- •Preface and Acknowledgments
- •Contents
- •Contributors
- •1: Embryology for Urologists
- •Introduction
- •Renal Development
- •Pronephros
- •Mesonephros
- •Metanephros
- •Development of the Collecting System
- •Critical Steps in Further Development
- •Anomalies of the Kidney
- •Renal Agenesis
- •Renal Aplasia
- •Renal Hypoplasia
- •Renal Ectopia
- •Renal Fusion
- •Ureteral Development
- •Anomalies of Origin
- •Anomalies of Number
- •Incomplete Ureteral Duplication
- •Complete Ureteral Duplication
- •Ureteral Ectopia
- •Embryology of Ectopia
- •Clinical Correlation
- •Location of Ectopic Ureteral Orifices – Male (in Descending Order According to Incidence)
- •Symptoms
- •Ureteroceles
- •Congenital Ureteral Obstruction
- •Pipestem Ureter
- •Megaureter-Megacystis Syndrome
- •Prune Belly Syndrome
- •Vascular Ureteral Obstructions
- •Division of the Urogenital Sinus
- •Bladder Development
- •Urachal Anomalies
- •Cloacal Duct Anomalies
- •Other Bladder Anomalies
- •Bladder Diverticula
- •Bladder Extrophy
- •Gonadal Development
- •Testicular Differentiation
- •Ovarian Differentiation
- •Gonadal Anomalies
- •Genital Duct System
- •Disorders of Testicular Function
- •Female Ductal Development
- •Prostatic Urethral Valves
- •Gonadal Duct Anomalies
- •External Genital Development
- •Male External Genital Development
- •Female External Genital Development
- •Anomalies of the External Genitalia
- •References
- •2: Gross and Laparoscopic Anatomy of the Upper Urinary Tract and Retroperitoneum
- •Overview
- •The Kidneys
- •The Renal Vasculature
- •The Renal Collecting System
- •The Ureters
- •Retroperitoneal Lymphatics
- •Retroperitoneal Nerves
- •The Adrenal Glands
- •References
- •3: Gross and Laparoscopic Anatomy of the Lower Urinary Tract and Pelvis
- •Introduction
- •Female Pelvis
- •Male Pelvis
- •Pelvic Floor
- •Urinary Bladder
- •Urethra
- •Male Urethra
- •Female Urethra
- •Sphincter Mechanisms
- •The Bladder Neck Component
- •The Urethral Wall Component
- •The External Urethral Sphincter
- •Summary
- •References
- •4: Anatomy of the Male Reproductive System
- •Testis and Scrotum
- •Spermatogenesis
- •Hormonal Regulation of Spermatogenesis
- •Genetic Regulation of Spermatogenesis
- •Epididymis and Ductus Deferens
- •Accessory Sex Glands
- •Prostate
- •Seminal Vesicles
- •Bulbourethral Glands
- •Penis
- •Erection and Ejaculation
- •References
- •5: Imaging of the Upper Tracts
- •Anatomy of the Upper Tracts and Introduction to Imaging Modalities
- •Introduction
- •Renal Upper Tract Basic Anatomy
- •Modalities Used for Imaging the Upper Tracts
- •Ultrasound
- •Radiation Issues
- •Contrast Issues
- •Renal and Upper Tract Tumors
- •Benign Renal Tumors
- •Transitional Cell Carcinoma
- •Renal Mass Biopsy
- •Renal Stone Disease
- •Ultrasound
- •Plain Radiographs and IVU
- •Renal Cystic Disease
- •Benign Renal Cysts
- •Hereditary Renal Cystic Disease
- •Complex Renal Cysts
- •Renal Trauma
- •References
- •Introduction
- •Pathophysiology
- •Susceptibility and Resistance
- •Epidemiological Breakpoints
- •Clinical Breakpoints
- •Pharmacodynamic Parameters
- •Pharmacokinetic Parameters
- •Fosfomycin
- •Nitrofurantoin
- •Pivmecillinam
- •b-Lactam-Antibiotics
- •Penicillins
- •Cephalosporins
- •Carbapenems
- •Aminoglycosides
- •Fluoroquinolones
- •Trimethoprim, Cotrimoxazole
- •Glycopeptides
- •Linezolid
- •Conclusion
- •References
- •7: An Overview of Renal Physiology
- •Introduction
- •Body Fluid Compartments
- •Regulation of Potassium Balance
- •Regulation of Acid–Base Balance
- •Diuretics
- •Suggested Reading
- •8: Ureteral Physiology and Pharmacology
- •Ureteral Anatomy
- •Modulation of Peristalsis
- •Ureteral Pharmacology
- •Conclusion
- •References
- •Introduction
- •Afferent Signaling Pathways
- •Efferent Signaling
- •Parasympathetic Nerves
- •Sympathetic Nerves
- •Vesico-Spinal-Vesical Micturition Reflex
- •Peripheral Targets
- •Afferent Signaling Mechanisms
- •Urothelium
- •Myocytes
- •Cholinergic Receptors
- •Muscarinic Receptors
- •Nicotinic Receptors
- •Adrenergic Receptors (ARs)
- •a-Adrenoceptors
- •b-Adrenoceptors
- •Transient Receptor Potential (TRP) Receptors
- •Phosphodiesterases (PDEs)
- •CNS Targets
- •Opioid Receptors
- •Serotonin (5-HT) Mechanisms
- •g-Amino Butyric Acid (GABA) Mechanisms
- •Gabapentin
- •Neurokinin and Neurokinin Receptors
- •Summary
- •References
- •10: Pharmacology of Sexual Function
- •Introduction
- •Sexual Desire/Arousal
- •Endocrinology
- •Steroids in the Male
- •Steroids in the Female
- •Neurohormones
- •Neurotransmitters
- •Dopamine
- •Serotonin
- •Pharmacological Strategies
- •CNS Drugs
- •Enzyme-inducing Antiepileptic Drugs
- •Erectile Function
- •Ejaculatory Function
- •Premature Ejaculation
- •Abnormal Ejaculation
- •Conclusions
- •References
- •Epidemiology
- •Calcium-Based Urolithiasis
- •Uric Acid Urolithiasis
- •Infectious Urolithiasis
- •Cystine-Based Urolithiasis
- •Aims
- •Who Deserves Metabolic Evaluation?
