Neurovascular Mechanisms of Erectile Dysfunction Following Androgen Deprivation Therapy

Abstract

For nearly eight decades, androgen deprivation therapy (ADT) has been a common prostate cancer treatment. Although ADT increases the prostate cancer survival rate, urogenital side effects such as erectile dysfunction (ED) impair the quality of life for prostate cancer survivors. Currently, there are no effective ED treatments for testosterone deficient men. Testosterone exerts a direct influence on multiple structures regulating erection function including peripheral nerves and pelvic vasculature. Considering the complex actions of testosterone, researchers have been unable to determine the mechanisms responsible for ED development in testosterone deficient men. Studies presented within this body of work aim to elucidate specific mechanisms responsible for ADT induced ED. Unlike most conventional ED studies which focus on penile pathology, we incorporate a broad physiological approach that examines peripheral nerves innervating the penis and the internal pudendal arteries (IPA) responsible for regulating penile blood flow. Here, we identify regional specific changes in IPA neurotransmitter release. Distal IPA and penile neurotransmitter relaxation both share a similar nitric oxide dependency. Castration causes significant IPA and penile endothelial dysfunction by reducing endothelial nitric oxide synthase (eNOS) dimer to monomer ratio. We demonstrate that Akt inhibition prevents IPA eNOS dedimerization and increases IPA and penile endothelial dependent relaxation. Endothelial nitric oxide production maintains an erection, but the pelvic nitrergic neurons responsible for initiating an erection are severely diminished by castration. The novel role of Schwann cells in castration induced nerve injury is described here for the first time. Following castration, we believe Schwann cells undergo a genotypic switch and become demyelinated. This genotypic switch reduces dorsal penile nerve conduction and decreases autonomic neuron populations. Schwann cells from control animals prevent castration induced nerve injury. Understanding how castration impacts Schwann cell function may be key to treating ADT induced pelvic nerve injury. We demonstrate the broad pathologic effects of castration on peripheral nerves, pre-penile vasculature, and the penis. Multiple potential therapeutic targets are identified within these studies; however, more research is needed to find an effective ED treatment for testosterone deficient prostate cancer survivors.