and Bladder Diaries The frequency-volume chart (FVC) is a patient-documented record of the time and volume of each void within a 24 h period. A bladder diary is a similar but more distinguished record including extra data such as volume and type of fluid intake, grading of urgency before voiding, incontinence episodes, and pad use [16]. According to the EAU Guidelines on Non-neurogenic Male LUTS [1,2], FVCs or bladder diaries should have a balanced duration for optimal precision [17,18], defined as at least 3 days (LE 2b; GR B), and should be used in patients with predominance of storage symptoms or nocturia (LE 3; GR B; Fig. 6.2); for the latter being particularly relevant to categorize the underlying mechanism(s) [19–21]. FVC and bladder diaries should be especially used in those men who need objective assessment of urinary frequency and voided volume at baseline or during treatment. These tools are helpful to discriminate between pollakisuria/nocturia due to increased fluid intake, bladder dysfunction, or (nocturnal) polyuria, and they also might be useful in selected patients to document the amount of fluid intake, severity of urgency, and the time of urinary incontinence. By calculating the fraction of urine production during the night (nocturnal polyuria index), nocturnal polyuria is detected (defined as excretion of urine during the night sleeping period 33% of the total 24 h urine volume). Nocturnal polyuria, which can be detected in up to 80% of men with nocturia, may be caused by

Diagnostic Workup of LUTS/BPH

increased fluid intake before sleeping, use of diuretics in the evening or night, cardiac insufficiency, obstructive sleep apnoea, or decrease of vasopressin secretion during the night.

Physical Examination and Digital-Rectal Examination According to the EAU Guidelines on Non-neurogenic Male LUTS [1,2], physical examination focusing on the suprapubic area, external genitalia, perineum, and lower limbs in particular, supplemented by digital-rectal examination (DRE), should be routinely performed in all men (LE 3; GR B; Fig. 6.2). Potential pathologies relevant for LUTS (urethral discharge, meatal stenosis, phimosis, penile cancer) can be detected. Trans-anal prostate palpation with the physician’s fingertip is the simplest method to judge the size of prostate, consistency of the prostatic parenchyma for PCa screening, glandular pain for exclusion of prostatitis or a prostate abscess, anal sphincter tone, and the surface of the rectum for exclusion of rectum carcinoma. DRE can sufficiently discriminate prostate volumes smaller or greater than 50 mL [5], but there is a general underestimation of the prostate size with increasing volume, particularly in prostates with a volume more than 30 mL (tends to be as high as 25% in glands >50 mL) [22]. It has to be kept in mind that the chance of PCa in patients with LUTS/BPH is low (approx. 5%–15%) and DRE has a low sensitivity and specificity to detect PCa (around 33% and 50%, respectively).

Urinalysis Despite the fact that dipstick or microscopic sediment analysis of mid-stream urine is recommended as a primary assessment tool of patients with LUTS [23,24], and must be used according to the EAU Guidelines on Non-neurogenic Male LUTS (LE 3; GR A; Fig. 6.2) [1,2], the evidence is limited and concerns exist that costs are outweighed by the benefits of its use [25]. In case of abnormal findings, the patients should be further evaluated accordingly [26–29]. Urinalysis can detect leukocytes, nitrite, erythrocytes/hemoglobin, and glucose. Leukocyte (leukocyte esterase activity) detection is a sign of urinary tract infection, usually caused by bacteria, with Escherichia coli being responsible for most cases [30], and might be the only cause of LUTS. In cases of leukocytes or positive leukocyte esterase activity detection, a urine sample should be sent for urine culture. All urinary tract infections in elderly men are considered complicated and, therefore, the underlying causes should always be evaluated. Physicians have to keep in mind that urinary tract infections with kidney involvement (pyelonephritis) are the most frequent causes of renal insufficiency. Despite the fact that around 20% of men with LUTS/BPH develop urinary tract infections over time, there is no clear relationship to postvoid residual (PVR) urine. Nitrite in the urine is also a sign of infection since it can be reduced from nitrate by a number of bacteria including E. coli or Proteus,

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Table 6.3 Most Frequent Causes of Urinary Tract Infections Microorganism

Gram Strain

Community (%)

Hospital (%)

E. coli Proteus mirabilis Klebsiella/Enterobacter species Enterococcus species Staphylococcus species Pseudomonas aeruginosa Others

   + +  

69.4 4.3 4.7 5.5 4.0 0 12.1

50.8 5.1 7.3 11.9 8.4 11.1 5.4

Klebsiella, Pseudomonas, and Staphylococcus species (Table 6.3). The appearance of erythrocytes or hemoglobin in the urine is the result of rupture of superficial prostatic vessels in patients with BPE, but they are also detected in cases with transitional cell carcinoma, urinary stones, urinary tract infections, or glomerulonephritis. Bladder cancer, bladder stones, distal ureter stones, or urinary tract infections might even be the only cause of LUTS. Therefore, all men with hematuria should be further assessed by ultrasound, urethro-cystoscopy, urine cytology, and X-ray investigations to exclude transitional cell carcinoma or stone disease. Most urine dipsticks are also able to detect glucose which, in some men, is the first sign of diabetes mellitus or diabetic bladder dysfunction (initially detrusor overactivity with or without urgency incontinence, later decreased bladder sensation, detrusor underactivity, PVR urine, or even urinary retention).

Blood Analysis Serum creatinine is used to judge renal function. However, increased concentration is only seen if 50% of nephrons are damaged. For better judgment of renal function, calculation of creatinine clearance is recommended (CockroftGault formula): ð140  Age ½yearsÞ  body weight ½kg ð72  serum  creatinine ½mg=dLÞ

Serum-creatinine concentration or clearance is useful before administration of intravenous contrast media, which might cause acute renal failure in patients with renal insufficiency (creatinine concentration >180 μmol/L), and for the adjustment of drug doses. Serum prostate-specific antigen (PSA) measurement can be useful in patients with LUTS/BPH. PSA, which is produced by prostatic stromal cells, is a glycoprotein of 237 amino acids and a total molecular weight of 33 kDa. It is

Diagnostic Workup of LUTS/BPH

Table 6.4 Causes for an Increase or Decrease in Serum PSA Concentration Causes of PSA Increase

Causes of PSA Decrease

BPE Prostatic inflammation PCa Prostate infarction Ejaculation Immediately after prostate manipulation: - DRE - Biopsy - Instrumentation

Prostate tissue removal (e.g., TURP) Castration (medical or surgical) Hypopituitarism Androgen receptor defects (inherited) 5α-reductase insufficiency (inherited) Medical treatment: - 5α-reductase inhibitors - antiandrogens - LH-RH

prostate—but not disease-specific. Therefore, total PSA concentration might be increased or decreased in several conditions or diseases (Table 6.4). For adequate judgment of serum PSA concentration, patient history and timing of PSA assessment are crucial. Serum half-life for total PSA is 2–3 days, which has to be taken into account before analysis and for the interpretation. PSA screening for PCa in the general population remains controversial but seems useful in elderly men with LUTS. In patients with a PSA concentration 4 ng/mL, there is an increasing chance of PCa with increasing of PSA-concentration (Table 6.5) [31]. Prostate biopsy may be indicated in these men but certainly in patients with PSA-concentrations >4.0 ng/mL or in those with palpable or visible tumors during DRE or prostate ultrasound. PSA-density (serum PSA concentration [ng/mL] divided by prostate volume [mL]; normal 90% of the cases [33,34]. Age-specific criteria for detecting glands over 40 mL are PSA >1.6 ng/mL, >2.0 ng/mL, and >2.3 ng/mL, for men with BPH in the age of 50, 60, and 70 years, respectively [35]. It has been reported that a PSA threshold of 1.5 ng/mL can best adequately predict a prostate volume of >30 mL [36]. Serum PSA is a stronger predictor of prostate growth than prostate volume assessment at baseline [37]. Patients with BPO seem to have a higher PSA level and larger prostate volumes. The positive predictive value of PSA for the detection of BPO is around 70% [38]. Elevated free PSA levels may also predict clinical BPH, independent of total PSA levels [39]. PSA also predicts changes in symptoms, QoL/bother, and maximum urinary flow rate (Qmax) [40], representing a highly significant predictor of clinical progression in LUTS/BPH patients managed conservatively [41–44]. In men without PCa, a higher serum PSA concentration is associated with BPH-disease progression (>1.6 ng/mL) and treatment benefit during 5α-reductase inhibitor therapy. The 5α-reductase inhibitors dutasteride and finasteride lower serum PSA-concentration; consequently, total serum PSA-concentration has to be multiplied by the factor 2 after 6–12 months of treatment in order to evaluate the true PSA-concentration.

Diagnostic Workup of LUTS/BPH

According to the EAU Guidelines on Non-neurogenic Male LUTS [1,2], serum PSA should only be measured in cases at risk of BPE progression, if it assists in decision-making, and in cases that PCa diagnosis will change management (LE 1b; GR A; Fig. 6.2). Creatinine must be measured in men suspicious of having impaired renal function, in cases with hydronephrosis or candidates for surgical treatment of LUTS (LE 3; GR A; Fig. 6.2).

PVR Urine Transabdominal ultrasonography (US), bladder scan, or catheterization can be used for the estimation of PVR urine volume. All young healthy men have a PVR urine volume 50 mL abnormal. Urinary retention is defined as the inability to empty the bladder or a PVR urine volume measurement of >300 mL. Relevant PVR (>50 mL) is associated with a higher likelihood of disease progression. Men with PVR values >50 mL have a threefold increased risk of acute urinary retention during a follow-up period of 3–4 years compared to men with lower PVR values. PVR can be caused by BPO but also by detrusor underactivity. A single PVR measurement is unreliable for BPO assessment when PVR volume is >50 mL. BPO is not necessarily associated with PVR; urodynamic studies in adult male patients with LUTS/BPH demonstrated that approximately 30% of men with PVR 50 mL do not have BPO, independent on the magnitude of PVR, and, vice versa, 24% of men with urodynamically confirmed BOO/BPO have PVR 100 mL should receive active treatment. Despite the fact that no threshold for treatment decision has been established, high baseline values may indicate poor treatment response and outcome as well as an increased risk of disease progression [42,43], while serial monitoring of changes may allow for detection of patients at risk of acute urinary retention [43]. PVR volume measurement is currently considered routine part of BPH/ LUTS assessment (LE 3; GR B) despite its limitations (Fig. 6.2) [1,2].

Uroflowmetry Uroflowmetry (measurement of urinary flow rate) is a screening tool to evaluate and quantify voiding at baseline and during follow-up. It is a noninvasive urodynamic test allowing correct judgment of the most important parameters or urinary flow (maximum urinary flow rate, Qmax and flow pattern—shape of the flow curve). The flow curve is a product of detrusor contraction strength and bladder outlet resistance. Diagnostic accuracy for BOO detection is substantially influenced by Qmax threshold values [48]. In patients with abnormal voiding, uroflowmetry is unable to discriminate between the underlying mechanisms of poor urinary flow [49,50]. Uroflowmetry cannot distinguish between reduced bladder contraction strength (due to inadequate bladder filling or

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detrusor underactivity) or increased bladder outlet resistance (due to BPE or bladder neck, urethral, or meatal stenosis). Uroflowmetry can be used for monitoring treatment outcomes and correlating symptoms with objective findings [51]. According to the EAU Guidelines on Non-neurogenic Male LUTS, this test may be performed in the initial assessment of patients with LUTS/BPH and should be performed prior to any active treatment (LE 2b; GR B; Fig. 6.2) [1,2]. The following considerations are helpful to correctly judge uroflowmetry results: 1. Qmax is prone to within-subject variation and voided volume should exceed 150 mL [52,53]. Repeated measurements increase the specificity and are useful, especially if voided volume is 8.5 mm and Shin et al. [68] a threshold of >5.5 mm for the diagnosis of BPO.

