Negative Cumulative Impact of Low Testosterone and Cavernous Nerve Injury on Pelvic Neuron Survival is Improved by Testosterone Supplementation

Abstract

Prostate cancer is often treated surgically with radical prostatectomy (RP). Following RP, erectile dysfunction (ED) occurs in 25–100% of men, negatively impacting their quality of life. RP induced ED is primarily attributed to injury of the cavernous nerves which branch from the major pelvic ganglia (MPG). Frequently men are 65 and older when diagnosed with prostate cancer and have low circulating testosterone (T) levels. Testosterone (T) is essential to maintaining neuronal health and to recovering nerve function. The objective of this study is to examine effects of RP‐induced cavernous nerve injury in an animal model of low T (castration) on MPG neuron survival and to assess if T supplementation can restore erectile function and MPG health.Male Sprague‐Dawley rats (12 weeks) were separated into control (no surgery; CON), castration (CAST), bilateral cavernous nerve injury (BCNI), CAST+BCNI (C+B), and CAST+BCNI and T supplementation (3mg/kg; C+B+T) groups (n=4/grp). After 4 weeks of CAST, rats underwent BCNI to mimic RP and the C+B+T group started T treatment for 2 weeks. At 18 weeks of age, erections were measured via stimulation of the cavernous nerve and direct measurement of intracavernosal to mean arterial pressure (ICP/MAP). Bilateral MPGs were collected, dissociated into neurons and cultured for 72 hours. Neurons were fixed and stained immunofluorescently for neuron‐specific class III beta‐tubulin to measure axonal branching and length and then co‐stained with TUNEL assay to identify apoptotic neurons. Additional neurons were stained with sympathetic (tyrosine hydroxylase) or nitrergic (neuronal nitric oxide synthase) markers.Overall, CAST, BCNI and C+B decreased ICP/MAP, neurite growth and branching, increased apoptosis, elevated sympathetic neuron populations, and reduced nitrergic neurons compared to CON (p<0.05). CAST and BCNI alone both caused 25% decrease in neurite length, 20% decrease in branching and 2‐fold increase in apoptosis (p<0.05 vs CON). However, C+B caused a greater decrease in neurite length by 33%, decreased branching by 50% and doubled apoptosis (p<0.05 vs CON). The population of pro‐erectile nitrergic neurons were reduced by 60% in the CAST or BCNI alone and decreased by 70% in the C+B (p<0.05 vs CON). In contrast, the anti‐erectile sympathetic neurons were increased 30% with BCNI and 40% C+B (p<0.05 vs CON). Supplementation with T restored neurite length in C+B but did not improve neurite branching. Neuronal apoptosis was reduced 50% in C+B+T; however was still elevated above CON (p<0.05). T supplementation restored nitrergic and sympathetic neuron populations to control levels. In addition, T restored erectile function as measured by ICP/MAP in C+B rats (p<0.05).Nerve injury in a low androgen state (C+B) markedly impaired neuritogenesis and caused a greater decrease in nitrergic, pro‐erectile neurons compared to CON, CAST or BCNI alone. These data indicate that recovery of erectile function following RP‐induced nerve damage in a state of low T is unlikely and will lead to a higher incidence and severity of ED. T improves both erectile function and neuronal health, and should be considered for prostate cancer survivors.Support or Funding InformationSMSNA, SNCURCS, ECU URCAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.