Prostate Cancer and Prostatic Diseases (2000) 3, 76±83 ß 2000 Macmillan Publishers Ltd All rights reserved 1365±7852/00 $15.00 www.nature.com/pcan a1-Adrenoceptor selectivity and the treatment of benign prostatic hyperplasia and lower urinary tract symptoms

R Kirby1*, KE Andersson2, H Lepor3 & WD Steers4 1Urology Department, St George's Hospital, London, UK; 2Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden; 3Department of Urology, New York University Medical Center, New York, NY, USA; and 4Department of Urology, University of Virginia School of Medicine, Charlottesville, VA, USA

The storage (irritative) and voiding (obstructive) symptoms associated with benign prostatic hyperplasia are generally attributed to prostate enlargement and increased prostatic smooth muscle tone mediated by the prevailing a1-adreno- ceptors in the bladder neck and prostate. This results in obstruction and subsequent secondary changes to the bladder. However, there is growing evidence that many of these symptoms may be due to changes in extraprostatic a1-adrenoceptors, possibly a1D-adrenoceptors. Findings from the VA cooperative trial challenge the current theory that the common side effects associated with these agents are due to vascular action of a1-adrenoceptor blockers. Prostate Cancer and Prostatic Diseases (2000) 3, 76±83.

Keywords: benign prostatic hyperplasia; a, adrenoceptor blocker; a1-adrenoceptor subtype selectivity

Introduction evidence that suggests that these effects might be mediated, at least in part, via an effect on the central Benign prostatic hyperplasia (BPH) is usually a slowly nervous system. progressive condition, which is associated with bother- some storage (irritative) and voiding (obstructive) symp- toms. The voiding symptoms have traditionally been considered to be due to an enlarged prostate impinging Relationships between lower urinary on the urethra (the static component) and contraction of prostatic smooth muscle within the stroma (the dynamic tract symptoms, prostate enlargement, component).1 Storage symptoms may also be related and obstruction to bladder dysfunction secondary to increased out¯ow resistance. Connections between lower urinary tract symptoms, For years, the accepted consensus suggested that the prostate enlargement and bladder outlet obstruction are unclear.2 The severity of lower urinary tract symptoms ef®cacy of a1-adrenoceptor blockers in BPH is mediated (LUTS) does not correlate with prostate size or obstruc- through the a1-adrenoceptors in the prostate smooth muscle and bladder neck, while their side effects, such tion.3,4 Furthermore, many patients continue to experi- ence storage symptoms despite relief of obstruction via as asthenia and dizziness, are mediated via a1-adreno- ceptors within the vasculature. This article describes prostatectomy.5 Conversely, Schapiro et al found that a sub-group of men undergoing transurethral resection of the prostate (TURP) had no evidence of obstruction but *Correspondence: RS Kirby, Department of Urology, St George's experienced similar improvements in voiding symptoms Healthcare, St George's Hospital, Blackshaw Road, London SW17 0QT, UK. as those patients with obstruction who also underwent Received 15 March 2000; revised 18 May 2000; accepted 24 May 2000 TURP.2 a1-Adrenoceptor selectivity in BPH treatment R Kirby et al