Ultrasound Measurement of DWT Bladder wall hypertrophy and increased bladder weight are the physiologic responses of the urinary bladder to BOO/BPO. The longer BOO/BPO exists the thicker the bladder wall and heavier the bladder become in both animals and humans. Initial investigations focused on the ultrasound appearance of the bladder wall and demonstrated that the detrusor appears as a hypoechogenic (black) area sandwiched between the hyperechogenic (white) mucosa and adventitia (Fig. 6.6) [69]. The thicknesses of the lateral, ventral, and dorsal bladder walls as well as trigone and dome are comparable and not significantly different in individual men. Therefore, DWT measurement can be performed at any location of the bladder but, however, is preferably done at the anterior bladder wall due to the high resolution and precise placement of the calipers when using high-frequency probes (7.5 MHz) positioned on the skin of the lower abdomen. For the measurement of DWT, it is necessary to enlarge the image and position the calipers at the inner borders of the mucosa and adventitia and measure the distance in between these two calipers. The bladder should be filled with at least 250 mL of fluid after which DWT remains almost constant until bladder capacity [70]. With this technique, it is possible to visualize and quantify bladder wall hypertrophy and, indirectly, collect information on BOO/BPO in the individual patient in less than 1 min. Median DWT value in healthy adult men is 1.4 mm (interquartile range 1.33–1.50 mm) [70]. In contrast, DWT values 2 mm indicate BOO in 94% of patients (sensitivity 83%, specificity 95%, likelihood ratio for BOO 17.6) [47]. The higher the BOO-grade is the greater becomes DWT [71]. Both constrictive and compressive BOO/BPO result in significantly increased DWT measurement values. Comparison of the diagnostic values of DWT measurement, uroflowmetry, prostate volume (TRUS), measurement of PVR, and symptom assessment (IPSS) demonstrated that DWT is the most precise noninvasive or minimally invasive test to detect BOO/BPO [47,72]. In contrast, DWT values 445 mL, as documented in uroflowmetry or FVC) indicate detrusor underactivity in 100% of patients (sensitivity 42%, specificity 100%, likelihood ratio for detrusor underactivity 42) [73].

Diagnostic Workup of LUTS/BPH

4.6 cm

(A)

(B)

4.3 cm

(C)

3.2 cm

(D)

FIG. 6.6 Technique of ultrasound measurement of detrusor wall thickness (DWT) at the anterior bladder wall and bladder filled with 250 mL. (A) Positioning of a high frequency ultrasound scanner at the lower abdomen. (B) Identification of the anatomical structures of the lower abdomen and identification of the anterior bladder wall. (C) After enlargement of the ultrasound image, the structures of the anterior bladder wall are identified. The detrusor appears as a hypoechogenic (gray or black bar) sandwiched between the hyperechogenic (white) mucosa and adventitia. For DWT measurement, the calipers of the ultrasound machine are placed at the inner border of the mucosa and adventitia. DWT measurement in this patient is 0.9 mm and indicates detrusor underactivity. (D) DWT in another patient with LUTS/BPH with a measurement value of 2.9 mm indicating BOO/BPO. Note that the enlargement factor of the ultrasound image is identical to Fig. 6.5C. Modified from Gabuev A, Oelke M. Latest trends and recommendations on epidemiology, diagnosis, and treatment of benign prostatic hyperplasia (BPH). Aktuelle Urol 2011;42:167–78.

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[39] Meigs JB, Mohr B, Barry MJ, Collins MM, McKinlay JB. Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men. J Clin Epidemiol 2001;54:935–44. [40] Roehrborn CG, Boyle P, Bergner D, et al. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology 1999;54:662–9. [41] Djavan B, Fong YK, Harik M, et al. Longitudinal study of men with mild symptoms of bladder outlet obstruction treated with watchful waiting for four years. Urology 2004;64:1144–8. [42] McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387–98. [43] Roehrborn CG. Alfuzosin 10 mg once daily prevents overall clinical progression of benign prostatic hyperplasia but not acute urinary retention: results of a 2-year placebo-controlled study. BJU Int 2006;97:734–41. [44] Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County study of urinary symptoms and health status. J Urol 1999;162:1301–6. [45] Rule AD, Jacobson DJ, McGree ME, Girman CJ, Lieber MM, Jacobsen SJ. Longitudinal changes in post-void residual and voided volume among community dwelling men. J Urol 2005;174:1317–21 [discussion 21–2; author reply 22]. [46] Sullivan MP, Yalla SV. Detrusor contractility and compliance characteristics in adult male patients with obstructive and nonobstructive voiding dysfunction. J Urol 1996;155:1995–2000. [47] Oelke M, Hofner K, Jonas U, de la Rosette JJ, Ubbink DT, Wijkstra H. Diagnostic accuracy of noninvasive tests to evaluate bladder outlet obstruction in men: detrusor wall thickness, uroflowmetry, postvoid residual urine, and prostate volume. Eur Urol 2007;52:827–34. [48] Reynard JM, Yang Q, Donovan JL, et al. The ICS-“BPH” Study: uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. Br J Urol 1998;82:619–23. [49] Idzenga T, Pel JJ, van Mastrigt R. Accuracy of maximum flow rate for diagnosing bladder outlet obstruction can be estimated from the ICS nomogram. Neurourol Urodyn 2008;27:97–8. [50] Siroky MB, Olsson CA, Krane RJ. The flow rate nomogram: I Development. J Urol 1979;122:665–8. [51] Siroky MB, Olsson CA, Krane RJ. The flow rate nomogram: II Clinical correlation. J Urol 1980;123:208–10. [52] Jorgensen JB, Jensen KM, Mogensen P. Age-related variation in urinary flow variables and flow curve patterns in elderly males. Br J Urol 1992;69:265–71. [53] Kranse R, van Mastrigt R. Causes for variability in repeated pressure-flow measurements. Urology 2003;61:930–4 [discussion 4–5]. [54] Koch WF, Ezz el Din K, de Wildt MJ, Debruyne FM, de la Rosette JJ. The outcome of renal ultrasound in the assessment of 556 consecutive patients with benign prostatic hyperplasia. J Urol 1996;155:186–9. [55] Grossfeld GD, Coakley FV. Benign prostatic hyperplasia: clinical overview and value of diagnostic imaging. Radiol Clin N Am 2000;38:31–47. [56] Thorpe A, Neal D. Benign prostatic hyperplasia. Lancet 2003;361:1359–67. [57] Wilkinson AG, Wild SR. Is pre-operative imaging of the urinary tract worthwhile in the assessment of prostatism? Br J Urol 1992;70:53–7. [58] Loch AC, Bannowsky A, Baeurle L, et al. Technical and anatomical essentials for transrectal ultrasound of the prostate. World J Urol 2007;25:361–6.

Further Reading

[59] Stravodimos KG, Petrolekas A, Kapetanakis T, et al. TRUS versus transabdominal ultrasound as a predictor of enucleated adenoma weight in patients with BPH: a tool for standard preoperative work-up? Int Urol Nephrol 2009;41:767–71. [60] el Din KE, de Wildt MJ, Rosier PF, Wijkstra H, Debruyne FM, de la Rosette JJ. The correlation between urodynamic and cystoscopic findings in elderly men with voiding complaints. J Urol 1996;155:1018–22. [61] el Din KE, Kiemeney LA, de Wildt MJ, Rosier PF, Debruyne FM, de la Rosette JJ. The correlation between bladder outlet obstruction and lower urinary tract symptoms as measured by the international prostate symptom score. J Urol 1996;156:1020–5. [62] Shoukry I, Susset JG, Elhilali MM, Dutartre D. Role of uroflowmetry in the assessment of lower urinary tract obstruction in adult males. Br J Urol 1975;47:559–66. [63] Anikwe RM. Correlations between clinical findings and urinary flow rate in benign prostatic hypertrophy. Int Surg 1976;61:392–4. [64] Malde S, Nambiar AK, Umbach R, et al. Systematic review of the performance of noninvasive tests in diagnosing bladder outlet obstruction in men with lower urinary tract symptoms. Eur Urol 2017;71:391–402. [65] Chia SJ, Heng CT, Chan SP, Foo KT. Correlation of intravesical prostatic protrusion with bladder outlet obstruction. BJU Int 2003;91:371–4. [66] Arnolds M, Oelke M. Positioning invasive versus noninvasive urodynamics in the assessment of bladder outlet obstruction. Curr Opin Urol 2009;19:55–62. [67] Keqin Z, Zhishun X, Jing Z, Haixin W, Dongqing Z, Benkang S. Clinical significance of intravesical prostatic protrusion in patients with benign prostatic enlargement. Urology 2007;70:1096–9. [68] Shin SH, Kim JW, Kim JW, Oh MM, Moon DG. Defining the degree of intravesical prostatic protrusion in association with bladder outlet obstruction. Korean J Urol 2013;54:369–72. [69] Kojima M, Inui E, Ochiai A, Naya Y, Ukimura O, Watanabe H. Ultrasonic estimation of bladder weight as a measure of bladder hypertrophy in men with infravesical obstruction: a preliminary report. Urology 1996;47:942–7. [70] Oelke M, Hofner K, Jonas U, Ubbink D, de la Rosette J, Wijkstra H. Ultrasound measurement of detrusor wall thickness in healthy adults. Neurourol Urodyn 2006;25:308–17 [discussion 18]. [71] Oelke M, Hofner K, Wiese B, Grunewald V, Jonas U. Increase in detrusor wall thickness indicates bladder outlet obstruction (BOO) in men. World J Urol 2002;19:443–52. [72] El Saied WMA, El Fayoumy H, El Ghoniemy M, Ziada A, El Ghamrawy H, Ibrahim A, et al. Detrusor wall thickness compared to other non-invasive methods in diagnosing men with bladder outlet obstruction: a prospective controlled study. Afr J Urol 2013;19:160–4. [73] Rademakers KL, van Koeveringe GA, Oelke M. Force Research Group M, Hannover. Ultrasound detrusor wall thickness measurement in combination with bladder capacity can safely detect detrusor underactivity in adult men. World J Urol 2017;35:153–9.

Further Reading Hald T. Urodynamics in benign prostatic hyperplasia: a survey. Prostate Suppl 1989;2:69–77. Gabuev A, Oelke M. Latest trends and recommendations on epidemiology, diagnosis, and treatment of benign prostatic hyperplasia (BPH). Aktuelle Urol 2011;42:167–78.

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CHAPTER 7

Phytotherapy in Benign Prostatic Hyperplasia Giuseppe Morgia, Salvatore Privitera University of Catania, Catania, Italy

INTRODUCTION Benign prostatic hyperplasia (BPH) is one of the most common urologic conditions affecting the elderly male [1]. Current management options for BPH and for lower urinary tract symptoms (LUTS) related to BPH include lifestyle changes, drugs, and surgical treatment. A comprehensive spectrum of drugs for the treatment of LUTS is available, ranging from adrenoceptor antagonists (alpha-blockers), 5-alpha-reductase inhibitors (5-ARIs), phosphodiesterase type 5 inhibitor (PDE5-i), antimuscarinics, beta-3-adrenoceptor agonist, vasopressin analogs, and phytotherapeutic agents [2]. Phytotherapy, a science-based medical practice based on the study of extracts of natural origin in the treatment and prevention of disease, probably born with men. The observation that animals preferred certain plants when they were injured or ill may have helped to guide primitive man in the search of cures for his ailments. Knowledge of the medicinal value of these plants was initially transferred on verbally, then with the development of society and written language, records on the use of medicinal plants were preserved in writing [3]. The oldest written evidence of medicinal plants’ usage for preparation of drugs has been found on a Sumerian clay slab from Nagpur, approximately 5000 years old [4]. The Egyptians had extensive knowledge of plants derived from their technique of embalming. The Ebers Papyrus (about 1550 BC) presents a large number of crude drugs that are still of great importance (castor seed, gum arabic, aloe, etc.). Knowledge of the virtues of medicinal plants later spread to Greece and other countries of the ancient Western World. The 15th, 16th, and 17th centuries were the great age of herbals; the use of, and search for, drugs and dietary supplements derived from plants have further accelerated in recent years. Pharmacologists, microbiologists, and botanists are combing the Earth Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. https://doi.org/10.1016/B978-0-12-811397-4.00007-X © 2018 Elsevier Inc. All rights reserved.

