Penson et al. analyzed the data from the large Prostate Cancer Outcomes Study which included 1,213 men who underwent prostatectomy for prostate cancer. They reported on urinary and sexual outcomes at up to 5 years postopera- tively. Compared to baseline rates of 81% with erections firm enough for penetration, rates at 6, 12, 24 and 60 months were 9, 17, 22, and 28% respectively. Notably, the data was collected on men diagnosed from 1994 to 1995 and the 60 month survey was distributed in 2000. Thus, all patients theoretically were exposed to intracavernous injection in the early postoperative period, but sildenafil was not available until around 3 years postoperatively. Consequently, this provides a relatively good estimation of the natural history of erectile dysfunction post- prostatectomy, though the improvement in erec- tile function seen between years 2–5 could have been significantly affected by the introduction of PDE5 inhibitors. Indeed, 43% of the study patients had used sildenafil at least one time and of these 520 patients, 32% reported achieving an erection suitable for intercourse. Of the technologies available around the beginning of the study, intracavernous injection was tried by 17%, vacuum erection devices were tried by 25%, “other” therapies including MUSE™ were used in 7%, and penile prostheses were implanted in 4% of the men.

Treatment of erectile dysfunction in post-prostatectomy men is unique compared with ED caused by other factors; in that rehabilitation (ED recovery) from treatment induced nerve and vascular injury are plausible. Thus, treatment of post-prostatectomy ED must keep two goals in mind: immediate erectile function facilitated by medication use and ultimate return to pre-pros- tatectomy erection status without use of adjunctive medications.

Penile injections do not require neuronal integrity to function. Injections have been shown to have the highest functional erection success rates following RRP with multiple studies showing ³90% efficacy at 6 months post-op. Like penile injections, MUSE™ works independent of nerve status. This medication has been shown to be effec- tive in men with ED after RRP, producing an erection thought to be sufficient for intercourse in the clinic in 70% of subjects, and leading to successful intercourse at home in 40% of subjects compared to 7% in placebo. Similar results were found in a study where 55% of subjects had successful intercourse and 48% effectively used MUSE™ long term (2 years) after RRP.

The potential to regain some erectile function with time (typically maximized at 18–24 months) after radical prostatectomy is well established in the literature. The potential of pharmacotherapy to aid in return to pre-op, baseline erectile function status with return of spontaneous, medication unassisted erections adequate for penetration is not only theoretically intuitive, but also has been reported in numerous small studies. The theoretical support is drawn from the results of denervating the cavernosum of rats and observation of the ensuing hypoxia and fibrosis coupled with the knowledge that erections increase the oxygenation of the cavernosum.

Phosphodiesterase inhibitors are likely the most commonly used rehabilitative pharmaceutical though they have lower theoretical rehabilitative potential than ICI or MUSE™ as they require a threshold level of neural integrity to be effective. McCullough et al. published a study using 50 and 100 mg nightly doses of sildenafil followed by an 8 week washout period. This study showed that men on daily sildenafil treatment had much higher rates of erectile function than those taking placebo, namely 24% for 50 mg sildenafil and 33% for 100 mg sildenafil versus 5% for placebo. Rates of return to spontaneous erection with ICI and MUSE™ should theoretically be higher because they are more effective at producing erections during the neurapraxic period post pros-tatectomy. Montorsi et al. published one of the first papers on erectile rehabilitation comparing 3 months of t.i.w. ICI alprostadil to patients receiving no treatment. Patients were assessed at a 6 month follow up, i.e. after a 2 month period without t.i.w. alprostadil. Eight (67%) were noted to have return of spontaneous erection which only required the use of ICI alprostadil one in 4.2 times for successful intercourse. The other four patients in the ICI group reported needing to use ICI greater than 50% of the time to achieve successful intercourse.

Only 20% of the placebo group reported spontaneous erections that were sufficient for intercourse. This study, although often cited, likely suffers from methodological flaws as no other studies have replicated these impressive results. A larger study by Mulhall et al. examined a group of men with functional preoperative erections prior to prostatectomy and who were non-responders to sildenafil in the early post- operative period. At 18 months postop, men who followed a regimen of t.i.w. ICI were compared to those who did not follow the protocol. Of the 58 men in the protocol group, 52% had a return of spontaneous erections compared to 19% of the 74 men in the non-protocol group. Althoughencouraging, this study suffers from a high degree of self selection bias, as the patients who were not hav- ing success and ultimately stopped treatment, but adhered to follow-up were simply included in the non-protocol group. The efficacy of MUSE™ in penile rehabilitation has also been tested. Raina et al. reported on 97 men post-prostatectomy, 56 of whom used t.i.w. MUSE™ for 6 months and 35 of whom used only p.r.n. erectile aids. Those who used MUSE™ attained a fourfold higher rate of spontaneous erections than those who did not (40% vs. 11%).

