Although the etiology of BPH remains unknown, it has been suggested that BPH has two components: a static component that is related to prostatic enlargement and a dynamic component that reflects contraction of smooth muscle within the gland [1, 12]. The static component is under parasympathetic control and regulated by androgen, while the stromal smooth muscle is sympathetically influenced [20, 21]. Thus, drugs that relax smooth muscle within the prostate, such as α-adrenergic receptor blockers, and drugs that shrink the volume, such as 5 α reductase inhibitors, are used for the treatment of BPH.
Recent evidence suggests that BPH could be originated from neural dysregulation of the prostate and alterations in local neuropeptides . The prostatic neuroendocrine peptides may regulate the synthesis of prostatic secretory product, growth, and function [20, 21]. Thus, BTX-A which has a cholinergic receptor predilection in its action on nerve terminals as well as inhibition of release of noradrenalin might regulate the neural control of prostate and relieve the symptoms of benign prostatic obstruction.
There are some differences between the canine and human prostate, nevertheless, experimental findings on the canine prostate can be regarded as valuable information. Previous studies have used the canine mode to elucidate the effects of orchiectomy and androgen on the prostate [15, 22]. In the canine model, we used BTX-A 100 U for prostate injection, which dose might be about 2 times of the dose used in human (100 U for 15 kg in canine/200 U for 60 kg in human). However, the component of human prostate is different from the canine prostate. Species differences might have different responses to BTX-A treatment , therefore, the selected dose of BTX-A 100 U for the canine model cannot be completely interpreted to the human dose. Our present results suggest that injection of BTX-A into the canine prostate induced marked atrophy and diffuse apoptosis of prostate glands. The effect persisted for at least 3 months without any notable side effects. Doggweiler suggested that denervation can alter growth-factor expression in the prostate and resulted in programmed cell death . Kyprianou demonstrated that the suppression of sympathetic tone on the prostate induced prostate apoptosis . Expression of specific prostate apoptosis related genes, such as bcl2 and transforming growth factor-β has been implicated in the pathogenesis of BPH . Thus, apoptotic changes in the prostate after BTX-A treatment are likely to be related with reduced neurotrophic influence on the gland. Therefore, the induction of apoptosis may emerge as an attractive target for the management of BPH. As BPH might arise from neural dysregulation, BTX-A could potentially affect these neural mechanisms. Further study with staining of various neuropeptide markers in the dog prostate is undergoing for future report.
Although one of our patients did not reveal volume shrinkage, all of the 8 patients had improved in maximal flow rate, residual urine, IPSS score and quality of life indices, and had no side effects after BTX-A injection. The pathological features of BPH are heterogenous and include varying abnormalities of epithelium, smooth muscle and fibrous stroma. The relative proportion of epithelium and stroma is from 1:2 to 1:5 . It is possible that the predominant component of the BPH nodule may determines the response to specific therapy, for example, smooth muscle predominant nodules would respond to α-blockers and epithelial nodules to androgen-deprivation therapy [1, 24]. The possibility of BTX-A effects on the dynamic component of BPH might explain the patient without volume shrinkage, but improved in lower urinary symptoms. Taken together, BTX-A might reduce the benign prostatic obstruction no matter what the detrusor contractility is.
The effects of denervation provided by the BTX-A will wear off, as new axons re-sprout in approximately 6 months . Phelan et al reported that BTX-A effects on sphincter injection have prolonged subjective clinical efficacy beyond 6 months . The beneficial results of the present study were evident within 1 month, and they continued throughout the follow-up period. The duration of BTX-A effects might depend on the different characteristic of targeted tissue, therapeutic dose, and intervals. Patients will determine if and when subsequent injections are necessary. Since the application of BTX-A on the treatment of lower urinary dysfunction is currently off-level use in Taiwan, it was necessary to be approved by the institutional review board for the human use and animal study. In support of evidence based medicine practices, caution should be applied until larger randomized clinical studies are completed that will guide physicians in making decisions about the use of botulinum toxin in the prostate.