Male Sexual Medicine -- What's New?

Wayne J. G. Hellstrom, MD, FACS

Disclosures

June 14, 2004

Editorial Collaboration

Medscape &

The field of sexual medicine is now a clearly defined discipline in clinical medicine. With the recognition of a substantial prevalence of erectile dysfunction (ED) in the general population and the establishment of effective therapies, researchers are now focusing on other areas of investigation and expanding the boundaries of sexual medicine.

A significant amount of information was presented at the 2004 Annual Meeting of the American Urological Association (AUA) from over 200 published abstracts, various podium and poster sessions, educational courses, and the daylong session sponsored by the Sexual Medicine Society of North America (SMSNA). Four selected areas of interest are covered in this overview.

Oral ED Therapy

Oral agents are the primary therapy for the majority of men presenting with ED. A current hypothesis is that nocturnal erections contribute to the morphodynamic integrity of human corpora cavernosal smooth muscle cells. It has been reported that sildenafil at bedtime significantly improves nocturnal erections. Researchers from Cologne, Germany, prospectively studied the effect of long-term sildenafil therapy.[1] In a prospective, randomized, controlled trial, 76 men (mean age, 47 years) with ED > 6 months were administered nightly sildenafil 50 mg or sildenafil 50-100 mg on demand for 1 year. A third group did not receive any medical therapy.

Following the yearlong study and after a 1-month washout with no therapy, 59% of the nightly dosing group and 10% of the on-demand group had moved into the normal International Index of Erectile Function (IIEF) domain range. Similarly, the nightly dosing group documented significantly improved cavernosal arterial inflows on penile duplex Doppler studies (from 29 ± 9.8 to 38 ± 10 cm/s, P < .05), whereas the on-demand group had a slight but nonsignificant improvement in this parameter, and the untreated group declined slightly. Further follow-up after another 6 months with no ED therapy revealed sustained benefits in penile duplex Doppler parameters and IIEF scores in the nightly dosed patients.

These preliminary data suggest that chronic phosphodiesterase-5 (PDE-5) inhibitor therapy may induce both structural and physiologic changes in the penis. This may reverse or even cure men suffering from organic ED, and this novel concept potentially opens a new area of study in reference to PDE-5 inhibitor mechanisms. Undoubtedly, focus on endothelial dysfunction in cavernosal tissues will be the target of future research in this area.

Although all 3 PDE-5 inhibitors have been available to the US market for < 6 months, Europeans have been exposed to all 3 drugs for > 18 months. Real-world, nonpharmaceutical company-sponsored studies on efficacy, safety, and preference generate much clinical interest.

In a multicenter PDE-5 inhibitor naive study, 237 men were randomized to 6 weeks maximum of approved doses of sildenafil (S, 100 mg), tadalafil (T, 20 mg), vardenafil (V, 20 mg), or placebo (P), whereas another 211 men received half doses of each.[2] One-week washouts were required between medication changes. Primary endpoints were changes from baseline in Q3 (vaginal penetration), Q4 (erection maintenance), IIEF domains, global assessment question, and patient preference scores. At time of abstract submission, partial data analysis for maximum dose changes from baseline for Q3 were P: 03, S: 1.5, T: 1.5, and V: 1.6 (P < .001), and for Q4 were P: 0.5, S: 1.7, T: 1.6, and V: 1.9 (P < .001). Patient preference for maximum dose administration was V: 43%, S: 17%, and T: 40%, and for half dose V: 50%, S: 31%, and T: 19%.

Another study from Germany sought to determine patients' PDE-5 inhibitor preference when offered all 3 drugs in an open-label trial.[3] Four hundred five patients (mean age, 59.4 years) with ED (mean duration, 5.7 years) were exposed to an arbitrary sequence of all 3 PDE-5 inhibitors. All patients underwent comprehensive work-ups, including IIEF, duplex Doppler, and preference modules. The overall preference rates were T: 45%, V: 29%, S: 14%, and none: 22%.

Among the 96 diabetics (mean age, 58.8 years) with ED (mean duration, 5.0 years), the preference rates were T: 36%, V: 29%, S: 13%, and none: 22%. In reference to the reasons for preference for each respective agent, 84% claimed duration of action for T; 74% stated confidence medication works every time for V; and 75% cited better efficacy (hardness) for S. The side effects were as illustrated in the Table.

Table. Side Effects of the 3 PDE-5 Inhibitors
  Sildenafil Vardenafil Tadalafil
Headache 20% 17% 12%
Dyspepsia 6% 6% 5%
Rhinitis 7% 6% 4%
Flush 16% 10% 7%
Myalgia/back pain < 1% < 1% 3%
Visual disturbance/eye pressure 6% 3% < 1%
Prostate Cancer

The introduction of nerve-sparing radical retropubic prostatectomy (NSRRP) with eventual preservation of erectile function has done much to make radical retropubic prostatectomy a mainstream therapy for men diagnosed with localized prostate cancer. Recently, sural nerve interposition has been advocated for men undergoing NSRRP as a means to preserve potency.

