Supplements BPH and Comorbid Conditions: Optimizing Treatment for the Aging Man
BPH: Epidemiology and Comorbidities
Recently published data suggest that clinical benign prostatic hyperplasia (BPH), which is hallmarked by the occurrence of moderate-to-severe lower urinary tract symptoms (LUTS), occurs in about one quarter of men in their 50s, one third of men in their 60s, and about half of all men 80 years or older. Although effective treatments for LUTS/BPH are available, this condition often occurs in the context of common, age-related comorbidities such as cardiovascular disease, hypertension, and erectile dysfunction. Alpha1-selective adrenergic receptor (α1-AR) antagonists (eg, alfuzosin, doxazosin, tamsulosin, terazosin) remain the cornerstone of therapy for LUTS/BPH. In addition, 5-alpha-reductase inhibitors (ie, dutasteride, finasteride) have been associated with improvements in LUTS/BPH in men with larger prostates, especially when used in combination with a1-AR antagonists. Although all these drugs have been shown to be beneficial for the treatment of BPH, there are differences in side-effect profiles. When selecting an appropriate course of therapy, these side effects and any impact they may have on existing comorbid conditions must be considered.
(Am J Manag Care. 2006;12:S122-S128)
Overview. Benign prostatic hyperplasia (BPH) is characterized by the nonmalignant overgrowth of prostatic tissue surrounding the urethra, ultimately constricting the urethral opening and giving rise to associated lower urinary tract symptoms (LUTS) such as urgency, frequency, nocturia, incomplete bladder emptying, and weak urine stream.1,2 Left untreated, serious complications can occur in men with BPH, including acute urinary retention (AUR), renal insufficiency and failure, urinary tract infection, and bladder stones.2 The exact etiology of BPH is not known; however, the similarity between BPH and the embryonic morphogenesis of the prostate has led to the hypothesis that BPH may result from a "reawakening" of embryonic induction processes in adulthood.3 It has also been postulated from anatomic and histologic studies of BPH at autopsy that BPH originates in the innermost aspect of the prostate gland (transition zone), which is located along the axis of the proximal urethra.3
Not all men with histologic BPH develop LUTS that requires intervention. Several processes, such as prostatic infarction, acute or chronic inflammation as a result of ongoing prostatitis, or in some cases, incidental adenocarcinomas of the gland, may foster the development of symptomatic BPH.3 The development of symptoms also depends on the enlargement of the individual prostate. As BPH nodules that originate in the transition zone grow, the remainder of the gland becomes compressed; if sufficient elasticity is present in the rest of the gland, little or no urethral compression will result. Conversely, if the remainder of the gland cannot expand freely, urethral constriction and obstruction of the urinary tract may occur.3 There is also a dynamic component to BPH, which can show substantive variation between individuals, relating to the neuronal control over prostatic smooth muscle tone by alpha1A-adrenergic receptors (a1A-ARs).4 The interindividual differences in the static and dynamic components of BPH will determine which men are affected by LUTS and the degree of symptom bother.
Prevalence and Impact. Histologically distinguishable BPH is present in about 8% of men aged 31 to 40 years, and this prevalence increases markedly with age to about 90% by the ninth decade of life (Figure 1),5-7 establishing BPH as a chronic disease that spans decades. Nonetheless, as noted above, not all men with BPH will go on to develop LUTS requiring treatment. The Urologic Diseases in America BPH Project examined the US prevalence of moderate-to-severe LUTS, defined by an American Urological Association (AUA) Symptom Index (SI) score of =8.1 Results from the Olmsted County Study (OCS) showed a progressive increase in the prevalence of moderate-to-severe LUTS, rising to nearly 50% by the eighth decade of life (Figure 2).2,8 The presence of moderate-to-severe LUTS was also associated with the development of AUR as a symptom of BPH progression, increasing from an incidence of 6.8 episodes per 1000 patient-years of follow-up in the overall OCS population to a high of 34.7 episodes in persons 70 years or older with moderate-to-severe LUTS.2,9 Risk factors were also established for BPH in OCS; these include age, prostatic volume, and peak urinary flow rate (Qmax).2 The odds of developing moderate-to-severe symptoms increased progressively after age 50 years (Table), and were 3.5- and 2.4-fold greater in men with a prostate volume >50 mL and in those with a flow rate of <10 mL/sec, respectively.2
Although BPH is not a life-threatening condition, the impact of BPH on quality of life (QOL) can be significant and should not be underestimated. A self-administered questionnaire completed by 117 patients reported sleep, anxiety/worry over the condition, mobility, leisure, activities of daily living, and, to a larger extent, the effect on sexual activities as the most important concerns among patients with prostate symptoms (International Prostate Symptom Score [IPSS] >7).10 The impact of BPH-associated LUTS has also been studied in a community-based population in the United Kingdom. A random sample of approximately 1500 individuals aged 50 years or older was assessed for BPH symptoms and their impact on QOL using a self-administered survey.11 Moderate-to-severe LUTS was seen in 41% of the patients (as assessed by an IPSS of =8), although only 18% reported they had been diagnosed with BPH.11 Respondents experienced decrements in both QOL and health status as symptomatic severity increased, with most men experiencing problems with mobility, self-care, activities of daily living, pain or discomfort, and anxiety or depression. Despite the high prevalence of LUTS reported in this survey, only 11% were aware of the pharmacologic or surgical interventions available to treat BPH; watchful waiting was the most common primary treatment (34%).11 The findings of this study underscore the need for better education about BPH and its treatments.
