Ejaculatory dysfunction: why all α-blockers are not equal


M.G. Wyllie, Urodoc Ltd, Maryland, Ridgeway Road, Herne, Kent, CT6 7LN, UK.
e-mail: mike@urodoc.co.uk

It has been suggested recently that the sympathetic nervous system may provide the link between the LUTS and sexual dysfunction observed in patients with BPH [1]. This would appear to extend an earlier suggestion that aberrant sympathetic nervous system activity in patients with BPH was the underlying basis for both the LUTS and the hypertension found in up to a third of these patients [2]. Epidemiological studies certainly confirm the high degree of comorbid hypertension and erectile dysfunction (ED) in patients with BPH [3] and the close correlation between the severity of LUTS and ED [4]. On this basis the clinical profiles of the most widely used class of BPH therapy, α-blockers, at equivalent α-blocking doses, would be expected to be qualitatively similar for urodynamic and cardiovascular actions, and effects on sexuality in the population with BPH.

Indeed, the conclusions of the α-blocker committee at the 5th International Consultation on BPH were that for clinical uroselectivity any differences in general between α-adrenoceptor antagonists were restricted to pharmacokinetic ones [5]. At equivalent doses, the urodynamic and symptom score improvements, cardiovascular side-effects and relative haemodynamic effects on normotensive (unchanged) and hypertensive (lowered) blood pressure were considered to be similar; there were quantitative rather than qualitative differences. Any changes in erectile function were modest and, if anything, depending on circumstance, could be positive, i.e. beneficial in patients with baseline ED. Thus, the clinical profile would appear to be entirely consistent with the pharmacological actions of the individual drugs. Under most laboratory conditions there are no dramatic (i.e. > 10-fold) differences in selectivity for any one α1-adrenoceptor subtype for any marketed agent [6].

However, ED is only one aspect of male sexual dysfunction and the Multinational Survey of the Ageing Male showed that ejaculatory dysfunction is also highly prevalent in patients with BPH, and the degree of ‘bother’ is at least as troublesome as ED and is highly correlated with the severity of LUTS [4]. Based on knowledge of the autonomic control within the urogenital sinus, it would not be unreasonable to assume that the sympathetic system might also be involved and, on this basis, α-blockers would be predicted to have equivalent effects on ejaculatory function. Unfortunately, considerably less is known about the peripheral and central control of ejaculation and the pathophysiology of ejaculatory disorders [7] than is the case for the integrated control of erection and the deficits associated with ED [8].

In general it appears that, except for tamsulosin, α-blockers have relatively little propensity to produce abnormal ejaculatory function, i.e. there is a < 1% incidence across all clinical trials [5,9]. In contrast, tamsulosin appears to produce a dose-dependent incidence of ejaculatory dysfunction of 4–18% in clinical trials [9,10] and up to 30% in open-label extensions [11]. At the time of approval the medical examiner concluded that this was not a class effect [12]. It is not documented whether this represents anejaculation or retrograde ejaculation. Differences between tamsulosin and other α-blockers have also been reported in rodent models of ejaculatory function [13].

Originally it was felt likely that this difference from other α-blockers could reflect the relatively high affinity of tamsulosin for the α1A-adrenoceptor subtype, found at the bladder neck, seminal vesicles and/or vas deferens. However, the overall receptor-binding profile of tamsulosin across the adrenoceptor subtypes is similar to other α-blockers [6] that do not produce ejaculatory dysfunction to the same degree, so another explanation is possible. Intriguingly, tamsulosin has an affinity almost equivalent to its α1A affinity for dopamine (D3) and 5-HT1A receptors (KIs 0.14, 0.28 and 0.74 nmol/L, respectively) [14]. On this basis, at clinically effective doses of tamsulosin, there will be occupancy of not only α1A subtypes but also ≈α1D subtypes and these nonadrenergic sites [15]. The precise contribution of these nonadrenergic actions to the characteristic ejaculatory dysfunction-inducing actions of tamsulosin could potentially be determined in animal models [13].