- •Metabolic Workup for Stone Producers
- •Medical History and Physical Examination
- •Stone Analysis
- •Serum Chemistry
- •Urine Evaluation
- •Urine Cultures
- •Urinalysis
- •Twenty-Four Hour Urine Collections
- •Radiologic Imaging
- •Medical Management
- •Conservative Management
- •Increased Fluid Intake
- •Citrus Juices
- •Dietary Restrictions
- •Restricted Oxalate Diet
- •Conservative Measures
- •Selective Medical Therapy
- •Absorptive Hypercalciuria
- •Thiazide
- •Orthophosphate
- •Renal Hypercalciuria
- •Primary Hyperparathyroidism
- •Hyperuricosuric Calcium Oxalate Nephrolithiasis
- •Enteric Hyperoxaluria
- •Hypocitraturic Calcium Oxalate Nephrolithiasis
- •Distal Renal Tubular Acidosis
- •Chronic Diarrheal States
- •Thiazide-Induced Hypocitraturia
- •Idiopathic Hypocitraturic Calcium Oxalate Nephrolithiasis
- •Hypomagnesiuric Calcium Nephrolithiasis
- •Gouty Diathesis
- •Cystinuria
- •Infection Lithiasis
- •Summary
- •References
- •12: Molecular Biology for Urologists
- •Introduction
- •Inherited Changes in Cancer Cells
- •VEGR and Cell Signaling
- •Targeting mTOR
- •Conclusion
- •References
- •13: Chemotherapeutic Agents for Urologic Oncology
- •Introduction
- •Bladder Cancer
- •Muscle Invasive Bladder Cancer
- •Metastatic Bladder Cancer
- •Conclusion
- •Prostate Cancer
- •Other Chemotherapeutic Drugs or Combinations for Treating HRPC
- •Conclusion
- •Renal Cell Carcinoma
- •Chemotherapy
- •Immunotherapy
- •Angiogenesis Inhibitor Drugs
- •Conclusion
- •Testicular Cancer
- •Stage I Seminoma
- •Stage I non-seminomatous Germ Cell Tumours (NSGCT)
- •Metastatic Germ Cell Tumours
- •Low-Volume Metastatic Disease (Stage II A/B)
- •Advanced Metastatic Disease
- •Salvage Chemotherapy for Relapsed or Refractory Disease
- •Conclusion
- •Penile Cancer
- •Side Effects of Chemotherapy
- •Conclusion
- •References
- •14: Tumor and Transplant Immunology
- •Antibodies
- •Cytotoxic and T-helper Cells
- •Immunosuppression
- •Induction Therapy
- •Maintenance Therapy
- •Rejection
- •Posttransplant Lymphoproliferative Disease
- •Summary
- •References
- •15: Pathophysiology of Renal Obstruction
- •Causes of Renal Obstruction
- •Effects on Prenatal Development
- •Prenatal Hydronephrosis
- •Spectrum of Renal Abnormalities
- •Renal Functional Changes
- •Renal Growth/Counterbalance
- •Vascular Changes
- •Inflammatory Mediators
- •Glomerular Development Changes
- •Mechanical Stretch of Renal Tubules
- •Unilateral Versus Bilateral
- •Limitations of Animal Models
- •Future Research
- •Issues in Patient Management
- •Diagnostic Imaging
- •Ultrasound
- •Intravenous Urography
- •Antegrade Urography and the Whitaker Test
- •Nuclear Renography
- •Computed Tomography
- •Magnetic Resonance Urography
- •Hypertension
- •Postobstructive Diuresis
- •References
- •Introduction
- •The Normal Lower Urinary Tract
- •Anatomy
- •Storage Function
- •Voiding Function
- •Neural Control
- •Symptoms
- •Flow Rate and Post-void Residual
- •Voiding Cystometry
- •Male
- •Female
- •Neurourology
- •Conclusions
- •References
- •17: Urologic Endocrinology
- •The Testis
- •Normal Androgen Metabolism
- •Epidemiological Aspects
- •Prostate
- •Brain
- •Muscle Mass and Adipose Tissue
- •Bones
- •Ematopoiesis
- •Metabolism
- •Cardiovascular System
- •Clinical Assessment
- •Biochemical Assessment
- •Treatment Modalities
- •Oral Preparations
- •Parenteral Preparations
- •Transdermal Preparations
- •Side Effects and Treatment Monitoring
- •Body Composition
- •Cognitive Decline
- •Bone Metabolism
- •The Kidneys
- •Endocrine Functions of the Kidney
- •Erythropoietin
- •Calcitriol
- •Renin
- •Paraneoplastic Syndromes
- •Hypercalcemia
- •Hypertension
- •Polycythemia
- •Other Endocrine Abnormalities
- •References
- •General Physiology
- •Prostate Innervation
- •Summary
- •References
- •Wound Healing
- •Inflammation
- •Proliferation
- •Remodeling
- •Principles of Plastic Surgery
- •Tissue Characteristics
- •Grafts
- •Flap
- •References
- •Lower Urinary Tract Symptoms
- •Storage Phase
- •Voiding Phase
- •Return to Storage Phase
- •Urodynamic Parameters
- •Urodynamic Techniques
- •Volume Voided Charts
- •Pad Testing
- •Typical Test Schedule
- •Uroflowmetry
- •Post Voiding Residual
- •Further Diagnostic Evaluation of Patients
- •Cystometry with or Without Video
- •Cystometry
