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PURPOSE - To assess whether BIO 300, a synthetic genistein nanosuspension, improves the therapeutic index in prostate cancer treatment by preventing radiation-induced erectile dysfunction (ED) without reducing tumor radiosensitivity.
METHODS AND MATERIALS - Male Sprague-Dawley rats were exposed to 25 Gy of 220-kV prostate-confined x-rays. Animals were randomized to receive sham radiation therapy (RT), RT alone, RT with daily BIO 300 at 2 experimental dosing regimens, or RT with daily genistein. Erectile response was evaluated over time. Penile shaft tissue was harvested for histologic analyses. Murine xenograft studies using prostate cancer cell lines determined the effects of BIO 300 dosing on RT efficacy.
RESULTS - Prostate-confined RT significantly decreased apomorphine-induced erectile response (P < .05 vs sham RT). Erection frequency in animals receiving prophylactic treatment with BIO 300 starting 3 days before RT was similar to sham controls after RT. Treatment with synthetic genistein did not mitigate loss in erectile frequency. At week 14, post-RT treatment with BIO 300 resulted in significantly higher quality of erectile function compared with both the RT arm and the RT arm receiving genistein starting 3 days before irradiation (P < .05). In hormone-sensitive and insensitive prostate tumor-bearing mice, BIO 300 administration did not negatively affect radiation-induced tumor growth delay.
CONCLUSIONS - BIO 300 prevents radiation-induced ED, measured by erection frequency, erectile function, and erection quality, when administered 3 days before RT and continued daily for up to 14 weeks. Data also suggest that BIO 300 administered starting 2 hours after RT mitigates radiation-induced ED. Data provide strong nonclinical evidence to support clinical translation of BIO 300 for mitigation of ED while maintaining treatment response to RT.
Copyright © 2019. Published by Elsevier Inc.
PURPOSE/OBJECTIVES - Radiation-induced erectile-dysfunction (RiED) is one of the most common side effects of radiation therapy (RT) and significantly reduces the quality of life (QoL) of cancer patients. Approximately 50% of prostate cancer patients experience RiED within 3 to 5 years after completion of RT. A series of vascular, muscular, and neurogenic injuries after prostate RT lead to RiED; however, the precise role of RT-induced neurogenic injury in RiED has not been fully established. The cavernous nerves (CN) are postganglionic parasympathetic nerves located beside the prostate gland that assist in penile erection. This study was designed to investigate the role of CN injury, tissue damage, and altered signaling pathways in an RiED rat model.
METHODS AND MATERIALS - Male rats were exposed to a single dose of 25 Gy prostate-confined RT. Erectile function was evaluated by intracavernous pressure (ICP) measurements conducted both 9 and 14 weeks after RT. Neuronal injury was evaluated in the CN using quantitative polymerase chain reaction, conduction studies, transmission electron microscopy, and immunoblotting. Masson trichrome staining was performed to elucidate fibrosis level in penile tissues.
RESULTS - There were significant alterations in the ICP (P<.0001) of RT rats versus non-RT rats. TEM analysis showed decreased myelination, increased microvascular damage, and progressive axonal atrophy of the CN fibers after RT. Electrophysiologic analysis showed significant impairment of the CN conduction velocity after RT. RT also significantly increased RhoA/Rho-associated protein kinase 1 (ROCK1) mRNA and protein expression. In addition, penile tissue showed increased apoptosis and fibrosis 14 weeks after RT.
CONCLUSIONS - RT-induced CN injury may contribute to RiED; this is therefore a rationale for developing novel therapeutic strategies to mitigate CN and tissue damage. Moreover, further investigation of the RhoA/ROCK pathway's role in mitigating RiED is necessary.
Copyright © 2017 Elsevier Inc. All rights reserved.
OBJECTIVE - Few studies of hypospadias repair in childhood have used validated questionnaires to investigate outcomes of cosmesis, urinary function, and sexual function in adulthood. We sought to investigate long-term outcomes in adult patients who had undergone severe hypospadias repair as children using an existing web-based application available to multiple institutions in order to develop an online patient survey of previously validated questionnaires.
MATERIALS AND METHODS - Patients aged 18 years or older who underwent severe hypospadias repair between 1992 and 1997 at our institution were contacted to complete an online survey. Through medical chart reviews, we analyzed the location of meatus, type of repair, and complications. The online survey included questions about penile appearance, and validated questionnaires to assess urinary and sexual function.
