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Benign enlargement of prostate . medical therapy

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Benign enlargement of prostate . medical therapy

  1. 1. 04/20/1804/20/18 PATKIPATKI 11 Management of BPHManagement of BPH DR P S PATKI
  2. 2. 22 Campbell’s textbook of urology, 8th edition Worldwide PrevalenceWorldwide Prevalence 0 10 20 30 40 50 60 70 80 90 100 20-29 30-39 40-49 50-59 60-69 70-79 80-89 Prevalence(%) Pradhan (1975) Swyer (1944) Franks (1954) Moore (1943) Harbitz (1972) Holund (1980) Baron (1941) Fang-Liu (1991) Karube (1961) Age (y)
  3. 3. 33 DefinitionsDefinitions LUTS = Lower Urinary Tract SymptomsLUTS = Lower Urinary Tract Symptoms Benign Prostatic Hyperplasia Benign Prostatic Enlargement Bladder Outlet Obstruction
  4. 4. 44 Benign Prostatic HyperplasiaBenign Prostatic Hyperplasia BPH = Histological termBPH = Histological term Static componentStatic component  Hyperplasia narrows the urethral lumenHyperplasia narrows the urethral lumen Dynamic componentDynamic component  ↑↑ Prostatic smooth muscle tone obstructs the bladder outletProstatic smooth muscle tone obstructs the bladder outlet  Mediated by alpha - adrenergic receptorsMediated by alpha - adrenergic receptors
  5. 5. 55 Nordling J et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia, lymouth, UK: Health Publication Ltd; 2001:107-166 LUTS (Symptoms) BPH (Hyperplasia)BOO (Obstruction) Common Urological ProblemsCommon Urological Problems
  6. 6. 66 HistologicalHistological  HyperplasiaHyperplasia 22 ClinicalClinical  LUTSLUTS 11 AnatomicalAnatomical  BPEBPE 11 PathophysiologicalPathophysiological  BOOBOO 11 1. Nordling J et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK : Health Publication Ltd; 2001:107-166 2. Roehrborn C. Rev Urol. 2002;3:139-145 Histologic BPH All Men >40 y `BOO Obstruction BPE Enlargement LUTS/ Bother BPH ChangesBPH Changes
  7. 7. 77 Homma Y et al. Scand J Urol Nephrol suppl. 1994;157:27-30 0 10 20 30 40 50 60 70 80 90 <49 50-59 60-69 70-79 80-84 Age (y) Subjects(%) Weak Stream Urgency Frequency Nocturia Prevalence of LUTSPrevalence of LUTS
  8. 8. 88 Girman CJ et al. J Urol. 1993;150:887-892 MedianPeak FlowRate(mL/s) 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75+ 20.3 19 18 16 16 14.3 13 11.5 0 7 14 21 28 35 N = 2113 Age (y) Prevalence of LUTSPrevalence of LUTS
  9. 9. 99 1. Schwinn DA. BJU Int. 2000;86(suppl 2):11-22 αα - Adrenergic Tone & LUTS- Adrenergic Tone & LUTS Prostate smooth muscle tone mediated viaProstate smooth muscle tone mediated via αα11-adrenergic receptors-adrenergic receptors 11 ↑↑ tone leads to reduction in flow ratetone leads to reduction in flow rate 11 Blockage of the receptorBlockage of the receptor ↑↑ flow rate and LUTSflow rate and LUTS 11 CentralCentral αα - receptors play an additional role- receptors play an additional role Density of these receptors changes with prostate size andDensity of these receptors changes with prostate size and ageage ThreeThree αα11-adrenergic receptor subtypes-adrenergic receptor subtypes  αα11 (( A, B, DA, B, D)) 11
  10. 10. 1010 BPH & UroflowmetryBPH & Uroflowmetry
  11. 11. 1111 Etiological factorsEtiological factors AndrogensAndrogens  Testosterone + DHTTestosterone + DHT EstrogensEstrogens  Role not clearRole not clear Stromal & epithelial interactionsStromal & epithelial interactions  Paracrine growth factorParacrine growth factor signalingsignaling →→ Cell proliferationCell proliferation + Apoptosis+ Apoptosis Inflammatory cellsInflammatory cells Adrenergic nervesAdrenergic nerves
  12. 12. 1212 Altered function of prostate cells Proliferation Angiogenesis Apoptosis Prostatic enlargement BPH • BOO • LUTS • AUR McConnell, Campbell’s Urology, 7th ed PathophysiologyPathophysiology
  13. 13. 1313 SymptomsSymptoms Symptoms ofSymptoms of ““ bladder obstruction “bladder obstruction “  HesitancyHesitancy  Weakness of urinary streamWeakness of urinary stream  Intermittent urinary streamIntermittent urinary stream  A feeling of incomplete bladderA feeling of incomplete bladder emptyingemptying  A need for repeat voidingA need for repeat voiding Symptoms ofSymptoms of ““ bladder irritability “bladder irritability “  Urinary frequencyUrinary frequency  NocturiaNocturia  Urinary urgencyUrinary urgency
  14. 14. 1414 Jensen JV, et al. Urol Clin North Am. 1988;25:545-554 ComplicationsComplications Urinary retentionUrinary retention Renal impairmentRenal impairment Urinary tract infectionUrinary tract infection HaematuriaHaematuria Bladder stonesBladder stones Bladder decompensationBladder decompensation Overflow incontinenceOverflow incontinence