- •Videocystometrography (Cystometry + Cystourethrography)
- •Cystometric Findings
- •Comment:
- •Measurements During the Storage Phase:
- •Measurements During the Voiding Phase:
- •Abnormal Function
- •Disorders of Sensation
- •Causes of Hypersensitive Bladder Sensation
- •Causes of Hyposensitive Bladder Sensation
- •Disorders of Detrusor Motor Function
- •Bladder Outflow Tract Dysfunction
- •Detrusor–Urethral Dyssynergia
- •Detrusor–Bladder Neck Dyssynergia
- •Detrusor–Sphincter Dyssynergia
- •Complex Urodynamic Investigation
- •Urethral Pressure Measurement
- •Technique
- •Neurophysiological Evaluation
- •Conclusion
- •References
- •Endoscopy
- •Cystourethroscopy
- •Ureteroscopy and Ureteropyeloscopy
- •Nephroscopy
- •Virtual Reality Simulators
- •Lasers
- •Clinical Application of Lasers
- •Condylomata Acuminata
- •Urolithiasis
- •Benign Prostatic Hyperplasia
- •Ureteral and Urethral Strictures
- •Conclusion
- •References
- •Introduction
- •The Prostatitis Syndromes
- •The Scope of the Problem
- •Category III CP/CPPS
- •The Goal of Treatment
- •Conservative Management
- •Drug Therapy
- •Antibiotics
- •Anti-inflammatories
- •Alpha blockers
- •Hormone Therapies
- •Phytotherapies
- •Analgesics, muscle relaxants and neuromodulators
- •Surgery
- •A Practical Management Plan
- •References
- •Orchitis
- •Definition and Etiology
- •Clinical Signs and Symptoms
- •Diagnostic Evaluation
- •Treatment of Infectious Orchitis
- •Epididymitis
- •Definition and Etiology
- •Clinical Signs and Symptoms
- •Diagnostic Evaluation of Epididymitis
- •Treatment of Acute Epididymitis
- •Treatment of Chronic Epididymitis
- •Treatment of Spermatic Cord Torsion
- •Fournier’s Gangrene
- •Definition and Etiology
- •Risk Factors
- •Clinical Signs and Symptoms
- •Diagnostic Evaluation
- •Treatment
- •References
- •Fungal Infections
- •Candidiasis
- •Aspergillosis
- •Cryptococcosis
- •Blastomycosis
- •Coccidioidomycosis
- •Histoplasmosis
- •Radiographic Findings
- •Treatment
- •Tuberculosis
- •Clinical Manifestations
- •Diagnosis
- •Treatment
- •Schistosomiasis
- •Clinical Manifestations
- •Diagnosis
- •Treatment
- •Filariasis
- •Clinical Manifestations
- •Diagnosis
- •Treatment
- •Onchocerciasis
- •References
- •25: Sexually Transmitted Infections
- •Introduction
- •STIs Associated with Genital Ulcers
- •Herpes Simplex Virus
- •Diagnosis
- •Treatment
- •Chancroid
- •Diagnosis
- •Treatment
- •Syphilis
- •Diagnosis
- •Treatment
- •Lymphogranuloma Venereum
- •Diagnosis
- •Treatment
- •Chlamydia
- •Diagnosis
- •Treatment
- •Gonorrhea
- •Diagnosis
- •Treatment
- •Trichomoniasis
- •Diagnosis
- •Treatment
- •Human Papilloma Virus
- •Diagnosis
- •Treatment
- •Scabies
- •Diagnosis
- •Treatment
- •References
- •26: Hematuria: Evaluation and Management
- •Introduction
- •Classification of Hematuria
- •Macroscopic Hematuria
- •Microscopic Hematuria
- •Dipstick Hematuria
- •Pseudohematuria
- •Factitious Hematuria
- •Menstruation
- •Aetiology
- •Malignancy
- •Urinary Calculi
- •Infection and Inflammation
- •Benign Prostatic Hyperplasia
- •Trauma
- •Drugs
- •Nephrological Causes
- •Assessment
- •History
- •Examination
- •Investigations
- •Dipstick Urinalysis
- •Cytology
- •Molecular Tests
- •Blood Tests
- •Flexible Cystoscopy
- •Upper Urinary Tract Evaluation
- •Renal USS
- •KUB Abdominal X-Ray
- •Intravenous Urography (IVU)
- •Computed Tomography (CT)
- •Retrograde Urogram Studies
- •Magnetic Resonance Imaging (MRI)
- •Additional Tests and Renal Biopsy
- •Intractable Hematuria
- •Loin Pain Hematuria Syndrome
- •References
- •27: Benign Prostatic Hyperplasia (BPH)
- •Historical Background
- •Pathophysiology
- •Patient Assessment
- •Treatment of BPH
- •Watchful Waiting
- •Drug Therapy
- •Interventional Therapies
- •Conclusions
- •References
- •28: Practical Guidelines for the Treatment of Erectile Dysfunction and Peyronie´s Disease
- •Erectile Dysfunction
- •Introduction
- •Diagnosis
- •Basic Evaluation
- •Cardiovascular System and Sexual Activity
- •Optional Tests
- •Treatment
- •Medical Treatment
- •Oral Agents
- •Phosphodiesterase Type 5 (PDE 5) Inhibitors
- •Nonresponders to PDE5 Inhibitors
- •Apomorphine SL
- •Yohimbine
- •Intracavernosal and Intraurethral Therapy
- •Intracavernosal Injection (ICI) Therapy
- •Intraurethral Therapy
- •Vacuum Constriction Devices
