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Treatment of male sexual dysfunction

Treatment of male sexual dysfunction
Author:
Mohit Khera, MD, MBA, MPH
Section Editors:
Peter J Snyder, MD
Michael P O'Leary, MD, MPH
Deputy Editor:
Kathryn A Martin, MD
Literature review current through: Feb 2022. | This topic last updated: Jul 28, 2021.

INTRODUCTION — Three of the most common male sexual dysfunctions are decreased libido, erectile dysfunction (ED), and ejaculatory dysfunction (including premature ejaculation [PE] in men ages 18 to 59 years). One or more conditions can coexist in an individual. The inability to achieve and/or maintain an erection sufficient for satisfactory sexual intercourse is a distressing and common symptom, affecting up to one-third of adult men [1].

ED is common in men with systemic disorders such as hypertension, ischemic heart disease, and diabetes mellitus, and its prevalence increases with age (figure 1). Although sexual dysfunction is more common in older men, it also affects younger men (ages 18 to 25 years) [2]. Health care professionals should therefore ask men of all ages about sexual dysfunction as part of their routine psychosocial assessment. ED can also be seen commonly in men who undergo radical prostatectomy for prostate cancer.

The nonsurgical management of male sexual dysfunction is reviewed here. The etiology and evaluation of sexual dysfunction, the surgical management of ED, and the management in men with cardiovascular disease are discussed in detail separately.

(See "Epidemiology and etiologies of male sexual dysfunction" and "Evaluation of male sexual dysfunction".)

(See "Surgical treatment of erectile dysfunction".)

(See "Sexual activity in patients with cardiovascular disease", section on 'Treatment of sexual dysfunction'.)

GENERAL PRINCIPLES — Therapy of men with sexual dysfunction is aimed at improving libido and addressing the two vital sexual functions: the capacity to acquire and sustain penile erections and treating premature ejaculation (PE).

Optimal treatment varies, depending upon the factor(s) that have reduced libido or caused erectile or ejaculatory dysfunction (table 1 and table 2A-B).

With respect to erectile dysfunction (ED) therapy, oral phosphodiesterase-5 (PDE5) inhibitors, penile self-injections with vasoactive drugs, intraurethral suppositories, vacuum erection devices, or penile prostheses allow many men with vasculogenic, neurogenic, or psychogenic ED to treat their ED by acquiring and maintaining erections (figure 2).

Guidelines — Guidelines from the American Urological Association (AUA) have been published for the treatment of ED [3] and PE [4]. The American College of Physicians (ACP) [5] and the American Association of Clinical Endocrinologists (AACE) have also issued treatment guidelines [6]. The Endocrine Society has published guidelines for the diagnosis and treatment of hypogonadism [7].

DECREASED LIBIDO — The prevalence of reduced libido is estimated to be 5 to 10 percent in men [8]. It increases with age, and it frequently accompanies other types of sexual dysfunction. Men with erectile dysfunction (ED) may experience loss of libido as a secondary consequence of ED. This usually is ascertained from a detailed sexual history, including the chronology of the disorder. However, most patients who complain of ED do not complain of reduced libido or sexual desire. Low libido is often secondary to medications, depression, systemic illness, or testosterone deficiency, but it can also be due to psychogenic causes. Most of these conditions are potentially treatable. (See "Epidemiology and etiologies of male sexual dysfunction", section on 'Decreased libido'.)

The most common causes of decreased libido and their treatment include:

Psychological, which is treated with formal or informal psychotherapy. (See 'Therapies for psychogenic ED' below.)

Low testosterone, the most common hormone associated with low libido is treated with testosterone replacement therapy (see "Testosterone treatment of male hypogonadism"). Other hormones that should be assessed in men with low libido include serum prolactin, TSH, and estradiol.

Medications, most commonly selective serotonin reuptake inhibitors (SSRIs) [9]. Treatment strategies for SSRI-associated sexual side effects are reviewed separately. (See "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Management".)

Sexual dysfunction is common in men who use opioids chronically [10]. These individuals usually have low testosterone levels. (See "Causes of secondary hypogonadism in males", section on 'Opioids'.)

Partner interactions. (See "Epidemiology and etiologies of male sexual dysfunction", section on 'Decreased libido'.)