RESULTS - Of 58 patients who met the inclusion criteria, we contacted 19, and 13 completed the survey. Fifty-nine percent had complications, with an average of 2.2 procedures per patient. Most (85.0%) were satisfied with penile appearance, although 38.0% had residual penile curvature. Hypospadias patients had mean lower orgasmic function than normal controls. Mean scores for urinary function and other domains of sexual function were similar to normal controls.
CONCLUSIONS - Although the majority of adult patients were satisfied with the outcomes of penile appearance, urinary function, and sexual function, our online survey suggests decreased lower orgasmic function as measured by validated questionnaire. An online survey accessible to multiple institutions with validated questionnaires may facilitate assessment of long-term hypospadias results.
Copyright © 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
OBJECTIVE - To describe the relationship between the International Index of Erectile Function (IIEF) erectile domain score, and nocturnal penile tumescence and rigidity values measured by RigiScan (Timm Medical Technologies, Eden Prairie, MN).
PATIENTS AND METHODS - In all, 73 men were evaluated with the IIEF and 2 nights of continuous penile monitoring with the RigiScan. Twenty-six men were evaluated before and after prostatectomy, for a total of 99 pairs of data points. We dichotomized the RigiScan results as 'adequate' (no erectile dysfunction, ED), or 'inadequate' (having ED), based on the 'best erectile event' over the 2 nights of monitoring. Two separate criteria for adequate erectile function were used, one of >70% rigidity for > or = 10 min, and the other >60% rigidity for > or = 10 min. The erectile domain score of the IIEF was calculated in the standard fashion.
RESULTS - Using both the 70% and the 60% rigidity criteria, there was a statistically significant association between the IIEF erectile domain scores and the RigiScan data (r = 0.27, P = 0.008 and r = 0.29, P = 0.003, respectively). However, the sensitivity of the IIEF to predict ED based on RigiScan results using the 70% rigidity criteria was 68.9%, and the specificity was 57.1%. When the IIEF was used as a continuous predictor of RigiScan results, the area under the receiver-operating characteristic (ROC) curve was 0.66. Using the 60% criteria, the sensitivity was 55.8% and the specificity was 73.2%; the area under the ROC curve was 0.72.
CONCLUSIONS - IIEF erectile domain scores and nocturnal penile tumescence and rigidity measurements are weakly associated, and the clinical utility of one test to predict the other is limited. However, because of the differences in the measured outcomes (perception of erectile function vs physiological capacity), a weak association does not disqualify either test's individual utility.
Penile erection is a nitric oxide (NO)-mediated process that has been shown to be androgen dependent in rats. Castration reduces the activity of the penile enzyme involved in NO synthesis, nitric oxide synthase (NOS). To determine whether adrenal androgens and/or corticosteroids contribute to this control, the following groups of Fischer 344 adult male rats (n = 5-7) were studied: 1) intact, 2) castrated, 3) adrenalectomized alone, 4) castrated/adrenalectomized, 5) castrated/adrenalectomized with aldosterone (1.25 mg/kg, s.c.) and hydrocortisone (12 mg/kg, s.c.), 6) castrated/adrenalectomized with dihydrotestosterone (1.2-cm SILASTIC-brand tubing pellet; Dow Corning, Midland, MI), 7) castrated/adrenalectomized with dehydroepiandrosterone (2-cm tubing), 8) castrated/adrenalectomized with aldosterone (1.25 mg/kg, s.c.), and 9) castrated/adrenalectomized with hydrocortisone (12 mg/kg, s.c.). After 1 week, EFS was applied, and the maximal intracavernosal pressure (MIP) and mean arterial pressure (MAP) were recorded. The MIP/MAP ratio in the adrenalectomized group (0.37) was reduced to values found in the castrated group (0.40). The values in both groups were significantly less than those in intact controls (0.75). The most significant reduction in MIP/MAP was seen in the adrenalectomized/castrated group (0.16). Erectile response in animals submitted to adrenalectomy and castration was restored close to intact values with the administration of hydrocortisone and aldosterone (0.63). Similar results were obtained by the administration of either of the substances alone (0.56 and 0.67, respectively). Penile NOS activity assayed by the L-arginine/citrulline conversion was decreased by 55% in the castrated group compared with that in the intact group, but was not further reduced in the adrenalectomized/castrated or adrenalectomized groups. Penile neuronal NOS protein content, estimated by Western blot, was decreased only in the adrenalectomized/castrated animals (35%), and endothelial NOS content was not affected. These data suggest that the rat adrenal gland contributes to the maintenance of the erectile mechanism and may affect neuronal NOS content in the penis in the rat model. The possibility that hypotension may play a role in the erectile dysfunction observed in adrenalectomized rats cannot be discarded.