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Managing the Multiple Symptoms of Benign Prostatic Hyperplasia
Managing the Multiple Symptoms of Benign Prostatic Hyperplasia — CME
Managing Type 2 Diabetes in Men
Meeting New Challenges with Antiplatelet Therapy in Primary Care
Dr. Miner has disclosed that he is a consultant for Eli Lilly.
SUPPORT
This activity was supported by an educational grant from Lilly USA, LLC.
This article reviews screening tools for benign prostatic hyperplasia (BPH) and steps to be taken to confirm a diagnosis of BPH. Among the treatment options for BPH, emphasis is placed on pharmacologic treatment with alpha1-adrenergic blockers (AABs), 5-alpha-reductase inhibitors (5-ARIs), and phosphodiesterase-5 inhibitors (PDE-5Is). The two newest agents silodosin and tadalafil are discussed in greater detail.
LEARNING OBJECTIVES
After reviewing this activity on benign prostatic hyperplasia, the reader will be able to:
- Describe the key diagnostic steps.
- Describe the role of non-pharmacologic interventions.
- Compare the efficacy and safety of alpha1- adrenergic blockers, 5-alpha-reductase inhibitors, and phosphodiesterase-5 inhibitors.
- Describe strategies for treating multiple symptoms.
TARGET AUDIENCE
Family physicians and clinicians who wish to gain increased knowledge and greater competency regarding the management of patients with multiple symptoms of benign prostatic hyperplasia.
ACKNOWLEDGEMENT
Dr. Miner was paid an honorarium by and received editorial assistance from the Primary Care Education Consortium in the development of this activity.
DISCLOSURES
As a continuing medical education provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Primary Care Education Consortium (PCEC) to require any individual in a position to influence educational content to disclose the existence of any financial interest or other personal relationship with the manufacturer(s) of any commercial product(s).
Dr. Miner has disclosed that he is a consultant for Eli Lilly.
The medical accuracy and continuing medical education (CME) reviewer for this activity, Dr. Ron Pollack, has no real or apparent conflicts of interest to report.
PRIMARY CARE EDUCATION CONSORTIUM STAFF
Dr. Brunton has disclosed that he is on the advisory boards and speakers’ bureaus for Boehringer Ingelheim, Eli Lilly, Kowa, Novo Nordisk, Inc, and Teva Pharmaceuticals, and is on the advisory boards for Abbott and Sunovion.
Other PCEC staff have provided financial disclosure and have no conflicts of interest to resolve related to this activity.
CONFLICTS OF INTEREST
When individuals in a position to control content have reported financial relationships with one or more commercial interests, the Primary Care Education Consortium works with them to resolve such conflicts to ensure that the content presented is free of commercial bias. The content of this activity was vetted by the following mechanisms and modified as required to meet this standard:
- Content peer-review by an external topic expert
- Content peer-review by an external CME reviewer
- Content validation by internal Primary Care Education Consortium clinical editorial staff
OFF-LABEL DISCLOSURE
In accordance with ACCME guidelines, the faculty author has been asked to disclose discussion on unlabeled or unapproved uses of drugs or devices during the course of the activity.
SPONSORSHIP
This activity is sponsored by the Primary Care Education Consortium.
ACCREDITATION
This journal-based CME activity, Managing the Multiple Symptoms of Benign Prostatic Hyperplasia, has been reviewed and is acceptable for up to 1.0 prescribed credit by the American Academy of Family Physicians. AAFP accreditation begins June 1, 2012. Term of approval is for one year from this date with option for yearly renewal.
Physicians should claim only the credit commensurate with the extent of their participation in the activity.
MEDIUM
Text publication in the form of a journal article.
METHOD OF PHYSICIAN PARTICIPATION
To receive CME credit, please read the journal article, and upon completion go to: www.pceconsortium.org/menshealthBPH to complete the online evaluation to receive your certification of completion.
SUPPORT
This activity was supported by an educational grant from Lilly USA, LLC.
RI is a 53-year-old African-American man who is being seen by his family physician for a follow-up for dyslipidemia and hypertension. He reports that he is feeling well and that he has not observed any adverse events (AEs) from his medications. His current medications are an intermediate-dose statin, a thiazide diuretic, and a calcium channel blocker. RI reports that he has been very compliant with his medications, missing at most 1 dose every week or two.
During the visit, his physician notices that RI has yawned several times and that he appears tired. When asked how many hours he sleeps each night, RI indicates that he sleeps 7.5 to 8 hours most nights. On further questioning, RI admits that for the past 4 or 5 years, he has had to get up to go to the bathroom during the night, after which he often has trouble falling asleep, and that this nocturia currently occurs 3 or 4 times a night. When asked whether he has noticed any other changes over the past few years, RI says that he has noted an increase in his waist circumference (now 38.5 inches) and a few more aches and pains. When asked whether he has experienced any changes in sexual function, RI acknowledges that occasionally he has had difficulty maintaining an erection. He also indicates that he has accepted that these changes are a result of getting older.
Introduction
BPH is commonly experienced in men as they age. Lower urinary tract symptoms (LUTS) associated with BPH often begin in the fourth decade of life and affect nearly 3 in 4 men by the seventh decade of life.1,2 Lower urinary tract symptoms that prompt men to seek medical care typically include nocturia, frequency, incomplete emptying, and urgency.3,4 Men typically wait almost 2 years before seeking medical care for their urinary symptoms. Among men who do not seek medical care for LUTS, the most common reason is the belief that urinary symptoms are an inevitable part of aging. Many men who do not seek treatment indicate that they would rather accept their urinary symptoms than discuss them with a physician.4
In addition to urinary symptoms, BPH has been associated with symptoms of sexual dysfunction independent of the effects of aging and other comorbidities (eg, diabetes) and lifestyle factors.5-8 Erectile dysfunction and ejaculatory dysfunction are the most common symptoms of sexual dysfunction in men with BPH.9-11 Symptoms of sexual dysfunction may also be caused by some pharmacologic agents used for the treatment of BPH.6,9,10
Evaluation
Although BPH and the symptoms associated with it are not often life-threatening, ruling out other causes such as prostate cancer, diabetes mellitus, or Parkinson disease is an important diagnostic goal.
Screening
Because many men are slow to seek medical care and reluctant to speak with a physician about their symptoms, it is important that family physicians routinely inquire about urinary function in men over the age of 50 years. Beyond simply asking whether there have been changes in urinary function, posing the last question on the International Prostate Symptom Score (IPSS) questionnaire may be helpful: “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?”12 This question may be followed with, “Are you bothered enough by your symptoms that you would accept taking a medication?” Inquiries such as these, coupled with education to help the patient to understand that LUTS are not simply due to aging and that effective treatments are available, may motivate patients to share their concerns regarding urinary function. In addition, helping patients to understand that BPH is not a risk factor for prostate cancer, but that there are other causes of LUTS, which are best detected early, may be helpful.
Assessment
A history and focused urologic examination are crucial for the diagnosis of BPH. The medical history should identify a patient’s LUTS and their severity. To do this, a questionnaire such as the IPSS or the American Urological Association BPH Symptom Score Index Questionnaire can be administered [www.adultpediatricuro.com/apuauass.pdf]. As noted earlier, the eighth question on the IPSS questionnaire is useful for assessing the degree to which a patient is bothered by LUTS, with a higher score suggesting a greater willingness of the patient to be treated.13 Lower urinary tract symptoms are generally categorized into storage or bladder-emptying symptoms, with the latter subclassified as voiding or postmicturition symptoms.14 Storage problems are generally of greater concern to patients. Possible sexual dysfunction should also be assessed. A thorough medication history must be taken to identify AEs possibly related to the use of diuretics, anticholinergics, opioids, or decongestants.
The digital rectal examination (DRE) and prostate specific antigen (PSA) test are helpful to rule out a diagnosis of prostate cancer.15,16 The DRE is used for assessing the size, shape, symmetry, nodularity, and consistency of the prostate. The suprapubic area and genitals should be examined as well.17 The PSA test is also useful in the diagnosis and treatment of BPH because the PSA level rises as the prostate increases in size.13,14 A PSA level of 1.5 ng/mL roughly correlates with a prostate size of 30 mL.18 A urinalysis is needed to screen for urinary tract infections, bladder cancer, and kidney stones. Other laboratory analyses such as a fasting plasma glucose test may be needed based on the patient’s history and other findings.17
RI returns 3 weeks later for further evaluation. History confirms nocturia 3 or 4 times per night, as well as occasional erectile dysfunction and sometimes an inability to ejaculate. His IPSS questionnaire reveals a score of 9 (moderate symptoms), with occasional urinary frequency and straining. His LUTS are more bothersome than his occasional erectile dysfunction. It is decided that he will discontinue treatment with the thiazide diuretic because it may be contributing to his LUTS. An alternative antihypertensive agent will be initiated based on the results of the evaluation. The DRE reveals a boggy, slightly enlarged but normally shaped prostate with no nodules. The remainder of the urologic examination is normal. His PSA level is 0.8 ng/mL, and the urinalysis is normal. Further evaluation rules out prostate cancer and other causes of his symptoms.
A diagnosis of BPH is confirmed, with evidence of storage (ie, nocturia) and voiding (ie, urinary intermittency and straining) problems, as well as erectile dysfunction and occasional ejaculatory dysfunction.
Treatment
Goals
Because BPH is not often life-threatening, the focus of treatment has typically been to alleviate bothersome LUTS and other symptoms. With advances in treatment, additional goals include the alteration of disease progression and the prevention of associated complications such as recurrent urinary tract infections, hematuria, or acute urinary retention, particularly in men with an enlarged prostate (ie, volume >30 mL or PSA >1.5 ng/mL), since disease progression is more likely in these patients.17,19 A recent Medline-based systematic review reported that men prefer therapies that affect long-term progression over therapies that provide short-term symptom improvement.20 These results were consistent with those from a 2006 survey of 400 men with an enlarged prostate, which also reported that men are generally willing to wait up to 3 months for symptom relief if treatment would resolve the underlying condition.21 It is, therefore, important to discuss with the patient the natural history of BPH and its complications, and the benefits and risks of currently available noninvasive and invasive treatment options.