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for phytochemicals and leads that could be developed for treatment of various diseases; in fact, according to the World Health Organization, approximately 25% of modern drugs used in the United States have been derived from plants [5]. Unfortunately, the interpretation and acceptance of such evidence for phytotherapeutic practices varies: in some countries, it is considered sufficient to license phytotherapeutic products as medicines, whereas in other countries, phytotherapy is viewed as a form of traditional medicine. While many consider herbal medicines with a well-defined use profile (one based on scientific and medical evidence) as phytotherapeutic products, others consider such products to be food supplements; the latter implies that medicines based on herbal substances are unproven therapies, and in some countries they are treated that way [6,7]. The phytotherapeutic agents, which have gained widespread use since about 1990, are a heterogeneous group of products that may contain different concentrations of the active ingredient(s) [8]. Despite The EAU Guidelines Panel have not made any specific recommendations on phytotherapy for the treatment of male LUTS because of product heterogeneity, limited regulatory framework, and methodological limitations of the published trials and metaanalyses, the use of phytotherapy for the treatment of BPH has become increasingly prevalent, especially in some countries where it use is as high as 50% of prescriptions [9]. The TRIUMPH (TransEuropean Research Into the Use of Management Policies for LUTS suggestive of BPH in Primary Healthcare) Study compared the management of LUTS suggestive of BPH in real-life practice in six European countries (France, Germany, Italy, Poland, Spain, and the United Kingdom): although national levels of prescriptions varied from country to country, α-blockers were the most popular class in all countries (79%) followed by phytotherapy (16%) and 5-α-reductase (5%) [10]. Similar data was published by Fourcade et al. in an observational, cross-sectional study that was carried out in primary care in Germany, France, Spain, and Portugal. Overall, α-blocker monotherapy was the most frequently prescribed treatment for LUTS/BPH (63%), phytotherapy given as monotherapy was the second most prescribed class of drugs (24%), and 5-αreductase inhibitors were prescribed as monotherapy in only 4% of patients [9]. In the United States, about 40% of men opting for nonsurgical therapy for BPH use herbal supplements alone or in conjunction with other medical preparation, and that number continues to grow [11]. In the United States, in fact, the complementary and alternative medicines (CAMs) market is an extremely lucrative enterprise with revenues reaching close to US$ 6.4 billion in sales for the 2014 [12]. The widespread availability of these products in health food stores, vitamin shops, traditional pharmacies, and supermarkets, as well as on numerous websites on the Internet, has contributed to their use and reflects the demand for these phytotherapeutic agents.

Introduction

The different phytotherapeutic products are extracts from the roots, the leaves, the seeds, the bark, or the fruits of the various plants used. Although single plant preparations are available, many companies manufacture combination products (two or more plant extracts) or add vitamins in an attempt to improve efficacy, to improve marketability, and to provide a single product. In addition, the extraction procedure is not standardized so that different plant extracts from different producers cannot be reliably compared. The plant extracts contain a wide variety of chemical compounds, which include phytosterols, plant oils, fatty acids, and phytoestrogens (see Fig. 7.1) [13,14]. Experimental data have suggested numerous possible mechanisms of action for the phytotherapeutic agents; study in vitro have demonstrated that plant extracts can have antiinflammatory, antiandrogenic, and estrogenic effects; decrease sexual hormone binding globulin; inhibit aromatase, lipoxygenase, growth factor-stimulated proliferation of prostatic cells, α-adrenoceptors, 5-α-reductase, muscarinic receptors, dihydropyridine and vanilloid receptors; and neutralize free radicals [14–19]. These effects have not been confirmed in vivo, and the detailed mechanisms of action of plant extracts remain unclear (see Fig. 7.2). There have been more than 30 phytotherapeutic compounds described for the management of BPH (see Fig. 7.3), the most widely used are Cucurbita pepo, Hypoxis rooperi, Pygeum africanum, Secale cereale, Urtica dioica, and Serenoa repens [20].

Phytosterols β-Sitosterol Δ5-Sterol Δ7-Sterol Stigmasterol Campesterol

21 18

22 24 20 17 23 26 13 25 1 9 C 14D 16 2 27 15 10 8 B 3 A 7 5 HO HO 6 4

Phytoestrogens Coumestrol Genistein (isoflavone) Flavonoids Fatty acids Free Esterified Terpenoids Lectins Polysaccharides Aliphatic alcohols Plant oils

FIG. 7.1 Components of plant extracts.

12

11 19

HO

Cholesterol

O Coumestans O

H O

65 78

R2 Isoflavones

4′ 1′ 2′

4

3 1 2 O

4′

H O

O

O

O P

P O

O 21 3 4

8 5

O 7 6

1′

R1

CH3 H2C

β-Sitosterol

Campesterol

O

–

O

O– O–

Chemical structure of the terpenoid

O

R1

R2

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Principal mechanisms of action of plant extracts Inhibition of 5-α-reductase Anti-inflammatory action Interference with growth factors Antiandrogenic effects Estrogenic effects Inhibition of aromatase Decrease of sex hormone-binding globulin Alteration of cholesterol metabolism Action on α-adrenergic receptors Free radical scavenging Alteration of lipid peroxidation Modulation of prolactin-induced prostatic growth Protection of bladder and detrusor function Placebo effect

FIG. 7.2 Suggested mechanisms of action of plant extracts.

List of phytotherapeutics known to be used for BPH management Plants Allium sativum Althea officinalis Arctostaphylos uva-ursi Asteracantha longifolia Cucurbita pepo Curculigo orchioides Echinacea spp. Epilobium spp. Equisetum arvense Ganoderma lucidum Hypoxis rooperi Lactuca scariola Lycopersicum esculentum Opuntia ficus-indica Orbignya speciosa Parmellia perlata Phellodendron amurense Pinus pinaster Pygeum africanum Roystonea regia Saxifraga stolonifera Secale cereale Serenoa repens Telfairia occidentalis Urtica dioica Vaccaria segatalis Zea mays

Description and locale Garlic extract, found internationally Root extract of this perennial species native to Africa Extract of this shrub found in mostly northern latitudes Seed and root extract of this plant found mostly in India Extract from pumpkin seeds found in multiple locales Extract of flowering plant species found in Asia Root extract of flowering plant found in North America Extract of flowering plant found in temperate tropical areas Extract of herbaceous plant fund in northern hemisphere Extract of the fruit of the plant found in Asia Extract of plant native to South Africa Extract of biennial plant native to Europe and North Africa Compound within the common tomato plant also known as lycopene Extract of cactus plant found in semi-arid regions of the world Extract of bark and root of Brazilian native palm tree Extract of lichen species found in temperate climate zones Bark extract of deciduous trees native to eastern Asia Extract of pine tree native to Southwest Mediterranean region Extract of evergreen tree native to regions of sub-Saharan Africa Extract of palm native to Florida and Mexico Extract of perennial flowering plant native to Asia Extract of this common grass gown as grain in fields internationally Extract of saw palmetto berry found in the southeastern USA Extract of this vine and seeds grown in West Africa Extract of flowering plant found in Europe and Asia Extract of herbaceous plant found in Eurasia Extract of common corn found in multiple locales

FIG. 7.3 List of plants extract most commonly used for BPH management.

Serenoa Repens

SERENOA REPENS Saw Palmetto (SP), also known as S. repens (SR) or Dwarf palm plant (also known by its botanical name of Sabal serrulatum), consist of the dried ripe fruit of a dwarf palm native to the West Indies and the South-Eastern United States (Florida, South Carolina). The plant itself is a bush with leaves having 18–24 sharp ending segments. The flowers are on short branches; the fruits are globular (2–3
1.5 cm), mono-seed, and bluish to black at maturity. The plant grows on dunes and pine forest. The fruit contains fatty acids and their glycerides (oleic, caprilic, myristic, lauric, stearic, palmitic, etc.), phytosterols (sitosterol, campesterol, cycloartenol), and sitosterol derivatives. Other constituents are organic acids (caffeic, chlorogenic, anthranilic, etc.) polysaccharides, tannin, sugars, volatile oil, and flavonoids. Extracts of the fruits are mainly prepared with hexane, ethanol, or supercritical CO2 [21,22]. The use of S. repens (Sr) originates from America where the Native Americans used it to manage genitourinary disturbances and enhance testicular function and breast size. The use of the whole berries as a tonic was later adopted by colonists. The first reports in the literature about use in urinary complaints date from the beginning of the 20th century. S. repens has been traditionally used as water and ethanol extracts. It is stated to possess diuretic, urinary antiseptic, endocrinological, and anabolic properties. Traditionally it has been used for chronic or subacute cystitis, testicular atrophy, sex hormone disorders, and most specifically for prostatic enlargement. Also inflammation of lactic glands in the breast, eczema, bronchial pathology, and cough are mentioned as indications in traditional medicine. It has been deemed to enhance sexual desire even if there is no scientific support for these traditional applications [22]. S. repens is undisputedly the most common phytotherapeutic agent used for symptomatic management of BPH. Preparations are used to alleviate micturition disorders such as dysuria, urinary frequency, nocturia, and urine retention [23].

Mechanism of Action It is theorized that the chemically active component of S. repens extracts is mainly free fatty acids (FFA), with more than 90% comprising of oleic acid, lauric acid, myristic acid, and palmitic acid. FFA have been implicated in inhibition of both the type 1 and type 2 iso-enzymes of 5-α-reductase, an enzyme catalyzing the conversion of testosterone into dihydrotestosterone (DHT), thereby reducing growth of the prostate gland [18,24–27]. Dose-dependent and noncompetitive inhibition of 5-α-reductase was observed in both the prostatic epithelium and the stroma in vitro experiments mainly due to FFA in the saponifiable fraction. The nonsaponifiable fraction, containing phytosterols,

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SHBG Adrenal glands Testosterone

5-α-reductase Testicles

–

Saw palmetto Dihydrotestosterone Saw palmetto

FIG. 7.4 Saw palmetto block the enzyme 5-a-reductase, which catalyzes the conversion of testosterone to dihydrotestosterone, furthermore reduces the binding of dihydrotestosterone to its receptor.

triterpenes, and fatty alcohols, and the hydrophilic components proved to be inactive. In a comparative study with finasteride, IC50 values of between 5.6 and 40 μg/mL were obtained with the various lipophilic extracts (hexane, ethanol, hypercritical CO2), compared to an IC50 of 1 ng/mL for finasteride [28] (see Fig. 7.4). Abe et al. have also demonstrated in an in vitro experiment with rat liver that S. repens extract and in particular its major constituents, lauric acid, oleic acid, myristic acid, palmitic acid, and linoleic acid, exerted binding activities of α1adrenergic, muscarinic, and 1,4-dihydropyridine (1,4-DHP) receptors and inhibited 5-α-reductase activity [29]. In another study in vitro, Suzuki et al. have shown that Saw Palmetto extract exerts significant binding activities on alpha 1-adrenergic and muscarinic receptors in the rat lower urinary tract [30]. As recently highlighted by De la Taille et al., inflammation has a key role in the pathogenesis and progression of BPH and therefore represents a rational target for BPH therapy. Scientific evidence supports the conclusion that hexanic extract of S. repens inhibits prostaglandin synthesis by blocking the activity of phospholipase A2 in the arachidonic acid cascade and also acts by inhibiting the production of 5-lipoxygenase. In their study have demonstrated that addition of hexanic extract of S. repens decreased cell proliferation induced by FGF-2