  15. 15. 1515 DiagnosisDiagnosis AUA Symptom Score HistoryAUA Symptom Score History Neurovascular examinationNeurovascular examination Digital rectal examinationDigital rectal examination UrinalysisUrinalysis UrographyUrography CystoscopyCystoscopy
  16. 16. 1616 Additional testsAdditional tests UroflowmetryUroflowmetry Post void residual urine volumePost void residual urine volume Pressure flow studiesPressure flow studies  Urodynamic evaluationUrodynamic evaluation Prostate Specific AntigenProstate Specific Antigen ( PSA)( PSA)
  17. 17. 1717 631 white men631 white men 40- 79 yrs40- 79 yrs Prostate growth ratesProstate growth rates ↑↑ byby 1.6% / yr1.6% / yr Higher baseline prostateHigher baseline prostate volumevolume  Higher rates of prostateHigher rates of prostate growthgrowth Rhodes T et al. J Urol. 1999;161:1174-1179 Natural historyNatural history
  18. 18. 1818 Treatment optionsTreatment options LUTSLUTS Treatment optionsTreatment options Mild symptomsMild symptoms ReassuranceReassurance ObservationObservation Moderate symptomsModerate symptoms Medical therapyMedical therapy Minimally invasive therapyMinimally invasive therapy TURP + ObservationTURP + Observation Severe symptomsSevere symptoms Medical therapyMedical therapy MIT / TURPMIT / TURP Open surgeryOpen surgery
  19. 19. 1919 1. McConnell JD et al. Clinical Practice Guideline, Number 8. AHCPR Publication No. 94-0582 2. Roehrborn C (reviewer). Rev Urol. 2001;3:139-145 3. Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001;519-534 4. Sarma AV et al. J Urol. 2002;168:1446-1452 5. Brookes ST et al. BMJ. 2002;1059-1061 WatchfulWatchful WaitingWaiting Patient is followed annuallyPatient is followed annually  But receives no active intervention forBut receives no active intervention for LUTSLUTS 1,41,4  Mild or moderate symptomsMild or moderate symptoms 2, 32, 3 Variable progressionVariable progression 3,53,5  SymptomsSymptoms  Sexual dysfunctionSexual dysfunction  Urodynamic parametersUrodynamic parameters  Prostate sizeProstate size
  20. 20. 2020 Treatment optionsTreatment options Medical therapyMedical therapy  PhytotherapyPhytotherapy  55 αα - reductase inhibitors- reductase inhibitors  αα - blockers- blockers  Combination therapyCombination therapy
  21. 21. 2121 Surgical Treatment optionsSurgical Treatment options OPD based surgeryOPD based surgery  TUMT-microwaveTUMT-microwave  TUNA-needle ablationTUNA-needle ablation  WIT-water inducedWIT-water induced thermotherapythermotherapy In patient treatmentsIn patient treatments  TURP (TURP (gold standardgold standard)-resection)-resection  Open surgeryOpen surgery  TUIP-INCISIONTUIP-INCISION  ILC-INTERSTITIAL LASERILC-INTERSTITIAL LASER COAGULATIONCOAGULATION  VLAP-visual laser ablationVLAP-visual laser ablation  Prostatic stentsProstatic stents 1. Chatelain C et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001;519 2. 534. DeBruyne FMJ et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001;397-421 3. McConnell J. Presented at American Urological Association 2002 Annual Meeting (Abstract 1042)
  22. 22. 2222 Medical therapyMedical therapy 30 – 40 % of patients discontinue within a year30 – 40 % of patients discontinue within a year Problems : Efficacy + Side effects + ComplianceProblems : Efficacy + Side effects + Compliance Alpha blockersAlpha blockers  Terazosin (1970)Terazosin (1970)  Doxazosin (1995)Doxazosin (1995)  Tamsulosin (1997)Tamsulosin (1997)  First uroselective agentFirst uroselective agent  Blocks alpha-1a, alpha-1b receptorsBlocks alpha-1a, alpha-1b receptors 5 alpha - reductase inhibitors5 alpha - reductase inhibitors  Finasteride (1992)Finasteride (1992)
  23. 23. 2323 Current medical optionsCurrent medical options Alpha blockersAlpha blockers  Best monotherapy for immediate symptom reliefBest monotherapy for immediate symptom relief 5 alpha - reductase inhibitors5 alpha - reductase inhibitors  Prevent disease progressionPrevent disease progression Combination therapyCombination therapy  Moderate to severe symptomsModerate to severe symptoms
  24. 24. 2424 • α-1A adrenoreceptors • α- adrenoreceptors αα11- adrenergic blockers- adrenergic blockers Smooth muscle of bladderSmooth muscle of bladder neck, prostatic capsuleneck, prostatic capsule and adenomaand adenoma  αα11-- adrenergicadrenergic receptorsreceptors  80% of all80% of all receptors inreceptors in prostateprostate  αα1A1A
  25. 25. 2525 αα11 - Adrenoreceptors (ARs)- Adrenoreceptors (ARs) α1- ARs & LUTS Smooth muscle contraction α1A Irritative Symptoms α1D > α1A Control of Urinary function α 1D Younger patients α1A Older patients α1B > α1A DetrusorProstate Spinal cord Vessels Jardin A et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia, Plymouth, UK: Health Publication Ltd; 2001:459-477
