Long-term Consequences of Medical Therapy for Benign Prostatic Hyperplasia

Management Update

Management Update Long-term Consequences of Medical Therapy for Benign Prostatic Hyperplasia Eric M. Bortnick, MD, Vannita Simma-Chiang, MD, Steven A. Kaplan, MD Department of Urology, Mount Sinai Hospital, Icahn School of Medicine, New York, NY Benign prostatic hyperplasia (BPH) is a common disease in men. Although transurethral resection of the prostate (TURP) is the gold standard therapy for treatment of BPH and associated lower urinary tract symptoms (LUTS), many patients choose to avoid surgery and instead choose medical therapy. Until recently, medical therapy for BPH has been thought to be both safe and effective. However, new studies have shown that some of these medications can have significant neurocognitive, psychiatric, and sexual side effects, including dementia and depression. As most patients taking these medications will continue them for the long term, it is vital for physicians to explain these potential risks to the patient prior to prescribing them for a quality-of-life condition. [Rev Urol. 2019;21(4):154–157] © 2020 MedReviews®, LLC KEY WORDS Benign prostatic hyperplasia • Medical therapy • alpha-Blockers • 5-alpha-Reductase inhibitors • Dementia • Depression B enign prostatic hyperplasia (BPH) is a common disease in men, with the prevalence of histologically diagnosed BPH increasing from 8% in men age 31 to 40 years to over 80% in men older than 80 years.1 BPH is characterized by progressive enlargement of the prostate gland from nonmalignant proliferation of smooth muscle and epithelial cells. The enlargement manifests clinically as lower urinary tract symptoms (LUTS) such as nocturia, urgency, frequency, urinary retention, straining to 154 • Vol. 21 No. 4 • 2019 • Reviews in Urology urinate, and a weak urinary stream. Without treatment, many of these men will suffer from worsening voiding and storage symptoms as they continue to age that could potentially progress to acute urinary retention requiring placement of a Foley catheter. Many different treatment options for BPH with LUTS exist, including non-invasive medical therapy, minimally invasive office-based procedures, and surgical therapies. Transurethral resection of the prostate (TURP) is the gold standard treatment Long-term Consequences of Medical Therapy for BPH for men with BPH associated with LUTS; however, many patients are either not candidates for surgery or choose to avoid surgery if possible. Medical therapy for the treatment of BPH with LUTS has grown rapidly over the past 20 years and has been shown to be a feasible alternative to surgery. The major clinical trials that studied these medications, including MTOPS (Medical Therapy of Prostatic Symptoms) and CombAT (Combination of Avodart and Tamsulosin), found that these medications were acceptable treatment alternatives and that the medications were well tolerated with relatively few adverse effects. However, the initial follow-up period for the time patients were on these medications were relatively short. Throughout medicine, we are starting to learn that medications that we initially thought were safe to use may have unintended consequences if taken for an extended period. For example, studies in cardiology have now found a link between long-term statin use and cognitive function. Consequently, labeling for statin therapy now includes a warning for cognitive side effects of memory loss and confusion. Recently, there has been a growing concern that the long-term use of commonly prescribed medications for BPH, including alpha-blockers, 5-alpha reductase inhibitors (5-ARIs), and anticholinergics, could have negative neurocognitive and psychiatric consequences, amongst others. Given that BPH is essentially a quality-of-life disease, it is important to understand these new concerns to help guide our patients in discussion of treatment options. Dementia There is growing concern that 5-ARIs, alpha-blockers, and anticholinergics have neurocognitive side effects that can lead to an increased risk of dementia, as these medications have effects in the brain. alpha-1A receptors are present in the brain as well as the prostate, so using an antagonist against these receptors could have adverse effects. Tamsulosin is among the most selective alpha-1A antagonists of the alpha-blockers, and a recent study by Duan and colleagues studied the risk of dementia in older men who had taken tamsulosin.2 Using Medicare data, 253,136 men over age 65 years diagnosed with BPH who were taking tamsulosin were compared with a propensitymatched cohort of men who either used no BPH medication or a different