In benign prostatic hyperplasia (BPH), bladder outlet obstruction is considered to be due to a mechanical component caused by an enlarged gland and due to a dynamic component caused by the tone of prostatic stromal smooth muscle. The therapeutic goal of BPH has been to perfectly control both the mechanical and dynamic components. Several treatment options have been available. The treatments include watchful waiting, pharmacological therapy with an α-adrenergic antagonist and 5α-reductase inhibitor, and surgical therapies including simple prostatectomy and transurethral resection of the prostate (TURP).

Surgery and the 5α-reductase inhibitor have played an important role in the treatment of the mechanical component of BPH. The dynamic component of BPH is mediated mainly via α-adrenoceptor stimulation and has been one of the primary targets for therapeutic interventions with α-adrenergic antagonists.1 However, these traditional methods mainly charge one side between the mechanical and dynamic components. The traditional methods also have some adverse consequences. Although TURP has been the less invasive gold standard of treatment against the mechanical component of BPH, the procedure has some limitations. Up to 25% of patients who undergo surgery do not have satisfactory long-term outcomes.2 TURP also has some troublesome surgical complications. For these reasons, the goal for patients with BPH is to avoid surgery whenever possible and to seek a cost-effective alternative with at an acceptable level of risk for treatment-associated complications. While pharmacological therapies with α-adrenergic antagonists and 5α-reductase inhibitors have gained widespread acceptance as safe and effective treatments for BPH,3,4 they have adverse effects such as dizziness, asthenia, postural hypotension in patients taking α-adrenergic antagonists, and decreased libido and impotence in patients taking 5α-reductase inhibitors. Medical withdrawal is attributed to these adverse effects. Therefore, a number of minimally invasive alternatives to existing traditional treatment options of BPH have been introduced. The alternatives were devised to achieve symptomatic improvement without the surgery-associated morbidity, side effects, or compliance issues associated with medicine.

There has been much interest in botulinum toxin type A (BTA) as a powerful, versatile tool because of its safety, effectiveness, specificity, and reversibility. Urological applications of BTA have been associated with cases of detrusor external sphincter dyssynergia, dysfunctional voiding, detrusor over-activity, and chronic pain syndrome due to chronic prostatitis. Recent studies have suggested that BTA is able to be used as an alternative treatment for BPH, and it is effective enough to control both mechanical and dynamic components of BPH.5,6 These suggestions are based on studies which concluded that chemical denervation using BTA causes subsequent atrophy of the gland,5 that cholinergic stimulation causes prostatic stromal smooth muscle contraction,7 and that BTA blocks acetylcholine release at the neuromuscular junctions and in autonomic neurons. We evaluated the effect of BTA in treating patients with symptomatic BPH and deduced a putative intraprostatic mechanism of BTA. The conclusions were drawn from the analysis of BPH symptoms and the evaluation of values taken before and after BTA injection into the prostate.

This study was approved by the institutional review board of our hospital and all patients provided informed consent.

Fifty-two outpatients were selected after confirmation of eligibility according to the inclusion criteria and were randomized. Among these patients, 10 were biopsy-proven benign conditions. A biopsy was performed if the serum PSA level was more than 4.0 ng/mL and/or a palpable nodule was present in the prostate. Twenty-six received only BT (BT group), and 26 received both BT and one month of an α-adrenergic antagonist (BTα group). A follow-up of 52 patients was done at one month and three months. At the six-month follow-up, 23 patients between the ages of 54 to 81 years stayed in the study and underwent the same evaluations as performed at baseline, except PSA. No complications during the procedure were observed in any patient. Urinary incontinence, urinary retention, and adverse events of BTA enough to stop the study were not reported during the follow-up period.

Neural activity has been thought to be involved in normal growth and functioning of the prostate.8 Dysregulation of this neuronal activity may alter the morphology and behavior of the prostate. These pathological events are caused by significant alteration of neurotransmitter/growth factor influence on the prostate and may result in BPH. Therefore, normalization or favorable correction of altered neural activity could significantly reverse pathological processes and improve stressful BPH related symptoms.

The prostate is a heterogeneous tissue composed of epithelial cells, smooth muscle cells, fibroblasts, and connective tissue element. Bartsch and colleagues, using quantitative morphometry, demonstrated that the ratio of stroma to epithelium in the normal prostate is two to one. Bartsch also demonstrated that benign prostatic hyperplasia is primarily a stromal process, as the ratio of stroma to epithelium is five to one.9 Fibromuscular stroma, especially smooth muscle element, which has the principal to cause and aggravate BPH symptoms, has been the primary target for BPH therapy. Human prostate contains α-1 adrenergic, cholinergic, and non-adrenergic non-cholinergic (NANC) neuroreceptors under the influence of various differentiated autonomous innervation. 10-12 It is widely believed that the prostatic epithelium receives a cholinergic innervation while the stroma receives a predominantly noradrenergic innervation. The fact has been known that nerve fibers innervating the smooth muscle may be both noradrenergic and cholinergic or separate. The fibers can cause an increase of smooth muscle tone.13 Nitric oxide (NO) plays an important role in relaxation of the prostate smooth muscle.14 Additionally, It has been suggested that cholinergic nerves in the prostatic stroma could suppress the release of noradrenaline from adrenergic terminals.15 The α-adrenergic innervation may be antagonized by NANC-induced relaxation mediated by NO.16,17 The adrenergic, cholinergic, and nitrinergic innervations and their interaction may be related with prostate smooth muscle tone. Thus, they may play an important role in the dynamic component of benign prostatic hyperplasia. The cholinergic and nitrinergic innervation are reduced in BPH as compared to that in normal prostate tissue. However, adrenergic activity is increased.16

