Focus on Sexual Dysfunction, Tissue Engineering, Gene Therapy

First Fall Meeting, Society for the Study of Impotence

MEETING REVIEW Focus on Sexual Dysfunction, Tissue Engineering, Gene Therapy Highlights From the First Fall Meeting of the Society for the Study of Impotence October 1-3, 1999, Boston [Rev Urol. 2000;2(3):154-156] Key words: Gene therapy • Prostheses, penile • Sexual dysfunction • Tissue engineering M any of the major investigators in the field of impotence participated in this well-attended first meeting of the society (outside of the meetings held at the annual meeting of the American Urological Association [AUA]). Topics included both male and female sexual dysfunction. The proceedings of the meeting were published in a supplement to the International Journal of Impotence Research (1999;11[suppl 1]:S1-S92). Female Sexual Dysfunction One of the new aspects of the subspecialty of erectile dysfunction is the issue of women with sexual dysfunction (SD) problems. Female sexual dysfunction (FSD), as defined at the meeting, encompasses a variety of complaints, such as anorgasmia, lack of genital sensation, vaginismus, and lack of desire (Table). Interest in studying FSD comes from recent data from the National Health and Social Life Survey (NHSLS), which suggests that about 43% of women in the United States have some form of FSD.1 For purposes of comparison, this same Reviewed by Jacob Rajfer, MD, University of California at Los Angeles. 154 REVIEWS IN UROLOGY study identifies 31% of men who have some form of SD, the most common being premature ejaculation. Shabsigh and colleagues,2 from Columbia University in New York, presented data (using a rat model) showing the relationship between the rich vascular architecture of the vaginal wall and the epithelial cells of the vagina. Further studies are needed to determine the role these vascular channels play in the sexual response of the female. Perhaps if one were to determine how these interactions occur, a therapy could be developed with respect to lubrication disorders in the sexually active woman. Berman and coworkers,3 from Boston University, looked at the hemodynamics of the clitoris during sexual stimulation and found that it responds the same as the penis to external stimuli with an increase in tumescence (although with less intracorporeal pressure and, hence, less rigidity). Doppler studies of the clitoris showed an increase in cavernous arterial blood flow, although not as much as in the penis. In a group of 48 women who were studied for FSD, complaints included low arousal (67%), low desire (21%), difficulty in achieving orgasm (92%), and vaginismus (67%). The physiologic reasons for these com- SUMMER 2000 plaints still remain to be determined. Both physiologic and subjective components of the female sexual response have been difficult to measure objectively, compared with erectile dysfunction (ED) in males, in whom intracorporeal pressures are easily measured and recorded. The investigators offered methods for evaluating both components, including genital blood peak systolic velocity, vaginal pH, vaginal pressure/volume changes, and use of the Brief Index of Sexual Function Inventory. We are in the embryonic stages of the field of FSD. The next few years will be critical in elucidating some of the basic mechanisms involved in these processes. Grand Master Lectures Anthony Atala, MD,4 from Boston Children’s Hospital, presented his data on tissue engineering of the penis. Specifically, his group is trying to “manufacture” corporeal tissue. Although endothelial and corporeal smooth muscle cells can be engineered individually and together, the interaction of the two in a syncytial manner (as seen in normal corporeal tissue) still needs to be worked out. However, the futuristic thoughts of replacing corporeal tissue that is nonresponsive Impotence to pharmacologic stimulation with tissue from the laboratory that can work similarly to normal corporeal tissue is not too far-fetched. One of the common findings of aging-related ED in men is loss of corporeal smooth muscle integrity.5 It is believed that this “myopathy” is one of the major “hits” that the corpora sustain with aging. Another hit that theoretically occurs in the corpora is an abnormality in nitric oxide (NO) production and/or activity of the enzyme nitric oxide synthase (NOS) that produces NO. The NO–cyclic guanosine monophosphate pathway is considered the major pathway for inducing