BPH medication. After a mean follow-up of 19.8 months, men in the tamsulosin cohort had an incidence of dementia of 31.3/1000 person-years as compared with only 25.9/1000 person-years in the cohort taking no BPH medication. The overall risk of dementia was significantly higher in the tamsulosin cohort as compared with the noBPH-medication cohort and each of the alternative-BPH-medication cohorts, which included doxazosin, terazosin, alfuzosin, dutasteride, and finasteride.2 There is also a risk of neurocognitive deficit in patients that take anticholinergic medications. The cholinergic system in the brain plays an important role in attention, memory, awareness, psychomotor speed, and selection of relevant stimuli from the environment. By blocking this pathway in the central nervous system, anticholinergic medication could impair cognitive functions. The updated 2015 Beers Criteria for medication use in the elderly recommends avoiding anticholinergic use in this population as it increases the risk of confusion due to decreased clearance of the medication over time.3 In 2017, a retrospective analysis from the National Alzheimer’s Coordinating Center on enrollees age 65 years or older compared 698 new users of an antimuscarinic for bladder pathology with 7037 nonusers and found a significant risk of cognitive decline in antimuscarinic users based on Mini-Mental Status Examination (odds ratio [OR], 1.4; confidence interval [CI], 1.19-1.65) and Clinical Dementia Rating (OR, 1.21; CI, 1.03-1.42).4 Furthermore, a randomized, double-blind study in 2006 took 150 healthy subjects over age 60 years and randomized them to receive darifenacin (a more selective bladder antimuscarinic), oxybutynin (a nonselective antimuscarinic), or placebo for 3 weeks. Results showed that, based on accuracy of a Name-Face Association Test, oxybutynin intake resulted in memory impairment, with significantly lower scores than either the placebo or darifenacin groups after 3 weeks (P 5 0.011 and P 5 0.022, respectively).5 More recently, a prospective, population-based cohort study by Gray and colleagues looked at 3434 patients over age 65 years with no dementia over a mean follow-up of 7.3 years. At the start of the study, 668 participants (19.5%) were taking an anticholinergic for bladder- or BPH-related disease. Of the total participants, 797 (23.3%) developed dementia (79.9% of whom developed Alzheimer disease). A 10-year cumulative dose-response relationship of anticholinergic intake was observed for dementia and Alzheimer disease (test for trend, P , 0.001), showing that higher cumulative anticholinergic use is associated with increased risk of dementia.6 Given the effects of testosterone and 5-ARIs on the brain, there was also a concern that 5-ARIs may lead to increased incidence dementia if taken for an extended period. A Canadian propensity-matched Vol. 21 No. 4 • 2019 • Reviews in Urology • 155 Long-term Consequences of Medical Therapy for BPH continued cohort study of 81,162 men by Welk and colleagues found that, in men who started a 5-ARI compared with an equal number of those who did not, there was an increased risk of dementia during the first 2 years of taking a 5-ARI. However, this association did not stay significant for those that had been taking the medication longer. This finding suggests that a mild cognitive impairment that coexists with urinary symptoms during the first 2 years of medical therapy with a 5-ARI may eventually progress to a diagnosis of dementia.7 Depression Along with the neurocognitive effects of dementia, there is also evidence that BPH medications could be associated with depression. As 5-ARIs reduce the synthesis of several neuroactive steroids, the modulation of the neuroendocrine stress response may lead to depression. Many studies have shown correlations between 5-ARIs and depression. Some of the initial studies linking 5-ARIs to depression were found in men taking low-dose finasteride for male pattern baldness. In 2006, a prospective study of 182 men (mean age, 25.8) with androgenic alopecia were given both a Beck Depression Inventory (BDI) questionnaire and Hospital Anxiety and Depression Scale (HADS) before starting finasteride, 1 mg/day, treatment and 2 months after treatment. Finasteride treatment increased both the BDI (P , 0.001) and HADS score (P , 0.005) significantly.8 Similarly, in 2012, Irwig gave 61 former users of finasteride with persistent sexual side effects and 29 control patients that had history of male pattern baldness with no former use of finasteride standardized interviews including the Beck Depression Inventory II (BDI-II). Rates of depressive symptoms were significantly