The Aging Bladder

BLADDER DYSFUNCTION The Aging Bladder M. B. Siroky, MD Department of Urology, Boston University School of Medicine, Boston, MA Although it is well established that lower urinary tract symptoms increase in frequency with aging, there are few studies of the mechanisms that underlie bladder dysfunction. Age-related reduction in bladder capacity, uninhibited contractions, decreased urinary flow rate, diminished urethral pressure profile, and increased postvoid residual volume warrant investigation and require differentiation between symptoms associated with aging and those related to comorbid conditions. Here, the current data are reviewed, including those from muscle bath investigations of bladder tissue contractility, in vivo studies using animal models, and clinical studies in the aging population. [Rev Urol. 2004;6(suppl 1):S3-S7] © 2004 MedReviews, LLC Key words: Aging • Bladder dysfunction • Detrusor instability • Urodynamics he normal functions of the urinary bladder are urine storage and expulsion of urine at an appropriate time. The sympathetic nervous system exerts a tonic inhibitory influence on the bladder and a stimulatory influence on the urethra to facilitate urine storage. This influence acts primarily by stimulating -adrenergic receptors in the bladder base and urethra and ß-adrenergic receptors in the bladder body. Micturition reflex is prompted primarily through activation of a cholinergic (muscarinic) pathway to the detrusor, although a purinergic system has also been described.1,2 T VOL. 6 SUPPL. 1 2004 REVIEWS IN UROLOGY S3 The Aging Bladder continued Aging is associated with declining function in nearly every physiologic system.3-5 Symptoms in the lower urinary tract are more prevalent among the elderly,6,7 and clinical urodynamic studies have demonstrated advancing age to be associated with a reduced bladder capacity, an increase both old and young rats.14 In the bladder body, a larger contraction,14 a lessened contraction,15 and a similar contraction17,18 have all been observed in response to muscarinic stimulation in old versus young rats. Norepinephrine-induced contractile response was greater in the bladder body of old rats but about the same in the bladder base of old and young rats.19 In addition, the relaxant effects of the ß-adrenergic agent isoproterenol on precontracted rat bladder dome strips decreased with increasing age.20 Adenosine triphosphate–induced contractile response was similar to that seen with norepinephrine.14,21 All of these changes would tend to reduce bladder compliance and increase the risk of detrusor instability (Table 1). Because almost all in vitro studies of bladder function have examined the response of longitudinal detrusor fibers, there is little information on the response of circular smooth muscles in the bladder. Data from a recently published study show that aging has differing effects on the contractile responses of various regions of the rat bladder.20 In young circular detru- same response in the bladder base of old and young rats.14 Another study demonstrated no difference in electrically evoked isometric contractions but reduced shortening velocity in longitudinal detrusor fibers of the bladder body from old rats compared with those from young rats.15 In Some investigators have reported larger contractions in the bladder base of old versus young rats in response to acetylcholine. in uninhibited contractions, decreased urinary flow rate, diminished urethral pressure profile (particularly in women), and increased postvoid residual urine volume.8-11 The aging bladder specifically may be described as manifesting detrusor overactivity, impaired contractility, or a combination of both.12,13 Few studies have focused on understanding the pathophysiologic mechanisms underlying symptoms in the aging bladder. This may be because of the need for invasive procedures, such as catheterization, for urodynamic studies. Even when studies are conducted, it is often difficult to differentiate between dysfunction due to disease (such as prostatic enlargement) and changes that are purely age-related. In addition, medications taken by many older patients may further confuse the interpretation of clinical studies in this field. Here, the evidence available regarding the mechanisms that underlie geriatric bladder dysfunction is reviewed. Muscle bath studies of isolated detrusor strips from the body and base of bladders of young and old animals have provided inconsistent results. In one study, electrical field stimulation produced a greater contractile response in the bladder body of old rats but approximately the VOL. 6 SUPPL. 