Options
Treatment options for BPH are watchful waiting, lifestyle and behavioral management, pharmacologic therapy, and surgical intervention. Many men use phytobotannical therapy such as saw palmetto, African plum tree, pumpkin seed, rye pollen, stinging nettle, South African star grass, and quercetin to relieve LUTS, although investigations regarding their use are often of poor quality. Saw palmetto is the best studied, yet a Cochrane review found few high-quality studies. The authors of the review concluded that saw palmetto was not more effective than placebo for treatment of LUTS.22 Similar results were observed in a randomized, double-blind, placebo-controlled trial more recently published by the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group.23
Watchful waiting is appropriate when only LUTS are present, with or without some degree of nonsuspicious prostate enlargement, and the symptoms are not particularly bothersome to the patient or if the patient does not want treatment.19 Lifestyle management and behavioral modification should generally be used in combination with other treatment options in an effort to alleviate symptoms, especially in men in whom storage symptoms predominate. Lifestyle management may include reducing fluid intake (particularly if polyuria is present), increasing physical activity, achieving a normal weight, timed voiding (bladder retraining), pelvic floor exercises, treatment for constipation, and avoidance of irritative foods and beverages.17,19 Epidemiologic evidence over 7 years of surveillance suggests that a diet low in fat and red meat and high in protein and vegetables, as well as regular alcohol consumption (>1 drink/month), may reduce the risk of symptomatic BPH.24 Evidence was weak concerning the benefits of lycopene, zinc, and supplemental vitamin D. No dietary supplement, combination phytotherapeutic agent, or other nonconventional therapy is recommended by the American Urological Association (AUA) for the management of LUTS secondary to BPH.19
Surgical intervention is considered appropriate in patients with moderate to severe LUTS in whom other medical therapies have not achieved treatment goals and in those in whom benign prostatic obstruction has led to complications such as renal insufficiency, urinary retention, recurrent urinary tract infections, bladder calculi, or hydronephrosis. Patients in whom surgical intervention is contemplated should be referred to a urologist.17,19
Pharmacologic Options
Three classes of pharmacologic agents have been approved by the US Food and Drug Administration (FDA) for the treatment of symptomatic BPH: AABs, 5-ARIs, and PDE-5Is. The AABs include alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin, and target the dynamic (smooth muscle tone) component of BPH-induced bladder outlet obstruction. The 5-ARIs finasteride and dutasteride target the static (prostate mass) component of BPH-induced bladder outlet obstruction. The PDE-5Is (ie, sildenafil, tadalafil, and vardenafil) increase the amount of cyclic guanosine monophosphate in the smooth muscle of the corpus cavernosum, prostate, and bladder.
Alpha1-Adrenergic Blockers. The four older AABs (ie, alfuzosin, doxazosin, tamsulosin, and terazosin) have been extensively investigated in clinical trials and widely used in the management of BPH. A 2010 review by the AUA concluded that the minor efficacy differences reported among the 4 older AABs were not clinically significant.19 Although ejaculatory dysfunction may occur with the use of the AABs, these agents are generally well-tolerated, with dizziness the most common AE, occurring in 2% to 14% of men. Ejaculatory dysfunction may be a part of the disease process itself, as noted earlier.
The newest AAB, silodosin, at a dosage of 8 mg/d was reported to have efficacy similar to tamsulosin 0.2 to 0.4 mg/d in reducing storage and voiding LUTS in three 12-week trials.25-27 Silodosin has also been associated with a significant improvement in patients’ quality of life. The most frequent AE related to silodosin use was abnormal ejaculation, occurring in 10% to 22% and causing discontinuation in 1% to 3%.25-27 One 12-week study reported that systolic blood pressure (BP) decreased 0.1 and 4.2 mm Hg in the silodosin and tamsulosin groups, respectively.25 The negligible reduction in BP observed with silodosin is likely due to the selectivity of silodosin for the alpha1A-adrenergic receptor rather than the alpha1B-adrenergic receptor, the blockade of which reduces BP.
5-Alpha-Reductase Inhibitors. The efficacy of 5-ARIs in preventing progression of LUTS secondary to BPH and their tolerability are well-established. Dutasteride was associated with a greater reduction in dihydrotestosterone in prostate tissues compared with finasteride (94% vs 80%, respectively) and has a longer elimination half-life.19 Finasteride was reported to be less effective than an AAB in improving LUTS. Dutasteride may have been more effective in reducing the relative risk for acute urinary retention and BPH-related surgery compared with tamsulosin over 4 years, but more research is needed.28 The 5-ARIs should not be used in men with LUTS secondary to BPH without prostatic enlargement, but may be used to prevent the progression of LUTS secondary to BPH and to reduce the risk for urinary retention and future prostate-related surgery.19 Prostate size ≥30 mL or PSA level ≥1.5 ng/dL is usually used as the threshold for considering 5-ARI therapy.19 As expected, because of the effects on dihydrotestosterone, AEs are primarily sexually related and include decreased libido, ejaculation disorders, and erectile dysfunction.19
Phosphodiesterase-5 Inhibitors. Approved by the FDA for erectile dysfunction, several observations led to the investigation of PDE-5Is for LUTS related to BPH.8,29 One was that the prevalences of BPH, LUTS, and erectile dysfunction increase as a man ages. Second was that LUTS have been identified as a risk factor for sexual dysfunction in aging men. Third was that limited evidence had suggested that PDE-5Is might be effective in treating LUTS and erectile dysfunction. Further investigation suggested beneficial effects on LUTS with each of the 3 PDE-5Is (ie, sildenafil, tadalafil, and vardenafil).30-32 Subsequent extensive investigation with tadalafil demonstrated its efficacy in reducing the storage and voiding symptoms of BPH and led to the approval by the FDA of tadalafil for symptoms of BPH alone or with erectile dysfunction.33-37
The clinical studies investigating the efficacy and tolerability of tadalafil for LUTS associated with BPH have included a 12-week study with a 1-year extension.38 Patients with BPH-associated LUTS (N = 1058) were randomized to tadalafil 2.5, 5, 10, or 20 mg/d or placebo once daily for 12 weeks. The total IPSS score was significantly improved at 12 weeks compared with baseline in each of the tadalafil groups relative to placebo (2.5 mg/d: –3.9, P = .015; 5 mg/d: –4.9, P < .001; 10 mg/d: –5.2, P < .001; 20 mg/d: –5.2, P < .001; placebo: –2.3). The use of tadalafil 5, 10, or 20 mg once daily was associated with significant improvements in the IPSS irritative (eg, frequency, nocturia, and urgency) and obstructive (eg, incomplete emptying, intermittency, slow stream, and straining) subscores, as well as scores on the IPSS quality-of-life measure, the BPH Impact Index (except 10 mg), and the LUTS Global Assessment Question. In sexually active men with erectile dysfunction, all doses of tadalafil were associated with significant improvements in scores on the International Index of Erectile Function–Erectile Function domain compared with placebo. Peak flow rate was not improved at any dose of tadalafil compared with placebo.
In total, 427 men who completed the 12-week study elected to receive tadalafil 5 mg once daily for an additional year.37 Patients who were switched from placebo or who had the dose increased from 2.5 mg/d had a significant reduction in total IPSS score from week 12 to week 16, and this change was maintained until the end of follow-up at week 64. Patients who had received tadalafil 5, 10, or 20 mg/d maintained the changes observed at the end of the 12-week study. Similarly, sexually active men with erectile dysfunction and who had a female partner maintained the improvements observed at the end of 12 weeks. The mean postvoid residual volume was decreased from 61 to 42 mL. At least 1 treatment-emergent AE (TEAE) was reported in 58% of patients, with 89% of events being either mild or moderate in severity. Treatment was discontinued in 5% due to a TEAE. The most common TEAEs were dyspepsia (4%), gastroesophageal reflux disease (4%), back pain (4%), headache (3%), sinusitis (3%), hypertension (3%), and cough (2%). In this study, the improvement in LUTS, sexual function, and quality of life observed after 12 weeks of tadalafil were maintained over the additional year with tadalafil 5 mg once daily.
Treatment options for RI are watchful waiting, an AAB with or without a PDE-5I, a 5-ARI, or tadalafil. RI indicates that he would rather not have his symptoms for the rest of his life, so watchful waiting is not appropriate. Because his prostate is only slightly enlarged, a 5-ARI is also not appropriate. An AAB or tadalafil should provide good relief to his LUTS within a few weeks. Tadalafil would also treat his erectile dysfunction. Alternatively, tadalafil or another PDE-5I could be combined with an AAB, which has been reported to provide added benefit in symptom improvement over an AAB alone.39
Plan
Following discussion of the benefits and risks of the different treatment options, RI elects to begin treatment with an AAB alone. For this reason, treatment with another antihypertensive to replace the diuretic will not be started. To promote self-management, educational materials and an action plan are reviewed with RI. Lifestyle management changes are discussed, including reducing his daily water intake by 25% to 2 quarts with no consumption of fluids within 3 to 4 hours of bedtime. He is assured that adjustments to his treatment plan will be made based on his symptoms and concerns.
3-Month Follow-Up
RI reports that his symptoms have improved, with a modest improvement of nocturia; he gets up once during the night 1 or 2 times every 2 weeks or so. He strains less frequently, but intermittency is unchanged. His IPSS is 7 (improved by 2 points vs before treatment). The findings on his physical examination are unchanged except that his BP has decreased slightly, to 124/72 mm Hg. He has noted 1 or 2 episodes of dizziness. Feeling better than 3 months ago, RI asks whether further improvement of his LUTS is possible. He wonders whether his erectile dysfunction can be treated.
