点击显示 收起
美国泌尿学会2005年会
American Urological Association 2005 Annual Meeting
2005年5月21－26日
美国德克萨斯州圣安东尼奥
May 21 - 26, 2005, San Antonio, Texas
Issues in Male Sexual Function
Wayne J. G. Hellstrom, MD, FACS
Introduction
It has been a little more than 7 years since the oral phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of erectile dysfunction (ED) were introduced on the American market. Since that time sildenafil (Viagra, Pfizer), vardenafil (Levitra, GlaxoSmithKline and Schering), and tadalafil (Cialis, Lilly ICOS) have netted sales of many billions of dollars. The gradual maturation of the PDE-5 inhibitor market has not stopped the relentless growth in other areas of demand in sexual medicine.
This review will limit its coverage to Peyronie's disease (PD); the connections among lower urinary tract symptoms (LUTS), benign prostatic hyperplasia (BPH), and ED; penile rehabilitation after prostatectomy; and new observations in the basic and clinical sciences of PDE-5 inhibitors. Premature ejaculation (PE) is an area of sexual medicine that is poised to enter the clinician's landscape and will be covered separately by another author. Surgical andrology, male hormone replacement, and female sexual dysfunction will not be covered in this review as they have for the past number of years.
PD is an enigma in regard to etiology and mechanism of causation, and it has so far proven resistant to truly effective treatments. This condition, which is aptly considered to be a wound-healing disorder, has a reported prevalence of 3% to 9%. PD causes significant psychological and physical distress for many men who would like to seek advice from their physicians.
An interesting study sought to evaluate the understanding and practices of primary care physicians (PCPs) and urologists in relation to PD.[1] A 20-question multiple-choice survey on PD was sent to > 300 PCPs and > 200 urologists throughout Illinois, Wisconsin, and Indiana. The answers reflected an overall poor understanding of PD and its available treatments. For example, 17% of PCPs and 38% of urologists believed that PD spontaneously resolves in > 50% of cases; 48% of PCPs and 37% of urologists thought that PD does not occur with ED; and 51% of PCPs and 1% of urologists were unsure if there are any effective therapies for PD.
This incorrect knowledge base regarding PD will likely lead to delays in diagnosis, referral, and treatment. The authors suggest a need for improved education about PD for PCPs and urologists to help the many men afflicted with this condition. (A nonprofit, totally patient-supported Web site catering to men with PD is now available. Refer patients to http://peyroniesassoc.org for unbiased education, available treatments, location of qualified PD-treating urologists, and links to associated information sources on PD.)
A better understanding of the causes and treatment of PD will no doubt need to be based on knowledge gained in basic scientific research. Two papers were of interest in this regard. The first paper noted an increase of plasminogen activator inhibitor 1 (PAI-1) in a variety of fibrotic conditions and PD.[2] PAI-1 is an inhibitor of both fibrinolysis and collagenolysis. Tissue obtained from the tunica albuginea (TA) from men with PD and men undergoing prosthesis implantation who did not have PD and cells cultured from these tissues underwent assay of PAI-1 expression at the transcriptional and protein levels and were found to be significantly different. The authors have suggested that PAI-1 is a key profibrotic factor and that future therapy should move in the direction suggested by this. In the question-and-answer period, the study authors reported that any drug that increases nitric oxide bioavailability to PD tissues will reduce fibrosis, including inducible nitric oxide synthase. This is in itself a new concept worthy of further academic exploration.
Researchers from Chicago, Illinois, reported that collagen-degrading enzymes or collagenases are reduced in the TA of older men.[3] This age-dependent decrease may contribute to the increase of PD with aging. In particular, they evaluated collagenase inhibitors known as tissue inhibitors of metalloproteinases (TIMPs) and found higher levels in the TA of men with PD compared with men without PD and also in young postmortem patients. The discovery of TIMPs may open up other important avenues for future clinical research.