higher in former finasteride users as compared the control group (P , 0.0001) and moderate or severe depressive symptoms were present only in patients that had taken finasteride (64% of finasteride users vs 0% of controls).9 Studies specific to men with BPH taking 5-ARIs have found similar results. An observational Polish study of 4035 men by Pietrzyk and colleagues found that, based on results of a BDI, International Prostate Symptom Score (IPSS), and International Index of Erectile Function (IEFF-5) surveys, the occurrence of depressive symptoms and erectile dysfunction were significantly associated with the use of 5ARIs.10 A 2016 study by Unger and colleagues linked data from the Prostate Cancer Prevention Trial (PCPT) and Medicare claims of 13,935 men to compare finasteride with placebo over 7 years in the PCPT and found that the use of finasteride had a 10% higher risk of new claims for depression (P , 0.04), with a number needed to harm of 76.9 patients.11 Similarly, a population-based, retrospective, propensity-matched Canadian cohort study of 93,197 men older than age 66 years on 5-ARIs for a median duration of 1.57 years by Welk and colleagues found that depression risk was elevated during the initial 18 months after starting a 5-ARI and remained elevated, although to a lesser extent, throughout the remainder of the study period. Risk of self-harm was also significantly elevated during the initial 18 months on a 5-ARI, although there was no increased risk of suicide.12 Sexual Function Another concerning long-term side effect of medical therapy for BPH is that of sexual function. It is 156 • Vol. 21 No. 4 • 2019 • Reviews in Urology well known that in the short term, medications such as alpha-blockers can have sexual side effects in the form of ejaculatory dysfunction. However, more recently there is growing concern that some sexual side effects can present later and possibly be permanent. In what has become known as post-finasteride syndrome (PFS), studies have shown that sexual dysfunction can persist even after stopping the medication. In a single-group study of 11,909 men that had previously taken 5-ARIs, duration of 5-ARI exposure was associated with persistent erectile dysfunction (ED) after stopping the 5-ARI with a persistent median of 1348 days.13 A retrospective review of 2783 men from the MTOPS trial who completed the Brief Male Sexual Function Inventory (BMSFI) found that those men who were on either finasteride or combination therapy experienced statistically significant worsening of ejaculatory function when compared with the placebo group, as did those on combination therapy. No difference in any portion of the BMSFI was found between doxazosin and placebo.14 Ultimately, the clinical relevance is highly dependent on the patient. Degrees of bother are variable based on age, culture, and expectation. Nevertheless, both patients and prescribers should be cognizant of these data prior to initiating therapy. Multiple systematic reviews and meta-analyses have found similar results. A 2017 review of 24,463 men taking a 5-ARI and 22,270 men on placebo by Corona and colleagues found that after a mean follow-up of 99 weeks, those on 5-ARIs were at an increased risk of hypoactive sexual desire (OR, 1.54; P , 0.0001) and ED (OR, 1.47; P , 0.0001).15 A review of five randomized, controlled trials involving 6131 men found that Long-term Consequences of Medical Therapy for BPH the overall prevalence of ED and libido alterations were significantly higher in the combination therapy group than the alpha-blocker-only group, and that combination therapy increased the prevalence of ED compared with the 5-ARI-only group.16 Another meta-analysis including 23,395 patients found that 5-ARI treatment resulted in significantly higher incidence of decreased libido, ejaculatory disorder, gynecomastia, and impotence.17 One retrospective review and meta-analysis of 23 articles even found that the effectiveness of the BPH medication was associated with worsening sexual dysfunction. For patients on alpha-blockers, ejaculatory dysfunction was independently associated with improvement in both IPSS and Qmax scores on multivariate analysis.18 Miscellaneous Possible negative consequences of prolonged BPH medical therapy go beyond the neurocognitive and sexual effects. A 2017 retrospective study of 460 men by Traish and colleagues compared long-term dutasteride to tamsulosin for BPH. Although dutasteride was associated with significant improvement of LUTS, there were also significant increases in blood glucose, glyclated hemoglobin, total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, and liver enzymes, along with reduction in total testosterone. No changes were seen in the cohort of men taking tamsulosin. Overall, the study suggests that dutasteride may induce a negative imbalance of metabolic function.19 There is also evidence that some BPH medical therapy can negatively affect quality of life in other ways. One article documented that both alfuzosin- and doxazosin-induced severe rhinorrhea in patients that were taking the medication for BPH-related LUTS, with a high likelihood that the alpha-antagonist was the cause of the severe rhinorrhea based on the Naranjo Adverse Drug Reaction Probability Scale, an algorithm to determine if an adverse reaction is due to the drug itself or other factors.20 4. 