John P. Mulhall

ERECTILE DYSFUNCTION AFTER RADICAL PROSTATECTOMY: HEMODYNAMIC PROFILES AND THEIR CORRELATION WITH THE RECOVERY OF ERECTILE FUNCTION

PURPOSEnDespite the advent of nerve sparing radical prostatectomy some men experience erectile dysfunction. Many of these men have vasculogenic erectile impairment in the form of arterial insufficiency or venous leakage. Recent data imply that early postoperative injection therapy may decrease the rate of erectile dysfunction. We defined hemodynamic patterns in patients who underwent bilateral nerve sparing radical prostatectomy to assess the chronology of venous leakage development and explore the correlation of hemodynamic profiles with the return of functional erection 12 months postoperatively.nnnMATERIALS AND METHODSnPatients with excellent preoperative erectile function who underwent bilateral nerve sparing surgery and had no pharmacological support for erectile dysfunction in the initial 12 months after surgery received vascular evaluation at presentation. Vascular evaluation involved cavernosometry or penile ultrasonography. Patients were then interviewed again at least 12 months postoperatively to assess the ability to achieve sexual intercourse.nnnRESULTSnOur study group comprised 96 men with a mean age plus or minus standard deviation of 54 +/- 12 years who met all inclusion criteria. All patients had pathologically proved organ confined disease. Mean time to the initial postoperative presentation was 6 +/- 5 months. Patients were divided into 4 groups according to the time of vascular studies postoperatively, namely less than 4 to 8, 9 to 12 and greater than 12 months. Normal vascular status, arterial insufficiency and venous leakage were diagnosed in 35%, 59% and 26% of the group, respectively. No difference in the incidence of arterial insufficiency was noted in the 4 time groups. Time postoperatively was significantly associated with the incidence of venous leakage (14% at less than 4 months and 35% at between 9 and 12). In regard to the correlation of the vascular diagnosis with the return to functional erection 47% of the normal, 31% of the arteriogenic and 9% of the venous leakage group achieved sexual intercourse 12 months postoperatively.nnnCONCLUSIONSnThese data imply that the longer the duration of erectile dysfunction after radical prostatectomy, the greater the risk of venous leakage. Furthermore, it appears that the prognosis for the return of functional erection is worst when venous leakage is present.

The timing of penile rehabilitation after bilateral nerve-sparing radical prostatectomy affects the recovery of erectile function

Study Type – Therapy (case series)u2028Level of Evidenceu20034

Radiation exposure to the corporeal bodies during 3-dimensional conformal radiation therapy for prostate cancer.

PURPOSEnRadiation therapy for prostate cancer is associated with the development of post-treatment erectile dysfunction. Use of 3-dimensional (D) conformal delivery techniques has reduced delivery of radiation to periprostatic tissues. However, the exact magnitude of radiation that the corporeal bodies are exposed to using this delivery technique is currently unknown. This study was undertaken to calculate the radiation dose delivered to the corporeal bodies during 3-D conformal radiotherapy.nnnMATERIALS AND METHODSnTen patients with proven prostate adenocarcinoma who underwent pre-therapy computerized tomography simulation and radiation delivery planning had the proximal corporeal bodies outlined on axial computerized tomography. The dose to the proximal penile tissues was then calculated using computer modeling.nnnRESULTSnThe total dose of radiation administered to the prostate and seminal vesicles was 73.8 Gy. Mean radiation delivered to the most proximal 2 cm. of the corporeal bodies was 31 +/- 12.8 Gy., equating to 43% of the total dose of radiation delivered to the prostate and seminal vesicles.nnnCONCLUSIONSnThese data indicate that large doses of radiation are being delivered to erectile tissue in the proximal penis despite careful pretreatment planning for 3-D conformal radiation therapy for prostate cancer. These data should encourage the development of radiation delivery strategies that minimize corporeal tissue exposure.

Role of IMRT in reducing penile doses in dose escalation for prostate cancer

PURPOSEnIn three-dimensional conformal radiotherapy (3D-CRT), penile tissues adjacent to the prostate are exposed to significant doses of radiation. This is likely to be a factor in development of posttreatment erectile dysfunction. In this study, we investigate whether intensity-modulated radiation therapy (IMRT) leads to lower radiation exposure to proximal penile tissues (PPT) when compared with 3D-CRT.nnnMATERIALS AND METHODSnTen randomly selected patients with clinically localized prostate cancer constituted the study group. Using identical structure sets, 3D-CRT and IMRT plans were designed for each patient. For IMRT, both tomographic (TOMO) and step-and-shoot (SS) techniques were used. Treatment plans were developed using 18 MV photons for 3D-CRT, 6 MV photons for TOMO, and 6 MV and 18 MV photons for SS plans. The PPT up to the beginning of the penile shaft (usually measuring 2-3 cm) was outlined by a team composed of a board-certified urologist and a radiation oncologist. The outlined PPT was subdivided into three segments (P1, P2, P3), and the radiation dose to each segment and to the entire structure was calculated. In addition, PPT was subdivided into corporal cavernosa (CC) and corpus spongiosum (bulb). The prostate dose was escalated from 73.8 Gy to 81 Gy to 90 Gy. Target D(95) (dose to 95% volume), critical structure D(5) (dose to 5% volume), and D(mean) (mean dose) were used in the comparison among treatment plans. Because 3D-CRT uses larger field margins than does IMRT, target and critical structure doses were recalculated in 3D-CRT plans employing field margins obtained from IMRT plans. Planning target volumes in original and modified 3D-CRT plans were the same.nnnRESULTSnCompared with 3D-CRT plans, the mean PPT doses were reduced by 40.2%, 43.6%, and 46.2%, respectively, at the three prescription dose levels in TOMO plans. The average D(mean) for CC was lower by 46.4%, 48.4%, and 51.4%, whereas the average bulb D(mean) was reduced by 44.2%, 44.9%, and 47.9%, respectively. There was also considerable sparing of P1, with a reduction in average D(mean) of 41.9%, 45.5%, and 48.5% compared with 3D-CRT. All differences between 3D-CRT and IMRT doses were statistically significant (p < 0.001). Similar improvements were noticed in maximum doses (D(5)) for penile structures. The percent dose reduction with IMRT plans improved as prostate dose was escalated. When compared with 3D-CRT plans with reduced fields, IMRT plans showed slightly smaller but still significant improvements in critical structure doses (p < 0.001). Compared with SS plans, TOMO plans produced improved sparing of dose to critical structures.nnnCONCLUSIONSnIMRT allows for dose escalation in prostate cancer while keeping penile tissue doses significantly lower compared to conformal radiotherapy. This may result in improved potency rates over current results observed with 3D-CRT.

Basic fibroblast growth factor expression in Peyronie's disease.

PURPOSEnPeyronies disease is a fibromatosis resulting in scarring of the tunica albuginea. While the inciting event is believed to be trauma to the erect penis, little is understood about the cascade of cellular events that leads to the formation of the plaque. Dysregulated wound healing serves as a paradigm for the study of this condition. Previous work has demonstrated a role for fibrogenic cytokines in wound healing, fibromatoses, including Peyronies disease. We analyze the expression of the fibrogenic cytokine, basic fibroblast growth factor (FGF), by fibroblasts derived from Peyronies disease tissue.nnnMATERIALS AND METHODSnPatients with Peyronies disease undergoing either penile prosthesis insertion or Nesbit penile plication surgery had biopsy specimens removed from the plaque and from normal tunical tissue remote from the plaque. Cell cultures were derived from these specimens. Cultured cells were characterized using immunofluorescence staining and immunosorbent digital imaging. The cell culture supernatants were analyzed using an enzyme-linked immunosorbent assay for the production of basic FGF. Foreskin tissue from men without Peyronies disease was used as control cells.nnnRESULTSnFive independent cell lines were established from plaque tissue and 4 independent cell lines were established from normal tunica from the same subjects. Intracellular antigen expression was consistent with the cells being myofibroblasts. Production of basic FGF by the plaque derived myofibroblasts was significantly greater compared to production by normal tunical myofibroblasts and foreskin fibroblasts.nnnCONCLUSIONSnThese data demonstrate the successful establishment of cell lines from plaque tissue and normal tunica from men with Peyronies disease. The findings indicate a potential role for basic FGF over expression in the tunical fibrosis that occurs in this condition. This information may allow a better understanding of the basic mechanisms involved in the development of this disease. Furthermore, it may permit the elaboration of therapeutic strategies to prevent or reduce tunical scarring and plaque formation.

Analysis of the consistency of intraurethral prostaglandin E1 (MUSE) during at-home use

OBJECTIVESnTo determine the consistency of a successful response to intraurethral prostaglandin E(1) (MUSE), an effective treatment for a proportion of patients with erectile dysfunction, during at-home use in men who had a successful response in the office, to define the factors that correlated with the consistency of the response, and to determine whether patients continued long-term use.nnnMETHODSnThe study group consisted of men with documented erectile dysfunction who had a successful response (grade 3 or 4 erection) to MUSE during an initial in-office dose. All enrollees completed a home diary assessing the treatment success during at least five medication administrations. Factors such as patient age, vascular risk factor status, and degree of in-office response were prospectively evaluated as correlates of response consistency. Finally, patient follow-up was conducted in an attempt to define how many patients were continuing to use this medication as a long-term treatment modality.nnnRESULTSnTwo hundred twelve patients underwent screening and 72 (34%) patients had in-office success. The overall per patient at-home consistency rate was 51%. None of the aforementioned factors correlated with the consistency of the response. At a mean of 9 months after beginning treatment, only 31% of the in-office responders were continuing to use MUSE.nnnCONCLUSIONSnAlthough MUSE is an appropriate and safe treatment for many patients with erectile dysfunction, the lack of consistency is a significant consideration. Clinicians should pay close attention to patient education in an effort to promote realistic expectations for MUSE therapy. Furthermore, the lack of consistency may significantly lower the patients interest in continuing this treatment long term.

An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction

BACKGROUNDnBecause apomorphine is a dopamine agonist that acts on areas of the central nervous system believed to mediate penile erection, its use in erectile dysfunction (ED) has been investigated. However, it also produces nausea by dopamine-receptor stimulation of the chemotrigger zone in the brain. Therefore, a low plasma concentration, achieved rapidly, would be selective for the desired erectile response but would be below the dopamine threshold for nausea.nnnOBJECTIVEnWe evaluated the efficacy and tolerability of a dose-optimized regimen of a sublingual formulation of apomorphine (apomorphine SL) in the treatment of ED.nnnMETHODSnThis was a multicenter, open-label, uncontrolled, Phase III dose-optimization study of apomorphine SL in heterosexual men with ED. The 2-week screening period, during which baseline severity of ED was determined using the International Index of Erectile Function, was followed by a 3-week dose-optimization period beginning at a dose of 2 mg. Patients were to make at least 2 attempts at intercourse per week throughout the study, placing 1 apomorphine tablet under the tongue beforehand. At the end of the first week, the dose could be increased to 3 mg at the discretion of the investigator; at the end of the second week, the dose could be increased to a maximum of 4 mg or decreased as needed. In the following 4-week treatment period, patients took their individual optimal doses. The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse, as assessed by investigators review of data from patients diaries. Secondary variables included the percentage of attempts resulting in successful intercourse, time to erection, and duration of erection. Information about adverse events, including their severity and relation to treatment, was determined on the basis of direct questioning, spontaneous reports, and review of patient diaries.nnnRESULTSnThe study enrolled 849 heterosexual men whose ages ranged from 31 to 78 years (mean, 58.1 years). They had a mean 5.7-year history of ED of varbus causes. ED was mild in 11.5% of the men, moderate in 23.8 c, and severe in 48.1%. When results of the last 8 attempts were pooled, representing the period during which patients were taking their optimal doses of apomorphine SL, the mean percentage of attempts resulting in erections firm enough for intercourse was 39.4%, compared with 13.1% at baseline; attempts resulting in intercourse increased from a mean of 12.7% at baseline to 38.3% with treatment. The average median time to erection was 23 minutes, and the average median duration of erection was 13 minutes. Nausea, the most common treatment-related adverse event (11.7%). was dose related and diminished with continued dosing. One patient had a single syncopal episode that was judged to be related to apomorphine SL.nnnCONCLUSIONSnIn the present study, a dose-optimization regimen of apomorphine SL-with dosing initiated at 2 mg and adjusted up to a maximum of 4 mg as needed-was effective and well tolerated in the treatment of ED, regardless of its cause or severity.

Drugs for the treatment of impotence

SummaryPenile erection is a complex neurovascular event that represents a balance between corporal smooth muscle relaxation and contraction. This balance is determined by the interaction between proerectile and antierectile neurotransmitters. It is believed that nitric oxide is the primary erectogenic neurotransmitter and that noradrenaline (norepinephrine) is the primary erectolytic neurotransmitter. There are a number of pharmacological approaches to the management of erectile dysfunction and manipulation of the neurotransmitter systems. These involve direct delivery of drugs into the erectile chambers (intracavernosal injection therapy), administration of medications into the urethra (transurethral delivery), application of medications to the skin (transdermal delivery) and it is hoped that oral agents will be available in the very near future. This article reviews the world literature on the medications that have been investigated to date and their delivery routes.

Medical treatment of erectile dysfunction

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual relations. Data from the Massachusetts Male Aging Study have indicated that the prevalence of erectile dysfunction of any degree is 39% in 40-year old men, and 67% in those aged 70 years. Effective therapy has been available for some time, but it has commonly involved surgery, external devices or penile self-injection. For many men, these represent unacceptable barriers to seeking therapy. Recently, however, an effective oral medication has become available. This article reviews the physiology and pharmacology of ED. The literature currently available on the effectiveness and safety of various drugs used for ED is summarized, with particular attention to newly available oral agents. Guidelines for work-up and drug treatment of patients with ED are given. Detailed history and physical examination are crucial to the safe and effective treatment of men with erectile impotence. An extensive review of the literature shows that based on safety, effectiveness and ease of use, oral sildenafil citrate is an excellent choice for first-line therapy. Patients who use organic nitrates of any kind in any capacity should not be offered sildenafil. Based solely on effectiveness intracavernosal injection therapy remains the golden standard and should also be offered as an option for first-line therapy for the appropriate patients. Many alternatives are available for men who cannot use sildenafil or injection therapy. A thorough knowledge of existing medications is essential for proper treatment of ED.

Erectile haemodynamic status after radical prostatectomy correlates with erectile functional outcome

To define haemodynamic changes after radical retropubic prostatectomy (RP) and the predictive value of these for the outcome of erectile function (EF), as although there are predictors of the recovery of EF, penile vascular changes might also affect the recovery of EF.