A small but significant percentage of men who use 5-alpha-reductase inhibitors (finasteride, dutasteride) to treat benign prostatic hyperplasia (BPH) or male-pattern baldness may experience a decrease in libido, ED, and/or ejaculatory dysfunction [11]. Depending upon the diagnosis, it may be possible to stop the drug to see if this improves the man's libido. In one report of men ages 18 to 45 years, persistent sexual dysfunction with finasteride therapy was associated with a possible increased risk of suicidal ideation. Further studies are underway to understand the pathophysiology associated with post-finasteride syndrome.

Alcoholism is also recognized to reduce libido. Studies have demonstrated that intake of 40 grams of alcohol per day (approximately three drinks) can lead to impaired testosterone production. Making the patient aware of this association may help to reduce or stop the excessive alcohol intake; however, professional counseling usually is required. Low libido may also be a function of partner issues. For example, marital strife, marital guilt, or a naturally or surgically induced postmenopausal female partner who has diminished or absent sexual interest can create low libido in the male partner. (See "Evaluation of male sexual dysfunction", section on 'Hormonal testing' and "Epidemiology and etiologies of male sexual dysfunction", section on 'Decreased libido'.)

ERECTILE DYSFUNCTION

Overview of management approach — Our approach to management includes:

Identifying etiology – Identifying the underlying etiology, including drugs such as antidepressants or antihypertensive agents that may be causing or contributing to the erectile dysfunction (ED) (table 3). Nonsteroidal antiinflammatory drug (NSAID) use has not been associated with ED risk [12]. (See "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Management" and "Epidemiology and etiologies of male sexual dysfunction", section on 'Drugs'.)

Identifying cardiovascular risk factors Identifying and treating cardiovascular risk factors such as smoking, obesity, hypertension, and dyslipidemia, as both lifestyle measures and pharmacotherapy for risk factor reduction, are sometimes effective for prevention and treatment of ED (table 4). (See 'Lifestyle changes' below.)

Initiating medical therapy – The 2018 American Urological Association (AUA) ED Guidelines no longer advocate first-, second-, or third-line therapy for erectile dysfunction. The principles of shared decision making are now recommended. A patient presenting with erectile dysfunction should be counseled about the risk, benefits, and alternatives to all the treatment options for ED and can then select whichever form of therapy best fits their needs (figure 2). Despite the shared decision-making model, most clinicians still first recommend the phosphodiesterase-5 (PDE5) inhibitors because of their efficacy, ease of use, and favorable side-effect profile (see 'Phosphodiesterase-5 inhibitors' below). Sildenafil, vardenafil, tadalafil, and avanafil appear to be equally effective, but tadalafil has a longer duration of action. Avanafil and orodispersible (ODT) vardenafil have a more rapid onset [13,14]. (See 'Choice of drug' below.)

PDE5 inhibitors are contraindicated in men taking nitrates and should be used cautiously in men receiving an alpha-adrenergic blocker, due to an increased risk of hypotension.

Men with hypogonadism Treating men with ED and unequivocally low serum testosterone levels (ie, hypogonadism) with testosterone replacement, unless there are contraindications. According to the AUA ED Guidelines, testosterone should be evaluated in all men presenting with ED. However, testosterone therapy is currently not recommended as monotherapy for ED. Testosterone is prescribed to hypogonadal men with ED to enhance the efficacy of the PDE5 inhibitors, particularly if they are not effective. (See "Testosterone treatment of male hypogonadism".)

Treatment if PDE5 inhibitors are ineffective – If PDE5 inhibitors are ineffective, we suggest vacuum devices, penile self-injectable drugs, and intraurethral alprostadil as second-line therapy (figure 2). We often suggest trying a vacuum device first because it is noninvasive and less expensive than the other options. (See 'Penile self-injection' below and 'Vacuum-assisted erection devices' below.)

Surgery Surgical implantation of a penile prosthesis for men who cannot use or who have not responded to other therapies (figure 2). (See 'Penile prostheses' below and "Surgical treatment of erectile dysfunction".)

Penile revascularization is rarely required but can be beneficial in men with poor arterial inflow to the corpora cavernosa. According to the 2018 AUA ED guidelines, penile venous surgery is not recommended. (See "Surgical treatment of erectile dysfunction".)

Men with depression or anxiety Psychotherapy alone or in combination with psychoactive drugs in men with ED caused by depression or anxiety. (See 'Therapies for psychogenic ED' below.)

Men with cardiovascular disease or risks Therapy of ED in men with known cardiovascular disease or cardiovascular risk factors is reviewed separately [15,16]. (See "Sexual activity in patients with cardiovascular disease".)