1 2004 Table 1 Summary of Selected Literature on Detrusor Response to Various Stimuli Stimuli Study K+ NE ATP 5-HT Saito et al16 0 + + + Saito et al 0 Ordway et al 21 Yu et al28 Pagala et al Longitudinal Circular Trigone ACh EFS 0 body/+ base 17 Lieu et al18 Muscle Bath Studies S4 the bladder body, potassium chloride (KCl)-induced depolarization has been reported to be similar16 or greater14 in old rats compared with young rats. In contrast, calcium-induced depolarization produced lower tension in old rats.16 Results of studies in which muscarinic agents were used to induce contraction are particularly confusing. Some investigators have reported larger contractions in the bladder base of old versus young rats in response to acetylcholine.17 However, when carbachol was used, contraction in the bladder base was about the same in 0 + + + 0 + + + 0 – – – 0 0 + – – 0 – 0 + – 20 K+, potassium; NE, norepinephrine; ATP, adenosine triphosphate; 5-HT, serotonin; ACh, acetylcholine; EFS, electrical field stimulation; 0, no change; +, increased in older animals; –, increased in younger animals. REVIEWS IN UROLOGY The Aging Bladder responsiveness to prostaglandin F2 alpha in the aging rat bladder. Aging rats tend to have an increased bladder volume and a reduced response to direct pelvic nerve stimulation.24 This contrasts with findings of a study of conscious female rats that demonstrated higher spontaneous voiding pressure in aged rats. Bladder instability was seen in 60% of aged female rats but only 25% of younger rats.25 Bladder Compliance (mL/cm H2O) 100 75 50 25 0 30 40 50 60 70 80 90 100 Clinical Studies Age (y) Figure 1. Bladder compliance over time. Adapted from Ameda K et al. J Urol. 1999;162:142-146.30 sor fibers, the contractile responses evoked by electrical stimulation, KCl, or bethanechol were significantly less than the responses of young longitudinal detrusor.20 In old circular detrusor fibers, contractile responses evoked by electrical stimulation were significantly larger, contractions evoked by KCl were slightly larger, and contractions evoked by bethanechol were similar compared with those of young circular detrusor. The lack of a significant difference in the contractile response to bethanechol indicates that increased responses to electrical stimulation and KCl may be caused by diminished compliance in old versus young circular detrusor. fibrosis in the aging human bladder,27 no significant collagenosis has been described in the aging rat bladder.25 Contractility of the detrusor muscle is generally preserved in aging animals.28 In particular, the response to depolarizing agents, such as KCl and purinergic agonists, was found to be normal in senescent female rats.25 As mentioned above, the response to muscarinic stimulation has been reported by some investigators to be unchanged in the aged detrusor.17,25 In Vivo Studies Chun and colleagues22 demonstrated an increased frequency of micturition and much higher voiding pressure in aging male rats compared with young rats. Because there was no difference in mean volume voided, the increased frequency can be mostly attributed to polyuria in the aging rat. In the isolated whole-bladder model, contractile response to bethanechol, phenylephrine, and isoproterenol did not change with aging.23 The same investigators demonstrated some increased Studies of bladder function in the intact aging animal are scarce. Most studies have been performed in anesthetized rats,22-24 whereas other investigations have employed conscious animals.25,26 Most investigators have found increased bladder weight in the aging rat.14,22,23,25 The aging rat bladder seems to have a thickened muscularis layer similar to that seen after obstruction.25 However, in contrast to the finding of Age-related changes in the lower urinary tract include decreased bladder capacity, loss of compliance (Figure 1), and increased detrusor instability.29,30 Ameda and colleagues29 showed that men requiring prostatectomy have increasing evidence of detrusor denervation with aging. Another study by Ameda and colleagues30 showed that bladder contractility did not necessarily deteriorate as men aged but that instability became more common.30 A urodynamic study of 436 men and women showed that, in both sexes, postvoid residual volume increased and peak flow rate decreased with age.11 Bladder capacity also diminished with aging. However, max- In the isolated whole-bladder model, contractile response to bethanechol, phenylephrine, and isoproterenol did not change with aging. imum detrusor pressure and detrusor pressure at peak flow rate did not correlate with age. The fact that isometric pressure is maintained but flow is diminished, even in aging women, indicates that detrusor contraction velocity, rather than contraction strength, is diminished. This has been demonstrated in a study of 1715 patients that found failure of isotonic detrusor function in elderly women.13 It has been demonstrated that, as women age, flow rate, voided volume, VOL. 6 SUPPL. 