Obtaining reliable and valid data in general is a difficult undertaking. Information and data collected optimally is both precise (repeatable) and accurate (degree to which a variable represents what it is supposed to represent).

Common meth- odologies to increase precision for studies include the standardization of measurement with an operation manual, training and certification of the observer, refinement of instruments, automation of instruments, and repetition of measurements with value averaging . These techniques ultimately attempt to minimize the role of chance or random error. Similar techniques are used to maximize accuracy, where bias by the subject, observer, or instrument creates systematic errors in the data. Additional techniques utilized in addition to those previously mentioned to maximize precision, include making unobtrusive measurements, instrument calibration, and blinding.

The most common pitfalls to internal validity include the definition of ED, ED measurement, time frame for measurement, patient versus MD recording of data, attrition bias, and the role of chance.

Sexual dysfunction exists as one of the most significant detractors to the quality of life measures in patients treated for localized cancer of the prostate (CAP). A study in 2003 found that even as long as 92 months after radical retropubic prostatectomy (RRP), more than 75% of the treated men were sad or tearful about ED and over 70% felt that the quality of life was adversely affected. ED is an unfortunate consequence that accompanies CAP treatment.

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After an extensive abstraction process, an AUA prostate cancer guideline update panel task force attempted to establish ED prevalence rates after RRP, XRT, and brachytherapy, with non-specific results from 31 articles. The article noted that subcategorization of results according to specific variables was not feasible due to imprecise or absent descriptions of these variables in the original articles. In an attempt to develop a basic source for patients and physicians to look up the likelihood of the developing ED after the various prostate cancer treatments stratified by risk factors that were listed, we summarize the 31 articles previously abstracted in addition to articles commenting on cryotherapy, androgen ablation, and prostate cancer treatment comparison studies.

In selecting these articles, we placed importance on studies with high power, or those that elaborated on important patient factors (age, medical comorbidities, and preoperative erectile status) and those that used consistent ED definitions and validated ED information collection tools. Our experience was similar to that of the AUA task force, finding unacceptably large vari- ance in the data and the quality of study methodology.

Although not mandatory, questionnaires might be helpful to assess the presence or severity of ED, especially in those settings where the interviewer is not familiar with the condition and when a measurable clinical response is needed. Although questionnaires are a subjective tool with information from the patient’s interpretation and self-response, it can serve as objective data to assess treatment response or disease progression.

One of the most widely used questionnaires is the International Index of Erectile Function (IIEF); this is a 15-item questionnaire covering five domains including desire, erection, orgasm, ejaculation and satisfaction, with scores ranging from 1 to 5 per question.

A lengthy questionnaire, it is often used in clinical trials, but might be a tedious task during consultation. An abbreviated version of this questionnaire is the IIEF-Erectile Function Domain, one comprised of six questions focused on the erection domain and sexual satisfaction with a maximum score of 30. Men with a normal erectile function will have a score of 25.

Another short questionnaire derived from the IIEF is called the Sexual Health Inventory for Men (SHIM) includes five questions on erectile function related to the prior 6 months, and has a total score ranging from 5 to 25: a score of 22–25 means normal erectile function, 17–21 mild ED, 12–16 mild to moderate ED, 8–11 moderate ED, and <7 severe ED.

It is not uncommon to find risk factors unknown by the patient such as diabetes, dyslipidemia, or hypertension. In 1999, a panel of experts elaborated the guidelines for cardiovascular evaluation in patients with ED, then revised and published them for the second Princeton consensus.

These guidelines recommend an evaluation for ED patients, and establish three levels of cardiovascular risk:

• Low-risk category: Asymptomatic; <3 risk factors for coronary artery disease ([CAD] excluding gender); uncomplicated past myocardial infarction (MI); left ventricular dysfunction (LVD)/ congestive heart failure (CHF) (New York Heart Association [NYHA] class I); mild, stable angina (evaluated and/or being treated); post-successful coronary revascularization; controlled hypertension; mild valvular disease.
• Intermediate-risk category: >3 risk factors for CAD (excluding gender); recent MI (>2, <6 weeks); moderate, stable angina; LVD/CHF (NYHA class II); non-cardiac sequelae of atherosclerotic disease (e.g., stroke, peripheral vascular disease).
• High-risk category: High-risk arrhythmias; unstable or refractory angina; recent MI (<2 weeks); LVD/CHF (NYHA class III/IV); uncontrolled hypertension; moderate-to-severe valvular disease; hypertrophic obstructive, and other cardiomyopathies.