  26. 26. 2626 αα11 - blockers- blockers YES - 10 mg Alfuzosin YES + / -0.4, 0.8 mgTamsulosin NO + 1, 2, 4, 8 mgDoxazosin NO+ 1, 2, 5, 10 mgTerazosin UroselectiveTitrationDosingAgent
  27. 27. 2727 Benefits with alpha blockersBenefits with alpha blockers Rapid improvement of urinary flowRapid improvement of urinary flow Reduce symptoms of LUTSReduce symptoms of LUTS Similar efficacy of agents in this classSimilar efficacy of agents in this class Modest effects on sexual dysfunctionModest effects on sexual dysfunction  Except TamsulosinExcept Tamsulosin
  28. 28. 2828 Alpha blockers : Adverse eventsAlpha blockers : Adverse events Cardiovascular + CNSCardiovascular + CNS  Orthostatic hypotensionOrthostatic hypotension  Dizziness + Vertigo + SyncopeDizziness + Vertigo + Syncope  Edema + Angina + ArrhythmiaEdema + Angina + Arrhythmia  Headache +FatigueHeadache +Fatigue GenitourinaryGenitourinary  Impotence + Decreased libidoImpotence + Decreased libido  Retrograde ejaculationRetrograde ejaculation Dyspnea + wheezingDyspnea + wheezing RhinitisRhinitis
  29. 29. 2929 55 αα-Reductase inhibitors-Reductase inhibitors Androgens play a role in pathogenesis of BPHAndrogens play a role in pathogenesis of BPH  Dihydrotestosterone (DHT)Dihydrotestosterone (DHT)  55αα-reduced form of testosterone (T)-reduced form of testosterone (T)  10-fold higher binding affinity to AR than T10-fold higher binding affinity to AR than T Serum T converted to DHTSerum T converted to DHT  by type I and type II 5by type I and type II 5αα-reductase (5AR)-reductase (5AR)  Type II is predominant in prostateType II is predominant in prostate DHT promotesDHT promotes  Prostate cell proliferationProstate cell proliferation  Suppression of prostate cellSuppression of prostate cell apoptosisapoptosis  Increased prostate vascularizationIncreased prostate vascularization (angiogenesis)(angiogenesis)
  30. 30. 3030 55 αα-Reductase inhibitors-Reductase inhibitors Men deficient in Type II 5 ARIMen deficient in Type II 5 ARI  Do not develop BPH / Prostate cancerDo not develop BPH / Prostate cancer Inhibition of 5AR enzymes (5ARIs)Inhibition of 5AR enzymes (5ARIs)  Reduce DHT in serum and prostateReduce DHT in serum and prostate Decreased androgenic activityDecreased androgenic activity  Epithelial atrophyEpithelial atrophy  Shrinkage of the prostateShrinkage of the prostate  Improving - LUTS & flow rateImproving - LUTS & flow rate Bartsch G et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia, Plymouth, UK: Health Publication Ltd; 2001:423-457
  31. 31. 3131 FinasterideFinasteride Inhibits conversion of testosterone to DHTInhibits conversion of testosterone to DHT ↓↓ overall gland sizeoverall gland size ↓↓ obstruction & obstructive eventsobstruction & obstructive events ↓↓ need for surgery in glands greater than 40 gmsneed for surgery in glands greater than 40 gms Adverse events minimalAdverse events minimal Must be taken for at least 3 monthsMust be taken for at least 3 months 50% reduction in serum PSA levels50% reduction in serum PSA levels
  32. 32. 04/20/1804/20/18 PATKIPATKI 3232 Testosterone Finasteride Testosterone Type II 5 α-Reductase Type II 5 α-Reductase DHT DHT Finasteride ↓ the amount of testosterone converted to dihydrotestosterone Finasteride
  33. 33. 3333 80 - 90% inhibition of type II 5 α -reductase ↓ DHT  70% in serum  90% in prostate  34% in skin T ↑ by 10% ↓ PSA by 50% ↓ Total prostate volume by 15%–25% FinasterideFinasteride
  34. 34. 3434 55αα-Reductase Inhibitors-Reductase Inhibitors Finasteride and DutasterideFinasteride and Dutasteride  Similar efficacy in improvingSimilar efficacy in improving  LUTSLUTS  Urinary flow rateUrinary flow rate Similar effect onSimilar effect on  Prostate volumeProstate volume  Serum PSASerum PSA  AURAUR similar adverse event profilessimilar adverse event profiles No known differences in their useNo known differences in their use
  35. 35. 3535 5-alpha reductase inhibitors5-alpha reductase inhibitors Adverse eventsAdverse events ImpotenceImpotence Decreased libidoDecreased libido Reduction in semen during ejaculationReduction in semen during ejaculation Reduction in PSA levelsReduction in PSA levels  May interfere with screening for Ca prostateMay interfere with screening for Ca prostate
  36. 36. HERBAL DRUGSHERBAL DRUGS 3636
  37. 37. HERBALSHERBALS HIMPLASIAHIMPLASIA We will discuss on thisWe will discuss on this product in next set .product in next set . 3737