In a German study, NSRRP was performed in 688 men with 82.3% completing all ED questionnaires and 432 having normal preoperative erectile function.[4] Final analysis included 138 men after unilateral NSRRP, 273 men after bilateral NSRRP, and 21 men after unilateral NSRRP and contralateral sural nerve interposition. Erectile function following unilateral NSRRP with unilateral sural nerve interposition was not significantly different as compared with unilateral NSRRP alone and was, as expected, significantly worse than bilateral NSRRP. At this juncture, the investigators infer that sural nerve interposition grafting is experimental and in need of more long-term study.

At last year's AUA meeting, improvement in unassisted erectile function was reported in 76 men treated with nightly sildenafil for 9 months after bilateral NSRRP. This year, the same study authors report on long-term RigiScan monitoring in a subset of 54 such men with normal preoperative erectile function, defined as a combined score of ≥ 8 (Q3 and Q4 from IIEF) and normal RigiScan results (≥ 10 continuous minutes of base rigidity).[5]

Patients were randomized to 50 mg or 100 mg of sildenafil, or placebo 4 weeks post-surgery and received 7 months of double-blind nightly treatment. Two consecutive RigiScan nights were done at 4, 12, 24, 36, and 48 weeks post-surgery. In this subset, 10 of 35 (29%) sildenafil-treated and 1 of 19 (5%) placebo-treated patients demonstrated the return of spontaneous erections. There was no significant difference in preoperative minutes of tip and base rigidity greater than 55% in all treatment groups. The most discriminating measure, at 48 weeks, between responders and nonresponders, was tip rigidity > 55%, and was longest in patients receiving 100 mg of sildenafil (Figure 1). Chronic PDE-5 inhibition may improve cavernosal tissue oxygenation by way of nocturnal erections and/or it may involve neuronal regeneration.

Figure 1. Presurgery and postsurgery results in patients with prostate cancer.
Prosthetic Surgery

Implantation of inflatable penile prostheses (IPPs) in men with end organ disease who have failed other less-invasive ED therapies continues to provide high rates of satisfaction. The innovation in design and the materials used for a penile prosthesis has translated into increased longevity. However, a major concern for patients and surgeons remains -- prosthesis infection, which occurs in 1% to 3% of virgin cases and 10% to 18% of revision cases. Both of the major manufacturers of penile prostheses in the United States have introduced products that aim to reduce the chance of prosthetic infection.

The AMS 700 CX implants are impregnated with minocycline and rifampin to target staphylococci, the most common pathogen in penile prosthesis infections. Data from revision cases from May 2001 to September 2003 for InhibiZone and non-InhibiZone prostheses were reviewed.[6] From 8754 revision cases, with implant times of 4-28 months, 5310 (60.7%) were non-InhibiZone and 3444 (39.3%) were InhibiZone revision implants. The infection rate of 2.41% with non-InhibiZone revision cases was reduced to 1.36% with the use of InhibiZone devices (44% decrease in infection rate).

The Mentor Titan IPP is coated with polyvinylpyrrolidine a hydrophilic substance that reduces bacterial adherence and absorbs and elutes the antibiotics the device is immersed in intraoperatively. From October 2002 to August 2003, 2357 Titan IPPs compared with 482 noncoated alpha-1 IPPs were implanted.[7] The infection rate for the coated Titan IPP was 1.06% (25/2357) vs 2.07% (P < .03) for the noncoated alpha-1 IPP. Staphylococcus species were the predominant microorganisms cultured in both groups. Long-term follow-up on both of these databases is required before these anti-infective innovations are considered the standard of care. Nevertheless, advances such as these should ultimately improve both patient satisfaction and the overall results.

The ease of the transcrotal approach for the implantation of an IPP and the proximity of the urethra has allowed for a new strategy of dual implantation of the artificial urinary sphincter and IPP (Figure 2). Concerns regarding increased infection rates and poor outcomes have prevented widespread acceptance of the simultaneous implantation technique. A multi-institutional evaluation of synchronous dual prosthesis implantations in 22 patients between 2000 and 2003 revealed 2 urethral erosions and a reservoir migration, but no postoperative infections.[8] Risk factors included diabetes in 7 patients (32%), hypertension in 6 (27%), and a history of radiation therapy in 6 (27%).

Figure 2. Dual implantation of an artificial urinary sphincter and IPP.

The overall revision rate was 14%. All patients reported < 1 pad per day of urinary leakage. High-risk patients with complex urologic issues were predisposed to a higher complication rate; however, the inherent advantage of a single anesthetic event for patients employing a single transcrotal incision should encourage acceptance of this technique.