Recent studies have suggested that BTA is able to be a prominent medical tool for BPH. BTA acts as a favorable controller of various neural activities that innervate the prostate. BTA has been known to reduce peripheral sensitization by inhibiting the release of acetylcholine at the presynaptic cholinergic junction. Though BTA exhibits prevalent cholinergic specificity in its action on nerve terminals, release of many neurotransmitters can be blocked when adequate concentrations of toxin are used.18

In our study, only subjective values like IPSS were improved. Objective values such as peak urinary flow rate and postvoid residual volume were not improved at the one-month follow-up. Most patients reported improvement of subjective values starting approximately one to three weeks, if improved. Improvement of objective values started after one month, reached a plateau within three months, and lasted for six months. IPSS 4, IPSS 6, and residual urine were more improved than other values. IPSS-SS improved more than IPSS-VS. On the contrary, the BT group patients complained of little effect of BTA on weak stream.

IPSS 5, PSA, peak urinary flow rate, and postvoid residual volume were not significantly different in the BT patients at one-month follow-up compared with baseline values. IPSS (except IPSS 5), quality of life, PSA, prostate volume, peak urinary flow rate, and postvoid residual volume urine were not significantly different between the BT and BTα groups at one-month follow-up. These facts mean that adrenergic nerve terminals were not affected by BTA. BTA has been suggested to be able to affect other neurotransmitters. If they were affected, peak urinary flow rate and postvoid residual volume should be improved in the BT patients. Additionally, the reinforcement of adrenergic activity may develop. These results could easily be deduced from the fact that little difference was found between the BT and BTα groups at the one-month follow-up. This means that the combined α-adrenergic antagonist in the BTα group did little work. Loss of acetylcholine-mediated suppression of adrenergic transmission from adrenergic terminals in the prostate may be one of the various putative BTA mechanisms to increase smooth muscle tone.

Prostate volume was reduced compared with baseline values at the one-month follow-up, but the change of prostate volume did not alter the PSA level to a lower level. Prostate volume was reduced only by 14.2% at the six-month follow-up. This is thought to result from the fact that BTA might induce atrophy and apoptosis of glandular epithelium. There was lesser effect on the stromal component of the transition zone, while the stromal component is dominant in BPH. However, pathological confirmation was not performed. It is easy to presume these findings from the fact that the rat prostate used in a recent study showed profound atrophy of the prostate gland which was mainly glandular.7 Also, BPH in human is primarily a stromal process as previously described.

Peak urinary flow rate was increased by 15.5% and 27.6% at the three and six-months follow-up, respectively. Residual urine was reduced by 34.3% and 45.3% at the three and six-months follow-up, respectively. This may result from the improvement of the mechanical component of BPH by glandular atrophy. It may also result from an improvement of the dynamic component by a disclosed effect of BTA related with the inhibition of acetylcholine release on the smooth muscle tone. The improvement of the dynamic component may be hidden at the one-month follow-up because of the transient contraction effect by stronger adrenergic activity. This may mask the relaxation effect of smooth muscle by inhibition of acetylcholine release by BTA. The good results in the parameters of the IPSS score and residual urine in patients at the six-months follow-up may be influenced by reduced objectives. Therefore, this study needs to be placebo-controlled in the future.

We found two interesting NO related events which were not expected in the study, and that it can induce an additional putative BTA mechanism. It has been reported that an NO donor, such as isosorbide dinitrate or glyceryl trinitrate medication, in ischemic heart disease patients improves micturition parameters in symptomatic BPH patients.19 Five patients who took oral isosorbide dinitrate for an ischemic heart disease and persisted stressful BPH symptoms received BTA injection. All patients showed no improvement of BPH related evaluation values during the follow-up period. Another unexpected effect was the improvement of erectile function. Nearly half of the improved patients (19/39; data not shown) at the three-month follow-up showed an improvement of erectile frequency [International Index of Erection Function (IIEF)]. This is likely caused by the diffusion of BTA to the adjacent nerve plexus outside the prostate. The prostate is surrounded by a dense nerve plexus derived from both hypogastric and pelvic nerves. These nerves project to other regions of the male genital tract including the corpus cavernosum. Acetylcholinesterase reactivity has been reported to be closely related to NO synthase immunoreactivity in the prostate.20 This suggests that there may be functional interactions between NO and acetylcholine in the prostate. Based on these facts, an additional mechanism of BTA, one that nitrinergic activity in the prostate is increased under inhibition of acetylcholine release by BTA, could be derived from the improvement of erectile dysfunction. The improvement of erectile function may be caused by accessory nerve sprouting or increased release of NO at the nitrinergic nerve endings.21 This increased nitrinergic activity does not occur when NO is sufficiently supplied to the prostate by oral nitrate.

In our study, there are several shortcomings of the baseline evaluation and study model. Firstly, the patients did not undergo urodynamic study at baseline evaluation. A second shortcoming was the lack of a placebo. These made it difficult to assess the true efficacy of BTA. Although a level of caution must be present in interpreting the results of the study, we believe that they may be a kind of guideline for more profound, generalized studies on the combination effect of BTA and existing BPH medicines.

In summary, we were able to deduce the intraprostatic mechanism of BTA from the difference between various evaluation values related to BPH before and after BTA injection. It is mainly related with the alteration of interactions between adrenergic, cholinergic, and nitrinergic activity. However, it is possible that more neurotransmitters than the three neurotransmitters mentioned are involved in making BPH. Additional histopathologic and pharmacophysiological investigations of BTA treatment are necessary before the effects of BTA seen in our results can be generalized in BPH treatment.