Serenoa Repens

in stromal and normal prostate cell lines and by IL-6 and IL-17 in the BPH-1 cell line. Exposure to hexanic extract of SeR, furthermore, led to significant underexpression of the human epidermal growth factor receptor 3 gene (ERBB3) and to significant overexpression of the human growth arrest-specific 1 gene (GAS1). These results would suggest, therefore, that hexanic extract of S. repens modifies the inflammatory status of BPH tissue through cytokine regulation and that reduction of inflammatory markers correlates significantly with improvement in clinical symptoms [31]. Sirab et al. in 2013 explored the effects of the lipidosterolic extract of S. repens (LSESr) on the mRNA gene expression profiles of two representative models of BPH, BPH1 cell line and primary stromal cells derived from BPH. Treatment of these cells with the extract significantly altered gene expression patterns as assessed by comparative gene expression profiling on gene chip arrays. Lipidosterolic extract of the dwarf palm plant showed a dose-dependent cytotoxic effect in cultured human epithelial and stromal cells; both cells line respond similarly to LSESr. The expression changes were manifested 3 h following in vitro administration of the extract, suggesting a rapid action for this compound. Among the genes most consistently affected by the treatment, the authors found numerous genes involved in cellular metabolism, cell cycle and differentiation, apoptosis, organ morphogenesis, hormone secretion, angiogenesis, phosphorylation, signal transduction, cellular responses to pathogens, and external stimulus. Validation studies using quantitative real-time PCR confirmed the deregulation (up- or downregulation) of genes known to exhibit key roles in these biological processes including IL1β (interleukin 1-beta), IL1α (interleukin 1-alpha), CXCL6 (chemokine C-X-C motif ligand 6), IL1R1 (interleukin 1 receptor), PTGS2 (prostaglandin-endoperoxide-synthase 2), ALOX5 (arachidonate5-lipoxygenase), GAS1 (growth arrest-specific 1), PHLDA1 (pleckstrin homology-like domain family A, member 1), IL6 (interleukin 6), IL8 (interleukin 8), NFkBIZ (nuclear factor of kappa light polypeptide gene enhancer in beta cells inhibitor zeta), NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in beta-1 cells), TFRC (transferrin receptor), JUN (jun oncogene), CDKN1β (cyclin-dependent kinase inhibitor 1β), and ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3). Subsequent analyses also indicated that treatment with the lipidosterolic extract of S. repens can impede the stimulatory effects of certain pro-inflammatory cytokines such as IL6, IL17, and IL15 in these cells. These results, therefore, suggest that LSESr treatment in BPH epithelial and stromal cells modulates the expression of genes involved in inflammation, cell growth, and survival pathways [32]. Recently, in a mouse model of prostate hyperplasia it was demonstrated that the daily administration of the lipidosterolic extract of S. repens Permixon significantly reduced the global inflammatory status of hyperplastic prostates by reducing the number of immune cell infiltrates and downregulating expression of several

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cytokines and chemokines such as CCR7, CXCL6, IL-6, and IL-17 [33]. The effect of Saw Palmetto extract on prostate inflammatory status was first described by Vela Navarette et al., in their study, in fact, they have shown a significant reduction in the number of B-lymphocytes and other immune response markers (TNFα and IL-1β) after treatment [34]. Similar antiinflammatory properties of the extract of S. repens were demonstrated studying the impact of the extract on monocyte chemo-attractant protein 1/chemokine (C-C motif ) ligand 2 (MCP-1/CCL2) and vascular cell adhesion molecule 1 (VCAM-1) expression. After pretreatment with hexane LSESr, human prostate (epithelial and myofibroblastic) cells and vascular endothelial cells were stimulated with pro-inflammatory cytokines (IFN-γ, IL-17, TNF-α) known to be secreted by prostate-infiltrating CD4 + cells in BPH. MCP-1/CCL2 and VCAM-1 mRNA expression was quantified by real-time PCR. Hexanic LSESr decrease inflammation by blocking crucial steps of leukocyte adhesion and migration, by inhibiting MCP-1/CCL2 production by prostate stroma cells and by reducing MCP-1/ CCL2 and VCAM-1 expression by vascular endothelial cells in an inflammatory environment [35]. The antiinflammatory activity of S. repens in men with BPHrelated LUTS was also evaluated by reduction of inflammation genes expression and by inhibition of prostate epithelial cell proliferation and antagonism with epidermal growth factor (EGF) receptor [36,37]. As mentioned previously, several trials have suggested that inflammation have a key role in BPH development and progression through activation of the transcription factor nuclear factor-kappa B (NF-B), increase of vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β), oxidative stress increased, production of several cytokines, overexpression of inducible-cyclooxygenase (COX-2), inducible-nitric-oxide-synthase (iNOS) and 5-lipoxygenase (5-LOX), resulting in release of prostaglandins, nitrates, and leukotrienes [38]. Although saw palmetto has a role in reducing the inflammation of the prostate and BPH-related LUTS, the combination of S. repens, selenium (Se), and lycopene (Ly) is more effective than S. repens alone to prevent hormone-dependent prostatic growth. In an experimental model on rats treated daily with testosterone propionate, in fact, Morgia et al. have shown that combined treatment with Ly-Se-SeR was more effective than S. repens alone for decreasing prostate weight and hyperplasia, increasing proapoptotic bcl-2-like protein 4 (Bax) and caspase-9, and reducing antiapoptotic Bcl-2 mRNA. Lycopene-Selenium-S. repens also markedly decreased epidermal growth factor and vascular endothelial growth factor expression. During testosteroneinduced growth there was overexpression of the growth factor EGF, which was exactly prevented by treatment with SeR and to a greater extent by combined Ly-Se-SeR [39]. In an in vitro and in vivo comparison study conducted by the same authors, it was demonstrated that the Ly-Se-SeR association caused a greater inhibitory effect on the expression of COX-2, 5-LOX, and iNOS

Serenoa Repens

expression. That association of plants extracts reduced oxidative stress and prostate pro-inflammatory phenotype, as well as hyperplasia, more efficiently than the single compounds; in particular the Ly-Se-SeR association showed a higher efficacy in reducing the loss of inhibitor κB-α (IκB-α), the increased Nuclear factor-kappa B (NF-κB) binding activity. The association of phytotherapeutic compounds was also the most effective treatment in reducing mRNA levels of Tumor necrosis factor-α (TNF-α) and caused a greater inhibitory effect on iNOS expression and nitrite release; Lycopene-Selenium-S. repens association was as effective in reducing malondialdehyde (MDA) [40]. The triple therapeutic association, finally, may have an antiinflammatory activity that could be of interest in the treatment of prostatic chronic inflammation in BPH patients. In the “Flogosis and Profluss® in prostatic and genital disease (FLOG),” a multicenter study involving nine urological Italian centers, we have demonstrated a significant difference of flogosis between treated versus control with a reduction both of extension and grading of inflammation and inflammatory infiltrate (B-lymphocytes CD20, T-lymphocytes CD3–CD8, and macrophages CD68). This antiinflammatory activity could be of interest, therefore, in the treatment of chronic prostate inflammation in BPH patients [41]. In 2014, finally, we have evaluated in an experimental model with BPH animals treated with testosterone the expression of four inhibitors of apoptosis proteins (IAPs) that influence apoptosis by direct inhibition of caspases and by the modulation of the transcription factors. BPH animals treated showed unchanged expression of cellular IAP-1 and cellular IAP-2 and increased expression of neuronal apoptosis inhibitory protein (NAIP), survivin, caspase-3, IL-6, and prostate specific membrane antigen (PSMA) levels when compared with sham animals. Immunofluorescence studies confirmed the enhanced expression of NAIP and survivin with a characteristic pattern of cellular localization. SeR-Se-Ly association showed the highest efficacy in reawakening apoptosis; additionally, this therapeutic cocktail significantly reduced IL-6 and PSMA levels. The administration of SeR, Se, and Ly significantly blunted prostate overweight and growth; moreover, the triple association was most effective in reducing prostate enlargement and growth by 43.3% in treated animals [16].

Variability of Products and Extraction Techniques A known difficulty in evaluating the literature pertaining to Saw Palmetto Berry is the absence of standard extraction and formulation. There are numerous branded S. repens products, and they differ both qualitatively and quantitatively because of differences in the source of the biological product and variations in the process used to extract the active ingredients. Several different extraction techniques with differences in terms of methodology, time, temperature, pressure, and solvents have been developed, also used in combination with other

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techniques in order to improve the recovery and, consequently, the pharmacological profile of their extracts. However, as a consequence of the differences among the extractive processes used by several companies, there is a discrepancy in the qualitative and quantitative composition of the extracts obtained from the same plant. Hence, despite the benefits obtained from SeR, the variety of the extractive techniques and strategies makes one extract different from another in terms of bioactives composition and this could affect the quality and the clinical effects of natural therapies of different brands even if derived from the same plant [42,43]. In order to define the proportional content of the different types of S. repens, the National Institute of Health’s Office of Dietary Supplements and the Food and Drug Administration’s Center for Drug Evaluation and Research are collaborating with the National Institute of Standards and Technology (NIST) to develop standard reference materials (SRMs) for selected dietary supplements including Saw Palmetto. In the case of saw palmetto, two reference materials have been developed: SRM 3250 S. repens fruit and SRM 3251 S. repens extract. SRM 3250 has certified concentration values for specific phytosterols and fatty acids (free or as triglycerides). On the other hand, the extract SRM 3251 has certified concentration values for phytosterols, fatty acids (free or as triglycerides), β-carotene and its isomers, and γ- and δ-tocopherol [44]. Numerous extraction techniques have been described and utilized; Permixon, for example, uses a hexanic (solvent) extraction method by which the bioactive compounds are dissolved from the ground plant and then extracted out for final collection (n-hexane lipidosterolic extract). A second extraction technique utilizes supercritical fluid extraction, whereby CO2 at low temperatures and pressures is used to recover essential oils; a third extraction technique is microwave-assisted extraction that utilizes solvents that absorb different electromagnetic radiation waves. Other extraction techniques include ultrasound-assisted extraction, ionic liquids, enzyme-assisted extraction, and pressurized liquid/fluid extraction [45–53] (see Table 7.1). Among those listed the lipidosterolic extract of S. repens obtained by solvent (hexane) extraction is the most widely studied product in clinical and experimental trials. An understanding of the composition of different brands of S. repens is essential to comprehensive whether they are likely to be bioequivalent. To this end, Habib et colleagues compared 14 brands of S. repens: the examination highlighted significant differences in composition among the different brands. In particular, the concentration of FFA, which have been suggested as the main active ingredients of S. repens, ranged between 41% and 81%. Each of the individual FFAs analyzed was found in similar proportions in all the products assayed, with lauric and oleic acids present at the highest concentrations in every sample assayed [42]. De monte et al., however, reported significant different in overall FFA content as well as differing proportions of the individual FFAs; Booker et al., furthermore, in 2014 demonstrated that only 9 of 57 Serenoa preparations contained the recommended dose of FFA as defined by the World Health Organization [43,54].

Serenoa Repens

Table 7.1 Different Extract of Different Brand of Serenoa repens Extract (Composition) Sabal Select (>90% free fatty acids or their esterified forms, 0.01%–0.15% fatty alcohols, 0.25%–0.50% total sterols, 0.15%–0.35% β-sitosterol)

Sabal Select (>90% free fatty acids or their esterified forms, 0.01%–0.15% fatty alcohols, 0.25%–0.50% total sterols, 0.15%–0.35% β-sitosterol)

Extraction Technique

Isolated Active Compound (%)

Supercritical CO2

Oleic acid (15%)

Supercritical CO2

Lauric acid (15%) Lauric acid (30.2%) Oleic acid (28.5%) Myristic acid (12.1%)

Permixon Free saturated and unsaturated fatty acids (>90%)

Prostasan (95% total content of free fatty acids) Prostasan (95% total content of free fatty acids) Prostasan (86% total content of free fatty acids) Saw Palmetto Berry Powder (SPBE) (Madis Botanical, Inc., New Jersey) (90% free fatty acids, alcohols, and sterols) PC-SPES Talso, Talso uno

Solvent (hexane) extraction

Solvent (96% ethanol) extraction Solvent (96% ethanol) extraction Solvent (96% ethanol) extraction Solvent (20% ethanol) extraction of (phyto)sterols

Solvent (70% ethanol) extraction Supercritical CO2

Palmitic acid (9.1%) Linoleic acid (4.6%) Free fatty acids/mixed triglycerides ratio: 55/45 Oleic acid (36.0%), lauric acid (27.5%), Myristic acid (12.0%) Palmitic acid (9.7%) Esterified FAs represent 7%, while the rest is composed of phytosterols, flavonoids, alcohols, and polyprenic compounds Not reported Not reported Not reported β-Sitosterol, stigmasterol, cholesterol

Not reported Acid lipophilic compounds, fatty alcohols and sterols as main components Continued

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Table 7.1 Different Extract of Different Brand of Serenoa repens—cont’d Extract (Composition)

Extraction Technique

Isolated Active Compound (%)

Prostamol Uno

Not reported

Prostate EZE Max

Not reported

Profluss

Oily extract

SeR

Solvent (ethanol) extraction

Saturated and unsaturated fatty acids and phytosteroids Serenoa repens standardized to fatty acids, Pygeum africanum standardized to β-sitosterol, Epilobium parvrflorum, Cucurbita pepo seed oil, lycopene Serenoa repens extract 85%, lycopene 6%, selenium Not reportedFrom De Monte C, Carradori S, Granese A, Di Pierro GB, Leonardo C, De Nunzio C. Modern extraction techniques and their impact on the pharmacological profile of Serenoa repens extracts for the treatment of lower urinary tract symptoms. BMC Urol 2014;14:63.