The benefits and risks of each of the 3 PDE-5Is are reviewed with RI. He elects to begin treatment with tadalafil 5 mg once daily because it is the only agent that is approved for the treatment of LUTS associated with BPH. Lifestyle management and his action plan are reviewed.
Continue to complete the online evaluation and receive your certification of completion.
1. Wei JT, Calhoun EA, Jacobsen SJ. Urologic Diseases in America: Benign prostatic hyperplasia. http://kidney.niddk.nih.gov/Statistics/UDA/Benign_Prostatic_Hyperplasia-Chapter02.pdf. Published 2007. Accessed May 16, 2012.
2. Miller DC, Saigal CS, Litwin MS. The demographic burden of urologic diseases in America. Urol Clin North Am. 2009;36(1):11-27, v.
3. Sarma AV, Wallner L, Jacobsen SJ, Dunn RL, Wei JT. Health seeking behavior for lower urinary tract symptoms in black men. J Urol. 2008;180(1):227-232.
4. Survey confirms prostate problems overlooked by men and doctors [press release]. Vienna, Austria: GlaxoSmithKline. October 3, 2011. http://www.ismh.org/en/sys/wp-content/uploads/2011/09/News-release-300911-BPH-survey-a-male-perspective.pdf. Accessed May 16, 2012.
5. Mirone V, Sessa A, Giuliano F, Berges R, Kirby M, Moncada I. Current benign prostatic hyperplasia treatment: impact on sexual function and management of related sexual adverse events. Int J Clin Pract. 2011;65(9):1005-1013.
6. Gacci M, Eardley I, Giuliano F, et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2011;60(4):809-825.
7. Hoesl CE, Woll EM, Burkart M, Altwein JE. Erectile dysfunction (ED) is prevalent, bothersome and underdiagnosed in patients consulting urologists for benign prostatic syndrome (BPS). Eur Urol. 2005;47(4):511-517.
8. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol. 2003;44(6):637-649.
9. Rosen RC, Wei JT, Althof SE, Seftel AD, Miner M, Perelman MA. for BPH Registry and Patient Survey Steering Committee. Association of sexual dysfunction with lower urinary tract symptoms of BPH and BPH medical therapies: results from the BPH Registry. Urology. 2009;73(3):562-566.
10. Rosen RC, Fitzpatrick JM. for ALF-LIFE Study Group. Ejaculatory dysfunction in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. BJU Int. 2009;104(7):974-983.
11. Seftel A, Rosen R, Kuritzky L. Physician perceptions of sexual dysfunction related to benign prostatic hyperplasia (BPH) symptoms and sexual side effects related to BPH medications. Int J Impot Res. 2007;19(4):386-392.
12. American Urological Association. American Urological Association BPH Symptom Score Index Questionnaire. http://www.adultpediatricuro.com/apuauass.pdf. Accessed May 16, 2012.
13. O’Leary MP. Validity of the “bother score” in the evaluation and treatment of symptomatic benign prostatic hyperplasia. Rev Urol. 2005;7(1):1-10.
14. Abrams P, Cardozo L, Fall M, et al. for Standardisation Sub-Committee of the International Continence Society. 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.
15. American Urological Association. Prostate-specific antigen best practice statement: 2009 update. http://www.auanet.org/content/media/psa09.pdf. Published 2009. Accessed May 16, 2012.
16. American Cancer Society. Can prostate cancer be found early? http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-detection. Published 2012. Accessed May 16, 2012.
17. Tanguay S, Awde M, Brock G, et al. Diagnosis and management of benign prostatic hyperplasia in primary care. Can Urol Assoc J. 2009;3(3 suppl 2):S92-S100.
18. Roehrborn CG, Boyle P, Gould AL, Waldstreicher J. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology. 1999;53(3):581-589.
19. McVary KT, Roehrborn CG, Avins AL, et al. American Urological Association guideline: Management of benign prostatic hyperplasia (BPH). http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.cfm?sub=bph. Published 2010. Accessed May 16, 2012.
20. Emberton M. Medical treatment of benign prostatic hyperplasia: physician and patient p and satisfaction. Int J Clin Pract. 2010;64(10):1425-1435.
21. Kaplan S, Naslund M. Public, patient, and professional attitudes towards the diagnosis and treatment of enlarged prostate: A landmark national US survey. Int J Clin Pract. 2006;60(10):1157-1165.
22. Tacklind J, MacDonald R, Rutks I, Wilt TJ. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2009;2:CD001423.-
23. Barry MJ, Meleth S, Lee JY, et al. for Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group. Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. JAMA. 2011;306(12):1344-1351.
24. Kristal AR, Arnold KB, Schenk JM, et al. Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol. 2008;167(8):925-934.
25. Yu HJ, Lin AT, Yang SS, et al. Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). BJU Int. 2011;108(11):1843-1848.
26. Chapple CR, Montorsi F, Tammela TL, Wirth M, Koldewijn E, Fernandez FE. for European Silodosin Study Group. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011;59(3):342-352.
27. Kawabe K, Yoshida M, Homma Y. for Silodosin Clinical Study Group. Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int. 2006;98(5):1019-1024.
28. Roehrborn CG, Siami P, Barkin J, et al. for CombAT Study Group. 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(1):123-131.
29. Kaplan SA, Gonzalez RR. Phosphodiesterase type 5 inhibitors for the treatment of male lower urinary tract symptoms. Rev Urol. 2007;9(2):73-77.
30. Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. J Sex Med. 2006;3(4):662-667.
31. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177(4):1401-1407.
32. Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. 2008;53(6):1236-1244.
33. Porst H, McVary KT, Montorsi F, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol. 2009;56(4):727-735.
34. Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology. 2010;75(6):1452-1458.
35. Porst H, Kim ED, Casabé AR, et al. LVHJ study team. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol. 2011;60(5):1105-1113.
36. Maselli G, Bergamasco L, Silvestri V, Gualà L, Pace G, Vicentini C. Tadalafil versus solifenacin for persistent storage symptoms after prostate surgery in patients with erectile dysfunction: a prospective randomized study. Int J Urol. 2011;18(7):515-520.
37. Donatucci CF, Brock GB, Goldfischer ER, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int. 2011;107(7):1110-1116.
38. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008;180(4):1228-1234.
39. Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with alpha-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012;61(5):994-1003.
Martin Miner, MD
Co-Director, Men’s Health Center, Chief of Family and Community Medicine, The Miriam Hospital, Clinical Associate Professor of Family Medicine and Urology, Warren Alpert Medical School, Brown University, Providence, RI
Martin Miner, MD
Co-Director, Men’s Health Center, Chief of Family and Community Medicine, The Miriam Hospital, Clinical Associate Professor of Family Medicine and Urology, Warren Alpert Medical School, Brown University, Providence, RI
Martin Miner, MD
Co-Director, Men’s Health Center, Chief of Family and Community Medicine, The Miriam Hospital, Clinical Associate Professor of Family Medicine and Urology, Warren Alpert Medical School, Brown University, Providence, RI
Managing the Multiple Symptoms of Benign Prostatic Hyperplasia — CME
Managing Type 2 Diabetes in Men
Meeting New Challenges with Antiplatelet Therapy in Primary Care
Dr. Miner has disclosed that he is a consultant for Eli Lilly.
SUPPORT
This activity was supported by an educational grant from Lilly USA, LLC.
This article reviews screening tools for benign prostatic hyperplasia (BPH) and steps to be taken to confirm a diagnosis of BPH. Among the treatment options for BPH, emphasis is placed on pharmacologic treatment with alpha1-adrenergic blockers (AABs), 5-alpha-reductase inhibitors (5-ARIs), and phosphodiesterase-5 inhibitors (PDE-5Is). The two newest agents silodosin and tadalafil are discussed in greater detail.
LEARNING OBJECTIVES
After reviewing this activity on benign prostatic hyperplasia, the reader will be able to:
- Describe the key diagnostic steps.
- Describe the role of non-pharmacologic interventions.
- Compare the efficacy and safety of alpha1- adrenergic blockers, 5-alpha-reductase inhibitors, and phosphodiesterase-5 inhibitors.
- Describe strategies for treating multiple symptoms.
TARGET AUDIENCE
Family physicians and clinicians who wish to gain increased knowledge and greater competency regarding the management of patients with multiple symptoms of benign prostatic hyperplasia.
ACKNOWLEDGEMENT
Dr. Miner was paid an honorarium by and received editorial assistance from the Primary Care Education Consortium in the development of this activity.
DISCLOSURES
As a continuing medical education provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Primary Care Education Consortium (PCEC) to require any individual in a position to influence educational content to disclose the existence of any financial interest or other personal relationship with the manufacturer(s) of any commercial product(s).
Dr. Miner has disclosed that he is a consultant for Eli Lilly.
The medical accuracy and continuing medical education (CME) reviewer for this activity, Dr. Ron Pollack, has no real or apparent conflicts of interest to report.
PRIMARY CARE EDUCATION CONSORTIUM STAFF
Dr. Brunton has disclosed that he is on the advisory boards and speakers’ bureaus for Boehringer Ingelheim, Eli Lilly, Kowa, Novo Nordisk, Inc, and Teva Pharmaceuticals, and is on the advisory boards for Abbott and Sunovion.
Other PCEC staff have provided financial disclosure and have no conflicts of interest to resolve related to this activity.
CONFLICTS OF INTEREST
When individuals in a position to control content have reported financial relationships with one or more commercial interests, the Primary Care Education Consortium works with them to resolve such conflicts to ensure that the content presented is free of commercial bias. The content of this activity was vetted by the following mechanisms and modified as required to meet this standard:
- Content peer-review by an external topic expert
- Content peer-review by an external CME reviewer
- Content validation by internal Primary Care Education Consortium clinical editorial staff
OFF-LABEL DISCLOSURE
In accordance with ACCME guidelines, the faculty author has been asked to disclose discussion on unlabeled or unapproved uses of drugs or devices during the course of the activity.
