Causes and Effects of Long-term Voiding Dysfunction

Our Division of Urology continues to pursue research in the clinical and basic translational sciences. This past July, CHOP urologists Matthew Christman, MD, and Thomas F. Kolon, MD, were the lead authors on a study published in the Journal of Urology looking at the reproducibility of the semen analysis in adolescents with varicoceles and a history of cryptorchidism.

This is an important addition to our growing body of work, in which we  seek to define the impact of the adolescent varicocele on subsequent fertility and paternity.

Our clinical research has also shown the efficacy of biofeedback training in the management of pediatric dysfunctional voiding. In a selected group of 50 patients with voiding dysfunction, two biofeedback sessions resulted in a statistically significant 4-point drop in the voiding symptom score for daytime wetting. This work was presented at the fall meeting of the Society for Pediatric Urology. The use of the symptom score allows our team to assess the efficacy of various treatment regimens for voiding dysfunction with the long-term goal of creating optimized algorithms for this group of disorders.

Our clinical research in voiding dysfunction also ties into our laboratory interests where we are investigating a mouse model of social-stress-induced voiding dysfunction. In response to social stress, 6-week-old mice develop urinary retention and their bladders enlarge. It is worrisome to note that the resulting voiding dysfunction does not resolve once the mice are removed from the stressor. Even as far as 6 months out, the abnormal voiding patterns persist. It is also of interest that this voiding dysfunction can be prevented; we have recently shown that mice with a genetic deletion for the NFATc4 transcription factor are resistant to the effects of social stress.

From work done in collaboration with Rita Valentino, PhD, behavioral neuroscientist with CHOP’s Neurosciences Research Group, we know that the stress hormone and neurotransmitter Corticotropin Releasing Factor (CRF) is increased in Barrington’s nucleus, the cluster of nerves within the brainstem that regulates bladder function. Valentino and urologist Stephen A. Zderic, MD, also showed that CRF acts as a brake to inhibit the voiding reflex and can thus lead to urinary retention. In recent work supported by a grant from the American Urological Association Foundation, our fellow Christopher Long, MD, was able to show that the mRNA coding for CRF is upregulated in Barrington’s nucleus following social stress, but remains unchanged for the NFATc4 knockout strain of mice. This molecular finding explains in part why this strain of mice demonstrates a normal voiding pattern despite their exposure to social stress. These findings represent small steps in the solution to a complex puzzle whereby stressful experiences (such as the dysuria associated with bladder infections) can result in long-term voiding dysfunction.

CRF in situ hybridizations were done with oligonucleotide probes to detect CRF mRNA. These probes were labeled with Texas Red fluorophore; all nuclei were stained with DAPI (blue fluorescence signal). Scanning of the region of Barrington's nucleus revealed minimal signal in the control (A) and stressed NFATc4-/- group (B). In contrast with social stress in the WT group, there was a significant rise in CRF mRNA expression (C).