Various studies also demonstrate that symptom relief clear whether this subtype differs structurally from the 77 provided by a1-adrenoceptor blockers does not correlate a1A-adrenoceptor or represents a distinct pharmacological 25,26 with severity of symptoms, prostate size or the presence site on the a1A-adrenoceptor. or absence of obstruction.6±8 In the VA cooperative trial, All three high-af®nity receptors are present in the 27,28 patients strati®ed by baseline peak ¯ow rate (quartiles: prostate. Quanti®cation of a1-adrenoceptor mRNA < 8.65, 8.65 ± 10.75, 10.75 ± 12.45, > 12.45 ml/s) responded expression within human prostatic tissue suggests that equally well to an a1-adrenoceptor blocker, and there was the distribution of subtypes might differ between normal no relationship between changes in symptom score and and hyperplastic prostates. Within normal prostates, the 7 ¯ow rate. Thus, patients with LUTS may or may not a1A-adrenoceptor predominates (63%), followed by have obstruction. a1D-adrenoceptor (31%), and a1B-adrenoceptor (6%). This BPH is an imprecise term that does not help predict predominance of the a1A-adrenoceptor is more marked in 29 which patients will respond to treatment. More precise the hyperplasic prostates (a1A:a1B:a1D, 85:1:14). The a1A- terms include benign prostate enlargement (BPE), bladder adrenoceptor is preferentially distributed to the stroma, outlet obstruction (BOO), and LUTS. As our under- a1B-adrenoceptor to the epithelium, and a1D-adrenoceptor standing of the pathophysiology of BPH improves, it to the stroma and blood vessels.30 should be possible to develop more precise and clinically Both a1A-adrenoceptor and a1L-adrenoceptor subtypes meaningful de®nitions of BPH. can be demonstrated as pharmacological entities in the human prostatic urethra.31 ± 33 The number of a1-adrenoceptors within the bladder is low, although some investigators have suggested that these receptors are up-regulated in hyperactive detrusor Pathophysiology of BPH muscle.34,35 These data are inconclusive, however, due to technical dif®culties in measuring the extremely low The causes of prostate growth with advancing age have number of receptors. yet to be con®rmed. The male hormone, testosterone, and its more active metabolite dihydrotestosterone (DHT) control the growth and development of the prostate. DHT stimulation of androgen receptors results in the transcription and translation of growth factors, which a1-Adrenoceptors in central and have yet to be identi®ed.9±11 There is also some evidence peripheral nervous structures that sympathetic overactivity may have a smooth muscle hypertrophic effect, although these data are controversial. Noradrenaline-containing neurones supply the sympa- On the other hand, physically active men have a low thetic, parasympathetic and somatic nuclei in the lumbo- 12 36 frequency of LUTS. sacral spinal cord. Excitatory a1-adrenoceptors may be Structural changes to the bladder, such as smooth involved in bladder activation via the bulbospinal path- muscle hypertrophy and connective tissue in®ltration, ways. Central, facilitatory a1-adrenoceptors appear to be result in detrusor instability in about half to two-thirds involved in the sympathetic and somatic neural control of of patients with BPH.13 However, it is unclear whether the cat lower urinary tract.37,38 Animal studies have also these changes are due to bladder outlet obstruction. In demonstrated facilitatory a1-adrenoceptors on cholinergic animal models, eg rats and guinea pigs, urethral obstruc- neurones in vesical ganglia of the cat39 and on cholinergic tion results in secondary changes to the detrusor terminals in the rat bladder.40 14,15 muscle. However, when the urethral obstruction is Although a2-adrenoceptors are the predominant recep- reversed in rats, there is a subset (20%) that continues to tor in the spinal cord, a1a-adrenoceptor, a1b-adrenoceptor have hyperactive voiding despite a reversal of the bladder and a1d-adrenoceptor mRNA are found in the para- hypertrophy.16 Findings from a study of human autopsies sympathetic nucleus in the human lumbosacral spinal also suggest that these changes are unrelated to obstruc- cord. The a1d-adrenoceptor subtype predominates over tion, since there is an increase in connective tissue relative the other a1-adrenoceptor subtypes in the sensory and to smooth muscle with age in both men and women.17 autonomic regions of the spinal cord.41

Adrenergic innervation of lower urinary a1-Adrenoceptors in the cardiovascular tract system

There is dense adrenergic innervation of the trigonal a1-Adrenoceptors regulate blood pressure, regional vas- region, the proximal urethra and the prostate.18 Although cular resistance and venous capacitance. However, the both a1-adrenoceptors and a2-adrenoceptors are found exact subtype mediating these effects is unknown. in the prostate,19,20 prostatic smooth muscle tone is Although distribution appears to be species and vessel- 19,21,22 mediated primarily by a1-adrenoceptors. dependent, a1A-adrenoceptor, a1B-adrenoceptor, a1D-adre- Three high-af®nity a1-adrenoceptor subtypes: a1A, a1B, noceptor, and a1L-adrenoceptor subtypes all appear to 23 42 ± 44 and a1D have been cloned and characterized. A fourth mediate the contractile response of vascular tissue. receptor subtype, the a1L-adrenoceptor with low af®nity The human a1A-adrenoceptor seems to be the predomi- 45 for prazosin, has also been pharmacologically de®ned but nant a1-adrenoceptor subtype in arterial smooth muscle, not fully characterized or cloned.24 However, it is not but this does not necessarily mean that this subtype