SPONSORSHIP
This activity is sponsored by the Primary Care Education Consortium.
ACCREDITATION
This journal-based CME activity, Managing the Multiple Symptoms of Benign Prostatic Hyperplasia, has been reviewed and is acceptable for up to 1.0 prescribed credit by the American Academy of Family Physicians. AAFP accreditation begins June 1, 2012. Term of approval is for one year from this date with option for yearly renewal.
Physicians should claim only the credit commensurate with the extent of their participation in the activity.
MEDIUM
Text publication in the form of a journal article.
METHOD OF PHYSICIAN PARTICIPATION
To receive CME credit, please read the journal article, and upon completion go to: www.pceconsortium.org/menshealthBPH to complete the online evaluation to receive your certification of completion.
SUPPORT
This activity was supported by an educational grant from Lilly USA, LLC.
RI is a 53-year-old African-American man who is being seen by his family physician for a follow-up for dyslipidemia and hypertension. He reports that he is feeling well and that he has not observed any adverse events (AEs) from his medications. His current medications are an intermediate-dose statin, a thiazide diuretic, and a calcium channel blocker. RI reports that he has been very compliant with his medications, missing at most 1 dose every week or two.
During the visit, his physician notices that RI has yawned several times and that he appears tired. When asked how many hours he sleeps each night, RI indicates that he sleeps 7.5 to 8 hours most nights. On further questioning, RI admits that for the past 4 or 5 years, he has had to get up to go to the bathroom during the night, after which he often has trouble falling asleep, and that this nocturia currently occurs 3 or 4 times a night. When asked whether he has noticed any other changes over the past few years, RI says that he has noted an increase in his waist circumference (now 38.5 inches) and a few more aches and pains. When asked whether he has experienced any changes in sexual function, RI acknowledges that occasionally he has had difficulty maintaining an erection. He also indicates that he has accepted that these changes are a result of getting older.
Introduction
BPH is commonly experienced in men as they age. Lower urinary tract symptoms (LUTS) associated with BPH often begin in the fourth decade of life and affect nearly 3 in 4 men by the seventh decade of life.1,2 Lower urinary tract symptoms that prompt men to seek medical care typically include nocturia, frequency, incomplete emptying, and urgency.3,4 Men typically wait almost 2 years before seeking medical care for their urinary symptoms. Among men who do not seek medical care for LUTS, the most common reason is the belief that urinary symptoms are an inevitable part of aging. Many men who do not seek treatment indicate that they would rather accept their urinary symptoms than discuss them with a physician.4
In addition to urinary symptoms, BPH has been associated with symptoms of sexual dysfunction independent of the effects of aging and other comorbidities (eg, diabetes) and lifestyle factors.5-8 Erectile dysfunction and ejaculatory dysfunction are the most common symptoms of sexual dysfunction in men with BPH.9-11 Symptoms of sexual dysfunction may also be caused by some pharmacologic agents used for the treatment of BPH.6,9,10
Evaluation
Although BPH and the symptoms associated with it are not often life-threatening, ruling out other causes such as prostate cancer, diabetes mellitus, or Parkinson disease is an important diagnostic goal.
Screening
Because many men are slow to seek medical care and reluctant to speak with a physician about their symptoms, it is important that family physicians routinely inquire about urinary function in men over the age of 50 years. Beyond simply asking whether there have been changes in urinary function, posing the last question on the International Prostate Symptom Score (IPSS) questionnaire may be helpful: “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?”12 This question may be followed with, “Are you bothered enough by your symptoms that you would accept taking a medication?” Inquiries such as these, coupled with education to help the patient to understand that LUTS are not simply due to aging and that effective treatments are available, may motivate patients to share their concerns regarding urinary function. In addition, helping patients to understand that BPH is not a risk factor for prostate cancer, but that there are other causes of LUTS, which are best detected early, may be helpful.
Assessment
A history and focused urologic examination are crucial for the diagnosis of BPH. The medical history should identify a patient’s LUTS and their severity. To do this, a questionnaire such as the IPSS or the American Urological Association BPH Symptom Score Index Questionnaire can be administered [www.adultpediatricuro.com/apuauass.pdf]. As noted earlier, the eighth question on the IPSS questionnaire is useful for assessing the degree to which a patient is bothered by LUTS, with a higher score suggesting a greater willingness of the patient to be treated.13 Lower urinary tract symptoms are generally categorized into storage or bladder-emptying symptoms, with the latter subclassified as voiding or postmicturition symptoms.14 Storage problems are generally of greater concern to patients. Possible sexual dysfunction should also be assessed. A thorough medication history must be taken to identify AEs possibly related to the use of diuretics, anticholinergics, opioids, or decongestants.
The digital rectal examination (DRE) and prostate specific antigen (PSA) test are helpful to rule out a diagnosis of prostate cancer.15,16 The DRE is used for assessing the size, shape, symmetry, nodularity, and consistency of the prostate. The suprapubic area and genitals should be examined as well.17 The PSA test is also useful in the diagnosis and treatment of BPH because the PSA level rises as the prostate increases in size.13,14 A PSA level of 1.5 ng/mL roughly correlates with a prostate size of 30 mL.18 A urinalysis is needed to screen for urinary tract infections, bladder cancer, and kidney stones. Other laboratory analyses such as a fasting plasma glucose test may be needed based on the patient’s history and other findings.17
RI returns 3 weeks later for further evaluation. History confirms nocturia 3 or 4 times per night, as well as occasional erectile dysfunction and sometimes an inability to ejaculate. His IPSS questionnaire reveals a score of 9 (moderate symptoms), with occasional urinary frequency and straining. His LUTS are more bothersome than his occasional erectile dysfunction. It is decided that he will discontinue treatment with the thiazide diuretic because it may be contributing to his LUTS. An alternative antihypertensive agent will be initiated based on the results of the evaluation. The DRE reveals a boggy, slightly enlarged but normally shaped prostate with no nodules. The remainder of the urologic examination is normal. His PSA level is 0.8 ng/mL, and the urinalysis is normal. Further evaluation rules out prostate cancer and other causes of his symptoms.
A diagnosis of BPH is confirmed, with evidence of storage (ie, nocturia) and voiding (ie, urinary intermittency and straining) problems, as well as erectile dysfunction and occasional ejaculatory dysfunction.
Treatment
Goals
Because BPH is not often life-threatening, the focus of treatment has typically been to alleviate bothersome LUTS and other symptoms. With advances in treatment, additional goals include the alteration of disease progression and the prevention of associated complications such as recurrent urinary tract infections, hematuria, or acute urinary retention, particularly in men with an enlarged prostate (ie, volume >30 mL or PSA >1.5 ng/mL), since disease progression is more likely in these patients.17,19 A recent Medline-based systematic review reported that men prefer therapies that affect long-term progression over therapies that provide short-term symptom improvement.20 These results were consistent with those from a 2006 survey of 400 men with an enlarged prostate, which also reported that men are generally willing to wait up to 3 months for symptom relief if treatment would resolve the underlying condition.21 It is, therefore, important to discuss with the patient the natural history of BPH and its complications, and the benefits and risks of currently available noninvasive and invasive treatment options.
Options
Treatment options for BPH are watchful waiting, lifestyle and behavioral management, pharmacologic therapy, and surgical intervention. Many men use phytobotannical therapy such as saw palmetto, African plum tree, pumpkin seed, rye pollen, stinging nettle, South African star grass, and quercetin to relieve LUTS, although investigations regarding their use are often of poor quality. Saw palmetto is the best studied, yet a Cochrane review found few high-quality studies. The authors of the review concluded that saw palmetto was not more effective than placebo for treatment of LUTS.22 Similar results were observed in a randomized, double-blind, placebo-controlled trial more recently published by the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group.23
Watchful waiting is appropriate when only LUTS are present, with or without some degree of nonsuspicious prostate enlargement, and the symptoms are not particularly bothersome to the patient or if the patient does not want treatment.19 Lifestyle management and behavioral modification should generally be used in combination with other treatment options in an effort to alleviate symptoms, especially in men in whom storage symptoms predominate. Lifestyle management may include reducing fluid intake (particularly if polyuria is present), increasing physical activity, achieving a normal weight, timed voiding (bladder retraining), pelvic floor exercises, treatment for constipation, and avoidance of irritative foods and beverages.17,19 Epidemiologic evidence over 7 years of surveillance suggests that a diet low in fat and red meat and high in protein and vegetables, as well as regular alcohol consumption (>1 drink/month), may reduce the risk of symptomatic BPH.24 Evidence was weak concerning the benefits of lycopene, zinc, and supplemental vitamin D. No dietary supplement, combination phytotherapeutic agent, or other nonconventional therapy is recommended by the American Urological Association (AUA) for the management of LUTS secondary to BPH.19
Surgical intervention is considered appropriate in patients with moderate to severe LUTS in whom other medical therapies have not achieved treatment goals and in those in whom benign prostatic obstruction has led to complications such as renal insufficiency, urinary retention, recurrent urinary tract infections, bladder calculi, or hydronephrosis. Patients in whom surgical intervention is contemplated should be referred to a urologist.17,19
Pharmacologic Options
Three classes of pharmacologic agents have been approved by the US Food and Drug Administration (FDA) for the treatment of symptomatic BPH: AABs, 5-ARIs, and PDE-5Is. The AABs include alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin, and target the dynamic (smooth muscle tone) component of BPH-induced bladder outlet obstruction. The 5-ARIs finasteride and dutasteride target the static (prostate mass) component of BPH-induced bladder outlet obstruction. The PDE-5Is (ie, sildenafil, tadalafil, and vardenafil) increase the amount of cyclic guanosine monophosphate in the smooth muscle of the corpus cavernosum, prostate, and bladder.