Another group investigated the relationship of penile vascular status and different types of penile deformities in patients with PD using penile duplex Doppler ultrasound.[4] A total of 523 PD patients were evaluated and categorized into 7 different groups according to deformity (dorsal, lateral, ventral, dorsolateral, ventrolateral, indentation, and hourglass) and varying definitions of vascular status (arterial insufficiency, veno-occlusive dysfunction, mixed vascular disease, and nonvascular). The mean +/- SD patient age was 54 +/- 1.5 years. The most frequently encountered type of deformity was dorsal (43.5%), followed by lateral (24.8%). The mean peak cavernosal systolic values were highest in the ventrolateral group, and these men were surprisingly the oldest (56.7 years). The hourglass group was the youngest (47.4 years), had the lowest degree of angulation, and had the poorest vascular status. Vascular dynamics are important to the surgeon in that they have an influence on postoperative erectile function.
In a study to determine the severity of curvature in PD patients and the relationship between different risk factors, 663 PD patients were retrospectively evaluated.[5] The mean +/- SD age of PD patients was 53 +/- 10.5 years. Half of the patients were in the acute phase (< 12 months) and the other half in the chronic phase (> 12-18 months) of the disease. Fifty percent of the patients had at least 1 vascular risk factor. The degree of deformity was measured: 43.2% had mild curvature (< 30°), 38.6% had moderate curvature (30° to 60°), and 17.9% had severe curvature (> 60°). Forty-three percent of patients had ED as a presenting symptom. Although diabetes showed a higher occurrence in the > 60° angle group, this was not significantly different from the rate found in men without diabetes. Thus, there was no correlation between systemic risk factors and the degree of penile curvature in PD. This is contrary to the opinion of many PD authorities who believe diabetes is a signal for more aggressive disease.
In a single-blind, multicenter, placebo-controlled study that compared intralesional injections of either interferon (IFN) alpha-2b or saline solution, 117 consecutive PD patients (62 control and 55 IFN alpha-2b) were studied.[6] Each patient received 6 biweekly injections for a total of 12 weeks. Penile curvature, validated questionnaires for erectile function, and penile hemodynamics were studied at baseline and after study completion. Penile curvature, plaque size, plaque density, and pain improved statistically in both the saline and IFN alpha-2b patients. However, the improvement was statistically greater in the IFN alpha-2b patients than in those receiving saline solution. The mean International Index of Erectile Function (IIEF) scores improved in both groups. A mean peak systolic cavernosal blood flow velocity improvement was observed only in the IFN alpha-2b group. Adverse effects (flu-like symptoms), which were frequently encountered in the IFN alpha-2b group patients, were mild, of short duration, and effectively treated with anti-inflammatory agents. The remarkable observation in this study is the significant benefit of saline injections alone. The authors hypothesize that the hydrostatic pressures from the saline injection or the elicitation of local factors may induce further local wound-healing activities.
A group from San Francisco, California, described a new surgical technique for PD in an unusual presentation.[7] Five PD patients had penile fracture during intercourse or manual manipulation. Penile ultrasound helped located the fracture site and either a circumcising or ventral midline incisional approach was used. The penile defect was closed primarily and opposing 2-0 Ticron sutures were used for plication to correct any persistent angulation. Four of the 5 patients did well; the fifth eventually required penile prosthesis implantation. Hence, patients with PD may be more prone to penile fracture because penile angulation can cause diminished fibroelasticity. A combined repair and plication procedure is recommended in this rare PD presentation.
At previous American Urological Association meetings, the Multinational Survey of Aging Males (MSAM-7) study documented LUTS as an independent risk factor for sexual dysfunction, with both ED and ejaculatory dysfunction (EjD) being equally common and bothersome in aging males. This relationship was further examined in a physician office-based population of men who presented with symptoms of BPH who enrolled in the BPH Registry and Patient Survey, the first observational BPH registry in the United States.[8]
Six hundred sixty men with BPH (mean age, 66.4 years) completed the 7-item International Prostate Symptom Score (IPSS), bother (ED and EjD) questions, and a number of validated questionnaires.[9] Both LUTS severity and IPSS bother scores increased and were significantly correlated with ED and EjD scores. This positive association between LUTS severity and bother with ED and EjD in men in the BPH registry confirms the previous findings from MSAM-7 and further supports the link between LUTS and sexual dysfunction.
