Changes in prostaglandin E2 in patients with idiopathic overactive bladder syndrome after botulinum toxin type A treatment: is there a clinical benefit?

The prevalence of idiopathic overactive bladder syndrome (OAB) in Europe is estimated at 16% in men and women [1]. Sixty-eight percent of the women and 60% of the men are bothered by OAB. It is a serious problem that negatively affects the quality of life [1, 2]. According to the International Continence Society (ICS), OAB syndrome is defined as urinary urgency usually accompanied by frequency and nocturia, with or without urge incontinence, in the absence of causative infection or pathological conditions [3]. The reasons for these symptoms are still unknown, although already many studies could uncover compounds and pathways inducing detrusor contractions and/or detrusor over activity (DO) [4‐6].

One of these compounds originates from arachidonic acid. Prostaglandin E2 (PGE2) is a cytoprotective eicosanoid, which is synthesized de novo from the detrusor muscle or urothelium [7]. It has been shown that PGE2 is increased in carcinogenesis, urinary tract infections and overactive bladder syndrome [8, 9]. The urinary PGE2 level is significantly increased in OAB and correlates negatively with the maximum cystometric capacity [10]. In rats, intravesical instillation of PGE2 triggers detrusor contractions, but topical application to the urethra leads to urethral relaxation in rats [11]. Bladder storage dysfunction and elevated urinary PGE2 levels have been proven to be enhanced in rats after causing severe damage to the urothelial barrier [12].

Once a patient is diagnosed with OAB syndrome, lifestyle modifications and bladder retraining is suggested. Pharmacological treatments are needed to improve quality of life if behavioural training fails. Due to many side effects the majority of patients discontinue anticholinergic medication [13]. Botulinum toxin (BTX) is a potent neurotoxin, used to treat different pathologies such as blepharospasm or spastic torticollis. It attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) at the neuromuscular junction, preventing vesicles from anchoring to the membrane to release acetylcholine. By inhibiting acetylcholine release, the toxin interferes with nerve impulses and causes flaccid paralysis of muscles [14].

BTX type A (BoNT-A) and Onabotulinum toxin are used to treat neurogenic and/or overactive bladder when oral anticholinergic medication is not successful or not tolerated.

Injected into the detrusor muscle, it reduces urgency and frequency and improves quality of life. Common but rare side effects are urinary retention and urinary tract infections [15‐17].

Cause and development of OAB are still unknown, thus further studies are needed to enhance diagnosis of OAB as well as to identify markers useful for daily clinical routine in verifying the presence of OAB and establishing treatment monitoring [18‐20].

The aim of this prospectively designed study was to test PGE2 in OAB and its changes after BoNT-A therapy.

OAB represents a rising health problem massively affecting quality of life. Intravesical BoNT–A administration has been shown to be a safe and effective therapy for refractory idiopathic OAB. It is a reasonable treatment of patients impossible to take anticholinergic medication [15‐17, 21, 22]. To date several studies tried to elucidate cause and mechanism of OAB, but it is still poorly understood [4, 18, 19, 23]. Up to now a marker for OAB is lacking. In general a biomarker should be able to indicate and define both the presence and severity of a disease as well as progression/relapse and response on therapy [20]. Prostanoids are inflammatory mediators induced by mitogens or proinflammatory agents. PGE2 associated physiological responses are found in the whole human system. Typical prostanoid-induced actions are smooth muscle relaxation and contraction and neuromodulation (inhibition or release of neurotransmitters, regulation of inflammatory mediation, thermoregulation or sleep induction). In the urinary bladder, PGE2 is released from the urothelium, smooth muscle [24, 25], glial cells and neurons as required [26, 27]. Our results clearly demonstrate the relationship between PGE2 and OAB reflected in significantly elevated serum levels of PGE2 in patients suffering from OAB. It is particularly noticeable that there is a wide range of sPGE2 levels with pronounced inter-individual differences. These findings are in line with studies trying to find a urinary marker to differentiate OAB, DO or interstitial cystitis (IC)/bladder pain syndrome (BPS). Recent studies showed significantly increased urinary PGE2 in male and female OAB patients, underlining the important but still unclear role of PGE2 [5, 8, 28]. Moreover, our data detect a correlation of sPGE2 levels with the severity of OAB reflected by significant higher levels in wet compared to dry OAB. This possible potential to differentiate between vairous OAB stages reveals PGE2 as promising for future use as a marker and additional helpful tool for therapeutic decision in OAB.

For the first time we present data that sPGE2 development is influenced by intravesical BoNT-A therapy in OAB. We found a significant decrease of sPGE2 levels 4 weeks after BoNT-A application. Furthermore, we detected a correlation between the success of therapy as well as the degree and duration of decreased sPGE2 levels. A shorter drug effect (<9 month) was significantly associated with less sPGE decrease. Non-responders even displayed a sPGE2 increase or only a slight decrease. A recent study examined PGE2 urine levels in female OAB patients treated with anticholinergics and no significant changes of PGE2 urine levels could be detected after 4 weeks of treatment [28]. These differences in PGE2 detection in urine and serum may be due to the different methods and body fluids used and due to the diverging administered therapeutic substances. But how far are local urinary levels of the inflammatory mediators relevant to the inflammatory process at all? In particular, anticholinergics and BoNT-A are acting by different receptor mediated signal transduction pathways affecting Ca⁺⁺ influx with impact on PGE2 release [29, 30]. The regulation and action of prostaglandins in the urinary bladder are still obscure. In addition, we verified a re-rise of sPGE2 when BoNT-A effects wore off and OAB relapsed. A limitation of this prospective single-center examination was the relatively small patient cohort of 58 OAB-patients. These first promising results, that show the potential of sPGE2 as a biomarker in OAB, have to be confirmed in further investigations with a larger population.

These promising first data are indicate the helpfulness of sPGE2 in OAB. sPGE2 seems to have the potential as a biomarker for OAB defining the presence, severity and response to therapy and relapse. Future investigations have to evaluate the relevance of sPGE2 to diagnose and monitor patients with OAB. BoNT-A treated patients could be monitored using sPGE2 as an early marker to anticipate decreasing effects of BoNT–A in combination with a voiding diary. Regarding the non-responder group, an efficient monitoring could filter these patients and lead to an alternative treatment. To what extent sPGE2 can be useful as such needs to be examined in further investigations.