Alpha1-Adrenergic Blockers. The four older AABs (ie, alfuzosin, doxazosin, tamsulosin, and terazosin) have been extensively investigated in clinical trials and widely used in the management of BPH. A 2010 review by the AUA concluded that the minor efficacy differences reported among the 4 older AABs were not clinically significant.19 Although ejaculatory dysfunction may occur with the use of the AABs, these agents are generally well-tolerated, with dizziness the most common AE, occurring in 2% to 14% of men. Ejaculatory dysfunction may be a part of the disease process itself, as noted earlier.
The newest AAB, silodosin, at a dosage of 8 mg/d was reported to have efficacy similar to tamsulosin 0.2 to 0.4 mg/d in reducing storage and voiding LUTS in three 12-week trials.25-27 Silodosin has also been associated with a significant improvement in patients’ quality of life. The most frequent AE related to silodosin use was abnormal ejaculation, occurring in 10% to 22% and causing discontinuation in 1% to 3%.25-27 One 12-week study reported that systolic blood pressure (BP) decreased 0.1 and 4.2 mm Hg in the silodosin and tamsulosin groups, respectively.25 The negligible reduction in BP observed with silodosin is likely due to the selectivity of silodosin for the alpha1A-adrenergic receptor rather than the alpha1B-adrenergic receptor, the blockade of which reduces BP.
5-Alpha-Reductase Inhibitors. The efficacy of 5-ARIs in preventing progression of LUTS secondary to BPH and their tolerability are well-established. Dutasteride was associated with a greater reduction in dihydrotestosterone in prostate tissues compared with finasteride (94% vs 80%, respectively) and has a longer elimination half-life.19 Finasteride was reported to be less effective than an AAB in improving LUTS. Dutasteride may have been more effective in reducing the relative risk for acute urinary retention and BPH-related surgery compared with tamsulosin over 4 years, but more research is needed.28 The 5-ARIs should not be used in men with LUTS secondary to BPH without prostatic enlargement, but may be used to prevent the progression of LUTS secondary to BPH and to reduce the risk for urinary retention and future prostate-related surgery.19 Prostate size ≥30 mL or PSA level ≥1.5 ng/dL is usually used as the threshold for considering 5-ARI therapy.19 As expected, because of the effects on dihydrotestosterone, AEs are primarily sexually related and include decreased libido, ejaculation disorders, and erectile dysfunction.19
Phosphodiesterase-5 Inhibitors. Approved by the FDA for erectile dysfunction, several observations led to the investigation of PDE-5Is for LUTS related to BPH.8,29 One was that the prevalences of BPH, LUTS, and erectile dysfunction increase as a man ages. Second was that LUTS have been identified as a risk factor for sexual dysfunction in aging men. Third was that limited evidence had suggested that PDE-5Is might be effective in treating LUTS and erectile dysfunction. Further investigation suggested beneficial effects on LUTS with each of the 3 PDE-5Is (ie, sildenafil, tadalafil, and vardenafil).30-32 Subsequent extensive investigation with tadalafil demonstrated its efficacy in reducing the storage and voiding symptoms of BPH and led to the approval by the FDA of tadalafil for symptoms of BPH alone or with erectile dysfunction.33-37
The clinical studies investigating the efficacy and tolerability of tadalafil for LUTS associated with BPH have included a 12-week study with a 1-year extension.38 Patients with BPH-associated LUTS (N = 1058) were randomized to tadalafil 2.5, 5, 10, or 20 mg/d or placebo once daily for 12 weeks. The total IPSS score was significantly improved at 12 weeks compared with baseline in each of the tadalafil groups relative to placebo (2.5 mg/d: –3.9, P = .015; 5 mg/d: –4.9, P < .001; 10 mg/d: –5.2, P < .001; 20 mg/d: –5.2, P < .001; placebo: –2.3). The use of tadalafil 5, 10, or 20 mg once daily was associated with significant improvements in the IPSS irritative (eg, frequency, nocturia, and urgency) and obstructive (eg, incomplete emptying, intermittency, slow stream, and straining) subscores, as well as scores on the IPSS quality-of-life measure, the BPH Impact Index (except 10 mg), and the LUTS Global Assessment Question. In sexually active men with erectile dysfunction, all doses of tadalafil were associated with significant improvements in scores on the International Index of Erectile Function–Erectile Function domain compared with placebo. Peak flow rate was not improved at any dose of tadalafil compared with placebo.
In total, 427 men who completed the 12-week study elected to receive tadalafil 5 mg once daily for an additional year.37 Patients who were switched from placebo or who had the dose increased from 2.5 mg/d had a significant reduction in total IPSS score from week 12 to week 16, and this change was maintained until the end of follow-up at week 64. Patients who had received tadalafil 5, 10, or 20 mg/d maintained the changes observed at the end of the 12-week study. Similarly, sexually active men with erectile dysfunction and who had a female partner maintained the improvements observed at the end of 12 weeks. The mean postvoid residual volume was decreased from 61 to 42 mL. At least 1 treatment-emergent AE (TEAE) was reported in 58% of patients, with 89% of events being either mild or moderate in severity. Treatment was discontinued in 5% due to a TEAE. The most common TEAEs were dyspepsia (4%), gastroesophageal reflux disease (4%), back pain (4%), headache (3%), sinusitis (3%), hypertension (3%), and cough (2%). In this study, the improvement in LUTS, sexual function, and quality of life observed after 12 weeks of tadalafil were maintained over the additional year with tadalafil 5 mg once daily.
Treatment options for RI are watchful waiting, an AAB with or without a PDE-5I, a 5-ARI, or tadalafil. RI indicates that he would rather not have his symptoms for the rest of his life, so watchful waiting is not appropriate. Because his prostate is only slightly enlarged, a 5-ARI is also not appropriate. An AAB or tadalafil should provide good relief to his LUTS within a few weeks. Tadalafil would also treat his erectile dysfunction. Alternatively, tadalafil or another PDE-5I could be combined with an AAB, which has been reported to provide added benefit in symptom improvement over an AAB alone.39
Plan
Following discussion of the benefits and risks of the different treatment options, RI elects to begin treatment with an AAB alone. For this reason, treatment with another antihypertensive to replace the diuretic will not be started. To promote self-management, educational materials and an action plan are reviewed with RI. Lifestyle management changes are discussed, including reducing his daily water intake by 25% to 2 quarts with no consumption of fluids within 3 to 4 hours of bedtime. He is assured that adjustments to his treatment plan will be made based on his symptoms and concerns.
3-Month Follow-Up
RI reports that his symptoms have improved, with a modest improvement of nocturia; he gets up once during the night 1 or 2 times every 2 weeks or so. He strains less frequently, but intermittency is unchanged. His IPSS is 7 (improved by 2 points vs before treatment). The findings on his physical examination are unchanged except that his BP has decreased slightly, to 124/72 mm Hg. He has noted 1 or 2 episodes of dizziness. Feeling better than 3 months ago, RI asks whether further improvement of his LUTS is possible. He wonders whether his erectile dysfunction can be treated.
The benefits and risks of each of the 3 PDE-5Is are reviewed with RI. He elects to begin treatment with tadalafil 5 mg once daily because it is the only agent that is approved for the treatment of LUTS associated with BPH. Lifestyle management and his action plan are reviewed.
Continue to complete the online evaluation and receive your certification of completion.
Managing the Multiple Symptoms of Benign Prostatic Hyperplasia — CME
Managing Type 2 Diabetes in Men
Meeting New Challenges with Antiplatelet Therapy in Primary Care
Dr. Miner has disclosed that he is a consultant for Eli Lilly.
SUPPORT
This activity was supported by an educational grant from Lilly USA, LLC.
This article reviews screening tools for benign prostatic hyperplasia (BPH) and steps to be taken to confirm a diagnosis of BPH. Among the treatment options for BPH, emphasis is placed on pharmacologic treatment with alpha1-adrenergic blockers (AABs), 5-alpha-reductase inhibitors (5-ARIs), and phosphodiesterase-5 inhibitors (PDE-5Is). The two newest agents silodosin and tadalafil are discussed in greater detail.
LEARNING OBJECTIVES
After reviewing this activity on benign prostatic hyperplasia, the reader will be able to:
- Describe the key diagnostic steps.
- Describe the role of non-pharmacologic interventions.
- Compare the efficacy and safety of alpha1- adrenergic blockers, 5-alpha-reductase inhibitors, and phosphodiesterase-5 inhibitors.
- Describe strategies for treating multiple symptoms.
TARGET AUDIENCE
Family physicians and clinicians who wish to gain increased knowledge and greater competency regarding the management of patients with multiple symptoms of benign prostatic hyperplasia.
ACKNOWLEDGEMENT
Dr. Miner was paid an honorarium by and received editorial assistance from the Primary Care Education Consortium in the development of this activity.
DISCLOSURES
As a continuing medical education provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Primary Care Education Consortium (PCEC) to require any individual in a position to influence educational content to disclose the existence of any financial interest or other personal relationship with the manufacturer(s) of any commercial product(s).
Dr. Miner has disclosed that he is a consultant for Eli Lilly.
The medical accuracy and continuing medical education (CME) reviewer for this activity, Dr. Ron Pollack, has no real or apparent conflicts of interest to report.
PRIMARY CARE EDUCATION CONSORTIUM STAFF
Dr. Brunton has disclosed that he is on the advisory boards and speakers’ bureaus for Boehringer Ingelheim, Eli Lilly, Kowa, Novo Nordisk, Inc, and Teva Pharmaceuticals, and is on the advisory boards for Abbott and Sunovion.
Other PCEC staff have provided financial disclosure and have no conflicts of interest to resolve related to this activity.