In consideration of the different compositions of the various brands of S. repens, in 2008 Scaglione et al. evaluated seven brands of S. repens available in Italy using a 5-α-reductase activity assay involving epithelial and fibroblast cells cocultured for 10 days. All extracts tested inhibited both isoforms of 5-α-reductase (I and II), although there was clear variation in potency between the different extracts and between different batches of the same extracts [55]. More recently, the same author repeated this study comparing the potency of lipidosterolic extracts from 10 different brands with similar results [56]. As highlighted by Raynaud and colleagues, the different efficacy of Serenoa repens in inhibiting the two isoform of 5-α-reductase depends on the length of the carbon chain and its saturation state. Particularly, lauric acid inhibits both 5-α-reductase type I and II, while myristic acid strongly inhibits only type II. Oleic acid and linoleic acid have a good activity on type I but not on type II while palmitic and stearic acids are inactive on both isoforms. Thus only the products with complete fatty acid compositions have the best inhibitory activity on 5-α-reductase [57]. However, the inevitable conclusion is that with over 100 varieties of Saw Palmetto berry extract marketed, comparison of products is essentially impossible.

Clinical Studies According to the European Association of Urology and to American Urological Association guidelines, the use of phytotherapy in treating LUTS and BPH has been popular in Europe and United States even if recent studies with more

Serenoa Repens

rigorous methods have generally failed to confirm a clinically important role for S. repens in the management of BPH and that more definitive evidence regarding the use of S. repens in BPH is needed. Have been published several clinical studies and multiple metaanalyses and review on Saw Palmetto berry extract and its effect on BPH; many of initial systematic reviews, including those by Wilt in 1998 and Boyle in 2004, suggest an efficacy of SeR to improve urinary symptoms in treated patients against placebo. In the metaanalysis by Wilt and colleagues of 18 trials involving nearly three thousand patients using various S. repens monopreparations and combination products, the mean weighted difference for nocturia between patients and individuals taking a placebo was  0.76 times per night. Boyle et al. carried out a metaanalysis of 17 studies (14 randomized clinical trial and 3 open-label trials) performed with the same commercially hexane extract (Permixon). In their study, the authors concluded that S. repens modestly but significantly improved peak urinary flow and nocturia: Permixon was associated with a mean reduction in the International Prostate Symptom Score (IPSS) of 4.78 points. The estimated effect of Permixon on peak urinary flow was an increase of 2.22 mL/s than placebo (where it was of 1.02 mL/s). The placebo effect is associated with a reduction in the mean number of episodes of nocturia of 0.63 which is further reduced to 1.01 episodes/night with Permixon therapy [58,59]. In order to correct methodological issues of previous studies, Bent et. al in 2006 published a randomized double-blinded trial in which were evaluated 225 men over the age of 49 years who had moderate-to-severe symptoms of BPH treated for 1 year with saw palmetto extract (160 mg twice a day) or placebo. The authors reported no significant difference between the saw palmetto and placebo groups in the change in American Urological Association Symptom Index (AUASI) score, maximal urinary flow rate, prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen levels during the 1-year study [60]. In 2011, the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) study, a double-blind, multicenter, placebo-controlled randomized trial conducted by Barry et colleagues founded that S. repens ethanolic extract used at up three times of the standard daily dose (320 mg/day) had no greater effect than placebo on LUTS. The study, however, showed the safety and tolerability of Saw Palmetto extract even at double and triple doses compared to placebo [61]. In the recent updated Cochrane review by Tacklind, MacDonald et al. 32 randomized controlled trials studying 5666 men with symptomatic BPH were evaluated to receive S. repens extract monotherapy for at least 4 weeks in comparison with placebo. Of the included trials, 12 used Permixon, five studies compared another standardized combination of SeR (160 mg) and U. dioica extracts (120 mg) known by the commercial name Prostagutt forte, fourteen trials used generic SeR alone or in combination with other phytotherapic (pumpkin seeds, vitamins A and E, nettle root, P. africanum).

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The authors concluded that even if S. repens extracts are widely used to treat symptomatic BPH, it did not improve LUTS or Qmax associated with BPH [62,63]. However, the wide variation in inclusion criteria of patients in the studies is cause of concern. In some studies patients were included starting from a score 6 on the IPSS: considering that the scale ranges from 0 to 35, it may be questionable to include patients with a value of 6 who are nearly considered as healthy. On the other hand, may be doubtful to include patients with an IPSS of more than 32 for a drug treatment (see Table 7.2).

Table 7.2 Outcome of Clinical Studies With Serenoa repens Reference

Outcome

Remarks

Tacklind et al. [62] Negative

Serenoa repens, at double and triple doses, did not improve urinary flow measures or prostate size in men with LUTS BPH related No difference between SR and PL for all parameters

Update of former Cochrane analysis. Based on 2 recent studies with different conditions [60,61] Extensive exclusion list 369 patients treated with doses up to 3
therapeutic dose. Ethanolic extract during 72 weeks 94 patients treated during 3 months with, a nondefined extract of SR

Barry et al. [61] Negative Shi et al. [166] Positive

Significant difference in % of patients improved: SR > PL (IPSS as primary outcome). Significantly higher flow rate and lower resistance for SR vs PL IPSS: no difference between groups

Hizli and Uygur [167] Equivalence Ulbricht et al. [168] Positive

Positive opinion about the therapeutic role of different SR preparations

Bent et al. [60] Negative

No difference between SR and PL for all parameters

Boyle et al. [59] Positive

Significant improvement of urinary flow and nocturia

Willetts et al. [169] Negative

No difference between SR and PL for all parameters

Debruyne et al. [170] Equivalence
main et al. [171] Gle Equivalence

Similar lowering of IPSS Lowering IPSS comparable in both groups

60 patients divided in three groups: T, SR (hexane extract), T + SR. Duration: 6 months Evidence-based systematic review of 33 studies with different preparations. Although several flaws were reported, the opinion of the authors is positive Broad inclusion criteria. 225 patients treated with normal doses of CO2 extract (different from extracts commercialized in EU) during 12 months Metaanalysis of 17 published and nonpublished studies with the same hexane extract. Only 7 of them reported on IPSS Considerable difference of IPSS between both groups at baseline 100 patients treated with normal doses of CO2 extract (different from extracts commercialized in EU) during 3 months 704 patients treated with a hexane extract or T during 12 months 329 patients treated with T or T + SR standardized hexane extract during 52 weeks

Serenoa Repens

Table 7.2 Outcome of Clinical Studies With Serenoa repens—cont’d Reference

Outcome

Remarks

Gerber et al. [172] Positive

SR significantly improves IPSS than PL

Braeckman et al. [173] Positive

Urinary frequency, nocturia, urgency, dysuria, and urinary volume significantly improved vs PL. Quality of life rated by patients and doctors better than with PL Similar IPSS

Responders to PL after 1 month were excluded. 85 patients were treated with an undefined extract during 6 months 238 patients treated with a critical CO2 extract or PL during 12 weeks

Carraro et al. [174] Equivalence Descotes et al. [175] Positive Grasso et al. [176] Equivalence €belenz et al. [177] Lo Negative Mattei et al. [178] Positive Reece-Smith et al. [179] Negative Cukier et al. [180] Positive Tasca et al. [181] Positive Champault et al. [182] Positive Emili et al. [183] Positive Boccafoschi and Annoscia [184] Positive

Statistically significant improvement toward PL of dysuria, urinating frequency (day and night), and urinary flow rate No difference No difference in urinary flow between SR and PL SR: significant improvement vs baseline PL: no significant improvement vs baseline Significant improvement in both SR and PL of LUTS. No difference between groups Urinary frequency and residual urinary volume significantly decreased with SR vs PL Peak urinary flow increased and urinary frequency decreased significantly with SR vs PL Significant improvement by SR toward PL of nocturia, urinary flow rate, and residual volume Dysuria improved more in SR than in PL Overall SR significantly better than PL

1098 patients treated with a hexane extract or finasteride during 26 weeks 215 patients treated with a hexane extract during 4 weeks 63 patients treated with a nonspecified SR extract or alfuzosin during 3 weeks 60 patients were treated during 6 weeks with an undefined extract. Study with several flaws 40 patients treated with a nondefined extract 80 patients treated with a hexane extract or PL during 12 weeks 168 patients treated with a hexane extract or PL during 10 weeks 30 patients treated with a hexane extract or PL during 8 weeks 110 patients treated with a hexane extract or PL during 4 weeks 30 patients treated with a hexane extract or PL during 4 weeks 22 patients treated with a hexane extract or PL during 8.5 weeks

PL, placebo; SR, Serenoa repens; T, tamsulosin.

In recent years, several studies have evaluated the combination therapy including saw palmetto and other plant extracts on urinary symptoms. In 2015 Marzano et al. published a comparative study to evaluate the effectiveness of cotreatment with S. repens (320 mg) plus Bromeline plus Nettle (Prostamev Plus) in comparison to S. repens alone in reducing the symptoms of prostatitis. After 2 months, the groups treated with Prostamev Plus in comparison to the groups treated with S. repens extract (saw palmetto) achieved better

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improvements of both IPSS, urinary flow and sexual life [64]. In 2013, Coulson et al. published results from a phase II clinical trial on ProstateEZE Max a combination supplement of five commonly used plants extract including C. pepo, Epilobium parviflorum, lycopene, P. africanum, and S. repens. The authors found a significant reduction in the IPSS score in the active group of 36% compared to 8% for the placebo group after 3 months follow-up [65]. As early as 2013, in fact, Minutoli et collaborators showed that the association of selenium, lycopene, and Serenoa increases their activity in BPH as recently reiterated by Russo, Salonia et al. [66,67]. Selenium (Se) is a mineral essential in the diet of humans. The major dietary sources of Se are plant foods including Brazilian nuts, whole grains, wheat germ, soybean, sunflower seeds, and fish. In human body, the highest Se concentrations are in the liver, kidneys, and thyroid gland. Selenium is usually integrated into proteins to form selenoproteins as glutathione peroxidases, thioredoxin reductases, and iodothyronine deiodinases which are involved in several biological functions in both animals and humans [68,69]. Although selenium could reduce the risk of developing prostate, lung, and colorectal cancer through epigenetic and antioxidant effect, its effectiveness has not yet been fully demonstrated [70–74]. Lycopene (Ly) is the red pigment of tomatoes showing a potent antioxidant and antiinflammatory activity twice as effective as β-carotene and 10-fold more activity than α-tocopherol. Lycopene concentrations are known to be elevated in human semen and in prostate gland [75–78]. The abundance of lycopene in prostatic tissue is indirectly implicated in the chemoprevention of pathologies as BPH and prostate cancer [79,80]. With the aim to evaluate the efficacy and tolerability of combination therapy between S. repens (SeR), Lycopene (Ly), and Selenium (Se) + tamsulosin versus single therapies in patients with LUTS, in 2014 Morgia et al. conducted the PROCOMB trial, an Italian multicenter double-dummy randomized study of 225 men with an age of 55–80 years old. Patients were randomized in group A (SeR-Se-Ly), group B (tamsulosin 0.4 mg), group C (SeR-Se-Ly + tamsulosin 0.4 mg); the primary endpoints of the study were the reduction of IPSS, postvoid residual urine (PVR), and increase of Qmax in group C versus monotherapy groups. Combination therapy has been demonstrated to be more effective than the individual monotherapies in terms of reduction of the IPSS and of increase of Qmax after 1 year. The association of Ser-Se-Ly with 0.4 mg of tamsulosin decreased the IPSS score by 18.2% versus a 13.8% and 14.3% decrease for only tamsulosin and only herbal treatments, respectively. The proportions of men with a decrease of at least three points and decrease of 25% for IPSS were greater for Group C but the proportion of men with an increase of at least 3 mL/s and of 30% of Qmax was not statistically different for combination therapy versus

Serenoa Repens

single monotherapies [81]. The efficacy of Se-Ly-SeR (Profluss) versus SeR alone was also evaluated by the same group of authors in patients suffering from category IIIa chronic prostatitis/chronic pelvic pain syndrome (CP/ CPPS); IPSS improved significantly in both group but more in the combination group [82]. Despite these findings, there is still significant heterogeneity in study design and methodological validity with small sample size and shortterm follow-up. There is need for larger randomized placebo-controlled studies to better assess SeR + Se + Ly in BPH patients, but current data seem to demonstrate greater effectiveness of Serenoa + Lycopene + Selenium compared to monotherapy with Saw Palmetto extract.