The physiology and pharmacology of EjD remain some of the least explored areas in urologic research. An interesting observation is that BPH patients being treated with tamsulosin (TAM), an adrenergic receptor blocker (alpha-blocker), experience a higher rate of EjD than men receiving other alpha-blockers. The nature and mechanisms of EjD as it is affected by TAM were explored in a study of a group of 60 young, healthy men (20-40 years) who received 5 days of TAM, 0.8 mg, alfuzosin, 10 mg, or placebo in a double-blinded manner.[10] To determine if EjD was local (retrograde ejaculation) or central (anejaculation), the endpoints included changes in antegrade ejaculatory volume and quantitation of postejaculation sperm concentration in urine (a marker of retrograde ejaculation). The authors noted that 90% of subjects had a > 20% reduction in antegrade ejaculatory volume and 1 of 3 had anejaculation while taking TAM but not while receiving alfuzosin or placebo. There were no differences in postejaculate urine sperm concentrations for the 3 arms of this study, suggesting that the EjD associated with TAM is not retrograde ejaculation but likely involves a central inhibition of the ejaculatory mechanism. Research in these areas will undoubtedly lead to novel pharmacologic therapies for premature, delayed, and other ejaculation syndromes.
Bilateral nerve-sparing radical retropubic prostatectomy (NSRRP) improves postoperative recovery of erectile function. However, the impact of neurovascular bundle preservation on longitudinal health-related quality of life outcomes has not been adequately assessed with validated questionnaires. A total of 342 patents who underwent NSRRP (20% unilateral and 75% bilateral) were studied using the UCLA Prostate Cancer Index (UCLA-PCI) questionnaire.[11] After adjustment for age and baseline sexual function, patients who received bilateral NSRRP had preservation of function that was significantly better at 3-6 months compared with patients who had received unilateral NSRRP. The 24-month likelihood of returning to baseline sexual function was 51% for bilateral and 32% for unilateral nerve-sparing techniques. Unfortunately, questions concerning the use of nightly sildenafil were not included in the UCLA-PCI questionnaire. The authors confessed that many of their patients were taking sildenafil. More than 90% of men eventually returned to their baseline urinary function and bother levels, regardless of nerve-sparing status. Overall, despite preservation of both neurovascular bundles, decline in health-related quality of life is common after NSRRP.
An interesting study from Milan, Italy, involved a multivariate analysis of 908 men (mean age, 61.8 years) undergoing bilateral NSRRP and correlated the results with several preoperative and postoperative parameters.[12] Patients were not stratified per postoperative erectile function treatments, but a surprising 50% of patients elected no treatment whatsoever. In regard to nightly vs on-demand use of PDE-5 inhibitors as rehabilitative treatments, there was no difference in long-term recovery of erections between groups. On-demand intracavernosal prostaglandin E1 (PGE1) provided the best IIEF intercourse satisfaction and orgasmic scores. Postoperative IIEF erectile function after bilateral NSRRP was directly correlated with postoperative sexual desire, mood, and urinary continence but not with body mass index, age, preoperative prostate-specific antigen level, and time since surgery. This study shows that many of our preconceived notions in regard to post-RRP ED therapies are incorrect. Preoperative communication between patient and urologist is essential.
In a 5-year follow-up regarding sildenafil efficacy and compliance after RRP, 68 men were studied.[13] Forty-five percent of initial sildenafil responders continued to do well; however, the other 55% of these men reported dissatisfaction. One third became unresponsive and switched to other forms of treatment (intracavernosal PGE1 vacuum tumescence device or medicated urethral system for erection ). One third developed a suboptimal response and used combination therapy, and one third discontinued use because of adverse effects (headache in 16%, flushing in 8%, and blurred vision in 8%) or change in circumstances (eg, loss of partner). In the question-and-answer period, it became apparent that many sexual function studies do not assess the partners' perceptions (eg, diminished interest). It is crucial that both partners be included in future studies on sexual function.
In another method for postprostatectomy penile rehabilitation, investigators from the Cleveland Clinic titrated one group of men to low-dose (125 or 250 mg) MUSE vs observation for 6 months.[14] They noted that more of the MUSE group patients had earlier returns of natural erections (53%) vs the controls (30%). Despite the fact that 47% of the MUSE group still required MUSE for intercourse, 68% of this group was satisfied. Seventy-one percent of the patients in the control group were dissatisfied and had moved to other forms of ED treatment. The MUSE discontinuation rate was 32% (half due to inadequate erections, a quarter due to loss of sexual interest, and a quarter to pain and burning). Early low-dose MUSE therapy may be a viable alternative for promoting recovery of erection after RRP.