Notas do Editor

  • Here we see an increased prevalence of BPH in men of all ages in newer studies compared with older studies.
  • This cartoon illustrates the difference between the histological change, BPH, benign enlargement of the prostate gland, which often is present without causing obstruction, and bladder outlet obstruction, which is due to benign enlargement of the prostate gland.
     
    Alterations in bladder and urethral function can occur with age. These changes may be manifested as only lower urinary tract symptoms, or by damage to the lower and/or upper urinary tract.
     
    Benign prostatic hyperplasia is the term used to describe the histological change associated with benign prostatic enlargement. Benign enlargement of the prostate gland also progresses with age and can cause bladder outlet obstruction. Aging and bladder outlet obstruction can each can trigger changes in the structure and function of the bladder wall and its nerve supply, which can lead to clinical symptoms.
  • Benign prostatic hyperplasia is clinically evident in 50% of men by age 50 and in 80% of men by age 80. Androgens, particularly dihydrotestosterone, appear to play a major role. Hyperplasia of the prostate, with subsequent increase in the fibromuscular stroma, results in a narrowing of the urethral lumen as it traverses the prostate. This is the static component. This narrowing obstructs the bladder outlet. In addition, prostatic smooth muscle tone, mediated through alpha-adrenergic receptors, creates further bladder outlet obstruction. This is the dynamic component.
  • Lower urinary tract symptoms are frequently present in aging men.
     
