Assessment of Potential Biomarkers in Women With Symptoms of Overactive Bladder and Pelvic Organ Prolapse

Pelvic organ prolapse Pelvic organ prolapse (POP) is a clinical condition that, although it is not life-threatening, significantly affects patients' quality of life. POP affects more than 30% of females in the general population. Among those, the majority is free of symptoms and do not need any medical assistance. However, according to US statistics, almost 20% of women will be candidates for some type of surgery to restore POP during their lifetime.

Urinary incontinence Urinary incontinence (UI) is used to describe any loss of urine through the urethra. It is a common patient complaint but not a specific disease. UI significantly affects patients' quality of life. UI is classified in 3 subtypes: stress UI (SUI) (loss of urine on effort, coughing etc.), urgency UI (UUI) (loss of urine involuntary and combined by urgency) and mixed UI (MUI) (combination of the two). UUI is the second most common type of UI in women, and it is estimated that 20-40% of women who visit outpatient clinic healthcare services have UUI. Regarding women with SUI, the surgical intervention by using a tension free vaginal tape is a successful method. Considering females with UUI, the pharmacological treatment is a long-lasting and effective alternative.

Pathophysiology of overactive bladder in women with POP Few evidence exist regarding the etiology of OAB in women with POP. POP itself is considered an important mechanism for the development of OAB. Several studies have suggested that patients with POP have a lower peak of maximum flow rate (Q max) during urination compared to patients without concomitant prolapse. In addition, the average flow rate (Q ave) in women with detrusor overactivity appears to be lower as well. It is possible that obstructive urination is involved in the creation of the detrusor overactivity in patients with POP . In studies with patients who underwent POP surgery, had improvement of OAB symptoms, and the urinary flow rates were mainly improved postoperatively.

The first theory that attempts to explain how prolapse induces the OAB symptoms is the possible damage of bladder nerve pathways that happens in women with obstructive voiding. In these patients, hypersensitivity and decreased secretion of acetylcholine (Ach), which is the major neurotransmitter of the urinary bladder, was found in comparison to asymptomatic patients. Ischemia and bladder wall hypoxia caused by bladder dilatation and contractions may play an important role in this damaged neural pathway in cases of prolapse and obstructive urination.

The second theory focuses on the bladder detrusor muscle. The urinary bladder is a hollow sac-like cavity connected with the ureters, where the urine is collected, and a funnel extension, the bladder neck connected to the urethra. The urinary bladder is lined with transitional epithelial tissue that is able to stretch significantly to accommodate large volumes of urine. The main part of the wall is formed by smooth muscle layers provide the urinary bladder with its ability to expand and contract. It is commonly referred to as the detrusor muscle. In cases where there is a reduction in the cell-site electrical activity propagation or in the cell membrane instability, the transmission of the cell-to-cell electrical activity signal is activated. As a result, the detrusor muscle becomes hypersensitive and the patient develops OAB symptoms.

According to the third theory, changes in the spinal reflexes are the cause of the OAB. In experimental animal studies, bladder obstruction has been shown to cause hypertrophy of the afferent neurons and is accompanied by increased expression of NGF in the bladder wall. Also, it was shown that obstruction is accompanied to a certain extent by a reduction in neuronal excitability leading to a more pronounced spinal reflex that could contribute to the development of OAB.

Other possible pathophysiological mechanisms of OAB in women suffering from POP is the dilatation of the bladder wall, which commonly appears in POP and which can induce receptor stimulation resulting in contractions of the detrusor muscle Finally, a large sized vaginal prolapse can drop down the bladder neck and the most common symptom is UI. This mechanism is known to cause detrusor overactivity (DO).

The role of biomarkers in the diagnosis and monitoring of overactive bladder A. The bladder wall thickness (BWT) There are numerous studies linking the increase in bladder wall thickness (BWT) with the symptoms of the OAB. It appears that BWT is affected by the increased muscle work that occurs due to DO. In several studies, ultrasound transvaginal scanning of the detrusor muscle over 5mm is significantly associated with OAB symptomatology. Finally, there is little evidence of altering the BWT in women with OAB after treatment with anticholinergics. To conclude, there are no studies to investigate BWT in women with POP and OAB symptoms.

1. Neurotrophic Growth Factor (NGF) Neurotrophins are responsible for the maintenance and the control of bladder nerve stimulation threshold and appear to be involved in the pathophysiology of the OAB symptoms. NGF is produced by urothelium and smooth muscles of the detrusor muscle and its urine levels seems to rise in OAB patients and to fall after a successful treatment. In studies where the objective was to investigate the role of NGF in the pathophysiology of lower urinary tract symptoms, it was found that urinary NGF levels were consistently low in asymptomatic women. In similar studies in patients with lower urinary tract symptoms, urinary NGF levels were found to be elevated. Finally, in studies in which the symptoms of OAB were successfully treated, urinary NGF levels were reduced. There are also no studies to investigate urinary NGF levels in women with prolapse and coexisting bladder symptomatology.

Are symptoms of OAB improved after treatment for POP? In literature, there are still no sufficient high quality studies to address this question. There is only one study with Stage I prolapse patients and a smaller group with Stage II prolapse, all of which had proven symptoms of OAB and urodynamically documented DO. After conservative pharmacological treatment with tolterodine, only 14.1% of Stage I patients and 39.2% of Stage II patients continued to experience OAB symptoms. This study showed an improvement in OAB in patients with vaginal prolapse (relative risk-RR) of 2.55, but improvement in women without prolapse was much higher (RR 7.09). The difference could be explained in some extent because of the fact that OAB is provoked by vaginal prolapse itself and continues to exist despite conservative treatment. In the other hand, there are more than 12 studies in the literature showing that symptoms of OAB are improved after surgical treatment for vaginal prolapse, including de novo overactive bladder postoperatively.

Detrusor overactivity (DO) The presence of vaginal prolapse appears to be a risk factor for the DO, since in urodynamic studies appear to co-exist at a rate of 10-50%. The majority of studies show improvement of DO activity after surgical repair of vaginal prolapse. Overall, it appears that there is a high probability of disappearance of DO after surgery, but these results do not seem to be verified in cases of concomitant OAB.

In summary, there is a large number of women suffering from POP and UI problems. There is the possibility to repair surgically both conditions in case of SUI with high rates of success. In case of UUI, the surgical repair of vaginal prolapse shows up to 50% improvement in UI postoperatively. However, it is not yet investigated whether there are some specific biomarkers that could help to assess and predict patients with POP and UUI who would be benefit by a surgical intervention.