From a research standpoint, most efforts are now directed toward neuroprotection and neural regrowth after radical prostatectomy. There have been positive reports of using recombinant human erythropoietin (rhEPO) in stroke patients. In a rat prostatic nerve damage model, investigators from Johns Hopkins University administered rhEPO before or on a daily basis after surgical insult to the cavernous nerve. They were able to document axonal regeneration and return of normal erectile physiology.[15] The affirmative erectile results from this study and the fact that the anticipated blood loss can be recovered in a few weeks after surgery should stimulate a clinical trial with rhEPO in the near future.
In reviewing the optimal dosing and safety of sildenafil, investigators reviewed 26 pooled studies.[16] They found that most men titrated to the 100-mg dose, even 63% of the men who were initially diagnosed as having only mild ED. The most commonly reported adverse effects were headache, flushing, gastrointestinal upset, and vision changes, which were mild to moderate in severity. Surprisingly, the adverse effects were not statistically different between the 50- and 100-mg doses of sildenafil. The authors suggest that sildenafil, 100 mg, should be the optimal dosage for initiating therapy (even in mild ED).
Two studies reported on the favorable cardiovascular safety of vardenafil and alpha-blockers.[17,18] Postmarketing studies of more than 30,000 patients showed no significant increase in myocardial infarction, stroke, or syncope when both agents were used together. These findings were no doubt the stimulus for the recent regulatory label change from a contraindication to a warning on the labeling of PDE-5 inhibitors and alpha-blockers.
A recent publication suggested that patients in whom sildenafil failed could be rescued by the newer, more potent PDE-5 inhibitors. In an illuminating study, 331 patients in whom sildenafil failed were tested with penile duplex Doppler ultrasound, with 57 of these men eventually being sent home on a trial of vardenafil.[19] Only 7 (12%) of the 57 men reported successful intercourse. The men who were unsuccessful were older and more likely to have arterial insufficiency by penile duplex studies. It is unlikely that patients in whom sildenafil fails will respond to the newer PDE-5 inhibitors. Provided that these men with more severe ED are educated properly on PDE-5 inhibitor use, most should be counseled early about alternative ED therapies.
Men with several severe comorbidities and ED are often not eligible for clinical studies because of strict exclusionary criteria. A recent study in such a group of men (n = 155) with multiple comorbid conditions (CMCs), such as cardiovascular disease, diabetes, hypertension, hyperlipidemia, depression, and postprostatectomy, were enrolled in a 12-week study with tadalafil, 20 mg.[20] Outcome measures included change in IIEF, sexual encounter profile, and global assessment question. When compared with results for a reference group with fewer comorbidities, the results for the CMC group were not especially impressive: the CMC group had an improvement of 7.6 in IIEF score compared with 10.5 for the control group, the sexual encounter profile score improved by 33% in the CMC group compared with 49% for control, and the global assessment question was 77% at the end of the trial for patients in the CMC group and 93% for control patients. However, the overall response for this difficult ED group of men compared with their baseline sexual activity was robust (eg, sexual encounter profile improved from 1% to 30%). Patients with multiple comorbidities should still be given a trial of PDE-5 inhibitor therapy.
Although clinical review of existing therapies in sexual medicine, such as PDE-5 inhibitors, is undergoing postmarketing evaluation and refinement, other areas of basic research offer new challenges and opportunities for discovery. In the coming years, we should see progress in our understanding of the central mechanisms that govern sexual activities in both men and women.
Premature ejaculation (PE) may be the most common male sexual disorder, with a prevalence between 27% and 34% among men 18 to 59 years old. In comparison, erectile dysfunction (ED) affects 10% to 12% of men in the same age group.[1] Since the introduction of sildenafil in 1998, the discussion of ED in the media and physician's office has become commonplace. On the other hand, PE is a relatively poorly understood male sexual disorder. It is also the most unspoken medical condition. Contemporary studies are dispelling many myths regarding PE, including the idea that men grow out of PE as they age. In fact, PE prevalence rates do not diminish with age. It is unclear how often PE and ED coexist or for that matter how often PE is misdiagnosed as ED.