Basic Research

There were many excellent papers on basic research in sexual medicine at the AUA 2004 meeting. Representative reports are discussed here for a few fields of investigation.

Nitric Oxide Synthase

The mechanisms governing erectile failure in diabetic patients are dependent on a number of factors, including endothelial dysfunction, neuropathy, oxidative stress, and structural changes in the penile vascular bed. Such alterations in the peripheral vasculature may underlie the high prevalence (> 50%) of ED in diabetic men. A major factor contributing to diabetic ED is a reduction in the number of nitric oxide synthase (NOS)-containing nerve fibers, constitutive NOS activity, and impaired endothelial- and neurogenic-mediated corporeal smooth muscle relaxation.

Recently, researchers have described the RhoA/Rho-kinase signaling pathway that influences corporal smooth muscle tone. This novel signaling cascade has been shown to suppress endothelial NOS in systemic vascular beds and, thus, reduce endothelial cell-derived nitric oxide. In the top abstract that was awarded the Yamanouchi Prize for ED research, researchers provided the first evidence, at both the molecular and functional levels, for the biological role of RhoA/Rho-kinase in regulating endothelial NOS (eNOS) expression and function in the diabetic corpora cavernosa.[9]

These data suggest a possible mechanism by which diabetic men may develop ED resulting from decreased nitric oxide (NO) production and upregulation of the RhoA/Rho-kinase signaling pathway in the corporal vasculature. Inhibition of RhoA/Rho-kinase, by adenoassociated viral gene transfer of the dominant negative RhoA mutant to the diabetic penis, enhanced penile eNOS expression, constitutive NOS activity, and cyclic guanosine monophosphate (cGMP) levels, thereby restoring endothelial-derived NO vasodilation and erectile function. Hence, RhoA/Rho-kinase may represent a novel therapeutic target for the treatment of diabetes-related ED.

Gene Therapy for ED?

With the advent of new vector systems for gene therapy, this novel therapeutic approach for the treatment of ED may become a reality. The use of a genetic approach to restore neuronal signaling in injured nerves of the neurovascular bundle in patients' postradical prostatectomy represents an attractive form of therapy also for this subset of patients with ED. In a German study,[10] researchers investigated the effect of delivering Schwann cells genetically modified with glial cell line-derived neurotrophic factor (GDNF) to the cavernous nerves after bilateral excision of the cavernous nerve in an experimental animal model.

Their findings demonstrated that animals undergoing cavernous nerve resection had significant impairments in erectile function as measured by cavernous nerve stimulation. However, cavernous nerve-resected rats receiving GDNF-hypersecreting Schwann cell grafts had significant improvements in erectile function, and axonal regeneration with new B and C fibers. These data suggest that GDNF-hypersecreting Schwann cell graft gene therapy might be applicable for the treatment of postradical prostatectomy ED owing to its regenerative capacity.

eNOS-Transduced Marrow Stromal Cells

One of the most important recent discoveries in biomedical research is that stem cells are found in many tissues of the adult and can provide new cells for normal tissue turnover, as well as contribute to regenerate damaged or diseased tissue. Marrow stromal cells (MSCs), also known as mesenchymal stem cells, are adult stem cells from bone marrow that have multilineage differentiation potential and contribute to the regeneration of mesenchymal tissue, such as bone, cartilage, fat, and muscle. Because MSCs are relatively easy to isolate, expand, and manipulate in vitro, genetically modified MSCs have recently been used for gene delivery and tissue regeneration in the treatment of a variety of diseases with little or no host-immune response.

Researchers reported a method for delivering eNOS-transduced rat MSC (rMSCs) to the penis of aged rats while evaluating the usefulness of gene therapy for the treatment of ED.[11] rMSCs gave rise to smooth muscle and endothelial cells that were functionally active. Overexpression of eNOS in the corpus cavernosum led to improvement of the corpus cavernosum function. These data suggest that this novel cell-based gene-therapy approach may be used to replace diseased endothelial and smooth muscle cells in the penis, thus restoring erectile function.

Priapism and PDE-5A Downregulation

Priapism is defined as an abnormally prolonged penile erection, which occurs unassociated with sexual interest. The term also refers to an actual sexual disorder affecting several clinical populations, including as many as 40% of men with sickle cell disease. Conventionally understood hematologic dyscrasias and traumatic insults of the penis or perineum affecting genital blood flow, as well as pharmacologic causes (namely, intracavernous injection of pharmacologic agents prostaglandin E1 and papaverine), fail to explain many divergent presentations of priapism. Therefore, the etiology of the disorder remains obscure. For many years, there has been no validated animal model to study the pathophysiology of priapism.