- •Surgical Therapy
- •Conclusion
- •Peyronie´s Disease (PD)
- •Introduction
- •Oral Drug Therapy
- •Intralesional Drug Therapy
- •Iontophoresis
- •Radiation Therapy
- •Surgical Therapy
- •References
- •29: Premature Ejaculation
- •Introduction
- •Epidemiology
- •Defining Premature Ejaculation
- •Voluntary Control
- •Sexual Satisfaction
- •Distress
- •Psychosexual Counseling
- •Pharmacological Treatment
- •On-Demand Treatment with Tramadol
- •Topical Anesthetics
- •Phosphodiesterase Inhibitors
- •Surgery
- •Conclusion
- •References
- •30: The Role of Interventional Management for Urinary Tract Calculi
- •Contraindications to ESWL
- •Complications of ESWL
- •PCNL Access
- •Instrumentation for PCNL
- •Nephrostomy Drains Post PCNL
- •Contraindications to PCNL
- •Complications of PCNL
- •Semirigid Ureteroscopy
- •Flexible Ureteroscopy
- •Electrohydraulic Lithotripsy (EHL)
- •Ultrasound
- •Ballistic Lithotripsy
- •Laser Lithotripsy
- •Ureteric Stents
- •Staghorn Calculi
- •Lower Pole Stones
- •Horseshoe Kidneys and Stones
- •Calyceal Diverticula Stones
- •Stones and PUJ Obstruction
- •Treatment of Ureteric Colic
- •Medical Expulsive Therapy (MET)
- •Intervention for Ureteric Stones
- •Stones in Pregnancy
- •Morbid Obesity
- •References
- •Anatomy and Function
- •Pathophysiology
- •Management
- •Optical Urethrotomy/Dilatation
- •Urethral Stents
- •Preoperative Assessment
- •Urethroplasty
- •Anastomotic Urethroplasty
- •Substitution Urethroplasty
- •Grafts Versus Flaps
- •Oral Mucosal Grafts
- •Tissue Engineering
- •Graft Position
- •Conclusion
- •References
- •32: Urinary Incontinence
- •Epidemiology and Risk Factors
- •Pathophysiology
- •Urge Incontinence
- •Conservative Treatments
- •Pharmacotherapy
- •Invasive/ Surgical Therapies
- •Stress Urinary Incontinence
- •Male SUI Therapies
- •Female SUI Therapies
- •Mixed Urinary Incontinence
- •Conclusions
- •References
- •33: Neurogenic Bladder
- •Introduction
- •Examination and Diagnostic Tests
- •History and Physical Examination
- •Imaging
- •Urodynamics (UDS)
- •Evoked Potentials
- •Classifications
- •Somatic Pathways
- •Brain Lesions
- •Cerebrovascular Accident (CVA)
- •Parkinson’s Disease (PD)
- •Multiple Sclerosis
- •Huntington’s Disease
- •Dementias
- •Normal Pressure Hydrocephalus (NPH)
- •Tumors
- •Psychiatric Disorders
- •Spinal Lesions and Pathology
- •Intervertebral Disk Prolapse
- •Spinal Cord Injury (SCI)
- •Transverse Myelitis
- •Peripheral Neuropathies
- •Metabolic Neuropathies
- •Pelvic Surgery
- •Treatment
- •Summary
- •References
- •34: Pelvic Prolapse
- •Introduction
- •Epidemiology
- •Anatomy and Pathophysiology
- •Evaluation and Diagnosis
- •Outcome Measures
- •Imaging
- •Urodynamics
- •Indications for Management
- •Biosynthetics
- •Surgical Management
- •Anterior Compartment Repair
- •Uterine/Apical Prolapse
- •Enterocele Repair
- •Conclusion
- •References
- •35: Urinary Tract Fistula
- •Introduction
- •Urogynecologic Fistula
- •Vesicovaginal Fistula
- •Etiology and Risk Factors
- •Clinical Factors
- •Evaluation and Diagnosis
- •Pelvic Examination
- •Cystoscopy
- •Imaging
- •Treatment
- •Conservative Management
- •Surgical Management
- •Urethrovaginal Fistula
- •Etiology and Presentation
- •Diagnosis and Management
- •Ureterovaginal Fistula
- •Etiology and Presentation
- •Diagnosis and Management
- •Vesicouterine Fistula
- •Etiology and Presentation
- •Diagnosis and Management
- •Uro-Enteric Fistula
- •Vesicoenteric Fistula
- •Pyeloenteric Fistula
- •Urethrorectal Fistula
- •References
- •36: Urologic Trauma
- •Introduction
- •Kidney
- •Expectant Management
- •Endovascular Therapy
- •Operative Intervention
- •Operative Management: Follow-up
- •Reno-Vascular Injuries
- •Pediatric Renal Injuries
- •Adrenal
- •Ureter
- •Diagnosis
- •Treatment
- •Delayed Diagnosis
- •Bladder and Posterior Urethra
- •Bladder Injuries: Initial Management
- •Bladder Injuries: Formal Repair
- •Anterior Urethral Trauma
- •Fractured Penis
- •Penile Amputation
- •Scrotal and Testicular Trauma
- •Imaging
- •CT-IVP (CT with Delayed Images)
- •Technique
- •Cystogram
- •Technique
- •Retrograde Urethrogram (RUG)
- •Technique
- •Retrograde Pyelogram (RPG)
- •Technique
- •One-Shot IVP
- •Technique
- •References
- •37: Bladder Cancer
- •Who Should Be Investigated?