CONFLICTS OF INTEREST
When individuals in a position to control content have reported financial relationships with one or more commercial interests, the Primary Care Education Consortium works with them to resolve such conflicts to ensure that the content presented is free of commercial bias. The content of this activity was vetted by the following mechanisms and modified as required to meet this standard:
- Content peer-review by an external topic expert
- Content peer-review by an external CME reviewer
- Content validation by internal Primary Care Education Consortium clinical editorial staff
OFF-LABEL DISCLOSURE
In accordance with ACCME guidelines, the faculty author has been asked to disclose discussion on unlabeled or unapproved uses of drugs or devices during the course of the activity.
SPONSORSHIP
This activity is sponsored by the Primary Care Education Consortium.
ACCREDITATION
This journal-based CME activity, Managing the Multiple Symptoms of Benign Prostatic Hyperplasia, has been reviewed and is acceptable for up to 1.0 prescribed credit by the American Academy of Family Physicians. AAFP accreditation begins June 1, 2012. Term of approval is for one year from this date with option for yearly renewal.
Physicians should claim only the credit commensurate with the extent of their participation in the activity.
MEDIUM
Text publication in the form of a journal article.
METHOD OF PHYSICIAN PARTICIPATION
To receive CME credit, please read the journal article, and upon completion go to: www.pceconsortium.org/menshealthBPH to complete the online evaluation to receive your certification of completion.
SUPPORT
This activity was supported by an educational grant from Lilly USA, LLC.
RI is a 53-year-old African-American man who is being seen by his family physician for a follow-up for dyslipidemia and hypertension. He reports that he is feeling well and that he has not observed any adverse events (AEs) from his medications. His current medications are an intermediate-dose statin, a thiazide diuretic, and a calcium channel blocker. RI reports that he has been very compliant with his medications, missing at most 1 dose every week or two.
During the visit, his physician notices that RI has yawned several times and that he appears tired. When asked how many hours he sleeps each night, RI indicates that he sleeps 7.5 to 8 hours most nights. On further questioning, RI admits that for the past 4 or 5 years, he has had to get up to go to the bathroom during the night, after which he often has trouble falling asleep, and that this nocturia currently occurs 3 or 4 times a night. When asked whether he has noticed any other changes over the past few years, RI says that he has noted an increase in his waist circumference (now 38.5 inches) and a few more aches and pains. When asked whether he has experienced any changes in sexual function, RI acknowledges that occasionally he has had difficulty maintaining an erection. He also indicates that he has accepted that these changes are a result of getting older.
Introduction
BPH is commonly experienced in men as they age. Lower urinary tract symptoms (LUTS) associated with BPH often begin in the fourth decade of life and affect nearly 3 in 4 men by the seventh decade of life.1,2 Lower urinary tract symptoms that prompt men to seek medical care typically include nocturia, frequency, incomplete emptying, and urgency.3,4 Men typically wait almost 2 years before seeking medical care for their urinary symptoms. Among men who do not seek medical care for LUTS, the most common reason is the belief that urinary symptoms are an inevitable part of aging. Many men who do not seek treatment indicate that they would rather accept their urinary symptoms than discuss them with a physician.4
In addition to urinary symptoms, BPH has been associated with symptoms of sexual dysfunction independent of the effects of aging and other comorbidities (eg, diabetes) and lifestyle factors.5-8 Erectile dysfunction and ejaculatory dysfunction are the most common symptoms of sexual dysfunction in men with BPH.9-11 Symptoms of sexual dysfunction may also be caused by some pharmacologic agents used for the treatment of BPH.6,9,10
Evaluation
Although BPH and the symptoms associated with it are not often life-threatening, ruling out other causes such as prostate cancer, diabetes mellitus, or Parkinson disease is an important diagnostic goal.
Screening
Because many men are slow to seek medical care and reluctant to speak with a physician about their symptoms, it is important that family physicians routinely inquire about urinary function in men over the age of 50 years. Beyond simply asking whether there have been changes in urinary function, posing the last question on the International Prostate Symptom Score (IPSS) questionnaire may be helpful: “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?”12 This question may be followed with, “Are you bothered enough by your symptoms that you would accept taking a medication?” Inquiries such as these, coupled with education to help the patient to understand that LUTS are not simply due to aging and that effective treatments are available, may motivate patients to share their concerns regarding urinary function. In addition, helping patients to understand that BPH is not a risk factor for prostate cancer, but that there are other causes of LUTS, which are best detected early, may be helpful.
Assessment
A history and focused urologic examination are crucial for the diagnosis of BPH. The medical history should identify a patient’s LUTS and their severity. To do this, a questionnaire such as the IPSS or the American Urological Association BPH Symptom Score Index Questionnaire can be administered [www.adultpediatricuro.com/apuauass.pdf]. As noted earlier, the eighth question on the IPSS questionnaire is useful for assessing the degree to which a patient is bothered by LUTS, with a higher score suggesting a greater willingness of the patient to be treated.13 Lower urinary tract symptoms are generally categorized into storage or bladder-emptying symptoms, with the latter subclassified as voiding or postmicturition symptoms.14 Storage problems are generally of greater concern to patients. Possible sexual dysfunction should also be assessed. A thorough medication history must be taken to identify AEs possibly related to the use of diuretics, anticholinergics, opioids, or decongestants.
The digital rectal examination (DRE) and prostate specific antigen (PSA) test are helpful to rule out a diagnosis of prostate cancer.15,16 The DRE is used for assessing the size, shape, symmetry, nodularity, and consistency of the prostate. The suprapubic area and genitals should be examined as well.17 The PSA test is also useful in the diagnosis and treatment of BPH because the PSA level rises as the prostate increases in size.13,14 A PSA level of 1.5 ng/mL roughly correlates with a prostate size of 30 mL.18 A urinalysis is needed to screen for urinary tract infections, bladder cancer, and kidney stones. Other laboratory analyses such as a fasting plasma glucose test may be needed based on the patient’s history and other findings.17
RI returns 3 weeks later for further evaluation. History confirms nocturia 3 or 4 times per night, as well as occasional erectile dysfunction and sometimes an inability to ejaculate. His IPSS questionnaire reveals a score of 9 (moderate symptoms), with occasional urinary frequency and straining. His LUTS are more bothersome than his occasional erectile dysfunction. It is decided that he will discontinue treatment with the thiazide diuretic because it may be contributing to his LUTS. An alternative antihypertensive agent will be initiated based on the results of the evaluation. The DRE reveals a boggy, slightly enlarged but normally shaped prostate with no nodules. The remainder of the urologic examination is normal. His PSA level is 0.8 ng/mL, and the urinalysis is normal. Further evaluation rules out prostate cancer and other causes of his symptoms.
A diagnosis of BPH is confirmed, with evidence of storage (ie, nocturia) and voiding (ie, urinary intermittency and straining) problems, as well as erectile dysfunction and occasional ejaculatory dysfunction.
Treatment
Goals
Because BPH is not often life-threatening, the focus of treatment has typically been to alleviate bothersome LUTS and other symptoms. With advances in treatment, additional goals include the alteration of disease progression and the prevention of associated complications such as recurrent urinary tract infections, hematuria, or acute urinary retention, particularly in men with an enlarged prostate (ie, volume >30 mL or PSA >1.5 ng/mL), since disease progression is more likely in these patients.17,19 A recent Medline-based systematic review reported that men prefer therapies that affect long-term progression over therapies that provide short-term symptom improvement.20 These results were consistent with those from a 2006 survey of 400 men with an enlarged prostate, which also reported that men are generally willing to wait up to 3 months for symptom relief if treatment would resolve the underlying condition.21 It is, therefore, important to discuss with the patient the natural history of BPH and its complications, and the benefits and risks of currently available noninvasive and invasive treatment options.
Options
Treatment options for BPH are watchful waiting, lifestyle and behavioral management, pharmacologic therapy, and surgical intervention. Many men use phytobotannical therapy such as saw palmetto, African plum tree, pumpkin seed, rye pollen, stinging nettle, South African star grass, and quercetin to relieve LUTS, although investigations regarding their use are often of poor quality. Saw palmetto is the best studied, yet a Cochrane review found few high-quality studies. The authors of the review concluded that saw palmetto was not more effective than placebo for treatment of LUTS.22 Similar results were observed in a randomized, double-blind, placebo-controlled trial more recently published by the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group.23
Watchful waiting is appropriate when only LUTS are present, with or without some degree of nonsuspicious prostate enlargement, and the symptoms are not particularly bothersome to the patient or if the patient does not want treatment.19 Lifestyle management and behavioral modification should generally be used in combination with other treatment options in an effort to alleviate symptoms, especially in men in whom storage symptoms predominate. Lifestyle management may include reducing fluid intake (particularly if polyuria is present), increasing physical activity, achieving a normal weight, timed voiding (bladder retraining), pelvic floor exercises, treatment for constipation, and avoidance of irritative foods and beverages.17,19 Epidemiologic evidence over 7 years of surveillance suggests that a diet low in fat and red meat and high in protein and vegetables, as well as regular alcohol consumption (>1 drink/month), may reduce the risk of symptomatic BPH.24 Evidence was weak concerning the benefits of lycopene, zinc, and supplemental vitamin D. No dietary supplement, combination phytotherapeutic agent, or other nonconventional therapy is recommended by the American Urological Association (AUA) for the management of LUTS secondary to BPH.19
Surgical intervention is considered appropriate in patients with moderate to severe LUTS in whom other medical therapies have not achieved treatment goals and in those in whom benign prostatic obstruction has led to complications such as renal insufficiency, urinary retention, recurrent urinary tract infections, bladder calculi, or hydronephrosis. Patients in whom surgical intervention is contemplated should be referred to a urologist.17,19
Pharmacologic Options
Three classes of pharmacologic agents have been approved by the US Food and Drug Administration (FDA) for the treatment of symptomatic BPH: AABs, 5-ARIs, and PDE-5Is. The AABs include alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin, and target the dynamic (smooth muscle tone) component of BPH-induced bladder outlet obstruction. The 5-ARIs finasteride and dutasteride target the static (prostate mass) component of BPH-induced bladder outlet obstruction. The PDE-5Is (ie, sildenafil, tadalafil, and vardenafil) increase the amount of cyclic guanosine monophosphate in the smooth muscle of the corpus cavernosum, prostate, and bladder.