Given the potential impact of BPH symptoms on overall health, greater communication between patients and their healthcare providers is warranted to facilitate the diagnosis of LUTS. In this regard, primary care physicians (PCPs) have been taking a greater role in the treatment of BPH; one study found that 86% of PCPs had prescribed BPH medications in the preceding year, although 66% admitted rarely or never using the AUA SI.12 Among the available drugs, a median of 12 and 2 patients per year had been prescribed alpha1-selective adrenergic receptor (a1-AR) antagonists and finasteride, respectively, in this study.12 For patients, the most important parameters motivating them to seek treatment of BPH are symptom severity and degree of bother associated with LUTS; these are also important considerations when assessing BPH and deciding when treatment is indicated.13
Medical Treatments. The advent of medical therapy has obviated the need for surgery in many patients with BPH.1 a1-AR antagonists are considered first-line medical therapy. They exert their effects by blocking a1-AR-mediated contraction of the prostatic smooth muscle cells and bladder neck.1,14 There are 3 a1-AR subtypes: a1A, a1B, and a1D; terazosin, doxazosin, and alfuzosin are a1-AR antagonists that show equal affinity for all a1-AR subtypes.4,15-17 Tamsulosin is selective for the a1A-and a1D-AR subtypes but has less affinity for the a1B subtype, which regulates blood pressure via vascular smooth muscle contraction.15-18 a1-AR antagonists are comparably effective in patients with BPH/LUTS, causing a 35% to 40% improvement in total symptom scores and a 15% to 30% improvement in Qmax.19 Furthermore, results suggest that a1-AR antagonists that do not require titration (eg, tamsulosin, alfuzosin) can be started at their appropriate therapeutic doses and accordingly have a more rapid onset of action than those requiring titration (eg, doxazosin, terazosin).19,20 Differences in the safety and tolerability profiles among a1-AR antagonists have been reported19-21 and will be discussed in the following article.
Androgen reduction therapy with 5-alpha-reductase inhibitors (eg, finasteride) has been found to decrease prostatic size by 20% to 30% within 3 to 6 months of treatment, underscoring the importance of androgens on BPH progression.22 Patients undergoing up to 4 years of finasteride therapy do not experience any additional regression, but no further growth of the gland is observed. Of note, the partial reduction in prostate size observed after androgen withdrawal may not always be sufficient to decrease resistance in the urethra22; thus, symptom improvement may not be as dramatic and quantifiable when comparing with placebo or with the immediate benefit after surgery (eg, transurethral resection of the prostate). The use of finasteride either alone or in combination with an a1-AR antagonist (doxazosin) has also been examined in the Medical Therapy of Prostatic Symptoms study; results of this study will be discussed in the following review article (see "Treatment and Pharmacologic Management of BPH in the Context of Common Comorbidities"). Overall, combination therapy yielded better symptom control; however, the use of finasteride as monotherapy or with doxazosin was associated with a significantly higher incidence of sexual side effects.21
Comorbidities in Aging Men
Cardiovascular (CV) Disease and Hypertension. CV disease, including coronary artery disease and stroke, accounts for 25% to 55% of deaths worldwide.22 Hypertension is a well-established risk factor for CV disease, and like BPH, the prevalence of hypertension increases with age.23 Although BPH and hypertension appear to involve separate disease processes, it has been postulated that age-related increases in sympathetic tone may play a role in their pathophysiologies.23 Studies from both the United States (Third National Health and Nutrition Examination Survey [NHANES III]) and the United Kingdom suggest that about 50% to 65% of people over the age of 60 years are hypertensive.23 These may be conservative estimates, because hypertension, like BPH, is a largely underdiagnosed condition.24,25 Using these estimates, however, it can be extrapolated that if about 50% of men have BPH by age 60 years and 50% have hypertension by age 60 years, then approximately 25% of men 60 years and older have BPH with comorbid hypertension.23 It is important, therefore, for urologists and cardiologists to recognize the frequent coexistence of these conditions and to consider hypertension and BPH in patients 60 years or older when deciding on a course of treatment.23
The Framingham Heart Study evaluated the prevalence of CV disease and its associated risk factors in an average American population over a period spanning more than 30 years. Data from a community-based, prospective cohort in the Framingham study have been used to estimate the residual lifetime risk (ie, the lifetime cumulative incidence, unadjusted for other mortality causes) for developing hypertension (defined as blood pressure =140/90 mm Hg).26 Among those aged either 55 or 65 years, the lifetime residual risk for developing hypertension was 90%, as was the risk for developing stage 1 high blood pressure (defined as =140/90 mm Hg in spite of treatment).26 This risk was found to be 60% higher among men over the period studied (1976-1998) compared with an earlier period (1952-1975). This temporal trend may be in part related to a concomitant trend in obesity.26 These findings suggest a very high likelihood of hypertension comorbidity with BPH in men aged 65 years or older.