- •Epidemiology
- •Risk Factors
- •Role of Screening
- •Signs and Symptoms
- •Imaging
- •Cystoscopy
- •Urine Tests
- •PDD-Assisted TUR
- •Pathology
- •NMIBC and Risk Groups
- •Intravesical Chemotherapy
- •Intravesical Immunotherapy
- •Immediate Cystectomy and CIS
- •Radical Cystectomy with Pelvic Lymph Node Dissection
- •sexual function-preserving techniques
- •Bladder-Preservation Treatments
- •Neoadjuvant Chemotherapy
- •Adjuvant Chemotherapy
- •Preoperative Radiotherapy
- •Follow-up After TUR in NMIBC
- •References
- •38: Prostate Cancer
- •Introduction
- •Epidemiology
- •Race
- •Geographic Variation
- •Risk Factors and Prevention
- •Family History
- •Diet and Lifestyle
- •Prevention
- •Screening and Diagnosis
- •Current Screening Recommendations
- •Biopsy
- •Pathology
- •Prognosis
- •Treatment of Prostate Cancer
- •Treatment for Localized Prostate Cancer (T1, T2)
- •Radical Prostatectomy
- •EBRT
- •IMRT
- •Brachytherapy
- •Treatment for Locally Advanced Prostate Cancer (T3, T4)
- •EBRT with ADT
- •Radical Prostatectomy
- •Androgen-Deprivation Therapy
- •Summary
- •References
- •39: The Management of Testis Cancer
- •Presentation and Diagnosis
- •Serum Tumor Markers
- •Primary Surgery
- •Testis Preserving Surgery
- •Risk Stratification
- •Surveillance Versus Primary RPLND
- •Primary RPLND
- •Adjuvant Treatment for High Risk
- •Clinical Stage 1 Seminoma
- •Risk-Stratified Adjuvant Treatment
- •Adjuvant Radiotherapy
- •Adjuvant Low Dose Chemotherapy
- •Primary Combination Chemotherapy
- •Late Toxicity
- •Salvage Strategies
- •Conclusion
- •References
- •Index
18
Physiology and Pharmacology
of the Prostate
William D. Steers
General Physiology
The physiological properties of the prostate resemble those of other exocrine glands. The precise functions of the prostate remain obscure but some inferences can be made. The prostate is ideally positioned to block the entrance of pathogens into the reproductive tract by secreting potent biological agents that are bacteriostatic. These substances include metal ions, proteases, and highly charged organic molecules such as spermine. The total contribution to seminal fluid (average 3 mL) made by prostate secretions is about 0.5 mL.The pH of these prostate secretions is relatively alkaline and varies from 6 to 8, possibly to counteract the acidic environment of the urethra and vagina.Seminal plasma may increase sperm motility or survival in the male urethra or female genital tract by buffering mechanisms. Constituents of prostatic fluid participate in the clotting (semenogelins I and II) and lysing (prostate specific antigen) of semen. This clotting, then liquefaction may somehow optimize fertility by allowing an initial higher dwell time in the female reproductive tract. A list of components of prostatic fluid is found in Table 18.1.
Access to prostatic fluid by constituents in the blood is limited. Iodine, ethanol, and some antibioticscandirectlydiffuseintosemen.Antibiotics that enter prostatic secretions by virtue of their high lipid solubility include fluoroquinolones, trimethoprim, tetracycline, sulfonamides, erythromycin, clindamycin, and chloramphenicol. 1
Prostate growth and development from the urogenital sinus is intimately associated with cell–cell communication, most notably stromal– epithelial interactions under endocrine and neural control. An understanding of the tissue matrix in the prostate provides insight into the physiology and growth of the prostate. Laminin surrounds a basement membrane of acinar epithelial cells, capillaries smooth muscle, and nerves. Laminin is important for cellular adhesion, proliferation, differentiation, growth, and migration. Communication via extracellular interactions with the intracellular cytoskeleton regulates prostate cell function.
Cell adhesion molecules determine cellular phenotype and function. Receptors for a number of adhesion molecules span the plasma membrane to bridge cells. Interactions via such receptors are key to the normal growth of the prostate, the pathogenesis of BPH, and the development of prostate cancer.2 Integrins link extracellular matrix to basement membrane.E-cadherins bind prostate epithelial cells to each other (Fig. 18.1). Selectins link carbohydrates. Immunoglobulins also have a role in cellular adhesion.
Role of Androgens
and Other Hormones
The growth, maintenance, and secretory function of the prostate are regulated by androgens, non-androgenic hormones, and growth factors.
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citric acid |
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through channels |
response elements (DNA sequences) on DNA to |
|
Phosphorylcholine |
reduced in cancer, |
influence transcription factors and mRNA pro- |
||
duction (Fig.18.2).The TATA box DNA sequence |
||||
Prostaglandins (15 types) |
regulates Psa binding |
|||
to semenogelins i and ii, |
determines the RNA polymerase binding start |
|||
|
|
antibacterial |
location and the androgen response element |
|
cholesterol/lipids |
|
dictates how frequently the mRNA is tran- |
||
|
scribed. These synthetic processes occur over |
|||
|
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|
||
Zinc |
|
hours to days. However, DHT can also trigger |
||
Psa |
inhibits Psa activity, |
rapid changes in cellular function through sepa- |
||
rate mechanisms. |
||||
Kallikrein 2 |
causes semen to clot |
|||
Besides DHT, estrogens and adrenal steroids |
||||
|
||||
semenogelins i and ii |
|
influence prostate function and growth. T can |
||
|
be converted to estradiol and estrone by aro- |
|||
Prostase KlK-l1 and 11 |
activates alternate |
|||
matase in adipose tissues. Another hormone, |
||||
Prostatic acid phosphatase |
pathway |
prolactin, regulates zinc metabolism, citrate and |
||
|
||||
Prostate-specific protein |
|
fructose production, as well as androgen uptake |
||
|