Safety Profile Clinical trials of Saw Palmetto have consistently demonstrated that therapy at a dose of 320 mg/day is well tolerated with a side effect that is generally mild and include headache, decreased libido, and gastrointestinal problems [63]. In a systematic review of adverse events of S. repens published in 2009, the majority of adverse events are mild, infrequent, and reversible, and similar to those with placebo. The most frequently reported adverse events are abdominal pain, diarrhea, nausea, fatigue, headache, decreased libido, and rhinitis [83]. More serious adverse events such as death, liver damage, pancreatitis, and cerebral hemorrhage are reported in isolated case reports and data from spontaneous reporting schemes, but causality is questionable [84–89]. There may be an increased response to anticoagulant treatment in patients who take SeR preparations. S. repens does not appear to have a clinically relevant effect on the majority of cytochrome P450 isoenzymes and no other interactions with S. repens have been found [90]. The S. repens extract used in the CAMUS trial showed no evidence of toxicity at doses up to three times the usual clinical dose over an 18-month period. Participants were randomized to 320, 640, and 960 mg daily of an ethanolic S. repens extract or to an identical-appearing placebo in an escalating manner at 6-month intervals for a total of 18 months of follow-up. Adverse event assessments, vital signs, and blood and urine laboratory tests were obtained at regular intervals. There were no statistically significant differences between the groups in the rates of serious or nonserious adverse events, changes in vital signs, digital prostate examination findings, or study withdrawal rates. Overall, there were no significant intergroup differences in laboratory test abnormalities, while differences in individual laboratory tests were rare and small in magnitude. No evidence of significant dose-response phenomena was identified [91]. S. repens inhibits both the type 1 and type 2 iso-enzymes of 5-α-reductase; furthermore, and this confirms the specificity and selectivity of SeR, 5-α-reductase activity is not inhibited after treatment with the plant extract in cells of

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nonprostate origin [23]. However, in contrast to other 5-α-reductase inhibitors, SeR induces its effects without interfering with the cellular capacity of the prostate to secrete prostate-specific antigen (PSA) in vitro and in vivo [92]. In 2013, Andriole et colleagues analyzed data on CAMUS trial demonstrating that Saw Palmetto extract did not alter PSA compared to placebo. PSA was shown, in fact, to be similar at baseline between treatment groups and the mean change during the trial for SPB and placebo was 0.23 and 0.16, respectively (P ¼ .5). They concluded that even at relatively high doses, Saw Palmetto berry did not affect serum PSA levels. Thus there is no concern that taking SPB may mask the ability to detect prostate cancer via PSA screening [93].

Conclusion Experimental and clinical studies suggest a crucial role for SeR as an alternative therapy (or as a complementary therapy) for the treatment of LUTS due to BPH. SrE, with its various ingredients, shows a wide range of biologic activities within the prostate and demonstrates a high specificity and selectivity for this organ. From in vitro experiments the following properties were identified: (1) inhibition of 5-α-reductase, (2) influence on androgen-receptor binding, (3) inhibition of alpha-receptor binding, (4) inhibition of eicosanoid synthesis, (5) spasmolytic effects, and (6) antiinflammatory effects. The activity can differ from one extract to another, probably dependent upon the content of fatty acids. Toxicity of the hexane extract appears low; there are no data on genotoxicity, carcinogenicity, or reproductive toxicity. As already said before, the main properties of SeR, confirmed in in vivo experiments, are its antiandrogenic, proapoptotic, and antiinflammatory effects, as well as its capacity to intercept each of these distinct pathways [94] (see Fig. 7.5).

PYGENUM AFRICANUM P. africanum (PA), a member of the Rosaceae family, is an evergreen species found across the entire continent of Africa at altitudes of 1000 m or higher. Pygenum consists of the bark of African plum tree, a tall tree usually 10–25 m high, with a straight cylindrical trunk and dense rounded crown. Leaves are deep green and glossy, 8–12 cm long with elliptic, weakly acuminate, and coriaceous. The bark is dark brown or red with strong cyanide smell when freshly cut; the young branchlets often are reddish. Flowers are small, white or whitish cream, fragrant, in axillary racemes 3–8 cm long. Fruits are cherry shaped, red to purplish-brown, 8–12 mm in diameter; are very bitter flesh and with bony stone. The major bark components are fat-soluble compounds. The main characteristic constituents are phytosterols (beta-sitosterol, betasitosterylglucoside, beta-sitostenone) and other sterols and steroid intermediates; triterpenoid pentacyclic acids (ursolic, oleanolic, and their homologs

Pygenum Africanum

Saw palmetto

Blockade aadrenoceptors

5-a-reductase Inhibition of Reduction of the Lipoxygenase and Testosterone receptor apoptosis-toCicloxygenase proliferation ratio

a1-Adrenoceptors antagonism

Antiinflammatory activity

Reducing resistance in urinary flow

Inhibit prostaglandin synthesis

Antiandrogenic activity

Antiproliferative activity

Reducing enlarged prostate

Reduction of symptoms of BPH FIG. 7.5 Principal mechanisms of action for hexanic extract of Serenoa repens in the treatment of benign prostatic hyperplasia.

sometimes acetylated by ferulic acid); alcohols especially docasanol, and C12– C22 fatty acids of which palmitic acid is the most predominant [7,95–97]. Interest in the species began in the 1700s when European travelers learned from South African tribes how to soothe bladder discomfort and treat “old man’s disease” with the bark of PA. Traditionally, the bark of African plum tree was collected and powdered then drunk as a tea; it has been used in Europe since the mid-1960s to treat men suffering from BPH. Currently, Pygeum is one of the most commonly used phytotherapic for BPH, backed by many doubleblind studies pointing to its efficacy for reducing its symptoms [98–102].

Mechanism of Action The mechanism of action of P. africanum has not been completely investigated. Several mechanisms could contribute to the therapeutic effect: these include the inhibition of prostatic fibroblast proliferation in response to growth factors, the antiinflammatory activity by inhibiting production of pro-inflammatory prostaglandins in the prostate (decreasing production of leukotrienes and other 5-lipoxygenase metabolites), a weak inhibition of 5-α-reductase. Particularly atraric acid, a phenolic ester with IUPAC name methyl 2,4-dihydroxy-3,6dimethylbenzoate is well known for its antiandrogenic activity through its

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capacity to inactivate the androgen receptor by inhibiting its nuclear translocation. Pygeum also contains pentacyclic triterpenes (ursolic and oleanic acids) that have antiedema properties, and ferulic acid nesters (n-docosanol and tetracosanol) that reduce prolactin levels and block the accumulation of cholesterol in the prostate. Prolactin is purported to increase the uptake of testosterone by the prostate, and cholesterol increases binding sites for DHT. The African prune tree has a positive effect not only on the prostate, but also on the bladder by protecting it by destructive effects of free radicals and degradative enzymes; it also modulates bladder contractility by reducing the sensitivity of the bladder to electrical stimulation, phenylephrine, adenosine triphosphate, and carbachol [99–106] (see Fig. 7.6). In animal models, Pygeum regenerates the secretory activity of the prostate epithelium, modulates the contractility of the bladder, and has antiinflammatory activity related to the inhibition of 5-lipoxygenase, with a consequent decrease of leukotrienes production and other 5-lipoxygenase metabolites [103]. The antiphlogistic action of Pygeum could partially depend on its ability to reduce the number of neutrophils and the TGF-β expression in these cells [107,108]. In 2010 Quiles et al. demonstrated the antiproliferative and apoptotic effects of the P. africanum on cultured prostate stromal cells from patients with BPH. Antiproliferative potency and apoptosis induced

Pygeum africanum

Protection from radicals and degradative enzymes

Antioxidant activity

Inhibition of lipoxygenase

Antiinflammatory activity

Competes with androgen precursors

Inhibition of growth factors

Antiandrogenic activity

Antiproliferative activity

Reduction of symptoms of BPH

FIG. 7.6 Principal mechanisms of action for Pygeum africanum in the treatment of benign prostatic hyperplasia.

Pygenum Africanum

by PA on stromal cells were increased in BPH versus non-BPH cells. Their results suggest that Pygeum mechanisms of action include inhibition of the proliferation of human prostatic fibroblasts and myofibroblasts but not on smooth muscle cells, and downregulation of transforming growth factor B1 (TGFB1) and inhibition of fibroblast growth factor 2 (FGF2) [109,110]. Finally, studies in vivo have shown a potential role of Pygeum in reduction of the incidence of prostate cancer [111,112].

Clinical Studies The literature on Pygeum for the treatment of BPH is limited by the short duration of studies and the variability in study design, the use of phytotherapeutic preparations, and the types of reported outcome. Two different daily dosage regimens for a lipophilic extract from pygeum bark were compared in a randomized study. Out of 235 BPH patients randomized 209 completed a 2-month double blind phase, receiving either 50 mg of the extract twice daily, morning and evening (group A, 101 patients) or 100 mg once daily in the evening (group B, 108 patients). Both treatments had similar efficacy after 2 months: in group A the IPSS decreased by 38%, the quality of life score improved by 28% and the maximum urinary flow rate increased by 16%; in group B the figures were 35%, 28%, and 19%. In a subsequent 10-month open phase, 174 patients took 100 mg of the extract once daily. After 12 months the overall IPSS had decreased by 46% and the maximum urinary flow rate had increased by 15% [113]. In a metaanalysis of 18 randomized controlled trials involving 1562 men, Ishani et al. have demonstrated that, although the duration of treatment was short and study designs and types of reported outcome varied greatly, P. africanum provided a moderately large improvement in urologic symptoms and flow measures (nocturia was reduced by 19%, residual urine volume by 24%, whereas peak urine flow was increased by 23%) [100].

Safety Profile The usual dosages are 100–200 mg a day. Adverse effects due to P. africanum were mild and comparable to placebo. The majority of the studies reported an absence of any significant adverse effects of Pygeum, although there have been rare complaints of diarrhea, constipation, dizziness, gastric pain, and visual disturbances [114,115]. One study demonstrated continued satisfactory safety profiles in 174 human subjects after 12 months of 100 mg daily doses [113]. Signs of toxicity in liver, kidney, and heart were observed only with very high doses; genotoxicity studies gave variable results [116,117].

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Conclusion P. africanum may be a useful treatment option for men with lower urinary symptoms consistent with BPH. However, the studies carried out up to nowadays were small in size and of short duration, used varied doses and preparations, and rarely reported outcomes using standardized validated measures of efficacy. Additional placebo-controlled trials are therefore needed.

URTICA DIOICA U. dioica (UD), often called common nettle or stinging nettle, is an herbaceous perennial flowering plant in the family Urticaceae. It is native to Europe, Asia, northern Africa, and western North America; it grows wild around rural houses, in piles of rubble and in ditches all over the world, in regions where the climate is humid and temperate. U. dioica is a perennial plant, 1–2 m tall in the summer and dying down to the ground in winter. The soft, green leaves with long triangular teeth are 3–15 cm long and are borne oppositely on an erect, wiry, green stem. The leaves have an acuminate tip with a terminal leaf tooth longer than adjacent laterals and contains sterols (sitosterol), glycoproteins, acids (salicylic, malic, carbonic and formic), flavonoids (rutin, kaempferol, quercetin, etc.), minerals (calcium, potassium), amines (histamine, etc.), tannins, etc. The roots contain polysaccharides, lectins, sterols and their glucosides (3-beta-sitosterol, sitosterol-3-D-glucoside, etc.), Iignans, fatty acids, and scopoletin [7]. This mixture of chemical compounds (histamine, formic acid, acetylcholine, acetic acid, butyric acid, leukotrienes, 5-hydroxytryptamine, and other irritants) causes a painful sting or paresthesia and the development of an erythematous macule, and itching or numbness for a period lasting from minutes to days. The plant has a long history of use as a source of medicine, food, and fiber. This herb dates the medieval times when it was used as a diuretic and as therapy for joint problems. Traditionally it is used as a depurative, for acne, diarrhea, diabetes, to improve circulation and low blood pressure; for external use the nettle is used as a remedy for hair loss, against seborrhea and dandruff of the scalp. Today, it is also used to treat BPH [118–122].