Alpha1-Adrenergic Blockers. The four older AABs (ie, alfuzosin, doxazosin, tamsulosin, and terazosin) have been extensively investigated in clinical trials and widely used in the management of BPH. A 2010 review by the AUA concluded that the minor efficacy differences reported among the 4 older AABs were not clinically significant.19 Although ejaculatory dysfunction may occur with the use of the AABs, these agents are generally well-tolerated, with dizziness the most common AE, occurring in 2% to 14% of men. Ejaculatory dysfunction may be a part of the disease process itself, as noted earlier.
The newest AAB, silodosin, at a dosage of 8 mg/d was reported to have efficacy similar to tamsulosin 0.2 to 0.4 mg/d in reducing storage and voiding LUTS in three 12-week trials.25-27 Silodosin has also been associated with a significant improvement in patients’ quality of life. The most frequent AE related to silodosin use was abnormal ejaculation, occurring in 10% to 22% and causing discontinuation in 1% to 3%.25-27 One 12-week study reported that systolic blood pressure (BP) decreased 0.1 and 4.2 mm Hg in the silodosin and tamsulosin groups, respectively.25 The negligible reduction in BP observed with silodosin is likely due to the selectivity of silodosin for the alpha1A-adrenergic receptor rather than the alpha1B-adrenergic receptor, the blockade of which reduces BP.
5-Alpha-Reductase Inhibitors. The efficacy of 5-ARIs in preventing progression of LUTS secondary to BPH and their tolerability are well-established. Dutasteride was associated with a greater reduction in dihydrotestosterone in prostate tissues compared with finasteride (94% vs 80%, respectively) and has a longer elimination half-life.19 Finasteride was reported to be less effective than an AAB in improving LUTS. Dutasteride may have been more effective in reducing the relative risk for acute urinary retention and BPH-related surgery compared with tamsulosin over 4 years, but more research is needed.28 The 5-ARIs should not be used in men with LUTS secondary to BPH without prostatic enlargement, but may be used to prevent the progression of LUTS secondary to BPH and to reduce the risk for urinary retention and future prostate-related surgery.19 Prostate size ≥30 mL or PSA level ≥1.5 ng/dL is usually used as the threshold for considering 5-ARI therapy.19 As expected, because of the effects on dihydrotestosterone, AEs are primarily sexually related and include decreased libido, ejaculation disorders, and erectile dysfunction.19
Phosphodiesterase-5 Inhibitors. Approved by the FDA for erectile dysfunction, several observations led to the investigation of PDE-5Is for LUTS related to BPH.8,29 One was that the prevalences of BPH, LUTS, and erectile dysfunction increase as a man ages. Second was that LUTS have been identified as a risk factor for sexual dysfunction in aging men. Third was that limited evidence had suggested that PDE-5Is might be effective in treating LUTS and erectile dysfunction. Further investigation suggested beneficial effects on LUTS with each of the 3 PDE-5Is (ie, sildenafil, tadalafil, and vardenafil).30-32 Subsequent extensive investigation with tadalafil demonstrated its efficacy in reducing the storage and voiding symptoms of BPH and led to the approval by the FDA of tadalafil for symptoms of BPH alone or with erectile dysfunction.33-37
The clinical studies investigating the efficacy and tolerability of tadalafil for LUTS associated with BPH have included a 12-week study with a 1-year extension.38 Patients with BPH-associated LUTS (N = 1058) were randomized to tadalafil 2.5, 5, 10, or 20 mg/d or placebo once daily for 12 weeks. The total IPSS score was significantly improved at 12 weeks compared with baseline in each of the tadalafil groups relative to placebo (2.5 mg/d: –3.9, P = .015; 5 mg/d: –4.9, P < .001; 10 mg/d: –5.2, P < .001; 20 mg/d: –5.2, P < .001; placebo: –2.3). The use of tadalafil 5, 10, or 20 mg once daily was associated with significant improvements in the IPSS irritative (eg, frequency, nocturia, and urgency) and obstructive (eg, incomplete emptying, intermittency, slow stream, and straining) subscores, as well as scores on the IPSS quality-of-life measure, the BPH Impact Index (except 10 mg), and the LUTS Global Assessment Question. In sexually active men with erectile dysfunction, all doses of tadalafil were associated with significant improvements in scores on the International Index of Erectile Function–Erectile Function domain compared with placebo. Peak flow rate was not improved at any dose of tadalafil compared with placebo.
In total, 427 men who completed the 12-week study elected to receive tadalafil 5 mg once daily for an additional year.37 Patients who were switched from placebo or who had the dose increased from 2.5 mg/d had a significant reduction in total IPSS score from week 12 to week 16, and this change was maintained until the end of follow-up at week 64. Patients who had received tadalafil 5, 10, or 20 mg/d maintained the changes observed at the end of the 12-week study. Similarly, sexually active men with erectile dysfunction and who had a female partner maintained the improvements observed at the end of 12 weeks. The mean postvoid residual volume was decreased from 61 to 42 mL. At least 1 treatment-emergent AE (TEAE) was reported in 58% of patients, with 89% of events being either mild or moderate in severity. Treatment was discontinued in 5% due to a TEAE. The most common TEAEs were dyspepsia (4%), gastroesophageal reflux disease (4%), back pain (4%), headache (3%), sinusitis (3%), hypertension (3%), and cough (2%). In this study, the improvement in LUTS, sexual function, and quality of life observed after 12 weeks of tadalafil were maintained over the additional year with tadalafil 5 mg once daily.
Treatment options for RI are watchful waiting, an AAB with or without a PDE-5I, a 5-ARI, or tadalafil. RI indicates that he would rather not have his symptoms for the rest of his life, so watchful waiting is not appropriate. Because his prostate is only slightly enlarged, a 5-ARI is also not appropriate. An AAB or tadalafil should provide good relief to his LUTS within a few weeks. Tadalafil would also treat his erectile dysfunction. Alternatively, tadalafil or another PDE-5I could be combined with an AAB, which has been reported to provide added benefit in symptom improvement over an AAB alone.39
Plan
Following discussion of the benefits and risks of the different treatment options, RI elects to begin treatment with an AAB alone. For this reason, treatment with another antihypertensive to replace the diuretic will not be started. To promote self-management, educational materials and an action plan are reviewed with RI. Lifestyle management changes are discussed, including reducing his daily water intake by 25% to 2 quarts with no consumption of fluids within 3 to 4 hours of bedtime. He is assured that adjustments to his treatment plan will be made based on his symptoms and concerns.
3-Month Follow-Up
RI reports that his symptoms have improved, with a modest improvement of nocturia; he gets up once during the night 1 or 2 times every 2 weeks or so. He strains less frequently, but intermittency is unchanged. His IPSS is 7 (improved by 2 points vs before treatment). The findings on his physical examination are unchanged except that his BP has decreased slightly, to 124/72 mm Hg. He has noted 1 or 2 episodes of dizziness. Feeling better than 3 months ago, RI asks whether further improvement of his LUTS is possible. He wonders whether his erectile dysfunction can be treated.
The benefits and risks of each of the 3 PDE-5Is are reviewed with RI. He elects to begin treatment with tadalafil 5 mg once daily because it is the only agent that is approved for the treatment of LUTS associated with BPH. Lifestyle management and his action plan are reviewed.
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1. Wei JT, Calhoun EA, Jacobsen SJ. Urologic Diseases in America: Benign prostatic hyperplasia. http://kidney.niddk.nih.gov/Statistics/UDA/Benign_Prostatic_Hyperplasia-Chapter02.pdf. Published 2007. Accessed May 16, 2012.
2. Miller DC, Saigal CS, Litwin MS. The demographic burden of urologic diseases in America. Urol Clin North Am. 2009;36(1):11-27, v.
3. Sarma AV, Wallner L, Jacobsen SJ, Dunn RL, Wei JT. Health seeking behavior for lower urinary tract symptoms in black men. J Urol. 2008;180(1):227-232.
4. Survey confirms prostate problems overlooked by men and doctors [press release]. Vienna, Austria: GlaxoSmithKline. October 3, 2011. http://www.ismh.org/en/sys/wp-content/uploads/2011/09/News-release-300911-BPH-survey-a-male-perspective.pdf. Accessed May 16, 2012.
5. Mirone V, Sessa A, Giuliano F, Berges R, Kirby M, Moncada I. Current benign prostatic hyperplasia treatment: impact on sexual function and management of related sexual adverse events. Int J Clin Pract. 2011;65(9):1005-1013.
6. Gacci M, Eardley I, Giuliano F, et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2011;60(4):809-825.
7. Hoesl CE, Woll EM, Burkart M, Altwein JE. Erectile dysfunction (ED) is prevalent, bothersome and underdiagnosed in patients consulting urologists for benign prostatic syndrome (BPS). Eur Urol. 2005;47(4):511-517.
8. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol. 2003;44(6):637-649.
9. Rosen RC, Wei JT, Althof SE, Seftel AD, Miner M, Perelman MA. for BPH Registry and Patient Survey Steering Committee. Association of sexual dysfunction with lower urinary tract symptoms of BPH and BPH medical therapies: results from the BPH Registry. Urology. 2009;73(3):562-566.
10. Rosen RC, Fitzpatrick JM. for ALF-LIFE Study Group. Ejaculatory dysfunction in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. BJU Int. 2009;104(7):974-983.