Prostate Cancer and Prostatic Diseases a1-Adrenoceptor selectivity in BPH treatment R Kirby et al

78 controls systemic blood pressure and orthostasis. One these agents are generally well tolerated,57 ± 67 larger could assume cardiovascular homeostasis depends on sample sizes are required to distinguish differences in all of the multiple subtypes, albeit to varying extents.45 ± 47 their side-effect pro®les. The comparative trial of alfuzo- sin vs tamsulosin was also underpowered to demonstrate any differences in the side-effect pro®les of the two agents.68 The incidences of adverse events must be inter- Uroselectivity preted relative to their effectiveness, since the ef®cacy and a -Adrenoceptor blockers were previously thought to tolerability of a1-adrenoceptor blockers are both dose 1 dependent. relieve symptoms in BPH by inhibiting a1A-adrenoceptors in the prostatic smooth muscle, while their vascular side- In individual placebo-controlled trials, between 4 and effects, such as hypotension, were attributed to their 16% of men discontinue a1-adrenoceptor blockers as inhibition of a -adrenoceptor within the vasculature. result of adverse events. Treatment-related incidences of 1B adverse events associated with terazosin and doxazosin However, although there is a correlation between a1A- adrenoceptor activity and prostatic contraction,48,49 the appear to be similar. The available data suggest that retrograde ejaculation and rhinitis are more common involvement of other prostatic a1-adrenoceptors cannot be excluded.25,26 Also, since all four subtypes appear to with tamsulosin than with terazosin and doxazosin, mediate contraction of vascular tissue, cardiovascular while dizziness and asthenia are more common with homeostasis may depend on multiple subtypes. terazosin and doxazosin. However, overall there are no clinically signi®cant differences in their side-effect There is some in vitro evidence that tamsulosin exhibits 57 ± 67 a 12-fold higher af®nity for a-adrenoceptors in the pros- pro®les. tate than in the aorta,50 and animal models of urethral and vascular hypertonia suggest that alfuzosin has a higher af®nity for the genitourinary than for the vascular 51 Evidence for a central effect of adverse a1-adrenoceptors. However, in a direct in vitro compara- tive study the current a -adrenoceptor blockers (prazosin, 1 events associated with a1-adrenoceptor doxazosin, terazosin, alfuzosin, and tamsulosin) exhibited little or no selectivity for any of three cloned subtypes.52 blockers Furthermore, selective a -adrenoceptor antagonists 1A Clinical consensus assumes that the common adverse can only be uroselective if the a -adrenoceptor subtype 1A events associated with a -adrenoceptor blockers (eg diz- is predominant in the prostate, bladder neck, and urethra, 1 ziness and asthenia) are due to vascular events. However, but not in other parts of the body. Since the a -adreno- 1A there is compelling evidence from the VA cooperative ceptor is ubiquitous, drugs selective for this subtype study that asthenia and dizziness are not due to vascular would not be expected to be uroselective. effects.69 Uroselectivity can also be de®ned from a functional or In the VA cooperative trial, dizziness, asthenia and physiological perspective ie agents that increase urinary postural hypotension were signi®cantly more common in ¯ow but do not have an effect on blood pressure could be the terazosin group than in the placebo group (Table 1). considered to be uroselective. Several animal models, Orthostatic changes, de®ned as a decrease in systolic including the spontaneously hypertensive rat (SHR), blood pressure of more than 20 mmHg between lying have been used to investigate the relationship between and standing, and postural symptoms, de®ned as light- changes in urethral pressure and blood pressure follow- headedness on standing, were also more common in the ing the administration of a -adrenoceptor blockers.51 ± 54 1 terazosin group (P < 0.001). When the incidence of Rec 15/2739 (SB 216469; a selective a -adrenoceptor 1A adverse events within the terazosin group was analysed antagonist) was found to be uroselective while prazosin, terazosin and doxazosin were not. Tamsulosin and alfu- zosin exhibited modest or no uroselectivity, depending on the models used. Therefore, these models are not predic- Table 1 Incidence of selected adverse events in men with benign tive of uroselectivity in humans, since the apparent uro- prostatic hyperplasia, according to treatment group selectivity tends to be species and assay dependent.55,56 Number of men (%) Also, these models do not include non-cardiovascular Treatment groups side effects, such as drowsiness and dizziness that may be dose-limiting clinically. Uroselectivity might also be Placebo Terazosin Adverse event (n ˆ 305) (n ˆ 305) P-value* related to the distribution of the a1-adrenoceptor blocker at the target sites relative to its distribution at the sites of Dizziness 22 (7) 79 (26) < 0.001 toxicity. Asthenia 21 (7) 41 (13) 0.010 Headache 10 (3) 18 (6) 0.175 Syncope 0 3 (1) 0.249 Sinusitis 8 (3) 11 (4) 0.642 Side effect pro®les of current Postural hypotension 2 (1) 20 (7) < 0.001 Orthostatic change 92 (15) 136 (23) 0.001 Postural symptoms 23 (4) 86 (4) < 0.001 a1-adrenoceptor blockers Orthostatic change and 15 (3) 54 (9) < 0.001 The multicentred, randomized, double-blind placebo- postural symptoms controlled trials of a1-adrenoceptor blockers are powered *P-values were calculated by Fisher's exact test (two-tail) for the difference to show differences in ef®cacy but not in safety. Since between placebo and terazosin.