Additionally, each level has corresponding management recommendations:

• Low-risk category: Primary care management, consider all first-line therapies, reassess at regular intervals (6–12 months).
• Intermediate-risk category: Specialized CV testing (e.g., exercise treadmill test [ETT], Echo), restratification into high risk or low risk based on the results of CV assessment.
• High-risk category: Priority referral for specialized CV management, treatment for sexual dysfunction to be deferred until cardiac condition stabilized and dependent on specialist recommendations.

Physical Examination A focused physical examination is mandatory in assessing the patient complaining of ED. Although not always revealing the exact etiology, it will certainly help in determining risk factors such as gynecomastia, hair distribution, abdominal circumference, peripheral pulses and measurement of the blood pressure and weight.

Special attention should be given to external genitalia including penile size, consistency, presence of penile plaques, foreskin retraction, prepubic fat, and testis shape and consistency. Rectal exam is important to assess rectal tone and reflexes as well in men over 50 years old who have a risk for prostate cancer.

One important aspect when evaluating a patient with ED is to consider the degree of cardiovascular risk. Laboratory Tests In view of the strong relationship of ED with vascular risk factors, it is important to dosed fasting glucose and lipids in every patient consulting for ED if these have not already been performed. Serum testosterone needs to be dosed, especially in those subjects with low libido and/or poor response to PDE5-Is, although many clinicians consider it mandatory in every patient with ED, since sexual function could be a marker for hypogonadism.

This controversy rises from many factors: clinical manifestations of hypogonadism is diverse and rarely complete, severity is also variable, and more than one laboratory measurement is required as there is a 40% rate of false positive results.

If this test is not part of the initial assessment, a more complete hormonal evaluation could be ordered when considering additional testing. Since the majority of the circulating testosterone is bound to the SHBG and to the albumin (bioavailable testosterone), the free portion of circulating testosterone is most important in terms of function, though a reliable laboratory dosing is very expensive and not widely performed. Calculated free testosterone (CFT) is a safe and reliable method to assess free testosterone using the values of total testosterone and SHBG on a table designed by Vermuelen.

Gonadotrophins (LH and FSH), dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS), prolactin, and thyroid hormones are only part of advanced hormonal assessment in special endocrine situations and treatment monitoring; routine use of these studies should be discouraged.

The first step in diagnosing ED is to confirm the symptom, since frequently the patient might confuse difficulty to maintain an erection with premature ejaculation or other sexual dysfunctions. It is important to establish the duration of the symptom (onset), as well as its severity and frequency (once, always, situational) to help confirm the dysfunction and help identify the diagnosis. The interviewer should use clear and simple language and make the patient feel as comfortable as possible to discuss his situation. Language too technical and distant will jeopardize the patient’s understanding and expression. Frequently, the patient needs permission to talk about ED with his physician, since he may think his doctor could feel uncomfortable with the discussion. This is easy to overcome by allowing the patient to discuss the issue, asking direct questions about the patient’s sex life.

Historytaking should follow a formula allowing the interviewer to identify the different risks and predisposing factors, with the intention to act on each of them with a clear therapeutic purpose. Also, a thorough review of the patient’s current medications is mandatory to rule out etiology and potential treatment contraindications.One important aspect to explore during the interview is the patient and partner’s degree of knowledge regarding the normal sexuality changes with aging, such as the progressive decrease of testosterone levels. This decrease may be due to a lower number of Leydig cells, a decrease of the LH peaks, an impaired tissue perfusion, and/or an increase of the serum sexhormone binding globulin (SHBG).

The concept that sexual dysfunctions are a part of the normal sexual changes accompanying aging is a common myth. It is important to explain to the patient that while the sexual responses may change with aging, they do not disappear. There are many reports supporting the concept of a continuing sexual interest and activity in the elderly, which could represent even a larger proportion of subjects if non-coital sexual activity were considered. The Massachusetts Male Aging Study showed a clear relationship of ED with age and reported a prevalence of ED as 52% of men over 50 years old. A decrease of sexual interest with age may reflect a hormonal imbalance. Also, there may be an adrenergic over-sensibility or hyperactivity, and a decrease of penile smooth muscle resulting in a lower intensity arousal phase, thus translating into difficulty to obtain and maintain an erection.