    Although lower urinary tract symptoms may be associated with enlargement of the prostate gland, bladder outlet obstruction, or the specific histopathological condition known as benign prostatic hyperplasia, this does not imply a causal relationship.
    However, Lower urinary tract symptoms may be caused by an enlarged prostate, which can also lead to bladder outlet obstruction.
     
    Lower urinary tract symptoms may be present in the absence of any of these conditions.
  • The definition of BPH is based on prostate size, symptoms, and obstruction.
    BPH may be associated with clinical signs, anatomic findings, and physiologic or pathophysiologic outcomes.
     
    Histologically, BPH is characterized by stromoglandular hyperplasia.
     
    Clinically, the patient has bothersome lower urinary tract symptoms or evidence of lower urinary tract deterioration or upper urinary tract damage.
     
    Anatomically, enlargement of the prostate gland or an enlarged transition zone can be demonstrated objectively.
    Pathophysiologically, compression of the urethra leads to obstruction, with compromised urinary flow.
  • A survey of 168 male and 101 female outpatients over 30 years of age who attended a urology clinic assessed the prevalence of self-reported urinary symptoms. Participants had no subjective complaints concerning urination, and male subjects had a prostate volume of less than 20 milliliters on transabdominal ultrasonography.
     
    Among the 168 men aged 34 to 84 who had no spontaneous complaints of lower urinary tract symptoms, the prevalence of symptoms such as weak stream, urgency, frequency and nocturia increased with increasing age.
     
    Nocturia showed the most dramatic increase from less than 10% in those under the age of 50 to more than 30% in those over the age of 70 and more than 60% in those over the age of 80. Symptoms of weak stream, urgency and frequency were 2 to 4 times more prevalent in those over the age of 70 compared to those under the age of 50. Urodynamic studies in 65 of the men with low symptom scores found a significant reduction in maximum flow rate with increasing age.
  • Urinary flow rates were measured in a randomly selected community sample of 2,113 men 40 to 79 years of age with no history of prostate surgery, prostate cancer, or other diseases known to interfere with normal voiding who were residing in Olmsted County, Minnesota.
    Data from the study showed a steady decrease in both peak and average urinary flow rates with increasing age. Peak flow rate (shown here) decreased from a median of 20.3 mL/s for men 40 to 44 years of age to 11.5 mL/s for those aged 75 to 79.
    Voided volume decreased as the men aged. The percentage of men unable to void 150 mL increased from 2.8% of men 40 to 44 years of age to 16% of those older than 75.
    These underscore those from prior studies indicating that peak urinary flow rate decreases with age. However, the suggestion of a decrease in voided volume with age is in contrast to other studies.The investigators point out that this decrease in volume could be caused by an increase in residual urine as men age and experience the obstructive symptoms of BPH, or something as easily explained as changes in bladder muscle tone due to aging.
    Girman CJ, Panser LA, Chute CC, et al. Natural history of prostatism: urinary flow rates in a community-based study. J Urol. 1993;150:887-892.
  • Prostate smooth muscle tone is mediated via 1-adrenergic receptors. Increased tone of the prostate smooth muscle leads to BOO and a reduction in urinary flow rate. Blockage of the 1-adrenergic receptor relaxes prostate smooth muscle and relieves BOO.1
    Studies indicate that, overall, 1-adrenergic receptor expression doubles with age (&amp;lt;55 y vs 65 y).2 To date, three 1-adrenergic receptor subtypes have been identified: 1A, 1B, and 1D.1
    Schwinn DA. Novel role for 1-adrenergic receptor subtypes in lower urinary tract symptoms. BJU Int. 2000;86(suppl 2):11-22.
    Rudner XL, Berkowitz DE, Booth JV, et al. Subtype specific regulation of human vascular 1-adrenergic receptors by vessel bed and age. Circulation. 1999;100:2336-2343.
  • As the prostate enlarges, it compresses and distorts that part of the urethra which passes through it, causing disruption to the normal flow of urine.
  • Several factors play important roles in the etiology of BPH. Of the androgens, testosterone and DHT are primarily involved.
    In the canine model, researchers have shown that estrogens play a significant role, but this role is less clear in humans.
    Increased cell proliferation and reduced apoptosis are mediated by paracrine growth factors, and may contribute to the development of BPH. Additional factors include inflammatory cells in the prostate, and smooth muscle cell tone controlled by the adrenergic nervous system. The autonomic nervous system has a permissive effect on maximal prostate growth.
  • Altered functioning of the prostate cells leads to increased cell proliferation and angiogenesis, and a decrease in the rate of apoptosis. These changes result in an increase in epithelial cell numbers, which acts to disrupt the growth equilibrium of the prostate gland, causing prostate enlargement, or BPH. The clinical manifestations of BPH include bladder outlet obstruction, lower urinary tract symptoms (LUTS), and acute urinary retention.
  • The symptoms of the bladder outlet obstruction that occurs with BPH include hesitancy, weakness of urinary stream, intermittency of urination, a feeling of incomplete bladder emptying, and bladder irritability, as manifested by urinary frequency, nocturia, and urinary urgency.
  • BPH is a progressive disease. If left untreated, it can result in complications including urinary retention, renal impairment, UTI, gross hematuria, bladder stones, bladder decompensation and incontinence. The most serious of these include acute urinary retention and the need for surgical intervention requiring hospitalization.
  • The accepted means of measuring the severity of BPH is by determining the patient’s symptom score based on criteria from the American Urological Association. Diagnosing BPH is based on a summary of symptoms, its pattern of development, physical exam and the exclusion of other medical diseases, which may confound the diagnosis.
     