Mechanism of Action Only a few components of the active principle have been identified and the mechanism of action is still unclear. It seems likely that sex hormone binding globulin (SHBG), aromatase, epidermal growth factor, and prostate steroid membrane receptors are involved in the antiprostatic effect, but less likely that 5-α-reductase or androgen receptors are involved; extract and a polysaccharide fraction were shown to exert antiinflammatory activity [120]. The lignans contained in the stinging nettle, in fact, inhibits the binding of the SHBG to its

Urtica Dioica

receptor in the membrane of human prostatic cells. The polysaccharides and lectins can block the binding between the epidermal growth factor, secreted by the prostate tissue, and its receptors, with suppression of prostate cellular metabolism and its growth. In addition, the lectines may contribute to the prostatic antiproliferative and antiinflammatory activities [118]. The steroidal compounds stigmasterol and campesterol have been shown to inhibit the prostatic sodium/potassium pump, which might contribute to nettle’s effects in BPH. The small quantity of beta-sitosterol in nettle root ( .05). Intraoperative floppy iris syndrome has also been described during cataract extraction in patients under alpha-blockers. This associate an inclination to iris prolapse through iris incision, an iris flaccidity and intraoperative loss of initial mydriasis, and tend to increase surgical difficulty [39]. Alpha-blockers should be stopped prior to surgery in patients undergoing cataract extraction.

CLINICAL USE General Indications/Single Therapy Alpha-blockers are recommended as a firstline option for moderate/severe LUTS/BPO whatever the age or prostate size, in case of bothersome voiding symptoms or mixed symptoms with predominant voiding symptoms. Obviously, adequate information about safety profile of the drugs proposed is mandatory and a follow-up at 3 months is required.

Associations Combination therapy can be proposed, notably in case of failure of single therapy with alpha-blockers. In case of persistence of voiding symptoms of the size of the prostate is over 40 mL, several studies have proven the positive effect of adding a 5-alpha-reductase inhibitor to the alpha-blocker treatment (Medical Therapy of Prostatic Symptoms (MTOPS), ComBAT studies [1]). The combination therapy is associated with a lower risk of AUR in the long term, improved IPSS and Qmax, and risk of surgery. Risk of clinical progression (AUR, infections, incontinence, or renal impairment) is reduced by combination therapy. Alpha1-blockers can be associated to antimuscarinics in case of persistence of storage symptoms after initial monotherapy management. No other strong recommendations are available, especially regarding the association of alpha-blockers with phytotherapy, phosphodiesterase type 5, or mirabegron, although some studies are ongoing.

CONCLUSION If the efficacy of all A1-AR blockers seems equivalent in long-term studies, it does not prevent AUR- and BPH-related surgery event. Furthermore, side effects vary within drugs and patients should be informed of the most frequent adverse event that can lead do treatment discontinuation.

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References [1] Gravas S, et al. EAU guidelines on lower urinary tract symptoms, including benign prostatic obstruction, http://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/#5_2. [2] Cornu JN, Cussenot O, Haab F, Lukacs B. A widespread population study of actual medical management of lower urinary tract symptoms related to benign prostatic hyperplasia across Europe and beyond official clinical guidelines. Eur Urol 2010;58(3):450–6. [3] Abrams P. New words for old: lower urinary tract symptoms for “prostatism” BMJ 1994;308 (6934):929–30. [4] Abrams P. Nocturia: escaping the “prostate-centric” approach. J Urol 2011;185(3):781–2. [5] Reynard J, Abrams P. Symptoms and symptom scores in BPH. Scand J Urol Nephrol Suppl 1994;157:137–45. [6] Chapple CR, Roehborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol 2006;49 (4):651–8. [7] Chapple CR, Osman NI, Birder L, van Koeveringe GA, Oelke M, Nitti VW, et al. The underactive bladder: a new clinical concept? Eur Urol 2015;68(3):351–3. [8] Shapiro E, Becich MJ, Hartanto V, Lepor H. The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostate hyperplasia. J Urol 1992;147:1293–7. [9] Walden PD, Gerardi C, Lepor H. Localization and expression of the alpha1A-1, alpha1B and alpha1D-adrenoceptors in hyperplastic and non-hyperplastic human prostate. J Urol 1999;161:635–40. [10] Kawabe K, Moriyama N, Hamada K, Ishima T. Density and localization of alpha 1-adrenoceptors in hypertrophied prostate. J Urol 1990;143:592–5. [11] Corvin S, et al. Videoimaging of prostatic stromal-cell contraction: an in vitro model for studying drug effects. Prostate 1998;37:209–14. [12] Brune ME, et al. Effect of fiduxosin, an antagonist selective for alpha(1A)- and alpha(1D)adrenoceptors, on intraurethral and arterial pressure responses in conscious dogs. J Pharmacol Exp Ther 2002;300:487–94. [13] Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 2006;147(Suppl. 2):S88–S119. [14] Yokoyama O. Pharmacological and genetic analysis of mechanisms underlying detrusor overactivity in rats. Neurourol Urodyn 2010;29(1):107–11. [15] Kadekawa K, Sugaya K, Nishijima S, Ashitomi K, Miyazato M, Ueda T, et al. Effect of naftopidil, an alpha1D/A-adrenoceptor antagonist, on the urinary bladder in rats with spinal cord injury. Life Sci 2013;92(20–21):1024–8. [16] Miyazato M, Oshiro T, Chancellor MB, de Groat WC, Yoshimura N, Saito S. An alpha1adrenoceptor blocker terazosin improves urine storage function in the spinal cord in spinal cord injured rats. Life Sci 2013;92(2):125–30. [17] Goi Y, Tomiyama Y, Maruyama I, Tatemichi S, Maruyama K, Kobayashi M, et al. Silodosin, an α(1A)-adrenoceptor antagonist, may ameliorate ischemia-induced bladder denervation and detrusor dysfunction by improving bladder blood flow. Pharmacology 2016;97 (3–4):161–70. [18] Cornu JN, Abrams P, Chapple CR, Dmochowski RR, Lemack GE, Michel MC, et al. A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management—a systematic review and meta-analysis. Eur Urol 2012;62(5):877–90.

References

[19] Akduman B, Crawford ED. Terazosin, doxazosin, and prazosin: current clinical experience. Urology 2001;58:49–54. [20] Muramatsu I, et al. Subtype selectivity of a new alpha 1-adrenoceptor antagonist, JTH-601: comparison with prazosin. Eur J Pharmacol 1996;300:155–7. [21] Forray C, et al. The alpha 1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype. Mol Pharmacol 1994;45:703–8. [22] Kenny BA, et al. Evaluation of the pharmacological selectivity profile of alpha 1 adrenoceptor antagonists at prostatic alpha 1 adrenoceptors: binding, functional and in vivo studies. Br J Pharmacol 1996;118:871–8. [23] Lowe FC. Role of the newer alpha, -adrenergic-receptor antagonists in the treatment of benign prostatic hyperplasia-related lower urinary tract symptoms. Clin Ther 2004;26:1701–13. [24] Mottet N, Bressolle F, Delmas V, Robert M, Costa P. Prostatic tissual distribution of alfuzosin in patients with benign prostatic hyperplasia following repeated oral administration. Eur Urol 2003;44:101–5. [25] Tatemichi S, et al. Uroselectivity in male dogs of silodosin (KMD-3213), a novel drug for the obstructive component of benign prostatic hyperplasia. Neurourol Urodyn 2006;25:792–9. discussion 800-801. [26] Michel MC, Mehlburger L, Bressel H-U, Goepel M. Comparison of tamsulosin efficacy in subgroups of patients with lower urinary tract symptoms. Prostate Cancer Prostatic Dis 1998;1:332–5. [27] MacDonald R, Wilt TJ, Howe RW. Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects. BJU Int 2004;94:1263–70. [28] McConnell JD, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387–98. [29] Kirby RS, et al. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the prospective european doxazosin and combination therapy (PREDICT) trial. Urology 2003;61:119–26. [30] Dong Z, et al. Tamsulosin versus terazosin for benign prostatic hyperplasia: a systematic review. Syst Biol Reprod Med 2009;55:129–36. [31] Dahm P, et al. Comparative effectiveness of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review and meta-analysis. Eur Urol 2017;71:570–81. [32] MacDonald R, Wilt TJ. Alfuzosin for treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia: a systematic review of efficacy and adverse effects. Urology 2005;66:780–8. [33] Fusco F, et al. α1-Blockers improve benign prostatic obstruction in men with lower urinary tract symptoms: a systematic review and meta-analysis of urodynamic studies. Eur Urol 2016;69:1091–101. [34] Vallancien G, et al. Alfuzosin 10 mg once daily for treating benign prostatic hyperplasia: a 3-year experience in real-life practice. BJU Int 2008;101:847–52. [35] Roehrborn CG, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol 2010;57:123–31.

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[36] Roehrborn CG. Three months’ treatment with the alpha1-blocker alfuzosin does not affect total or transition zone volume of the prostate. Prostate Cancer Prostatic Dis 2006;9:121–5. [37] Lukacs B, Cornu JN, Aout M, Tessier N, Hodee C, Haab F, et al. Management of lower urinary tract symptoms related to benign prostatic hyperplasia in real-life practice in France: a comprehensive population study. Eur Urol 2013;64(3):493–501. [38] Marks LS, Gittelman MC, Hill LA, Volinn W, Hoel G. Silodosin in the treatment of the signs and symptoms of benign prostatic hyperplasia: a 9-month, open-label extension study. Urology 2009;74:1318–22. [39] Neff KD, et al. Factors associated with intraoperative floppy iris syndrome. Ophthalmology 2009;116:658–63.

CHAPTER 9

Medical Aspects of the Treatment of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia: 5-Alpha Reductase Inhibitors Jaime A. Cavallo, Steven A. Kaplan Icahn School of Medicine at Mount Sinai, New York, NY, United States

MECHANISM OF ACTION Testosterone and Dihydrotestosterone Androgens are steroid molecules composed of 19 carbons and either a keto group (dehydroepiandrosterone and androstenedione) or a hydroxyl group (testosterone and dihydrotestosterone (DHT)) at carbon 17. Testosterone, the most abundant serum androgen in men, is intracellularized and converted by the enzyme 5-alpha reductase to DHT, a ligand with 2–5 times greater binding affinity for the androgen receptor (AR) and with approximately 10 times greater potency for AR transactivation than testosterone [1]. The resulting DHT-AR complex then translocates from the cytosol to the nucleus to induce transcription of androgen receptor-regulated genes (ARRGs). Through activated transcription of ARRGs, DHT is responsible for in utero male differentiation of the urogenital sinus into the urachus, part of the bladder, Cowper’s glands, the prostatic urethra, and the prostate gland; the urethral folds into the penile urethra; the genital tubercle into the penis; and the genital swellings into the scrotum; as well as pubertal growth of facial and body hair [1]. Dysregulation of DHT manifests in such disease processes as acne, hirsutism, male pattern baldness, benign prostatic hyperplasia (BPH), and prostate cancer [2].

5-Alpha Reductase Enzyme Family The 5-alpha reductase enzyme family is responsible for the conversion of testosterone to DHT. With cofactor nicotinamide adenine dinucleotide phosphate (NADPH), isoenzymes of the 5-alpha reductase enzyme family catalyze an irreversible break of the double bond between carbons 4 and 5 of the testosterone molecule resulting in conversion to the DHT molecule. The 5-alpha reductase Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia. https://doi.org/10.1016/B978-0-12-811397-4.00009-3 © 2018 Elsevier Inc. All rights reserved.