The ejaculatory volume and orgasmic intensity is lower, and with a decrease of ejaculatory contractions, the detumescence phase is faster and the refractory period is longer. These changes need to be discussed with the patients as they often result in a lower sexual frequency, a longer time needed to achieve a rigid erection, a need of a greater stimulus to obtain a similar response, lower penetration rigidity, lower ejaculatory volume, and faster detumescence. It is also important to discuss the normal physiologic changes which occur in their female partner, such as the physical and psychological changes occurring during menopause and female sexual dysfunction.

If relevant data (e.g. standard deviations) were not reported adequately, we attempted to calculate the needed parameters. Trials that did not report complete numerical information for relevant efficacy/harms outcomes (i.e., arm-specific mean endpoint or change in score, standard deviation, or standard error, proportion of patients with an outcome at followup) could not be incorporated in the meta-analyses. Trial reports presenting measures of variability (e.g. standard deviation) only graphically (i.e., no numerical data were available) were not pooled. Online Mexican Pharmacy

We calculated standard deviations from standard errors or 95 percent confidence intervals.

– For continuous outcomes (e.g. mean endpoint/change in the total score of IIEF), the absolute difference between treatment-specific means and corresponding standard deviations were ascertained for each individual study. A generic inverse variance method was used to calculate the response outcomes and corresponding 95 percent confidence intervals for the combined treatment groups.

– For dichotomous outcomes (e.g. improvement in erection GAQ), studies were grouped by type of treatment and dose to minimize clinical heterogeneity. The intent-to-treat group or number enrolled at the time of study was used for analyses and, when this information was unavailable, we used the number provided in the report.

Pooled relative risks with corresponding 95 percent confidence intervals were generated.

The DerSimonian and Laird random-effects model was used to obtain combined estimates across the studies. The degree of statistical heterogeneity was evaluated by using a chi-square test and the I2 statistic. An I2 of less than 25 percent is consistent with low heterogeneity; 25 to 50 percent with moderate heterogeneity; and over 50 percent with high heterogeneity. When statistically significant heterogeneity was identified, it was explored through subgroup and sensitivity analyses when appropriate. Sources of heterogeneity include reporting and methodological quality (e.g. methods for randomization, adequacy of allocation concealment, blinding, washout period for crossover trials, data analysis) as well as clinical heterogeneity (e.g. study population, dosing of therapeutic agent, duration of followup). Estimates from the heterogeneous groups must be interpreted with caution, especially when small numbers of trials are included.

We also performed a series of subgroup analyses to explore the consistency of the results.

The meta-analyses are presented as forest plots. Publication bias was explored through funnel plots (Figures D1-16, Appendix D) by plotting the relative measures of effect (relative risk) versus a measure of precision of the estimate (1/standard error). The visual asymmetry in funnel plots maybe be suggestive of publication bias, although other potential causes for asymmetry exist. The degree of funnel plot asymmetry was measured using the Egger regression test.

The human penis is composed of the paired dorsal corpora cavernosa and the ventrally placed corpus spongiosum. The corpus spongiosum contains the urethra and is contiguous with the glans penis distally. Each corpus is surrounded by a fibrous sheath, the tunica albuginea. Between the two corpora cavernosa is an incomplete perforated septum allowing them to function in unison.

Surrounding all three corpora is an additional fibrous layer, Buck’s fascia. Superficial to Buck’s fascia is Colles’ fascia extending from the base of the glans to the urogenital diaphragm where it is contiguous with Scarpa’s fascia.

Superficial to Colles’ fascia is the skin.
Proximally, the corpora cavernosa form the penile crura, which are anchored to the pubic rami and are covered by the ischiocavernosus muscles. The proximal corpus spongiosum forms the penile bulb, which is enveloped in the bulbospongiosus muscle. The suspensory ligament of the penis arises from the linea alba and pubic symphysis and inserts on the tunica albuginea to support the pendulous portion of the penis.

Corpora The corpora cavernosa are two spongy cylinders comprised primarily of arterial sinusoids and smooth muscle surrounded by the tunica albuginea. The cavernosal tunica albuginea is 2–3 mm thick in the flaccid state and is composed mostly of collagen fibers with a smaller portion being elastic fibers. The cavernosal tunica has an inner circular layer and an outer longitudinal layer of fibers. The histologic appearance of corpus spongiosum is similar to the corpora cavernosa and it contains larger sinusoids. Additionally, the tunica albuginea surrounding this corpus is thinner, has only one circular fiber layer, and contains more elastic fibers.