    Initial evaluation should also include a history physical exam that focuses on the lower extremities as well the saddle region and digital rectal examination, along with urinalysis and measurement of the serum creatinine level.
     
    Digital rectal examination may reveal an enlargement of the gland, prostatic firmness, or a nodule, which should increase the clinician’s suspicion of prostate cancer. A urinalysis that reveals greater than 4 red blood cells per high-power field in uninfected urine requires urinary tract imaging and cystoscopy to rule out alternate causes such as stones or tumors.
  • Further diagnostic testing such as uroflowmetry, post void residuals, more complex urodynamic evaluation, etc., may also be necessary. Serum PSA measurement is not part of the diagnostic evaluation of BPH, but may help exclude prostate cancer as a cause of urinary tract obstruction and should be performed in any man in which the potential for prostate cancer may influence treatment choice or eventual outcome.
  • The treatment options for men with BPH include watchful waiting, medical therapy, and surgical therapy. Therapy choices depend on symptomology. Patients with low symptom scores and a normal PSA are considered ideal candidates for observation and reassurance. These patients are seen on a yearly basis. Symptom scores should be checked over time; patients with increasing symptom scores will progress to more aggressive treatments. In patients with moderate symptoms, medical therapy, minimally invasive therapy, and observation are all accepted options. In those with severe symptomology, medical therapy, MIT, and open surgery comprise the choices for treatment.
  • A number of longitudinal epidemiological studies, and long-term follow-up observations from randomized placebo-controlled trials have demonstrated that many men with lower urinary tract symptoms can be followed without specific therapeutic intervention. However, this should not be considered “no management” but rather as an active surveillance.
     
    Lower urinary tract symptoms may be mild or moderate in severity, but individual patients may not find these symptoms bothersome enough to warrant active treatment. In the Olmstead County cohort of 2,1115 men, there was considerable variability between individuals in longitudinal changes in lower urinary tract symptoms’ severity and bother.
    Although benign prostatic enlargement may not progress in all patients, lower urinary tract symptoms and sexual dysfunction often increase in severity over time.
     
