Treatment of benign prostatic hyperplasia and abnormal ejaculation: live imaging reveals tamsulosin – but not tadalafil – induced dysfunction of prostate, seminal vesicles and epididymis

Abstract

Structures responsible for the emission phase of ejaculation are the seminal vesicles, the most distal part of the cauda epididymidis and the newly characterized prostate excretory ducts. The emission phase is mainly regulated by the sympathetic nervous system through alpha1-adrenergic receptor activation by noradrenaline at the targeted organs. Benign prostatic hyperplasia (BPH) treatment with alpha1A-adrenergic antagonists such as tamsulosin is known to result in ejaculation dysfunction, often leading to discontinuation of therapy. Mechanisms of this disturbance remain unclear. We established a rodent model system to predict drug responses in tissues involved in the emission phase of ejaculation. Imitating the therapeutic situation, prostate ducts, seminal vesicles and the distal cauda epididymal duct were pre-incubated with the SMC-relaxing BPH drugs tadalafil, a novel BPH treatment option and tamsulosin in an ex vivo-time-lapse imaging approach. Afterwards, noradrenergic responses in the relevant structures were investigated to simulate sympathetic activation. Noradrenaline induced strong contractions ultimately leading to secretion in structures without pre-treatment. Contractions were abolished by tamsulosin in prostate ducts and seminal vesicles and significantly decreased in the epididymal duct. Such effects were not observed with tadalafil pre-treatment. Data visualized a serious dysfunction of each organ involved in emission by affecting alpha1-adrenoceptors localized at the relevant structures, but not by targeting of smooth muscle cell-localized PDE5 by tadalafil. Our model system reveals the mechanism of tamsulosin resulting in adverse effects during ejaculation in patients treated for BPH. These adverse effects on contractility don’t apply to tadalafil treatment. This new knowledge translates directly to clinical medicine.

The oxytocin antagonist cligosiban reduces human prostate contractility: Implications for the treatment of benign prostatic hyperplasia

“…However, treatment with α 1adrenoceptor blockers often leads to side effects such as ejaculatory disorders (Narayan & Lepor, 2001) and systemic effects such as hypotension. In a previous study, we could show the negative side effects of tamsulosin on seminal vesicles, prostate duct and the spermreleasing part of the epididymis ex vivo (Seidensticker et al, 2022).…”

“…The inhibition of other pathways, e.g. the phosphodiesterase 5 (PDE5) (Mónica & de Nucci, 2019; Seidensticker et al, 2022), but possibly also oxytocin (OT) (Lee et al, 2021) to relax the smooth muscle cells of the prostate was suggested as an alternative therapeutic target. Although oxytocin and the OT receptor have been shown to be present in the male reproductive tract (Stadler et al, 2020), the pathway still remains unexploited as a therapeutic target.…”

“…Therefore, the organ bath may only record the sum of movement along the transducers (thus, some of the responses might be missed or minimized). In contrast to organ bath, live‐imaging, also used in male reproductive organs (Mietens et al, 2012; Mietens et al, 2014), including the prostate (Kügler et al, 2018; Seidensticker et al, 2022), detects very small, complex and multidirectional contractions. Most recently, the combination of live‐imaging, together with our novel image analysis method allowed the interrogation of movement over the entirety of the tissue, by dividing it into hundreds of regions of interests, quantifying the change in response at each point and comparing them (Stadler et al, 2021).…”