and metabolism. Estrogens combined with |
|||
|
|
|
||
Prostate-specific |
|
androgens and possibly prolactin are thought to |
||
membrane antigen |
|
play a role in the development of BPH.2 |
||
Prostate stem cell antigen |
|
It is not well understood how signals from |
||
|
neuroendocrine cells in the prostate such as |
|||
|
|
|
||
immunoglobulins-igg |
|
serotonin, paracrine factors (such as basic |
||
transferrin |
Binds iron |
fibroblast growth factor bFGF), and extracellu- |
||
lar matrix regulate the growth and function of |
||||
|
|
|
||
|
|
|
the prostate (Fig. 18.1). To a lesser extent DHT |
|
Androgens affect neural morphology, number, |
also regulates stromal growth factors termed |
|||
and autonomic receptor function.3-7 Castration |
andromedins. |
|||
reduces prostate size, the volume of prostatic |
Circulating catecholamines elicit contraction |
|||
secretion, muscarinic receptor expression, and |
of the prostatic capsule and stroma (norepi- |
|||
noradrenergic innervation of the prostate. The |
nephrine, oxytocin).9,10 Although experiments |
|||
major androgen-regulating prostate physiology |
show that adrenergic mechanisms trigger apop- |
|||
and growth is dihydrotestosterone (DHT).8 The |
tosis in vitro,11,12 their long-term administration |
|||
prostate contains five times more DHT than T. |
does not reduce prostate volume, prostate- |
|||
DHT is synthesized from testosterone (T) by the |
specific antigen (PSA), or cause histological |
|||
action of 5 reductase (5AR) (Fig. 18.2). It exists |
changes. |
|||
as two isoforms, Type I and type II. The prostate |
Afferent nerves transmit the discomfort of |
|||
contains mostly type II. Type I 5AR is found in |
prostatitis and are involved in pathogenesis of |
|||
skin and liver. Expression of 5AR is regulated by |
male pelvic pain syndrome.12 Prostate afferents |
|||
androgens. During development, both epithelial |
contain neuropeptides that can trigger inflam- |
|||
and mesenchymal cells contain DHT, which reg- |
matory and immune responses. Secretory prod- |
|||
ulates growth. In the adult 5AR is expressed by |
ucts,cytokines,and growth factors such as nerve |
|||
stromal tissues and basal epithelial cells. DHT is |
growth factor (NGF), epidermal growth factor |
|||
absent in secretory epithelium. |
(EGF), transforming growth factor beta(TGFb), |
|||
Free T enters cells by diffusion whereupon it |
insulin growth factor, and basic fibroblast |
|||
is converted to DHT. DHT in epithelial cells |
growth factor (bFGF) that are produced in the |
241
Physiology and PharMacology of thE ProstatE
|
Testosterone |
|
Extracellular |
bFGF |
matrix |
Integrins |
TGFb |
|
5aR |
Basal
cell
DHT
E-cadherin |
Epithelial |
|
cell |
Spermine
Prostaglandins
Citric acid
Semenogelin
thelial cells. secretory epithelia are attached to each other via cadherins.dht and other growth factors and hormones regulate synthesis of substances secreted from the epithelium such as the serine protease,prostate-specific antigen (Psa).interspersed throughout acini close to urethra and lumen are neuroendocrine cells which release a range of compounds.
prostate direct nerve growth and neurotrans- |
are millimeters from the neurovascular bundle |
mitter expression in addition to prostate growth |
supplying the penis and dissection of these |
and development.13-16 |
structures must avoid thermal injury. During |
|
robotic prostatectomy some nerve fibers within |
|
this capsule and fascia can be visualized.Prostatic |
Prostate Innervation |
nerves course within the posterior leaf of |
Denonvilliers fascia. Often these nerves are mis- |
|
Understanding the neurophysiology and auto- |
taken as branches of the cavernous nerves since |
those are also NAPHase positive and manufac- |
|
nomic pharmacology of the bladder outlet and |
ture nitric oxide (NO). Lastly, some branches |
prostate is of paramount importance for eluci- |
enter the prostate from the neurovascular bun- |
dating the etiology and designing treatments for |
dle near the apex. It is tempting to speculate that |
lower urinary tract symptoms (LUTS) associated |
this abundant innervation implies significant |
with benign prostatic hyperplasia (BPH). The |
functional importance. |
prostate receives input from parasympathetic |
Sympathetic nerves provide most of the effer- |
and sympathetic nerves.17-27 Noradrenergic, cho- |
ent neural input to the prostate. Nearly 80% of |
linergic, peptidergic, and nitrergic nerves have |
the prostate’s innervation is derived from sympa- |
been demonstrated in the prostate.19-21,28-34 Cell |
thetic outflow whereas 21–33% originates from |
bodies for these neurons reside in the capsule |
parasympathetic pathways.25 Nearly two-third of |
and near the base of the seminal vesicle.19,27 It is |
the neurons in the pelvic plexus supplying the |
crucial for surgeons to realize that nerves near |
prostate are noradrenergic.35 Noradrenergic |
the lateral aspect of the seminal vesicle |
nerve fibers are prominent around the prostatic |
242
Practical Urology: EssEntial PrinciPlEs and PracticE
Dynamic component
Static component
T |
5 |
αR |
DHT |
|
α1dAR |
|
|
NOS |
|
||||
|
Type II |
|
|
|
||
|
|
|
AR |
|
NE |
|
|
|
|
DNA |
|
NE |
|
|
|
|
|
|
||
|
|
|
|
|
α1AAR |
|
|
|
|
AR DHT |
HRE |
|
NE |
|
|
|
|
NO |
α1AAR |
NE |
|
|
|
|
|
|
|
|
|
|
|
NOS NO |
|
α1 blockers |
5αR inhibitors
PDE5 inhibitors
Figure 18.2. Prostate pharmacology.traditionally,lower urinary symptoms due to benign prostatic hyperplasia (BPh) is attributed to obstruction or increased urethral resistance from prostate growth regulated by dihydrotestosterone (dht) (static) or increased tone due to norepinephrine (nE) (dynaMic) released from noradrenergic postganglionic sympathetic nerves. dht is synthesized from testosterone by a 5 alpha reductase (5ar) type
ducts, especially near their openings into the posterior urethra.