    All active medical treatments and surgical intervention are superior to watchful waiting with regard to improvement in lower urinary tract symptoms and sexual function.
    1.McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign Prostatic Hyperplasia: Diagnosis and Treatment. Clinical Practice Guideline, Number 8. AHCPR Publication No. 94-0582. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. February 1994.
    2.
  • There are several options for treating lower urinary tract symptoms, BPH and bladder outlet obstruction. One option is watchful waiting. If medical therapy is necessary, the options include phytotherapy, 5 alpha reductase inhibitors, alpha blockers and combination therapy. Office-based treatments include transurethral microwave thermotherapy, transurethral needle ablation and water-induced thermotherapy. More surgical-center or hospital-based treatments include transurethral resection of the prostate, which is the gold standard, transurethral incision of the prostate, open surgery, transurethral vaporization of the prostate, interstitial laser coagulation, visual laser ablation of the prostate and prostatic stents.
  • Medical therapy is currently the mainstay of treatment for BPH. The advent of medical treatment for BPH began in the early 1970s, with the introduction of the alpha blockers. However, the lack of specificity and side effects of these agents limited their use. In 1992, finasteride, a 5 alpha reductase inhibitor, was approved for treatment of BPH. Shortly thereafter, the alpha blockers terazosin (1993) and doxazosin (1995) were approved specifically for use in patients with BPH. In 1997, tamsulosin became the first uroselective agent for the treatment of BPH. It blocked the alpha-1a and alpha-1b receptors found specifically in the bladder neck.
  • The alpha blockers and 5 alpha-reductase inhibitors are considered the primary medical therapies in the treatment of BPH. The alpha blocking agents are still considered by many to be the best monotherapy for IMMEDIATE symptomatic relief of BPH. Several large, well-designed studies, including PLESS and MTOPS, have shown that a 5 alpha-reductase inhibitor such as finasteride has significant benefits in preventing disease progression.
    Combination therapy with an alpha blocker and a 5 alpha-reductase inhibitor is considered most effective treatment for symptoms and progression of BPH. THIS COMBINATION THERAPY HAS THE GREATEST EFFICAY IN THOSE WITH INCREASED PROSTATE VOLUME
  • The rationale for alpha 1-adrenergic receptor blockade is related to the role of the alpha 1-adrenergic receptor in the contraction of prostate and bladder smooth muscle
    There is also a potential for the central nervous system to play a role in this regard.
    Smooth muscle of bladder neck, prostatic capsule, and adenoma have an abundance of type I alpha-adrenergic receptors, the stimulation of which mediates bladder outlet obstruction.
    Of the 3 alpha 1-receptors that have been cloned, alpha1A, alpha1B. and alpha1D, the alpha 1A subtype represents about 80% of all receptors in the prostate. With age the percentage of alpha 1D receptors increases.
  • Alpha 1-adrenoreceptors are expressed in a variety of tissues and they play an important role in the dynamic component of BPH. There are three major alpha 1-adrenoreceptor subtypes, alpha 1A, alpha 1B, and alpha 1D. These subtypes have different patterns of expression. Alpha 1A-adrenoreceptors are the dominant subtype in prostatic stromal tissue, accounting for approximately 85% of the alpha 1-adrenoreceptor messenger RNA, or mRNA, in this tissue. These receptors play a key role in muscle contraction mediated by noradrenergic input from the sympathetic nervous system. Alpha1-adrenoreceptors in the lumbrosacral spinal cord are also involved in the control of urinary function, and the alpha 1D subtype predominates in this tissue.
     