smooth muscle relaxation in the corpora. This deficient/defective NO theory is derived from animal data. The failure to secrete NO and/or activate the NO pathway, combined with less compliant and, hence, less responsive smooth muscle tissue, results in poor corporeal relaxation and a high incidence of “failure to store blood” in impotent men. If this aged corporeal smooth muscle tissue can be reengineered to become normal corporeal smooth muscle tissue, the success of this feat will have far-reaching implications not only in aging but also in other ED states, such as diabetes and priapism. Tom Lue, MD,6 in his overview of gene therapy for ED, stated that the 2 areas targeted for this type of research are the NOS gene and the hSlo (maxiK+ channel) gene.7 NO is synthesized by the NOS gene. There are 3 NOS genes in the body that produce the respective enzymes nNOS, iNOS, and eNOS. • nNOS—neuronal NOS, contained in nerve tissue throughout the body; as an example, it produces the neurotransmitter NO in the cavernous nerve. • iNOS—inducible NOS, which is found primarily in immune cells, such as macrophages. This NOS is responsible for the high NO levels produced during sepsis, since the iNOS gene is activated by bacterial Main Points • In the United States, 43% of women and 31% of men have some form of sexual dysfunction. • In the future, it may be possible to replace corporeal smooth muscle on the penis with laboratory-made tissue to help correct problems of erectile dysfunction. • At present, the most efficient form of gene delivery for erectile dysfunction is by transfection with a virus. lipopolysaccharides and tumor necrosis factor, for example. • eNOS—found in the endothelial cells of the vascular system and involved with tone of the vascular smooth muscle. nNOS and eNOS are constitutive enzymes (always present in the cells that contain them), while iNOS requires its induction (the gene to manufacture the iNOS enzyme is present in the cell, but no iNOS enzyme is made until the gene is activated). The hSlo gene encodes part of the maxi-K channel system that is involved with Ca++ flux within the smooth muscle cell in the corpora. The theory behind this product is that if the hSlo system is up-regulated, enhancement of the relaxation of the muscle is obtained. With gene therapy, it seems logical that if one were to try to up-regulate NO production by the cell, it should not make any difference which NOS gene is inserted as long as there is a mechanism to turn on and turn off the inserted gene. The 3 NOS genes (eNOS, iNOS, and nNOS) are available for NOS gene therapy to the penis. Investigators from Tulane8 presented preliminary data using the eNOS gene for modulation of NOS activity that seems to be present 24 hours after injection of the gene. The ideal for any form of gene therapy in the penis or any other tissue would be prolonged and sustained activity of the transfected gene. Therefore, additional data from this group are necessary to determine whether their method of gene delivery meets these 2 qualifications. The most efficient ways to deliver these genes to the target tissues still remain to be elucidated. Some examples of gene delivery techniques are: • Direct injection of the gene product into the tissue. • Injection of lipid-coated DNA. • Viral vectors. Direct gene delivery of the naked DNA into the tissue is not very successful and long-lasting, because integration into the cell is usually poor (although there are some reports of success in skeletal muscle). With lipidcoated DNA delivery, integration may be very high; however, what can be coated by the lipid is constrained by size. The most efficient form of gene delivery, at the present time, appears to be transfection with a virus—the adenovirus or adeno-associated virus. It is believed that these inert viruses do not cause disease states, but more information is needed on human gene therapy before the optimum delivery system is determined. One form of delivery may be best for one type of tis- Table Female Complaints of Sexual Dysfunction (National Health and Social Life Survey)1 Lack of interest in sex Anorgasmia Nonpleasurable sex Trouble with lubrication Vaginismus Performance anxiety SUMMER 2000 32% 26% 23% 21% 16% 12% REVIEWS IN UROLOGY 155 Impotence continued sue, while another form might be inefficient for the same tissue. The investigators stressed that the penis is the ideal organ for gene therapy in that it “sits” outside the