The prostate receives sparse parasympathetic innervation conveyed by the pelvic nerve.25 Most of the cholinergic fibers are sympathetic in origin. Although less numerous than noradrenergic fibers, cholinergic nerves travel in the dorsal capsule, the fibromuscular stroma, near acini and ducts, and surrounding the vasculature.29,33,36-38
Afferent axons whose cell bodies reside in the thoracolumbar and sacral dorsal root ganglia (DRG) travel from the prostate to the CNS in the hypogastric and pelvic nerves, respectively.25,35 This duality of sensory innervation is most apparent when assessing patterns of referred pain from the prostate. Suprapubic and groin discomfort correspond to referred pain from T12 to L2 levels conveyed from the prostate by
ii in the prostate. after binding to an androgen receptor (ar) the dht-ar dimmer is transported to the nucleus whereon it binds to a hormone response element (hrE) on dna to regulate transcription. nitric oxide (no) synthesized by nitric oxide synthase (nos) may also relax the outlet. this action can be enhanced by phosphodiestase type 5 inhibitors (PdE5) which prolong cyclic guanylate cyclase (cgMP) action in smooth muscle.
hypogastric nerves,39 whereas perineal pain signifies input from the pelvic nerve (S2–S4). Prostatic afferents transmit the sensations of pain or contraction, and relay information necessary for reflex phenomena such as emission and ejaculation to the thoracolumbar spinal cord where neurons controlling ejaculation reside.40 The location of urethral and prostatic nerves, especially sensory fibers, may be relevant for designing therapies for BPH. Thermotherapy for BPH appears to destroy these prostatic nerves or alter neurotransmitter receptor function.41,42 Relief of symptoms may rely on relative denervation or reduced neurotransmission. Indeed, the ability of prostatic injections of botulinum toxin to relieve symptoms and reduce prostate size suggests an important role for nerves.43
In the CNS, pathways receiving input from the prostate participate in an extensive neural
243
Physiology and PharMacology of thE ProstatE
network,which interacts with pathways involved |
relieves storage and voiding components of |
|||
in micturition and sexual function.26 In addi- |
LUTS in BPH patients.54-57 The a -adrenoceptor |
|||
tion to the expected labeling in autonomic |
|
|
1A |
|
is the dominant subtype representing about |
||||
centers, prostate-labeled neurons reside in Bar- |
60–85% of the a1-adrenoceptor population. The |
|||
rington’s nucleus (micturition center), raphe |
a1A-adrenoceptor mediates the contractile |
|||
magnus, reticular formation, A5, A7, periaque- |
response of the human prostate in vitro.58,59 |
|||
ductal gray, red nucleus, and subcoeruleus. The |
However, there is some variability in expression |
|||
physiological significance of these associations |
among men as indicated by differential responses |
|||
is unclear but they raise the possibility that the |
to alpha-subtype drugs that correlate with the |
|||
function of the prostate or prostatic urethra is |
a and a |
1b |
ratio in the specimens.60 |
|
somehow linked to that of the bladder/urethra |
1A |
|
||
Noradrenergic nerves are also considered |
||||
and penis. |
responsible for maintaining prostatic smooth |
|||
CGRP-immunoreactive nerves, considered to |
muscle tone,61 and approximately 50% of the |
|||
represent sensory nerves, are few compared to |
total urethral pressure in BPH patients may |
|||
the other phenotypes characterized. NOSand |
be due to a-adrenoceptor-mediated muscle |
|||
CGRP-immunoreactive terminals have similar |
tone.62,63 Conceivably a global increase in |
|||
profiles, but the immunoreactivities are not co- |
sympathetic tone leads to increased urethral |
|||
localized.29 Pituitary adenylate cyclase activat- |
resistance and prostatic tone. Thus a blockers |
|||
ing peptide (PACAP), presumably in pelvic |
have shown clinical utility for voiding symp- |
|||
afferents, is expressed by nerves supplying the |
toms or painful ejaculation in young anxious |
|||
prostate.29 The proximal central prostate con- |
men.64 |
|
|
|
tains more peptidergic fibers (vasoactive intes- |
In addition to causing contraction of the out- |
|||
tinal polypeptide [VIP] and opiate-related |
let, hypogastric nerve stimulation (sympathetic) |
|||
peptides metand Leuenkephalins [ENK],32,44 |
increases secretion.8,65-68 Yet this secretion is |
|||
neuropeptide Y [NPY], peptide histidine leucine |
blocked by the muscarinic agonist atropine,66-68 |
|||
[PHI], somatostatin [SOM], galanin [GAL], |
implying that sympathetic cholinergic nerves |
|||
bombesin [BOM], substance P [SP], calcitonin |
control exocrine function (see reviews by |
|||
gene-related peptide [CGRP], and pituitary ade- |
Elbadawi and Goodman,17 Dail,21, and Smith69). |
|||
nylate cyclase peptide [PCAP]) than the anterior |
Likewise, muscarinic agonists including pilo- |
|||
capsule, which exceeds the distal central zones, |
carpine and urecholine induce prostatic secre- |
|||
which in turn is greater than the peripheral |
tion.8,17,65,66,70 This secretion is mediated by |
|||
zone. |
muscarinic receptors expressed by epithelial |
|||
|
cells.46,71,72 Cholinomimetic drugs barely con- |
|||
Neurophysiology |
tract prostate capsule accounting for only |
|||
10–15% of that of a agonists. Anti-muscarinics |
||||
|
||||
and Neuropharmacology |
such as atropine completely block secretory |
|||
responses to these agonists as well as hypogas- |
||||
|
tric nerve-evoked secretion. Despite this obser- |
|||
Stimulation of the pelvic nerve produces a slight |
vation, a decrease in ejaculate volume is rarely a |
|||
contraction of the prostate, whereas hypogastric |
complaint of men on anticholinergics. Of the |
|||
nerve stimulation evokes a profound contrac- |
five molecular muscarinic receptor subtypes the |
|||
tion and secretion.45 Contraction of the prostatic |
M1 receptor is expressed by prostatic epithelium, |
|||
capsule, due to firing of the hypogastric nerve, |
whereas the stroma expresses the M2 receptor |
|||
increases bladder outlet resistance. Contractile |