The language of sexual medicine is robust when it comes to describing ED, but even the most experienced health care practitioners are at a loss for words when it comes to taking the sexual history regarding ejaculation. We all believe time is an essential element in the PE history, but how do we identify the patient with PE? In a recent observational study of 207 men diagnosed as having PE and 1380 age-matched men without PE, the median intravaginal ejaculatory time (IELT) was found to be 1.8 minutes for men with PE and 7.3 minutes for men without PE.[2] This study compared the evidence-based measure of IELT with subjective measures of control over ejaculation, satisfaction with sexual intercourse, and personal distress. These observations have added to our vocabulary on PE by demonstrating the statistical power of the patient- and partner-related outcomes when describing the presence and impact of PE.
The 2005 Annual Meeting of the American Urological Association featured several clinical papers on PE. Most were reports on dapoxetine, an investigational oral drug for the management of PE that is currently completing phase 3 clinical trials in the United States. At present, there are no prescription medications approved by the US Food and Drug Administration (FDA) specifically for the management of PE.
Rosen and colleagues[3] reported on a 4-week, multicenter, observational study held in the United States of men and their partners with and without PE (N = 1587). They used Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria to define PE: persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it, causing marked distress or interpersonal difficulty. The study authors compared IELT as measured by a stopwatch held by the female partner to a variety of patient-reported outcomes (PROs) administered by questionnaires. Clinicians diagnosed PE in 207 of 1380 participants. The authors conclude that IELT alone is not an optimal predictor of PE status. IELT combined with single-item PROs predicted PE with an 80.3% sensitivity and 94% specificity, compared with IELT alone, which had 80% sensitivity and 80.8% specificity. The strongest predictor of PE was the PRO control over ejaculation. The take-home message here is complex. We know that any definition of PE must include a time element, but clinicians debate just how long an IELT is normal and how short an IELT is pathognomonic of PE. Patients who present in an office are unlikely to take kindly to the advice that they need to go home and ask their partner to use a stopwatch to time IELT to diagnose PE or to follow treatment once a drug has been prescribed. This study suggests that a series of questions (PROs) is as statistically powerful as IELT data to diagnose PE and, furthermore, quantifies the impact on the patient and partner. What's missing here is some demonstration that an individual's own estimate of ejaculatory latency is accurately related to stopwatch data on IELT.
Selective serotonin reuptake inhibitors (SSRIs) when used for the management of depression have been associated with the notorious side effect of anorgasmia. These agents have been studied for their efficacy in treating men with PE. Mattos and Lucon[4] conducted a small double-blind study in 60 PE patients with no ED. The patients were divided into 4 treatment groups: tadalafil, 20 mg, plus a slow-release formulation of fluoxetine, 90 mg; tadalafil, 20 mg, plus placebo; fluoxetine, 90 mg, plus placebo; and placebo plus placebo. The greatest increases in IELT were in the tadalafil plus fluoxetine group, followed by fluoxetine plus placebo, then tadalafil plus placebo. The authors believe that this combination of a long half-life phosphodiesterase type 5 (PDE-5) inhibitor and a slow-release SSRI may be a preferable alternative for men taking a daily SSRI for PE. What they did not demonstrate was the efficacy of on-demand dosing with a PDE-5 inhibitor combined with a standard SSRI. Currently, on-demand dosing is the norm in male sexual dysfunction therapy. It remains to be determined if long-term dosing is preferable or even advisable for sexual function.
Sommer and colleagues[5] reported on the results of a small, open-label, crossover study in 37 men with primary (lifelong) or secondary (acquired) PE. The subjects were randomized to 6 weeks of vardenafil, 10 mg (30 minutes before intercourse), or sertraline, 50 mg (4 hours before intercourse). PE was graded on a scale from 0 (almost never) to 8 (almost always). At the outset, the mean PE grade was 6.14 and IELT was 0.54 minutes. After 6 weeks of treatment, PE grade improved 2.9 points in the vardenafil group vs 1.9 in the sertraline group, and IELT increased by 5.23 minutes in the vardenafil group and 2.87 minutes in the sertraline group. It should be kept in mind that this was an open trial with no placebo arm. One important consideration not mentioned in the abstract is that most subjects had secondary PE, presumably as a result of untreated ED. This is an interesting small study that highlights the need to properly identify patients in PE clinical trials as primary PE with no complaint of ED or secondary PE with ED. Ideally, the baseline International Index of Erectile Function or Erectile Function Domain scores should be near normal for primary PE subjects.