body; therefore, vascular dissemination of the gene delivery systems is not required for the desired genes to gain access into the penis. The gene product can be delivered directly into the penile corpora. At the present time, there are no known ongoing human trials for gene therapy for ED. John Mulcahy, MD,9 from Indiana University Medical Center, reported his data on immediate treatment/removal/ replacement of infected penile prostheses. His method yields a salvage rate of about 82% and should be considered by anyone who performs implant surgery.10 The group from the Robert Wood Johnson Medical School reviewed their data from the NHSLS,1,11 reminding urologists that age, health problems, and urinary tract infections can increase the risk of sexual dysfunction. Every student of ED should read the original paper by Laumann and coworkers; it sets the standard for epi- RESIDENTS IN UROLOGY YOU’RE INVITED demiology of ED. Kim and colleagues12,13 reviewed their early work on nerve grafting to replace the cavernous nerves during radical prostatectomy, and Morgentaler and DeWolf14 reported on the immediate placement of a penile prosthesis at the time of radical prostatectomy. Long-term results of such treatments will be needed before they are embraced by the urologic community as standard treatment. As a result of its success in drawing many experts in the field to the Boston meeting, a second meeting of the society (outside of the AUA venue) is being planned for fall 2000 in Cleveland. Anyone interested in impotence should find this meeting an excellent source of information. ■ References 1. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281:S37-S84. 2. Shabsigh A, Buttyan R, Burchardt T, et al. The microvascular architecture of the rat vagina revealed by image analysis of vascular corrosion casts. Int J Impot Res. 1999;11(suppl 1):S23-S30. 3. Berman JR, Berman LA, Werbin TJ, et al. Clinical evaluation of female sexual function: effects of age and estrogen status on subjective and physiologic sexual responses. Int J Impot Res. 1999; 11(suppl 1):S31-S38. 4. Atala A. Tissue engineering applications for erectile dysfunction. Int J Impot Res. 1999;11(suppl 1):S41-S47. 5. Jevitch MJ, Khawand NY, Vidic B. Clinical significance of ultrastructural findings in the corpora cavernosa of normal and impotent men. J Urol. 1990;143:289. 6. Lue TF. Future treatment for ED: growth factors and gene therapy. Int J Impot Res. 1999;11(suppl 1):S56-S57. 7. Christ GJ, Rehman J, Day N, et al. Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am J Physiol. 1998;275(2 pt 2):H600-H608. 8. Bivalacqua TJ, Champion HC, Ignarro LJ, et al. Gene-transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat. Int J Impot Res. 1999;11(suppl 1):S67. 9. Mulcahy JJ. Management of the infected penile implant—concepts on salvage techniques. Int J Impot Res. 1999;11(suppl 1):S58-S59. 10. Brant MD, Ludlow JK, Mulcahy JJ. The prosthesis salvage operation: immediate replacement of the infected penile prosthesis. J Urol. 1996;155:155157. 11. Laumann EO, Paik A, Rosen RC. The epidemiology of erectile dysfunction: results from the National Health and Social Life Survey. Int J Impot Res. 1999;11(suppl 1):S60-S64. 12. Kim ED, Scardino PT, Hampel O, et al. Interposition of sural nerve restores function of cavernous nerves resected during radical prostatectomy. J Urol. 1999;161:188-192. 13. Kim ED, Kadmon D, Miles BJ, et al. Bilateral nerve grafts during radical retropubic prostatectomy: a one-year follow-up. Int J Impot Res. 1999;11(suppl 1):S71. 14. Morgentaler A, DeWolf WC. Immediate sexual rehabilitation by simultaneous placement of penile prosthesis with radical prostatectomy: results in 100 patients. Int J Impot Res. 1999;11(suppl 1): S72. Write a Case Review, including history, evaluation, treatment, and discussion. Submit your Case Review by e-mail or mail (instructions below). Those approved by the Medical Editors and peer reviewers will be edited for publication in Reviews in Urology. The primary author of a published Case Review will receive $250. Name by the Medical Editors of Reviews in Urology to Submit a Case Review for Publication in Reviews in Urology Title Mailing address Telephone ________________Fax __________________E-mail __________________ Department head Case Review topic Mail to (include disk): Case Review, Reviews in Urology, 330 Boston Post Road, Darien, CT 06820-4027; E-mail to: herbert.lepor@med.nyu.edu 156 REVIEWS IN UROLOGY SUMMER 2000