Medical Meeting Reports

Summaries talks from the 2007 Winter SMSNA meeting
(Chicago, Il Dec 6-9, 2007).

Thursday

Metabolic Syndrome/ED/Dietary Factors

Kevin McKenna, PhD
Northwestern University
Chicago, Illinois

The prevalence of obesity has increased dramatically in the US during the last 30 years, with obesity defined as a body mass index (BMI) of 30 or greater (equivalent to being 30 pounds overweight if 5’4” tall). Obesity is often combined with diabetes, insulin resistance, hypertension, and hyperlipidemia; a constellation of conditions called the metabolic syndrome. The risk of erectile dysfunction increases with age and with the presence of the metabolic syndrome.

Although the causes of obesity are unknown; the increase in obesity has been accompanied by an increased caloric consumption, as people today consume on average, 300 calories more per day than was consumed by people 30 years ago. The increase in obesity has also been accompanied by increased use of high fructose corn syrup as a sweetener. This sweetener differs from many others in that it does not induce a satiety response after it is consumed.

Dr. Kevin McKenna examined the relationships between consumption of high fructose corn syrup, erectile function, and the metabolic syndrome using preclinical animal models. For 6 weeks, rats were fed chow in which the normal grains had been replaced with high fructose corn syrup. After 6 weeks, erectile function in the rats was greatly reduced; the reduction was comparable to that observed in diabetic rats. Over a longer time period the high fructose corn syrup-fed rats developed the metabolic syndrome. Physiological effects were observed in penile nerves, smooth muscle, and endothelium; some of these effects were irreversible. This study raises many questions, and the consequences of increased consumption of high fructose corn syrup need to be examined in other species. The study also emphasizes, that at least in this rat model, loss of erectile function precedes the development of the metabolic syndrome and the irreversible physiological changes that accompany it, and thus loss of erectile function may serve as an early warning signal along this road.

Gene Therapy Targets for Rx of ED

Christian Stief, MD
University Clinics München
Ludwig Maximilians-Universität
Germany

Professor Christian Stief, serving as the ESSM invited speaker, presented an overview of work from many laboratories on three ongoing strategies for using gene therapy to treat erectile dysfunction (ED). The first two strategies were designed to elevate cGMP in the penile smooth muscle; this leads to smooth muscle relaxation and increased blood flow into the corpus cavernosum. The goal of the first strategy was to increase endothelial nitric oxide synthase (eNOS), which makes cGMP, to compensate for decreased eNOS activity stemming from age and/or diabetes. Using a diabetic rat model, eNOS levels were increased following eNOS gene therapy. Erectile function increased, and improved even more fully with the addition of a PDE5 inhibitor. The second approach targeted PIN; this protein normally inhibits neuronal NOS (nNOS) function. After 4 weeks of silencing PIN expression with short hairpin RNA, nNOS activity increased, and erectile function improved. The third approach involved transfer of a gene encoding a potassium channel that is localized in the penile neuronal membranes (Slo or Maxi-K+ channel). The resulting hyperpolarization of the nerve led to a more responsive erectile response in the rats. Dr. Stief described a Phase I clinical study in humans that used this third approach. The Maxi-K+ gene therapy treatment pioneered by Arnold Melman’s lab in New York, appeared well tolerated and some early hints of efficacy were obtained.

He concluded that there is convincing animal data for the use of gene therapy to treat erectile dysfunction and promising results from a Phase I clinical study.

Stem Cells and the Treatment of Sexual Dysfunction

Tom Lue, MD
University of California
San Francisco, California

Dr. Tom Lue described the use of autologous adipose-derived stem cells to treat erectile function in several rat models; these included a nerve crush model in young rats, a bilateral cavernosal nerve crush model in older rats, and diabetic rats. The stem cells were tethered to biodegradable beads to keep them localized to the rat penis. Following injection of the stem cells, erectile function improved in each of these models. The stem cells do not replace the damaged neurons, thus the mechanism for the improvement in erectile function may involve cytokine secretion by the stem cells and is being studied further. Dr. Lue described the advantages of using autologous adipose-derived stem cells. They are readily accessible and can be isolated in large enough numbers that cell culturing is not needed; this avoids the genetic changes often induced by keeping stem cells in culture over time. The use of autologous cells also reduces immunological concerns.

The strength of this work is its potential widespread applicability. The ease of obtaining fat derived stem cells makes this form of rehabilitative research very exciting and powerful.

Sickle Cell Disease in ED: Update on Translational Model and Clinical Care

Arthur Burnett, MD
Johns Hopkins Hospital
Baltimore, Maryland

Ischemic priapism (prolonged penile erections) may lead to permanent erectile dysfunction. Approximately 40% of men with sickle cell disease have episodes of priapism; it can also be idiopathic in origin. Dr. Bud Burnett presented a model for the pathophysiology of priapism. In this model, priapism is caused by a cycle of nitric oxide imbalance, PDE5 down regulation, anoxia, and oxidative stress. This model championed by work at Hopkins by Dr Burnett, predicts chronic treatment with PDE5 inhibitors (sildenafil, vardenafil, tadalafil) will elevate cGMP levels, which in turn may normalize PDE5 expression levels and stop the cycle of events leading to priapism. Dr. Burnett presented data on PDE5 inhibitor therapy mice with sickle cell disease; this treatment reduced the frequency of spontaneous erections. The results of PDE5 inhibitor treatment of seven patients with stuttering priapism (3 idiopathic, 4 resulting from sickle cell anemia) were also presented. Six of the seven patients reported an improvement in their priapism after long-term therapy. These promising early results have led to the initiation of a placebo-controlled study of PDE5 inhibitors to treat priapism. Although descriptions of priapism have existed for centuries, the clinician is often faced with limited therapeutic options for those men with recurring priapism. This approach, if proven effective in large clinical trials, would represent a significant advance.