Glans The glans forms the distal portion of the penis. It is contiguous with the corpus spongiosum. It is covered with very thin, firmly adherent skin. Additionally, the tunica on the glans albuginea is absent.

The human penis is composed of the paired dorsal corpora cavernosa and the ventral corpus spongiosum each of which is encased within a fibrous sheath, the tunica albuginea, and then all of which are enclosed within Buck’s fascia, Colles’ fascia, and the skin.

The spongiosum contains the urethra and is contiguous with the glans distally. The arterial supply to the penis is from the four terminal branches of the paired penile arteries, which are themselves branches of the internal pudendal arteries. The external iliac, obturator, vesical, and femoral arteries provide accessory arterial supply to the penile artery in some cases.

Venous outflow originates from postcavernous venules that coalesce to form emissary veins. These veins empty into the cavernous vein, the deep dorsal vein, and the superficial dorsal vein depending on their origin within the penis. Efferent innervation is from parasympathetic, sympathetic, and somatic sources. Somatosensory afferents course from the penis to central sites.

The maintenance of penile flaccidity and the erectile response are controlled via intercommunicating supraspinal and spinal reflex pathways. During the flaccid state, antierectile neural input, primarily via sympathetic efferents, acts to limit blood flow to the penis to a quantity sufficient to meet physiologic needs but insufficient for erection. Following either physical or psychological sexual stimulation proerectile neural signals are sent to the penis primarily via parasympathetic tracts. This input initiates the erectile response via neurotransmitter release onto postsynaptic smooth muscle cells within the corporal bodies.

Nitric Oxide (NO) is the main proerectile neurotransmitter. The resultant molecular cascade leads to a decrease in intracellular Ca2+ and arteriolar smooth muscle relaxation.

This relaxation allows for increased blood flow and subsequent corporal engorgement with increasing penile rigidity. As the corpora become engorged, the emissary veins are compressed by within the tunica albuginea limiting venous outflow.

The increased arterial inflow and limited venous outflow increases intracorporal pressure and leads to erection. As proerectile input ceases, the secondary molecular messenger cGMP is hydrolyzed allowing for a rise intracellular Ca2+, subsequent smooth muscle contraction, decreased penile blood flow and a return to flaccid state physiology.

Overview of Trials

Two studies were identified and were judged to be eligible to address the present question. Both trials were randomized5,77 comparing the efficacy of combined treatment of testosterone (gel or patch) plus sildenafil to that of sildenafil alone in ED patients with low testosterone levels who failed to respond (score of 2–3 on IIEF–Q3/Q4) to prior treatment with sildenafil.

Gel testosterone plus sildenafil versus sildenafil. In this double-blind trial5 75 hypogonadal men (mean age: 58 years; total testosterone <400 ng/dL) with ED were randomized to 1 percent gel testosterone plus 100 mg sildenafil versus 100 mg sildenafil for 12 weeks. At the end of the study, the proportions of men with scores of 4-5 on IIEF–Q3/Q4 was statistically nonsignificantly greater in the combination therapy group than in the sildenafil only group (51.4 versus 39.4 percent; RR = 1.30, 95 percent CI 0.77–2.21). Men who received gel testosterone plus sildenafil also had greater mean change from baseline in the IIEF “EF” domain score at week 4 (4.4 versus 2.1, 95 percent CI: 0.3–4.7). One patient withdrew from the combination treatment arm due to an adverse event.

Testosterone patch plus sildenafil versus sildenafil. In this open label trial,77 20 hypogonadal men (mean age:56 years; total testosterone:10-13 nmol/L) with ED were randomized to receive either 5 mg patch testosterone plus 100 mg sildenafil or 100 mg sildenafil plus placebo patch. After one month of treatment, patients in the patch testosterone plus sildenafil group had either numerically or statistically significant improvements for the following outcomes:

• “EF domain” score (21.8 +/- 2.1 versus 14.2 +/- 0.7, WMD = 7.60, 95 percent CI: 6.23–8.97),
• number of sexual intercourses (2.8 +/- 0.9 versus 1.5 +/- 0.5, WMD = 1.30, 95 percent CI: 0.66–1.94),
• intercourse satisfaction (12.1 +/- 1.6 versus 7.7 +/- 1.2, WMD = 4.40, 95 percent CI: 3.16–5.64),
• reported improved erections (80 versus 10 percent, RR = 8.00, 95 percent CI: 1.21–52.69).