Prostate Cancer and Prostatic Diseases a1-Adrenoceptor selectivity in BPH treatment R Kirby et al 79 by the presence or absence of orthostatic changes, as Evidence that ef®cacy of a -adrenoceptor could be expected, postural symptoms were more 1 common in patients with orthostatic changes than in blockers in BPH has a centrally those without orthostatic changes. However, there was mediated component no signi®cant difference between the incidences of dizzi- ness and asthenia in patients with or without orthostatic Clinical data suggest that the LUTS observed in patients changes (Table 2). with BOO may be due to neurogenic changes. Prostatic Patients were also strati®ed according to whether they urethral anaesthesia with lidocaine and benoxinate had a  5 mmHg decrease or < 5 mmHg decrease in relieves BOO symptoms in patients with BPH.70 Also, sitting systolic blood pressure from baseline. Although therapies that do not relieve obstruction yet affect visceral not statistically signi®cant, dizziness was more common afferent nerves can be as effective for LUTS and abolish- in those patients with < 5 mmHg decrease in blood ing unstable bladder contractions as those which relieve pressure than in those with  5 mmHg decrease. Asthenia obstruction.71 was signi®cantly more common in patients with Evidence of neurogenic changes following BOO have < 5 mmHg decrease in systolic blood pressure. There also been observed in animal studies. In a study involving was no signi®cant difference in the incidence of postural rats with urethral ligation, 20% of animals continued to hypotension. These ®ndings suggest that orthostatic have persistent hyperactive voiding after urethral deliga- hypotension in men exposed to a1-adrenoceptor blockers tion, even though their bladder weights had normal- is the only adverse event mediated by vascular effects. ized.16 Increased levels of nerve growth factor (NGF) Dizziness and asthenia are potentially centrally mediated were also found in bladders and pelvic ganglia from effects. these animals, compared with those from animals who improved after deligation (Steers and Chai, personal communication). This suggests that there are changes in the sensory limb of the micturition re¯ex pathway follow- ing obstruction and that in some animals this neuroplas- ticity persists. NGF levels are also increased in human Comparative ef®cacy of the current obstructed bladders.72 agents Another study found that prazosin reduces urinary frequency in ligated animals, even though these animals Although there are limited long-term data, comparison of still had hypertrophic bladders.73 Since this effect cannot placebo-controlled trials suggests that the current agents be attributed to a relaxation of the urethral ligature in provide similar ef®cacy in terms of symptom relief. Data these animals, it could be potentially due to a central from these trials suggest that the current a1-adrenoceptor effect. Terazosin also reduces detrusor sphincter dyssy- blockers improve ¯ow rates by 10 ± 30%, and improve nergia in patients with bladder neck contracture, possibly symptoms by 20 ± 40% (Table 3). via a central effect.74

Table 2 Relationship between changes in orthostatic blood pressure or systolic blood pressure and adverse events in terazosin group

Number of men (%) Orthostatic changes Number of men (%) Systolic blood pressure change

Adverse event Yes (n ˆ 16) No (n ˆ 277) P-value*  5 mmHg decrease < 5 mmHg decrease P-value*

Dizziness 6 (38) 68 (25) 0.25 27 (21) 46 (28) 0.18 Asthenia 4 (25) 32 (12) 0.1 9 (7) 27 (17) 0.02 Postural symptoms 4 (25) 15 (5) 0.01 6 (5) 13 (8) 0.34

*Fisher's exact test (two-tail).

Table 3 Effects of a1-adrenoceptor blockers on total symptom scores Alfuzosin Terazosin Doxazosin Tamsulosin

Dose (mg/kg) 7.5 ± 10 10 5 ± 10 1 ± 10 2 ± 10 2 ± 8 4 0.4 0.4 0.4 n 518 390 610 147 2084 100 87 296 564 501 Percentage change in symptom score Drug 42 32 38 42 38 39 17 36 35 42 Placebo 32 16 11 18 17 1 24 26 28 Percentage change in maximum ¯ow rate Drug 12 29 26 30 23 30 13 16 18 Placebo 11 14 13 14 8 7 4 6 5 Reference Jardin Buzelin Lepor Brawer Roehrborn Fawzy Gillenwater Abrams Chapple Lepor et al et al et al et al (1996)65 et al et al et al et al et al (1991)63 (1997)64 (1996)67 (1993)66 (1995)59 (1995))107 (1995)61 (1996)108 (1998)109

Prostate Cancer and Prostatic Diseases a1-Adrenoceptor selectivity in BPH treatment R Kirby et al 80 Enhanced spinal re¯exes are also present in patients Thus, although a1-adrenoceptors are not as common in with obstruction and storage symptoms, as demonstrated the CNS as a2-adrenoceptors, they may be involved in the by the ice-water test that triggers a C ®bre, capsaicin- mode of action of a1-adrenoceptor blockers in the treat- sensitive spinal micturition re¯ex. This re¯ex, which is ment of BPH. Although the mode of action of a1-adreno- normally present only in the ®rst few months of life, ceptor blockers in the treatment of BPH cannot be inferred reoccurs in patients with suprasacral spinal injuries or from animal data, these data do raise questions concern- upper motor neurone disease.75, ± 78 Chai et al 79 found that ing their mode of action. Although voiding symptoms of the incidence of a positive ice water test was signi®cantly BPH are probably due to a peripheral effect, the storage higher among patients with obstruction (12 of 17; 71%) symptoms may be due to changes in the afferent neurones than in those without obstruction (3 of 44; 7%), when within the CNS, following bladder obstruction or in¯am- patients with neurological disease were excluded from mation. Spinal cord injuries have been shown to result in the analysis. In general, a positive ice water test was only changes within the sacral spinal cord,93 while in¯amma- observed in patients with LUTS if they also had BOO. The tory changes can change proto-oncogenes and receptor incidence of positive detrusor stability, however, was not regulation for transmitters such as glutamate.94 statistically different between patients with or without Of the currently available a1-adrenoceptor blockers, BOO. These ®ndings suggest that a positive ice water test doxazosin, terazosin, prazosin and tamsulosin appear to is associated with BOO and not LUTS.79 penetrate into the CNS. However, alfuzosin is thought If obstruction results in neurogenic changes, is the to not enter the CNS and yet is effective in BPH.95 A hyperactivity associated with LUTS and/or prostate comparison of ef®cacy for relief of storage symptoms growth related to sympathetic overactivity? Hypertension (irritative, LUTS) based on CNS penetration would be is an independent risk factor for LUTS, and increased of interest in this regard. Ef®cacy has usually been sympathetic activity can lead to hypertension, although determined from a composite scoring of symptom relief. most cases of essential hypertension are not related to Thus, if ¯ow rates and voiding symptoms comprise a sympathetic overactivity per se.80,81 major portion of the outcome analysis, subtle differences The SHR is a genetic model for hypertension.82 Sym- between agents could be missed. pathetic overactivity in the SHR has been suggested on the basis of behavioural overactivity,83 increased rates of sympathetic discharge in post-ganglionic nerves,84 and increased noradrenaline (norepinephrine) content of Future directions vascular and other tissues.85 Increased NGF levels are also observed in the spleen, aa1-adrenoceptor selectivity the sciatic nerve, and the mesenteric artery from young SHRs.86 Interestingly, prostates from SHRs demonstrate It is dif®cult to predict whether subtype selective a1- prostatic hyperplasia,87 and SHRs exhibit urinary fre- adrenoceptor blockers can provide improved ef®cacy quency and unstable bladder contractions.88 In second- and tolerability without fully elucidating the pathophy- generation (F1) rats resulting from cross-breeding siology of BPH and identifying which a1-adrenoceptor between SHR and their genetic counterparts Wistar ± subtypes are involved. As ef®cacy and tolerability of Kyoto (WKY), blood pressure was found to correlate a1-adrenoceptor blockers appear to have a centrally with urinary frequency.89 mediated component, an a1-adrenoceptor subtype prob- SHRs exhibit increased urinary frequency compared ably cannot be preferentially targeted as treatment for with control rats, independent of age and bladder size,90 BPH. Relief of storage symptoms appears to be mediated together with non-micturition contractions and reduced via a central action, and thus an a1A-adrenoceptor selec- sensory volume/pressure thresholds.91 Catecholamine tive agent would not be expected to provide improved ¯uorescent staining of bladders from SHRs demonstrates symptom relief since the a1D-adrenoceptor subtype is that they have increased noradrenergic innervation com- predominant in structures in the CNS involved with pared with their genetic controls (WKY).88 This is sup- micturition. In addition, asthenia and dizziness may be ported by the increased noradrenaline tissue content due to a central rather than vascular effect. Since the same observed in bladders and prostates from SHRs compared receptor subtype within the CNS may mediate these side with WKY controls.92 Elevated levels of NGF are also effects and the relief of storage symptoms, subtype selec- found in bladders of SHRs.90 Elevated NGF during tive agents may not provide improved tolerability. development would be expected to lead to increased Randomized double-blind placebo controlled trials adrenergic and sensory innervation. with antagonists that are selective for each of the three Intrathecal doxazosin reduces detrusor hyperactivity in a1-adrenoceptor subtypes would be required to determine SHRs, while peripherally administered doxazosin has no which subtypes are involved in relieving the symptoms of effect.91 Both doxazosin and the adrenergic neurone BPH and in mediating the side effects of the a1-adreno- blocker guanethidine increased the threshold volume in ceptor blockers. To date, there is no subtype-selective SHRs compared with WKY controls, and thus increased drug that has been shown in clinical studies to be superior the sensory threshold for the micturition re¯ex in these to the non-subtype-selective antagonists. animals. Centrally administered doxazosin was still effec- tive after the sympathetic innervation had been destroyed Alternative strategies with 6-hydroxydopamine, suggesting that efferent adre- nergic nerves are not mediating this effect. Thus by Combining the current a1-adrenoceptor blockers with default, visceral afferents may be involved in this over- other agents might also provide improved symptom activity (unpublished data). relief. Traditionally muscarinic receptor antagonists have

Prostate Cancer and Prostatic Diseases a1-Adrenoceptor selectivity in BPH treatment R Kirby et al been contraindicted in patients with BPH due to fears of 4 Sciarra A et al. Relationship among symptom score, prostate 81 urinary retention. However, this dogma has been ques- volume, and urinary ¯ow rates in 543 patients with and without tioned recently and there are now ongoing studies in benign prostatic hyperplasia. Prostate 1998; 34: 121 ± 128. 5 Andersson KE. The concept of uroselectivity. Eur Urol 1998; which a1-adrenoceptor blockers are being combined with 33(Suppl 2): 7 ± 11. muscarinic receptor antagonists. Since patients with BPH 6 Mobley DF, Dias N, Levenstein M. Effects of doxazosin in have detrusor instability, this combination might be patients with mild, intermediate, and severe benign prostatic bene®cial. hyperplasia. Clin Ther 1998; 20: 101 ± 109. 7 Lepor H et al. 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