European Urology

50th Volume Editorials

It is a great honour and a pleasure for me to participate in this celebration of the 50th volume of European Urology by commenting on this landmark review paper by Marco Caine, who was the pioneer of pharmacotherapy for lower urinary tract symptoms (LUTS) suggestive of benign prostatic outlet obstruction (BOO; previously referred to as symptomatic benign prostatic hyperplasia [BPH]), which are so common in ageing men. This paper contains a number of comments that remain equally correct 29 yr later in 2006!. “At the present stage our understanding of this field is relatively simplistic and does not take into account the close interdependence and integration that exists between the sympathetic and parasympathetic and perhaps also somatic nervous systems. There is steadily increasing evidence of both peripheral and central interactions between these systems” [1].

When Professor Caine wrote this review paper, the emphasis was on voiding dysfunction, as shown by the title “disorders of micturition” and, indeed, still has been until recently. We now realise that the most bothersome symptoms are those affecting storage and the emphasis of treatment is shifting to encompass both storage and voiding symptoms [2].

At the time Professor Caine wrote this innovative paper and certainly until 15 yr ago, surgery and watchful waiting were the only widely accepted management options for BPH/LUTS and benign prostatic obstruction (BPO). There has been an enormous decline in the popularity of surgery and it is now clearly apparent that medication is the most frequently used treatment modality for BPH/LUTS. Arguably, this has therefore been the most major change in urologic clinical practice in the last decade. Operative intervention is increasingly considered rather radical from the patient's perspective and not surprisingly many patients feel reluctant to undergo surgery and prefer a less invasive intervention such as medical therapy, before contemplating surgery. Although absolute indications for surgery still exist, in the last decade the number of patients undergoing operations for BPH has decreased by about 60% across Europe. This trend has been encouraged not only by increased patient awareness of the availability of effective contemporary pharmacotherapy, but has also been encouraged by an increased understanding of the complications of surgery, in particular that it can be associated with significant morbidity, such as irreversible incontinence and loss of sexual function with subsequent impairment of a patient's quality of life.

Professor Caine and his coworkers were the first to emphasise the importance of the α-adrenergic innervation of the bladder outflow tract and to carry out initial characterisation of these in man. The success of this work is evident if one considers that it is standard knowledge in urology that prostatic smooth muscle tone is dependent on the release of noradrenaline (NA) from adrenergic nerves, thereby stimulating α₁-adrenoceptors (ARs) on smooth muscle of the prostatic stroma, bladder neck, and urethra.

Although storage symptoms are clearly associated with bladder dysfunction, often assumed to be secondary to outflow obstruction, there is no convincing evidence for a direct correlation between the size of the prostate, BOO, and LUTS [2]. Prostatic and urethral α-ARs are considered to mediate the dynamic component of obstruction and α₁-AR antagonists improve both LUTS and flow rate in patients with BPH [3]. Conversely, a direct relationship between the amount of prostatic smooth muscle and dynamic obstruction (as assessed by the response to α₁-AR blockade) has been demonstrated [4]; therefore, it is logical to assume that these receptors mediate some of the symptoms. On the other hand, many patients who have undergone prostatectomy, which should relieve obstruction, still experience persistent storage symptoms [5]; clearly, mechanisms outside the prostate involving α₁-ARs may be involved in the pathogenesis of storage symptoms. LUTS can be caused by a number of factors and along with the prostate, there are several possible sites of action of α-AR antagonists:

• •Prostatic stroma-smooth musculature

• •Detrusor, trigone, urethral smooth muscle

• •Detrusor, trigone, urethral urothelium

• •Ganglia

• •Spinal or supraspinal structures within the central nervous system

It has become clear that the effects of α-blockers on relieving BOO are moderate at best [6], and this effect alone is insufficient to explain the improvement seen in storage symptoms. Therefore, newer concepts have been advanced, with the suggestion that α₁-adrenoceptors in the bladder or spinal cord are possible mediators of α-blocker-induced symptom relief [7], and [8]. Clearly this remains hypothetical and the specific mechanisms by which such effects could occur need to be defined. Although it is now clear that α-AR antagonist effects on BOO are mediated predominantly if not exclusively by α_1A-ARs in the bladder neck and prostate, it remains speculative that clinical effects on the bladder and spinal cord, if they occur, are via an action on α_1D-ARs. This needs to be verified by future research.

Despite the observations noted above, it must be concluded that just as suggested by Caine 29 yr ago, the principal motor control of the prostate is still, in 2006, considered to be via an action on α₁-ARs localised predominantly within the stromal compartment of the prostate. Although Caine introduced the nonselective α_1/2-antagonist phenoxybenzamine, its use was discontinued because of toxicity and side-effect issues; nevertheless, he was involved in the initial work using the first α₁-antagonist prazosin. The legacy of Caine's work is that α₁-AR antagonists are now well established as the most common treatment for BPH/LUTS. Indeed, systematic analysis of placebo-controlled studies shows that commonly used α₁-AR antagonists (doxazosin, terazosin, alfuzosin, tamsulosin) are similarly effective and statistically significantly superior to placebo in improving urinary flow and reducing symptoms [3].