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enzyme family is comprised of 3 subfamilies and 5 isoenzyme members: 5 alpha reductase-1 (5αR1; subfamily a), 5 alpha reductase-2 (5αR2; subfamily a), 5 alpha reductase-3 (5αR3; subfamily b), GPSN2 (subfamily c), and GPSN2L (subfamily c) [1]. Within a given species, the 5αR1 (259 amino acids, 29.5 kDa molecular weight; encoded on chromosome 5p15) and 5αR2 (254 amino acids, 28.4 kDa molecular weight; encoded on chromosome 2p23) isoenzymes share a mean amino acid sequence homology of 47% [1]. The 5αR1 and 5αR2 isoenzymes are both found embedded in a membrane lipid bilayer, attributable to a high content of hydrophobic amino acids. 5αR3 (318 amino acids; encoded on chromosome 4q12), GPSN2 (308 amino acids; encoded on chromosome 19p13.12), and GPSN2L (363 amino acids; encoded on chromosome 4q13.1) share a more limited degree of amino acid sequence homology [1]. The expression of the isoenzymes varies by stage of human development and tissue type, and can exhibit interindividual and intraindividual expression heterogeneity [1]. The most abundant isoenzymes in the prostate belong to subfamily a: 5αR2 and 5αR1. 5αR2 is more abundant and is predominantly expressed in the cytosol of stromal and basal prostate cells, whereas 5αR1 is predominantly expressed in the nucleus of prostate epithelial cells [1]. In BPH, the histologic diagnosis referring to proliferation of benign smooth muscle and epithelial cells within the prostatic transition zone [3], both the 5αR2 and 5αR1 isoenzymes are overexpressed [1], although 5αR2 is more highly concentrated [4]. Compared to benign and BPH prostate cells, increased expression of 5αR1 and decreased expression of 5αR2 have been demonstrated in prostate cancer cells [5]. Studies have also shown an increase in 5αR1 and 5αR2 in localized high-grade compared to localized low-grade prostate cancer. Furthermore, a significant decrease in 5αR1 and a significant increase in 5αR2 have been identified in BPH compared to benign tissue adjacent to prostate cancer [6]. In both androgen-stimulated and castrate recurrent prostate cancer cells, an increased expression of 5αR3 in the cytosol compared to benign prostate cells has also been described [7].

Rationale for 5-Alpha Reductase Inhibition in BPH With age, men experience an increase in the volume of prostrate stroma (histologically diagnosed as BPH; static component), and an increase in the alpha-1 adrenergic receptors in the prostate stroma (dynamic component). Either or both of these changes in synergy can result in lower urinary tract symptoms. Alpha-1 adrenergic receptors mediate smooth muscle contraction. The increased density of alpha-1 subtype a adrenergic receptors in the prostate stroma leads to increased muscle tone in the prostate and bladder neck that can restrict urine flow. Inhibitors of the alpha-1 subtype a adrenergic receptor relax the smooth muscle of the prostate and bladder neck potentially resulting in improved voiding, and the smooth muscle of the seminal vesicles and vas

5-Alpha Reductase Inhibitors

deferens potentially also resulting in retrograde ejaculation. Growth of the prostate stroma into the bladder, bladder neck, and prostatic urethra lumen can mechanically obstruct urine flow. Inhibitors of the 5-alpha reductase enzyme family block the conversion of testosterone to DHT and thus limit prostate stroma growth. Regardless of initial prostate volume, consistent use of 5αRIs can reduce prostate volume by as much as 17%–25% over the initial 12 months through prostatic epithelial cell apoptosis concentrated in the periurethral prostatic tissue [8–11].

5-ALPHA REDUCTASE INHIBITORS 5-Alpha reductase inhibitors (5αRIs) may act by one of three mechanisms: as a competitor of the substrate, as a competitor of the NADPH cofactor and substrate, or as a noncompetitor with the 5αR-NADP + complex [1]. The types of inhibitors most widely studied may be classified as either steroidal (which mimic the natural substrate of 5αR, testosterone) or nonsteroidal. 4-Azosteroids are 3-oxo 5-alpha steroids with a nitrogen atom bonded to carbon 4. Members of this class of steroids act as competitive substrates of the 5αR isoenzymes, and include United States Food and Drug Administration (FDA)approved drugs for the treatment of BPH such as finasteride and dutasteride [1].

Finasteride Finasteride, the first 5αRI approved for the treatment of BPH (5 mg po qday) and male pattern baldness (1 mg po qday), is a synthetic 4-azosteroid that acts as a potent competitive inhibitor of 5αR2 [IC50 ¼ 69 nM] and a less potent competitive inhibitor of 5αR1 [IC50 ¼ 360 nM] [1,12]. Finasteride also competitively inhibits 5αR3 [IC50 ¼ 17.4 nM] [1]. The half-life of finasteride is 6–8 h [1]. Mean serum DHT concentration has been shown to decrease by 75% after 6 months of treatment, whereas intraprostatic DHT concentration has been shown to decrease by 85% after 7 days of treatment, and by 68% after 6 months of treatment in men with BPH [10,13,14].

Dutasteride Dutasteride, the second 5αRI approved for the treatment of BPH (0.5 mg po qday), is a synthetic 4-azosteroid that acts as a potent competitive inhibitor of both 5αR1 [IC50 ¼ 7 nM] and 5αR2 [IC50 ¼ 6 nM]. In vitro studies have demonstrated that dutasteride also competitively inhibits 5αR3 [IC50 ¼ 0.33 nM] [15]. The half-life of dutasteride is 5 weeks [1]. Mean serum DHT concentration has been shown to decrease by 94.7% after 6 months of treatment in men with BPH and 89.7% after 4 months of treatment in men with prostate cancer [16,17]. Intraprostatic DHT concentration has been shown to decrease by

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94% after 3 months of treatment in men with BPH; whereas, intraprostatic DHT concentration has been shown to decrease by 97% after 6–10 weeks of treatment and by 93.1% after 4 months of treatment in men with prostate cancer [17–19].

5-ARI FOR THE TREATMENT OF BPH Indications for Treatment of BPH With 5-ARI Approximately 13% of males by age 50 years, and approximately 42% of males by age 80 years demonstrate clinical changes consistent with BPH [20]. Depending on the degree of disease progression, BPH may be associated with varying degrees of lower urinary tract symptoms. BPH does not progress in all patients: of BPH patients with baseline moderate lower urinary tract symptoms, as many as 46.1% demonstrate no change in their symptoms and 12.7% demonstrate improvement in their symptoms after 4 years; and of BPH patients with baseline severe lower urinary tract symptoms, as many as 37.9% demonstrate no change in their symptoms and 22.7% demonstrate improvement in their symptoms after 4 years [21]. The risk of BPH progression to worse lower urinary tract symptoms, development of urinary retention, and need for surgical intervention is higher in men of older age, higher initial prostate specific antigen (PSA), larger initial prostate size, lower urinary flow rates, greater post void residual urine volume, and more severe lower urinary tract symptoms [22,23]. The pharmacologic treatment goals for BPH include alleviation of bothersome lower urinary tract symptoms resulting from prostate enlargement; minimization of disease progression and need for surgical intervention; and prevention of complications of BPH including but not limited to urinary tract infection, urinary retention, and renal insufficiency. For the patient who presents with nonsuspicious prostate enlargement and minimal bother from lower urinary tract symptoms following appropriate history, physical, and diagnostic evaluation, reassurance is recommended. For the patient with nonsuspicious prostate enlargement and bothersome lower urinary tract symptoms, a shared decision-making process between the physician and the patient should guide treatment choice. For these patients, if behavioral modification results in insufficient lower urinary tract symptom improvement, pharmacologic treatment may be warranted. According to the 2011 update of the American Urologic Association (AUA) guidelines on BPH management, 5αRI therapy is an appropriate and effective treatment for men with lower urinary tract symptoms secondary to BPH and prostate enlargement as demonstrated by serum PSA, digital rectal exam, or transrectal ultrasound of the prostate. After initiation of 5αRI therapy, assessment of treatment response is recommended at an interval of at

5-ARI for the Treatment of BPH

least 3 months. If treatment with a 5αRI results in sufficient lower urinary tract symptom improvement, annual re-evaluation is recommended [3].

Clinical Effects of BPH Treatment With 5-ARI Treatment with 5αRIs is associated with a likely clinically insignificant 12%–25% increase in serum testosterone [24]. Furthermore, treatment with a 5αRI for a duration of 12 months is associated with a decrease in total serum PSA by approximately 50%: mean reduction from baseline PSA of 38.9% after 3 months and 47.7% after 12 months with finasteride therapy, mean reduction from baseline PSA of 40.3% after 3 months and 49.5% after 12 months with dutasteride therapy [25]. Of note, the effect on the serum PSA level is similar after 12 months of treatment with finasteride 1 mg po qday for male pattern baldness as it is after 12 months of treatment with finasteride 5 mg po qday for BPH. For patients who remain on 5αRI therapy, this reduction in PSA must be taken into account when assessing the PSA trend for a given patient. Some experts recommend adjustment of the PSA value by a multiplicative factor of 2 post 5αRI treatment [26–29]. Regardless of initial prostate volume, prostate volume can decrease by as much as 17%–25% over the initial 12 months of 5αRI treatment through prostatic epithelial cell apoptosis concentrated in the periurethral prostatic tissue [8–11]. While lower urinary tract symptom improvement and side effects may be experienced within several weeks of initiation of 5αRI therapy, appreciable changes in prostate size, and associated improvements in lower urinary tract symptoms are typically achieved after 6–12 months of treatment [10,30]. The Proscar® Long-term Efficacy and Safety Study (PLESS) was a randomized double-blind placebo-controlled study assessing the safety and efficacy of daily oral therapy with finasteride over a 4-year period in men with symptomatic BPH, enlarged prostates, and no evidence of prostate cancer. In the PLESS, 5αRI therapy was demonstrated to be effective in decreasing prostate volume, and improving lower urinary tract symptoms and urinary flow rate in men with a baseline PSA 1.4 ng/mL and a baseline prostate volume >40 g [9,30,31]. Furthermore, a subset analysis from the Medical Therapy of Prostate Symptoms (MTOPS) trial demonstrated that finasteride treatment was associated with a significant decrease in lower urinary tract symptoms reported on the American Urologic Association Symptom Score (AUASS), a significant decrease in prostate volume, a significant increase in maximum urinary flow rate, and a significant increase in the cumulative percentage of patients without clinical progression of BPH compared to placebo treatment in men with a baseline prostate volume 30 g, but not for men with a baseline prostate volume 50 years of age with a clinical diagnosis of BPH. Subjects were first treated with 4 weeks of placebo, then were randomized to the finasteride or dutasteride treatment for 48 weeks, after which subjects were given the option to participate in a 24-month open label study of dutasteride treatment. No significant differences between finasteride therapy and dutasteride therapy were noted with regard to reduction of prostate volume, change in maximum urinary flow rate, changes in AUASS, or in adverse events. Therefore, it was concluded that finasteride and dutasteride were of similar clinical effectiveness for the treatment of BPH in men with an enlarged prostate when administered for 12 months [25]. A single-center retrospective study of men treated with either finasteride or dutasteride monotherapy for BPH over 5 years found maintenance of therapy to be 57.4% for the finasteride group and 42.5% for the dutasteride group at 5 years. In this patient population, changes in International Prostate Symptom Score (IPSS), maximum urinary flow rate, postvoid residual volume, prostate volume, and PSA value were found to be similar for men in the finasteride and dutasteride groups [35]. Both comparative studies suggest that 5αR2

Sexual Side Effects of 5-Alpha Reductase Inhibitor Use

contributes more to the clinical development of BPH as inhibition of both 5αR1 and 5αR2 by dutasteride does not seem to offer additional benefit compared to inhibition of mostly 5αR2 by finasteride.

SEXUAL SIDE EFFECTS OF 5-ALPHA REDUCTASE INHIBITOR USE Sexual side effects of 5αRI therapy have been described, but the approximate incidence of these sexual side effects is low: