Medical Meeting Reports

SMSNA Fall Scientific Meeting 2008

Toronto, ON Canada
October 16-19, 2008

Basic Science Award Winning Abstracts

Novel periprostatic tissue imaging with multiphoton microscopy and second-harmonic generation: promising potential for improving potency outcomes during nerve-sparing radical prostatectomy.

Authors: Gerald Tan, Rajiv Yadav, Sushmita Mukherjee, Jay Jhaveri, Frederick Maxfield, Watt Webb, and Ash Tewari

Many men who undergo radical prostatectomy develop some degree of post-operative erectile dysfunction (ED). The ED presumably results from intra-operative injury of the periprostatic nerves, which are difficult to visualize during surgery. A new imaging technology that may provide better visualization of the peripristatic nerves in real time was described by Gerald Tan. The technology involves multiphoton microscopy (MPM), in combination with second harmonic generation (SHG). In the work to date, the method provided high resolution views of human prostate tissue samples. Future work will focus on further developing the method and extending the method to visualize bleeding prostatic tissue surfaces that would be encountered during a surgery. The long-term goal of this work is to incorporate this promising new technology into the laparoscopic and robotic platforms used for radical prostatectomies.

This type of cutting edge research is an important aspect of sexual health research and hopefully will lead the way to the development of improved surgical outcomes and reduced patient morbidity.

Erectile dysfunction and apparent veno-occlusive disorder in mice deficient in elastin: correlations to veno-occlusive disorder in Type II diabetic mice.

Authors: Kanchan Chitaley and Ian Luttrell

Kanchan Chitaley presented a study which examined the role of elastin in erectile dysfunction (ED). Diabetic mice and mice with reduced elastin levels had strikingly similar reductions in erectile function, measured as changes in intracavernosal pressure in response to cavernosal nerve stimulation. Furthermore, elastin levels were reduced in diabetic mice. These results are consistent with a veno-occlusive mechanism underlying the reduction in erectile function in diabetic mice: as the corpus cavernosa expand with blood during an erection, elastin fibers within the tunica albuginia compress the tissue and reduce the venous outflow. Lower levels of elastin would lead to less compression, increased venous leak, and lack of sustained erections. Future studies will examine the mechanism underlying the loss of elastin in type II diabetes and will examine whether age and smoking status also affect the elastin content of the penis.

The importance of the veno-occlusive mechanism in maintaining penile rigidity is believed to be at the root cause of ED in as many as 20% of men. These experimental insights and the ability to more carefully refine what they mean from a physiologic standpoint is an important first step. Ongoing research into determining which men are so affected and whether there exist treatment strategies to compensate for this pathology are logical next steps.

Increased cavernosal androgen activity in post prostatectomy patients with erectile dysfunction.

Authors: John Colen, Lianquin Harold Yang, Osama Mohamed, Wesley Ekenuo, Steven King, Larry Lipschultz, and Mohit Khera

The androgen activity and tissue morphology of cavernosal samples from patients undergoing penile prosthesis placements were compared to patients with erectile dysfunction (ED) subsequent to radical prostatectomy (PP-ED) and patients with organic ED (O-ED). In the study presented by John Colen, androgen receptor levels were higher in PP-ED tissue than in O-ED tissue, as were dihydrotestosterone (DHT) levels and 5 alpha reductase levels. Testosterone levels were similar for PP-ED and O-ED tissue samples. Cavernosal samples from O-ED patients had more fibrosis and fewer smooth muscle cell bundles than samples from PP-ED patients; and samples from PP-ED patients were similar to those from control samples from patients without ED. The authors suggest that the increased androgen activity in the PP-ED tissue may be why it has a healthier appearance than the O-ED tissue.

The precise role of the androgen receptors in various subpopulations of men with ED is an ongoing question, deserving of more studies like this one. The relationship between structure and function still needs greater elaboration however and ultimately treatment approaches developed to achieve the goal of restoration of function.

Posttranslational regulation of eNOS by estrogen in the rat vagina.

Authors: Biljana Musicki, Travis Strong, Tongyun Liu, Gwen Lagoda, Trinity Bivalacqua, and Arthur Burnett

Estrogen regulation of endothelial nitric oxide synthase (eNOS) in the rat vagina was examined in a study presented by Biljana Musicki and the Hopkins group. Estrogen deprivation led to decreased eNOS activity via changes in eNOS phosphorylation and increased binding of eNOS to the negative regulator caveolin-1. Estrogen replacement restored eNOS activity. Estrogen deprivation did not affect phosphodiesterase 5 levels in the vagina but did increase inducible-NOS activity, leading to increases in cGMP and protein kinase G (PKG) levels. Estrogen may control the blood flow to the rat vagina by constitutive post translational activation of eNOS.

While greater insights into the role played by testosterone and its metabolites in man are rapidly evolving, the regulatory role of estrogen in females still has many unanswered questions. This study revealed that estrogen in this animal model may have a direct post-translational role in mediating blood flow through eNOS. Interesting as the vaginal effect may be a signal that these estrogen effects may also impact other vascular beds as well.

Extract of horny goat weed (Epimedium koreanum) for penile rehabilitation in rats.

Authors: Alan Shindel, Yun-Ching Huang, Thomas Fandel, Benjamin Breyer, Guiting Lin, Olga Aminifard, Maurice Garcia, and Tom Lue

Icariin (ICA) is an extract of horny goat weed, a traditional Chinese treatment for impotence. Previous studies demonstrated that ICA is an inhibitor of phosphodiesterase type 5. Alan Shindel presented a study examining the effects of ICA in a rat model after 4 weeks of daily dosing following cavernosal nerve injury. Erectile function was assessed by measuring intracavernosal pressure following electrical stimulation of cavernosal nerves and the presence of penile neuronal cells containing neuronal nitric oxide synthase (nNOS) was assessed using staining techniques. Erectile function was improved and more nNOS positive neurons were observed in the ICA-treated animals than in the control group. Thus ICA may be useful as a penile rehabilitation therapy following cavernous nerve injury.

This study shows great interest for this agent in facilitating erectile function in an animal model following injury. The real question is whether it is superior to current agents and whether its mechanism of action is novel or similar. The side effect profile would also need to be further elaborated. The discovery of agents that may utilize novel pathways or have a more favorable adverse effect profile provides clinicians with great hope for future therapeutics in this field.

Time course of FKBP expressions in rat penis and pelvic ganglia after cavernous nerve injury and treatment with immunophilin ligands.

Authors : Gwen Lagoda, Sena F Sezen, and Arthur Burnett

In this study presented by Gwen Lagoda from the Burnett lab at John’s Hopkins, the effects of FK506 and rapamycin were examined in a rat cavernosal injury model. Erectile function was assessed by measuring intracavernosal pressure following electrical stimulation of cavernosal nerves. Five days of treatment with FK506 and rapamycin after cavernosal injury preserved erectile function, when compared with a control untreated group. FK506 and rapamycin are active when bound to specific protein partners. The expression patterns of these binding protein partners differed over time and by tissue location following cavernous nerve injury. This suggests that the FK506 and rapamycin may preserve erectile function by interacting with different binding proteins in different tissues and at different times after cavernosal injury.

Neurotropic and regenerative strategies for men undergoing prostatectomy remains an area of great interest as in spite of advances in surgical technique at least 50% of men currently undergoing surgery will have loss of sexual function as a consequence of their treatment. The potential for these agents to impact positively in this population of men is exciting and deserving of further study.

Non-cell line induced autologous adult adipose tissue derived stem cells enhance recovery of erectile function in the rat following bilateral cavernous nerve crush injury.

Authors : Anthony J Bella, Thomas M Fandel, Guiting Lin, Surat Phonsombat, CS Lin, Maurice M Garcia, William O Brant, Tom F Lue

In this study presented by Anthony J Bella, the effects of adult adipose derived stem cells (ADSCs) on erectile function were examined in a rat cavernosal injury model. Erectile function was assessed by measuring intracavernosal pressure following electrical stimulation of cavernosal nerves. Five weeks after cavernosal injury, ADSCs treatment preserved erectile function, when compared with an untreated control group. Injection of ADSCs at the site of cavernosal injury was less effective than injection both at the site of cavernosal injury and at pelvic ganglia. The stem cells were still alive after 5 weeks. Possible models for the effect of ADSCs include differentiation of the stem cells in the local environment or growth factors secreted by the ADSCs acting on the host cells of the rat.

Stem cell research is a controversial yet terribly powerful avenue of research. The advantage this group has in evaluating adipose derived stem cells is the lack of controversy in their use. They simply obtained adipose cells, which we all carry too many of, and allow study them. Interestingly it appears that they may have a means of minimizing the adverse effects of nerve injury, a topic of great interest to men undergoing prostatectomy for definitive treatment of prostate cancer.

Long-term treatment with 5-alpha reductase inhibitors impairs erectile response in rats

Authors: Andrew Harbin, Serap Gur, Fikret Erdemir, Irwin Goldstein, Wayne Hellstrom

Treatment with 5-alpha reductase inhibitors (5-ARIs) can lead to sexual dysfunction. To better understand how this occurs, the effect of long-term treatment with 5-ARIs on erectile function was assessed in two rat models: 1) measuring intracavernosal pressure following electrical stimulation of cavernosal nerves and 2) measuring contraction of corpus cavernosum muscle strips in a tissue bath. As presented by Andrew Harbin, 30 days treatment with 5-ARIs (finasteride or dutasteride) reduced the responses in both models, when compared with an untreated control group. This study suggests that treatment with 5-ARIs significantly reduces erectile function via impairment of nerve induced erections.

While their mechanism of action of the prostate are very well described, 5-ARI’s inhibition of testosterone metabolism may have a direct effect on erectile mechanisms as well. This report shows that in a biological as well as an in vivo prep measurable alterations in erectile function are seen.

Further work to define whether these same alterations can be determined to occur in man, over what length of time and their reversibility would be of great interest.

Relationship between visceral adipose tissue and erectile function in response to caloric restriction

Authors: Tina Maio, Marina Komolova, Johanna Hannon, Michael Adams

A high proportion of men with erectile dysfunction (ED) are obese. Tina Maio presented a study which used a rat model to test whether caloric restriction decreased visceral adipose tissue (VAT) and delayed the age-related progression of ED. Obese rats underwent moderate or aggressive weight reduction for 20 weeks. VAT decreased with caloric restriction and erectile function increased. The negative effect of weight gain on erectile function was greater in older rats, and also greater in hypertensive rats.

The relationship between fat , exercise and erectile dysfunction is important and reversible. There exist clear evidence in the peer reviewed literature that a concerted program of exercise, diet and psychological support can reduce rates of ED by 10 -30%. Work such as this report which attempt to define which populations are best targeted for this approach are of great value.

Sphingosine-1-Phospate induced contraction of human corpus cavernosum smooth muscle is mediated by the rho-kinase pathway and is upregulated by diabetes.

Authors: Xia Xinhua Zhang, Memduh Aydin, Arnold Melman, Michael DiSanto

Sphingosine-1 Phosphate (S1P) is a bioactive lipid found in blood. In this study presented by Michael DiSanto, S1P was shown to contract corpus cavernosal tissue obtained from patients with erectile dysfunction (ED). Tissue from diabetic patients was more responsive to S1P than was tissue from non-diabetic patients. In addition SIP levels were increased in tissue from patients with type I or type II diabetes, suggesting that SIP serum levels may serve as a biomarker for urogenital dysfunction.

The recent acceptance that ED may be an early marker for vascular disease and if shown to be accurate that S1P is an early marker of ED, may lead to further studies into the relationship between S1P and vascular disease risk.

Clinical Research Award Recipients

Testosterone therapy in men with untreated prostate cancer on active surveillance

Abraham Morgentaler, Richard Bennett, Osama Mohamed, Robert Chan, Mohit Khera, Larry Lipshultz

A history of prostate cancer has been considered a contraindication for testosterone therapy; testosterone was believed to cause rapid prostate cancer growth and disease progression. This view has been recently challenged by a number of studies. In this study presented by Richard Bennett, 13 hypogonadal men with prostate cancer (low volume Gleason 6) who were enrolled in an active surveillance protocol were treated with testosterone. After an average of 12 months testosterone treatment, average PSA values had not increased and prostate biopsy revealed that the cancers had not substantially progressed.

Few areas of urology and urologic dogma have been as controversial. The tide of opinion seems to be changing now to reflect that in certain low grade prostate cancer cases where close follow up is possible among symptomatic hypogonadal men, testosterone may be clinically indicated.

Does intralesional verapamil for treatment of Peyronie’s disease affect sexual behavior in between injections?

David Rosenberg, Andrew Nisbet, Stanton Honig

Six injections of intralesional verapamil were administered over 12 weeks to 13 patients with Peyronie’s disease and the effects on sexual activity were monitored. As presented by Stanton Honig, the treatments were well tolerated and most patients (12 of 13) had unchanged or increased sexual activity between injections. Thus intralesional verapamil injections do not appear to have a negative impact on sexual activity.

The greater question is whether this approach of intralesional injections is clinically beneficial for the men who choose to undergo this minimally invasive therapy. Most reports document about a 50% response rate but few placebo controlled trials exist. Its reassuring to see as reported here that their sexual activity is not negatively impacted and in some cases was increased indirectly indicating that some benefits were perceived by some patients.