5. 6. 7. 8. 9. 10. 11. Conclusions Although medical therapy for the treatment of BPH and LUTS has proliferated over the past two decades, initial studies that showed their minimal adverse effects may have been undersold. Recent studies suggest that alpha-blockers, 5-ARIs, and anticholinergics may negatively affect mental and psychological status, sexual function, and overall health. As most patients taking these medications will continue them for the long term, it is vital for physicians to explain these potential risks to the patient prior to prescribing them for a qualityof-life condition. References 1. 2. 3. 12. 13. 14. 15. 16. 17. 18. McVary KT. Epidemiology and pathogenesis of benign prostatic hyperplasia. UpToDate website. https://www. uptodate.com/contents/epidemiology-and-pathogenesis-of-benign-prostatic-hyperplasia. Last updated May 16, 2019. Accessed November 25, 2019. Duan Y, Grady JJ, Albertsen PC, Helen Wu Z. Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia. Pharmacoepidemiol Drug Saf. 2018;27:340-348. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63:2227-2246. 19. 20. Moga DC, Abner EL, Wu Q, Jicha GA. Bladder antimuscarinics and cognitive decline in elderly patients. Alzheimers Dement. 2017;3:139-148. Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50:317-326. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175:401-407. Welk B, McArthur E, Ordon M, et al. The risk of dementia with the use of 5 alpha reductase inhibitors. J Neuroi Sci. 2017;379:109-111. Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A. Finasteride induced depression: a prospective study. BMC Clin Pharmacol. 2006;6:7. Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012;73;1220-1223. Pietrzyk B, Olszanecka-Glinianowicz M, Owczarek A, et al. Depressive symptoms in patients diagnosed with benign prostatic hyperplasia. Int Urol Nephrol. 2015;47:431-440. Unger JM, Till C, Thompson IM Jr, et al. Longterm consequences of finasteride vs placebo in the Prostate Cancer Prevention Trial. J Natl Cancer Inst. 2016;108:djw168. Welk B, McArthur E, Ordon M, et al. Association of suicidality and depression with 5a-reductase inhibitors. JAMA Intern Med. 2017;177:683-691. Kiguradze T, Temps WH, Yarnold PR, et al. Persistent erectile dysfunction in men exposed to the 5a-reductase inhibitors finasteride or dutasteride. PeerJ. 2017;5:e3020. Fwu CW, Eggers PW, Kirkali Z, et al. Change in sexual function in men with lower urinary tract symptoms/ benign prostatic hyperplasia associated with longterm treatment with doxazosin, finasteride, and combined therapy. J Urol. 2014;191:1828-1834. Corona G, Tirabassi G, Santi D, et al. Sexual dysfunction in subjects treated with inhibitors of 5a-reductase for benign prostatic hyperplasia: a comprehensive review and meta-analysis. Andrology. 2017;5:671-678. Favilla V, Russo GI, Privitera S, et al. Impact of combination therapy 5-alpha reductase inhibitors plus alpha-blockers on erectile dysfunction and decrease of libido in patients with LUTS/BPH: a systematic review with meta-analysis. Aging Male. 2016;19: 175-181. Kim JH, Baek MJ, Sun HY, et al. Efficacy and safety of 5 alpha-reductase inhibitor monotherapy in patients with benign prostatic hyperplasia: a meta-analysis. PLos One. 2018;13:e0203479. Gacci M, Ficarra V, Sebastianelli A, et al. Impact of medical treatments for male lower urinary tract symptoms due to benign prostatic hyperplasia on ejaculatory function: a systematic review and meta-analysis. J Sex Med. 2014;11:1554-1566. Traish A, Haider KS, Doros G, Haider A. Long-term dutasteride therapy in men with benign prostatic hyperplasia alters glucose and lipid profiles and increases severity of erectile dysfunction. Horm Mol Biol Clin Investig. 2017;30: doi:10.1515/hmbci-20170015. Shahar E, Nassar L, Kedem E, Hassoun G. Alpha-1 adrenergic antagonists induced severe rhinitis in patients with benign prostatic hyperplasia. Curr Drug Saf. 2014;9:159-160. Vol. 21 No. 4 • 2019 • Reviews in Urology • 157