Impact of prostate cancer treatment on pelvic nerve injury and erectile function

Abstract

Following prostate cancer treatment, many men will experience urogenital side effects including erectile dysfunction (ED), a condition significantly affecting survivor quality of life. The cause of ED after treatment is frequently unknown, but injury to the inferior hypogastric plexus, a collection of nerves adjacent to the prostate that control significant urogenital function such as erection, is often implicated. In this work, we examined the effect of three different prostate cancer treatments: external beam radiation therapy (RT) alone, and androgen deprivation therapy (ADT) and radical prostatectomy (RP) both alone and in combination, on erectile function, penile physiology and neuronal health in male rats. These studies examined neurons from the major pelvic ganglia (MPG) in rodents, the correlate of the human inferior hypogastric plexus. Adult male Sprague-Dawley rats underwent prostate-confined, conformal, single fraction 22 Gy RT or sham treatment. Erectile function was assessed by cavernous nerve stimulated intracavernosal to mean arterial pressure (ICP/MAP) measurement and penile smooth muscle function was assessed at 2 or 10 weeks post-RT. MPGs were dissociated and neurons grown in culture to examine axon length and branching, and neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH) and TUNEL assay expression. MPG gene expression for neuron type, and markers of nerve injury and repair were measured. Although rats did not demonstrate ED post-RT, they did have impaired penile contraction. Pelvic neurons demonstrated chronic decreases in neuron length, branching and TH positive cells, as well as progressive neuronal apoptosis and loss of nNOS positive neurons. Markers of synaptic remodeling were increased at 10 weeks while genes related to nerve repair and regeneration were decreased. This is the first study to characterize the health and regeneration potential of dissociated MPG neurons following RT. Neuronal injury was apparent early post-RT and persisted or increased over time. The nerves are very susceptible to apoptosis and damage from prostatic RT, but even with significant injury, this model did not cause ED. In our second study, adult Sprague-Dawley rats were castrated (CAST) and experienced 4 weeks of androgen deprivation before undergoing bilateral cavernous nerve injury (BCNI). This paradigm mimics human patients undergoing ADT before RP and we would expect the combination to increase the severity of ED. At the time of BCNI, some rats received 2 weeks of supplemental testosterone to rescue erectile function and repair nerves. Rats undergoing CAST and BCNI demonstrated significantly decreased ICP/MAP that was further exacerbated in the both castrated and nerve injured (C+B) group. Penile contraction was markedly increased with CAST and C+B to endothelin-1, phenylephrine and electrical field stimulation (EFS). Additionally, relaxation was impaired to nitric oxide donors and non-adrenergic non-cholinergic EFS. Exogenous androgens restored normal erectile function in CAST, BCNI and C+B groups. Similarly, testosterone supplementation returned penile smooth muscle vasoreactivity to control levels. In cultured MPG neurons, C+B induced the greatest amount of apoptosis and had the fewest nNOS positive cells. Testosterone administration prevented the increase in apoptotic cells and restored nNOS positive neuron populations. Furthermore, testosterone increased both TH positive cells and neurite length, but had no effect on neurite branching. These data demonstrate increased MPG neuron injury during ADT that could be ameliorated with testosterone supplementation. Overall, this work demonstrates that prostate cancer treatments are causing significant damage to the surrounding pelvic neuronal structures and leading to penile smooth muscle dysfunction and ED. Furthermore, therapeutic strategies are required to preserve both the functional and structural integrity of the cavernous nerve and MPG to prevent and/or rescue ED in men with prostate cancer.