1 2004 REVIEWS IN UROLOGY S5 The Aging Bladder continued and bladder capacity decrease and postvoid residual urine volume increases.11 In contrast, indices of bladder contractility, such as maximum isometric detrusor pressure and maximum pressure at peak flow, were preserved in aging women. Aging men demonstrated comparable changes, only somewhat exaggerated.11 These findings indicate that there is increasing fibrosis of the bladder wall with aging that results in loss of functional capacity. They also support deterioration of bladder contraction speed rather than contraction strength. Although female urethral pressure tends to diminish with aging, flow rate deteriorates significantly, indicating a fall in isotonic detrusor function. Many of the observed urodynamic changes ascribed to prostatism in the aging man may in fact result from deterioration of bladder function. Discussion and Summary Several mechanisms have been proposed to explain the voiding dysfunctions observed in the elderly, including detrusor fibrosis and impaired contractility,31 collagen deposition,32 and loss of acetylcholinesterase-positive nerve terminals.33 Deposition of collagen and fibrosis are recognized phe- Figure 2. Interrelationship between bladder blood flow, ischemia, and changes in detrusor function. LUTS, lower urinary tract symptoms. Vascular insufficiency Outlet obstruction ↑ Intravesical pressure ↓ Bladder blood flow Ischemia, hypoxia ∆ Function ∆ Structure (compliance, instability, contractility) (fibrosis) LUTS nomena in the aging bladders of both men and women. These phenomena explain to some extent the gradual loss of compliance and capacity noted with aging. With respect to loss of cholinergic innervation, there is some evidence of muscarinic denervation in the aging bladder29; however, the relevance of this finding to clinical dysfunction remains unclear. The evidence reviewed herein indi- cates that deterioration of detrusor muscle function (especially isotonic function), bladder wall fibrosis (in humans), and increased sensitivity to neurotransmitters (especially norepinephrine) are important underlying mechanisms in geriatric voiding dysfunction. The reason for neurotransmitter supersensitivity is unclear but may be related to an increased number of adrenoceptors in aging persons.25 Main Points • Lower urinary tract symptoms are more prevalent among the elderly, and clinical urodynamic studies have demonstrated advancing age to be associated with a reduced bladder capacity, an increase in uninhibited contractions, decreased urinary flow rate, diminished urethral pressure profile (particularly in women), and increased postvoid residual urine volume. • Muscle bath studies of detrusor strips from bladder body and bladder base have demonstrated inconsistent results. In the bladder body, potassium chloride–induced depolarization has been reported to be similar or greater in old versus young rats, whereas calciuminduced depolarization produced lower tension in old rats. • The aging rat bladder appears to have a thickened muscularis layer similar to that seen after obstruction. Aging male rats have been shown to have an increased frequency of micturition and much higher voiding pressure compared with young rats. • A urodynamic study in men and women demonstrated that, in both sexes, postvoid residual volume increased with age, whereas peak flow rate and bladder capacity decreased; there was no correlation between age and maximum detrusor pressure or detrusor pressure at peak flow rate. • The key underlying mechanisms of voiding dysfunction in the elderly appear to include deterioration of detrusor muscle function, bladder wall fibrosis, and increased sensitivity to neurotransmitters (especially norepinephrine). S6 VOL. 6 SUPPL. 1 2004 REVIEWS IN UROLOGY The Aging Bladder Norepinephrine supersensitivity is of particular importance because it explains the well-known phenomenon of increased detrusor instability in the elderly and offers a clear avenue for therapeutic intervention. The cause of fibrosis in the aging bladder is unknown. In an animal model, pelvic ischemia has been shown to induce marked bladder wall fibrosis and loss of compliance.34 Animals with pelvic ischemia had smooth muscle content of 37%, compared with 66% in normal animals.34 Similarly, pelvic ischemia has been shown to cause detrusor instability in the absence of outflow obstruction.35 The mechanism by which pelvic ischemia causes detrusor instability is unclear (Figure 2). One well-known cause of detrusor instability in the elderly is outflow obstruction. However, detrusor instability frequently occurs in men without obstruction, as well as in elderly women. A relative overproduction of prostanoids and leukotrienes has been demonstrated in ischemic bladder tissue.36,37 These compounds tend to cause detrusor contraction and may be related to the increased incidence of detrusor instability. Finally, pelvic ischemia has been shown to cause hypercontractility of prostatic smooth muscle due to supersensitivity to catecholamines.38 Whether a similar supersensitivity occurs in ischemic bladder is at present unknown. References 1. 2. 3. 4. Alm Pelmer M. Adrenergic and cholinergic innervation of the rat urinary bladder. Acta Physiol Scand. 1975;94:36-45. Burnstock G. The past, present and future of purine nucleotides as signalling molecules. Neuropharmacology. 1997;36:1127-1139. Rossi A, Ganassini A, Tantucci C, Grassi V. Aging and the respiratory system. Aging (Milano). 1996; 8:143-161. Geokas MC, Conteas CN, Majumdar AP. The 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. aging gastrointestinal tract, liver, and pancreas. Clin Geriatr Med. 1985;1:177-205. Egashira K, Inou T, Hirooka Y, et al. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation. 1993;88:77-81. 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