11. Seftel A, Rosen R, Kuritzky L. Physician perceptions of sexual dysfunction related to benign prostatic hyperplasia (BPH) symptoms and sexual side effects related to BPH medications. Int J Impot Res. 2007;19(4):386-392.
12. American Urological Association. American Urological Association BPH Symptom Score Index Questionnaire. http://www.adultpediatricuro.com/apuauass.pdf. Accessed May 16, 2012.
13. O’Leary MP. Validity of the “bother score” in the evaluation and treatment of symptomatic benign prostatic hyperplasia. Rev Urol. 2005;7(1):1-10.
14. Abrams P, Cardozo L, Fall M, et al. for Standardisation Sub-Committee of the International Continence Society. 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.
15. American Urological Association. Prostate-specific antigen best practice statement: 2009 update. http://www.auanet.org/content/media/psa09.pdf. Published 2009. Accessed May 16, 2012.
16. American Cancer Society. Can prostate cancer be found early? http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-detection. Published 2012. Accessed May 16, 2012.
17. Tanguay S, Awde M, Brock G, et al. Diagnosis and management of benign prostatic hyperplasia in primary care. Can Urol Assoc J. 2009;3(3 suppl 2):S92-S100.
18. Roehrborn CG, Boyle P, Gould AL, Waldstreicher J. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology. 1999;53(3):581-589.
19. McVary KT, Roehrborn CG, Avins AL, et al. American Urological Association guideline: Management of benign prostatic hyperplasia (BPH). http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.cfm?sub=bph. Published 2010. Accessed May 16, 2012.
20. Emberton M. Medical treatment of benign prostatic hyperplasia: physician and patient p and satisfaction. Int J Clin Pract. 2010;64(10):1425-1435.
21. Kaplan S, Naslund M. Public, patient, and professional attitudes towards the diagnosis and treatment of enlarged prostate: A landmark national US survey. Int J Clin Pract. 2006;60(10):1157-1165.
22. Tacklind J, MacDonald R, Rutks I, Wilt TJ. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2009;2:CD001423.-
23. Barry MJ, Meleth S, Lee JY, et al. for Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group. Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. JAMA. 2011;306(12):1344-1351.
24. Kristal AR, Arnold KB, Schenk JM, et al. Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol. 2008;167(8):925-934.
25. Yu HJ, Lin AT, Yang SS, et al. Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). BJU Int. 2011;108(11):1843-1848.
26. Chapple CR, Montorsi F, Tammela TL, Wirth M, Koldewijn E, Fernandez FE. for European Silodosin Study Group. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011;59(3):342-352.
27. Kawabe K, Yoshida M, Homma Y. for Silodosin Clinical Study Group. Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int. 2006;98(5):1019-1024.
28. Roehrborn CG, Siami P, Barkin J, et al. for CombAT Study Group. 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(1):123-131.
29. Kaplan SA, Gonzalez RR. Phosphodiesterase type 5 inhibitors for the treatment of male lower urinary tract symptoms. Rev Urol. 2007;9(2):73-77.
30. Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. J Sex Med. 2006;3(4):662-667.
31. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177(4):1401-1407.
32. Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. 2008;53(6):1236-1244.
33. Porst H, McVary KT, Montorsi F, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol. 2009;56(4):727-735.
34. Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology. 2010;75(6):1452-1458.
35. Porst H, Kim ED, Casabé AR, et al. LVHJ study team. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol. 2011;60(5):1105-1113.
36. Maselli G, Bergamasco L, Silvestri V, Gualà L, Pace G, Vicentini C. Tadalafil versus solifenacin for persistent storage symptoms after prostate surgery in patients with erectile dysfunction: a prospective randomized study. Int J Urol. 2011;18(7):515-520.
37. Donatucci CF, Brock GB, Goldfischer ER, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int. 2011;107(7):1110-1116.
38. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008;180(4):1228-1234.
39. Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with alpha-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012;61(5):994-1003.
1. Wei JT, Calhoun EA, Jacobsen SJ. Urologic Diseases in America: Benign prostatic hyperplasia. http://kidney.niddk.nih.gov/Statistics/UDA/Benign_Prostatic_Hyperplasia-Chapter02.pdf. Published 2007. Accessed May 16, 2012.
2. Miller DC, Saigal CS, Litwin MS. The demographic burden of urologic diseases in America. Urol Clin North Am. 2009;36(1):11-27, v.
3. Sarma AV, Wallner L, Jacobsen SJ, Dunn RL, Wei JT. Health seeking behavior for lower urinary tract symptoms in black men. J Urol. 2008;180(1):227-232.
4. Survey confirms prostate problems overlooked by men and doctors [press release]. Vienna, Austria: GlaxoSmithKline. October 3, 2011. http://www.ismh.org/en/sys/wp-content/uploads/2011/09/News-release-300911-BPH-survey-a-male-perspective.pdf. Accessed May 16, 2012.
5. Mirone V, Sessa A, Giuliano F, Berges R, Kirby M, Moncada I. Current benign prostatic hyperplasia treatment: impact on sexual function and management of related sexual adverse events. Int J Clin Pract. 2011;65(9):1005-1013.
6. Gacci M, Eardley I, Giuliano F, et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2011;60(4):809-825.
7. Hoesl CE, Woll EM, Burkart M, Altwein JE. Erectile dysfunction (ED) is prevalent, bothersome and underdiagnosed in patients consulting urologists for benign prostatic syndrome (BPS). Eur Urol. 2005;47(4):511-517.
8. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol. 2003;44(6):637-649.
9. Rosen RC, Wei JT, Althof SE, Seftel AD, Miner M, Perelman MA. for BPH Registry and Patient Survey Steering Committee. Association of sexual dysfunction with lower urinary tract symptoms of BPH and BPH medical therapies: results from the BPH Registry. Urology. 2009;73(3):562-566.
10. Rosen RC, Fitzpatrick JM. for ALF-LIFE Study Group. Ejaculatory dysfunction in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. BJU Int. 2009;104(7):974-983.
11. Seftel A, Rosen R, Kuritzky L. Physician perceptions of sexual dysfunction related to benign prostatic hyperplasia (BPH) symptoms and sexual side effects related to BPH medications. Int J Impot Res. 2007;19(4):386-392.
12. American Urological Association. American Urological Association BPH Symptom Score Index Questionnaire. http://www.adultpediatricuro.com/apuauass.pdf. Accessed May 16, 2012.
13. O’Leary MP. Validity of the “bother score” in the evaluation and treatment of symptomatic benign prostatic hyperplasia. Rev Urol. 2005;7(1):1-10.
14. Abrams P, Cardozo L, Fall M, et al. for Standardisation Sub-Committee of the International Continence Society. 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.
15. American Urological Association. Prostate-specific antigen best practice statement: 2009 update. http://www.auanet.org/content/media/psa09.pdf. Published 2009. Accessed May 16, 2012.
16. American Cancer Society. Can prostate cancer be found early? http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-detection. Published 2012. Accessed May 16, 2012.
17. Tanguay S, Awde M, Brock G, et al. Diagnosis and management of benign prostatic hyperplasia in primary care. Can Urol Assoc J. 2009;3(3 suppl 2):S92-S100.
18. Roehrborn CG, Boyle P, Gould AL, Waldstreicher J. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology. 1999;53(3):581-589.
19. McVary KT, Roehrborn CG, Avins AL, et al. American Urological Association guideline: Management of benign prostatic hyperplasia (BPH). http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.cfm?sub=bph. Published 2010. Accessed May 16, 2012.
20. Emberton M. Medical treatment of benign prostatic hyperplasia: physician and patient p and satisfaction. Int J Clin Pract. 2010;64(10):1425-1435.
21. Kaplan S, Naslund M. Public, patient, and professional attitudes towards the diagnosis and treatment of enlarged prostate: A landmark national US survey. Int J Clin Pract. 2006;60(10):1157-1165.
22. Tacklind J, MacDonald R, Rutks I, Wilt TJ. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2009;2:CD001423.-
23. Barry MJ, Meleth S, Lee JY, et al. for Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group. Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. JAMA. 2011;306(12):1344-1351.
24. Kristal AR, Arnold KB, Schenk JM, et al. Dietary patterns, supplement use, and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol. 2008;167(8):925-934.
25. Yu HJ, Lin AT, Yang SS, et al. Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). BJU Int. 2011;108(11):1843-1848.
26. Chapple CR, Montorsi F, Tammela TL, Wirth M, Koldewijn E, Fernandez FE. for European Silodosin Study Group. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011;59(3):342-352.
27. Kawabe K, Yoshida M, Homma Y. for Silodosin Clinical Study Group. Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int. 2006;98(5):1019-1024.
28. Roehrborn CG, Siami P, Barkin J, et al. for CombAT Study Group. 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(1):123-131.
29. Kaplan SA, Gonzalez RR. Phosphodiesterase type 5 inhibitors for the treatment of male lower urinary tract symptoms. Rev Urol. 2007;9(2):73-77.
30. Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. J Sex Med. 2006;3(4):662-667.
31. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177(4):1401-1407.
32. Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. 2008;53(6):1236-1244.
33. Porst H, McVary KT, Montorsi F, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol. 2009;56(4):727-735.
34. Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology. 2010;75(6):1452-1458.
35. Porst H, Kim ED, Casabé AR, et al. LVHJ study team. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol. 2011;60(5):1105-1113.
36. Maselli G, Bergamasco L, Silvestri V, Gualà L, Pace G, Vicentini C. Tadalafil versus solifenacin for persistent storage symptoms after prostate surgery in patients with erectile dysfunction: a prospective randomized study. Int J Urol. 2011;18(7):515-520.
37. Donatucci CF, Brock GB, Goldfischer ER, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int. 2011;107(7):1110-1116.
38. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008;180(4):1228-1234.
39. Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with alpha-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012;61(5):994-1003.