Just as the study by Sommer and colleagues indirectly highlights the need to properly classify PE patients in drug trials for coexisting ED (when ED is the primary problem), it is reasonable to assume that patients undergoing therapy with a PDE-5 inhibitor might also be prescribed dapoxetine once it is available by prescription. Dresser and colleagues[6] examined the pharmacokinetics of dapoxetine, 60 mg, in healthy adult men in combination with either tadalafil, 20 mg, or sildenafil, 100 mg (highest recommended dosages). Dosing was separated by 6- to 14-day washouts. Plasma concentrations of tadalafil and sildenafil combined with dapoxetine were comparable to reports that document the pharmacokinetics of either preparation alone. The authors found no significant change in electrocardiograms or vital signs. What remains to be determined is whether adverse events most commonly reported with these agents would be statistically different when the drugs were used in combination for treatment of male sexual dysfunctions (ED and PE).
In a separate interaction study,[7] 24 healthy volunteers were challenged with dapoxetine, 60 mg, and 0.5 g/kg of ethanol mixed in ginger ale. Coadministration of ethanol and dapoxetine did not produce significant changes in dapoxetine pharmacokinetics or peak plasma concentrations of ethanol. No significant adverse hemodynamic events were noted, except for asymptomatic tachycardia in 1 patient. It is likely that patients who take dapoxetine will to some extent be coadministering a PDE-5 inhibitor or alcohol, mandating such interaction pharmacokinetic studies.
Phase 3 clinical trial data on dapoxetine were presented by Pryor and colleagues.[8] These data consisted of 2 large randomized, double-blind, placebo-controlled, multicenter trials conducted in the United States to evaluate the efficacy and tolerability of on-demand administration of dapoxetine in men with PE (N = 2614). Diagnosis of PE as described herein was based on the DSM-IV-TR definition. Each study had a 2-week baseline followed by 12 weeks of treatment. IELT, control over ejaculation, and satisfaction with sexual Intercourse were assessed at baseline and at 4, 8, and 12 weeks. Changes from baseline IELT to study endpoint for placebo, dapoxetine, 30 mg, and dapoxetine, 60 mg, were 0.9-1.75, 0.92-2.78, and 0.91-3.32 minutes, respectively. Change from baseline to endpoint in the percentage of men rating their control over ejaculation as fair, good, or very good were 3.5% to 26.4%, 2.5% to 51.8%, and 3.3% to 58.4% for placebo, dapoxetine, 30 mg, and dapoxetine, 60 mg, respectively. For sexual satisfaction with intercourse, the observed changes were 51.8% to 55.2%, 52.4% to 70.9%, and 56.7% to 79.2%, respectively. There were significant placebo response rates in the dapoxetine trials, but these are similar to changes noted in pivotal clinical trials for each of the 3 PDE-5 inhibitors. Most importantly, changes in the 30- and 60-mg groups were statistically significant compared with placebo and between dosages. Treatment-related adverse events with 30 and 60 mg of dapoxetine were nausea (8.7% and 20.1%, respectively) and headache (5.9% and 6.8%, respectively). Dizziness and diarrhea were noted in 6.8% and 6.2%, respectively, of men taking dapoxetine, 60 mg. Study withdrawals due to adverse events were 4% in the 30-mg group and 10% in the 60-mg group.
Subjects taking dapoxetine in these 2 clinical trials had significant increases in IELT at first dosage (of both 30 and 60 mg); increases were maintained throughout 12 weeks. Further open-label trials are needed to document ongoing efficacy, number of dosages to maximal benefit, and long-term changes in IELT. There is a real possibility for the motivated couple that combination pharmacotherapy with a PDE-5 inhibitor or behavioral techniques may yield greater improvements in IELT. These clinical trials and the observational study by Rosen and associates described herein have elaborated and tested a set of PROs that should be helpful in the clinic as a basis for patient-physician dialogue on PE.