Two groups from the Johns Hopkins Hospital, Baltimore, Maryland, and the University of California at San Francisco presented data pointing to a PDE-5 dysregulation in association with unregulated penile erection in 2 animal models of priapism. Investigators used small interference RNA (siRNA) to silence the PDE-5 isoform of corporal smooth muscle cells in vitro, and after intracavernous injection in the rat penis.[12] They demonstrated that, in rats, silencing of PDE-5 by siRNA resulted in prolonged accumulation of cGMP in CSMCs and prolonged erection to cavernous nerve stimulation. These investigators concluded that a reduction in PDE-5 may be associated with the prolonged erections of priapism.

Other researchers[13] demonstrated that the eNOS (eNOS -/-) and eNOS/nNOS (double NOS -/-) knockout mouse model had prolonged erections to cavernous nerve stimulation and to intracavernous injection of the NO donor, DEA/NO, in addition to reduced erectile responses to intracavernous injection of sildenafil, when compared with wild-type and nNOS -/- control mice. Of importance, there were significantly more spontaneous erections pre- and postcavernous nerve stimulation in the eNOS -/- and dNOS -/- mice. Examination of the PDE-5A isoform in the penises of the eNOS -/- and dNOS -/- mice demonstrated a significant reduction in PDE-5A protein, gene expression, and activity.

These investigators concluded that the priapic activity observed in eNOS -/- and dNOS -/- mice was associated with a reduction in corporal PDE-5A, suggesting that PDE-5A downregulation may play an important role in the causation of priapism. The priapic behavior in the eNOS -/- mice can be explained by a physiologically relevant supersensitization to cGMP following intense erectile stimulation. As a result of PDE-5 dysregulation, the abundance of cGMP generated locally after an episode of neurostimulation would produce unrestrained erectile tissue relaxation. These studies represent the first physiologic model of priapism and will hopefully lead to effective therapies for this disabling condition.

Conclusion

Molecular studies are in their infancy, but they will play an expanding role in understanding the mechanisms of male sexual function and its pathophysiology. Future developments are expected in Peyronie's disease, premature ejaculation, central acting agents, and gene-based therapies.

References
  1. Sommer F, Engelmann U. What are the long-term effects on erectile function of taking sildenafil on a daily basis? Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 903A.

  2. Porst H, Kleingarn M. The three PDE-5 inhibitors sildenafil, tadalafil and vardenafil -- results of a comparative preference trial in 222 patients with erectile dysfunction. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 1193A.

  3. Sommer F, Klotz T, Mathers M, Bondarenko B, Caspers H, Engelmann U. Which PDE-5 inhibitor do patients prefer? A comparative randomized placebo-controlled multicenter study. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 1192A.

  4. Michl U, Graefen M, Palisaar J, et al. Erection, potency, and sexual intercourse following unilateral nerve sparing prostatectomy with n. suralis transplantation contralateral compared to nerve sparing prostatectomy: a critical analysis of preoperative potent men. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 890A.

  5. Levine L, McCullough A, Padma-Nathan H. Longitudinal randomized placebo-controlled study of the return of nocturnal erections after nerve-sparing radical prostatectomy in men treated with nightly sildenafil citrate. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 875A.

  6. Carson C. Initial success with AMS 700 series inflatable penile prosthesis with inhibizone antibiotic surface treatment: a retrospective review of revision cases incidence and comparative results versus non-treated devices. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 894A.

  7. Wolter C, Rajpurkar A, Kendirci M, Dhabuwala C, Hellstrom W. Hydrophilic-coated inflatable penile prosthesis: one-year experience. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 896A.

  8. Shaw K, Morey A, Jones L, Hakim L, Shannon S, Hellstrom W. Synchronous prosthetic implantation through a trans-scrotal incision: an outcome analysis. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 898A.

  9. Bivalacqua T, Usta M, Champion H, et al. RhoA/RHo-kinase suppresses endothelial nitric oxide synthase in the penis: novel mechanism for diabetic-associated erectile dysfunction. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 1411A.

  10. May F, Weidner N, Matiasek K, et al. Bridging the gap: GDNF-hyperselecting Schwann cell grafts restore erectile function after ablations of cavernous nerve segments. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 1425A.

  11. Bivalacqua T, Usta M, Champion H, Deng W, Kadowitz P, Hellstrom W. Mesenchymal stem cells alone or modified with eNOS restore erectile function in the aged rat: cell-based gene therapy for erectile dysfunction. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 1417A.

  12. Lin C, Lin G, Lue T. Silencing of phosphodiesterase 5 (PDE5) expression by small interference RNA. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 1415A.

  13. Bivalacqua T, Champion H, Takimoto E, Kass D, Burnett A. PDE5 dysregulation in penile erectile tissue: mechanism of priapism. Program and abstracts of the American Urological Association 99th Annual Meeting; May 7-13, 2004; San Francisco, California. Abstract 1423A.

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