    The clinical significance of these receptors in the treatment of lower urinary tract symptoms remains to be determined. The action of norepinephrine at alpha 1D- and alpha 1A-adrenoreceptors in the detrusor muscle is thought to be involved in irritative symptoms associated with BPH. In young individuals, alpha 1A-adrenoreceptors are the dominant subtype in resistance vessels, but alpha 1B-adrenoreceptors become the most highly expressed subtype in older individuals.
    While the most advantageous subtype selectivity profile for an alpha 1-adrenoreceptor antagonist used for the treatment of BPH has not yet been determined, the concept of clinical uroselectivity, as defined in 2000 by the International Consultation on BPH, remains a valid concept.
    1. Schwinn DA. Novel role for alpha1-adrenergic receptor subtypes in lower urinary tract symptoms. BJU Int. 2000;86:11-22.
    2.Jardin A, Andersson K-E, Chapple C, et al. a1-adrenoreceptor antagonists in the treatment of BPH. In: Chatelain C, Denis L, Foo KT, et al. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001:459-477.
    3.Rudner XL, Berkowitz DE, Booth JV, et al. Subtype specific regulation of human vascular a1-adrenergic receptors by vessel bed and age. Circ. 1999;100:2336-2343.
  • All of the -blockers, with the exception of alfuzosin, require dose titration to minimize the potential for hypotensive effects.
    Each of these -blockers has a sufficiently long half-lives to permit once-daily administration.
    Terazosin and doxazosin are not pharmacoselective/uroselective and do not show selectivity between 1AR subtypes, whereas tamsulosin selectively blocks 1A- 1D-ARs, and alfuzosin, although not subtype selective, shows functional uroselectivity because it distributes preferentially in the prostate relative to the serum.
    Product information, Abbot Laboratories, Pfizer Inc., Boehringer Ingelheim Pharmaceuticals, Inc. Data on file, Sanofi-Synthelabo Inc
  • The alpha blockers work to improve urinary flow and reduce the symptoms of LUTS in patients with BPH. In addition, all but tamsulosin have beneficial effects on sexual dysfunction.
  • Adverse effects associated with alpha blockers include fatigue (6 to 10%); postural hypotension (6 to 8%); impotence; decreased libido;, retrograde ejaculation; edema of the feet, legs, or ankles; rhinitis; dyspnea; headache; and nausea; among others. Because of the potential for postural hypotension, the approved labeling for terazosin recommends dosing at bedtime. Adverse events are usually minor and reversible with dose reduction.
  • Androgens play a permissive role in the etiology and pathogenesis of BPH.
    Dihydrotestosterone (DHT), the 5-reduced form of testosterone, binds to the androgen receptor with 10-fold higher affinity compared with testosterone.
    In the prostate, serum testosterone is converted to DHT by the 5 alpha-reductase enzymes type I and type II, of which type II is the predominant 5 alpha-reductase in the prostate. DHT is required for prostate cell proliferation, suppression of prostate cell apoptosis, and increased angiogenesis.
    Given the importance of these processes in BPH, and that DHT is produced primarily by the type II isozyme of 5 alpha-reductase, inhibitors of this enzyme have been developed and extensively evaluated for the treatment of BPH.
  • 5 alpha-reductase isoenzymes convert testosterone, the main male sex hormone, to dihydrotestosterone. Type 2 5 alpha-reductase is the predominant isoenzyme found in the prostate.1
    During the 1960s the clinical phenotype of Type 2 5 alpha-reductase deficiency was first described. Adult men with this disorder have essentially nonpalpable prostates.1
    5 alpha-reductase inhibitors significantly reduce levels of dihydrotestosterone in serum and prostate without affecting levels of testosterone, which is critical for normal libido and sexual function.1
    The overall decrease in androgenic activity associated with inhibition of Type 2 5 alpha-reductase causes marked involution of the prostate epithelium.1 A 28% reduction in prostate size was seen in men treated with finasteride for 6 months. The reduction in prostate size was associated with improvements in LUTS and urinary flow rate.2
    1. Bartsch G, McConnell JD, Mahler C, et al. Endocrine treatment of benign prostatic hyperplasia. In: Chatelain C, Denis L, Foo KT, et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001: 423-457.
    2. Stoner E. The clinical effects of a 5 alpha-reductase inhibitor, finasteride, on benign prostatic hyperplasia. The Finasteride Study Group. J Urol. 1992;147:1298-1302.
  • The 5-alpha-reductase inhibitor, finasteride, inhibits the conversion of testosterone to dihydrotestosterone. It shrinks overall gland size, thus reducing the static component of obstruction, and decreases obstructive events and the need for surgery in glands &amp;gt; 50 g. A 3-month trial is necessary to determine if finasteride is effective. The adverse effects of finasteride are minimal. About 5% of patients develop sexual dysfunction (i.e., decreased libido, decreased ejaculatory volumes, erectile dysfunction). Finasteride also causes a 50% reduction in the serum PSA level; thus, a normal PSA level in men treated with finasteride is one half that of men not treated with this drug.
  • The body converts testosterone to dihydrotestosterone or DHT, using type II 5-alpha reductase. Finasteride works to reduce the amount of testosterone converted by the body to DHT.
  • Finasteride is the first type II 5-alpha reductase inhibitor. Finasteride inhibits type II 5-alpha-reductase by 80% to 90%. DHT is reduced in serum by 70%, in the prostate by 90%, and in the skin by 34%. With treatment, serum testosterone increases by 10%, while PSA levels are reduced by an average of 50%. Total prostate volume decreases as well, by 15 to 25%
  • Both finasteride and dutasteride have similar efficacy in improving lower urinary tract symptoms and urinary flow rate. Both have a similar effect on prostate volume, serum PSA, acute urinary retention surgery. Adverse event profiles are similar in that they are mainly sexually related complaints. There are no known differences in their use.
  • Side effects associated with the 5-alpha reductase inhibitors can include impotence, decreased sex drive, and reduced semen during ejaculation. These side effects occur in a relatively small percentage of patients and can be reversed with cessation of therapy. Also be aware that these agents reduce PSA levels and thus may interfere with PSA screening for prostate cancer.

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