protein. |
|
|
|
responses are mediated by noradrenergic rather |
Many prostatic nerves stain for nitric oxide |
|||
than cholinergic mechanisms. Noradrenaline |
synthase (NOS) or heme-oxygenase (HO), sug- |
|||
stimulates contraction-mediating a-adrenocep- |
gesting that they manufacture nitric oxide and |
|||
tors localized to predominately prostatic stroma. |
carbon monoxide.29,33,73-77 NOS is expressed by |
|||
Although both a1 and a2 receptors can be iden- |
both sensory and motoneurons. In men with |
|||
tified in the human prostate,46,47 the contractile |
BPH, this finding may explain the efficacy of |
|||
properties are mediated primarily by a1-adre- |
PDE5 inhibitors to reduce LUTS (Fig. 18.2). |
|||
noceptors.46,48-53 Many clinical investigations |
NO inhibits secretion and reduces contractile |
|||
have confirmed that a1-adrenoceptor blockade |
action. NO alone has no consistent effect in the |
|
|
|
|
|
244 |
|
|
|
|
||||
|
|
Practical Urology: EssEntial PrinciPlEs and PracticE |
||||
prostate yet relaxes the urethra.78 Relaxation of |
size (static component) may be too simplistic a |
|||||
NE-contracted prostatic tissue can be prevented |
concept and fails to reconcile data that men |
|||||
by NOS inhibition.29,42 Similar to its effect on the |
without urodynamic evidence of reduced |
|||||
urethra, exogenous NO relaxes prostatic tissues. |
obstruction and no change in voiding flow rates |
|||||
NO may play a role in controlling smooth mus- |
can benefit from these drugs (Fig. 18.2). Because |
|||||
cle tone in the prostate. Indeed, phosphodi- |
LUTS attributed to BPH is multifactorial |
|||||
esterase type 5 (PDE5) inhibitors which raise |
(increased resistance, changes in the detrusor, |
|||||
cGMP may increase urine flow rates and lower |
urothelium, interstitial cells, or nerves), drugs |
|||||
LUTS in men with BPH.79-81 Yet, a reduction in |
probably target multiple sites. Indeed, the asso- |
|||||
symptoms without a corresponding increase in |
ciation of LUTS with metabolic syndrome and |
|||||
urinary flow suggests actions at other sites than |
erectile dysfunction implies a complex interac- |
|||||
the outlet for PDE5 inhibitors. |
tion of pathophysiological processes. Moreover, |
|||||
Transmitters released from prostatic nerves |
the prevalence of overactive bladder (OAB) |
|||||
may alter the composition of prostatic secre- |
increases with age, especially in men. Thus, the |
|||||
tions.68,70,82,83 The concentration of sodium in |
multiple sequelae of obstruction combined with |
|||||
prostatic secretions is essentially the same as |
underlying OAB suggest that a wide range of |
|||||
that in plasma. In contrast, sodium and potas- |
therapies may be effective. In fact if one scans |
|||||
sium concentrations in neurally evoked pros- |
the literature for prospective randomized trials |
|||||
tatic secretions exceed those in plasma. |
for BPH and calculates the potential combina- |
|||||
In carbachol-stimulated secretions the pro- |
tions of |
approved |
5AR |
inhibitors (n = 2) |
||
tein concentration and prostatic acid phos- |
a-adrenergic antagonists (n = 7), PDE 5 inhibi- |
|||||
phatase activity were reduced compared to |
tors (n = 4), and antimuscarinics (n = 6) used |
|||||
noradrenalineor phenylephrine-stimulated |
singly, doubly, or in triple drug combinations, |
|||||
secretion.70 |
greater than 72 regimens can be identified! And |
|||||
Nerves maintain the functional integrity of |
this fails to include vasopressin analogs or botu- |
|||||
glandular tissue. Several studies have shown |
linum toxin. |
|
|
|||
that surgical denervation reduces prostatic |
In general, the rapid onset and relief of most |
|||||
weight and causes atrophy of acini.84-86 Similarly, |
bothersome storage symptoms of urgency, fre- |
|||||
chemical sympathectomy decreases the weight |
quency, and nocturia by a-adrenergic antago- |
|||||
of the prostate and glands appear dilated.87,88 |
nist has led to their use as drugs of first choice. |
|||||
Botulinum toxin, which prevents neurotrans- |
The evolution from non-a1 |
selective multidose |
||||
mitter release, causes long-term shrinkage of |
regimens |
(prazosin, |
phenoxybenzamine) to |
|||
prostate with a reduction in PSA.43 Interestingly, |
once-daily preparations (doxazosin, terazosin, |
|||||
men with longstanding spinal cord injury |
alfuzosin) and then to agents with fewer effects |
|||||
exhibit reduced prostate size, decreased mRNA |
on the vasculature due to a1A selectivity (tamsu- |
|||||
for the androgen receptor, and lower levels |
losin, silodosin) has occurred. Some agents such |
|||||
PSA.89 Whether this is due to changes in neural |
as doxazosin GITS with slow release allow initia- |
|||||
activity or chronic infections is unclear. |
tion at higher doses for non-subtype-selective |
|||||
|
|
blockers, thereby avoiding slow dose titration. |
||||
Treatment of LUTS Attributed |
In a meta-analysis comparing efficacy as indi- |
|||||
cated by symptom scores and maximal flow |
||||||
|
|
|||||
to BPH |
rates, all agents are similar.90 The only exception |
|||||
to this is suggested by a comparative trial |
||||||
|
|
between doxazosin and alfuzosin.91 Although |
||||
The treatment of LUTS due to BPH has been |
increases in urinary flow rates were similar, |
|||||
complicated by the proliferation of clinical trials |
symptom improvement was greater for dox- |
|||||
demonstrating efficacy of agents spanning sev- |
azosin. Given similar a-adrenergic antagonist |
|||||
eraldrugclassesrelativetoplacebo.Traditionally, |
properties, and the major difference being lack |
|||||
one is left to believe that LUTS due to BPH |
of CNS penetration for alfuzosin, implies that |
|||||
results from merely bladder outlet obstruction. |
central action on a blockers participates in |
|||||
Reduction in outlet resistance by relaxation of |
symptom relief especially for storage symptoms. |
|||||
the urethra and prostatic smooth muscle |
Because the a1A receptor regulates contraction |
|||||
(dynamic component) or a reduction in prostate |
of the seminal vesicles and vas deferens, agents |