Lifestyle changes — Both lifestyle modification (weight loss, physical activity) [17] and medical management of cardiovascular risk factors are effective for improving sexual function in some men with ED [18]. A study conducted in military veterans found that exercise for ≥18 metabolic equivalent (MET) hours/week is associated with better sexual function in both African Americans and White Americans [19]. In addition, gastric bypass surgery, which is usually associated with significant weight loss, may improve testosterone levels and erectile function [20]. In men with ED and sleep apnea, treatment with continuous positive airway pressure (CPAP) improved erectile function in some [21,22] and did not worsen obstructive sleep apnea [23], but not all [24,25], studies.

There is evidence that smoking increases the risk of ED and that stopping smoking can be beneficial [26,27].

The association of cardiovascular disease and the risk for later ED is discussed in detail separately. (See "Epidemiology and etiologies of male sexual dysfunction", section on 'Cardiovascular disease'.)

Phosphodiesterase-5 inhibitors — For initial therapy of ED, we recommend the PDE5 inhibitors because of their efficacy, ease of use, and favorable side-effect profile. Sildenafil, vardenafil, tadalafil, and the newest option, avanafil, appear to be equally effective, but tadalafil has a longer duration of action and avanafil has a more rapid onset (table 2A) [13,14]. (See 'Choice of drug' below.)

The rationale for the use of PDE5 inhibitors is based upon the role of nitric oxide-induced vasodilation, which is mediated by cyclic guanosine monophosphate (GMP) in initiating and maintaining an erection; detumescence is associated with catabolism of cyclic GMP by the PDE5 enzyme. PDE5 inhibitors act by increasing intracavernosal cyclic GMP levels by competitively inhibiting the PDE5 enzyme and, as a result, increase both the number and duration of erections in men with ED [28]. PDE5 inhibitors will not work without sufficient environmental and psychological cues that result in sufficient sexual arousal and stimulation to initiate the physiological changes in the penis.

An evaluation for the underlying cause of the sexual dysfunction should be done prior to initiating therapy with PDE5 inhibitors (figure 2) (see "Evaluation of male sexual dysfunction"). PDE inhibitors are contraindicated in men taking nitrates and should be used cautiously in men receiving an alpha-adrenergic blocker.

Erectile function can be objectively measured using the International Index of Erectile Function (IIEF), the commonly used validated instrument to assess male sexual function in clinical ED studies (table 5). A subset of the 15 IIEF questions (questions 1 through 5 and question 15) are termed the erectile function domain of the IIEF. Survey scores of men with ED are significantly lower than men without ED. IIEF scores remain low in placebo-treated men but may be comparable, in some treated men, with normal, healthy controls [29]. This is true even for men who have multiple factors contributing to their ED. A short form of the IIEF (the IIEF-5 or Sexual Health Inventory for Men [SHIM]) is a brief, more easily administered, and practical diagnostic tool in a clinical practice setting (table 6).

In the clinical trial setting, an increase of ≥4 on the erectile function domain of the IIEF is considered a minimally clinically important difference (MCID) [30].

An important factor in the success of PDE5 inhibitor therapy is instruction and counseling on proper use, including onset of action of the drug and taking medications on an empty stomach (table 2A). Repeat challenge with proper instruction and counseling of patients labeled as PDE5 inhibitor failures has been demonstrated to salvage approximately 25 to 30 percent of patients who were apparent initial nonresponders to PDE5 inhibitor therapy [31,32].

Sildenafil — Many clinical trials have demonstrated efficacy of sildenafil. In a quantitative meta-analysis of 27 trials in 6659 men with ED, a higher percentage of successful sexual intercourse was achieved with sildenafil compared with placebo (57 versus 21 percent, respectively) [33]. Similar results are seen in men with diabetes [34] and men with prostate cancer who have undergone prostatectomy or radiation therapy [35] (although most effective in those who have undergone nerve-sparing prostatectomy [36]). PDE5 inhibitors also may be effective in treating ED caused by spinal cord injury [37]. (See "Radical prostatectomy for localized prostate cancer", section on 'Impotence'.)

Men with mild ED and men who do not complain of ED but who have risk factors for ED and IIEF scores <25 may benefit from treatment with sildenafil [38,39]. Sildenafil also can provide emotional benefits in men with ED [40].

For maximum effectiveness, sildenafil should be taken orally on an empty stomach approximately one hour before a planned sexual encounter. The initial dose should be 50 mg, and it should be reduced to 25 mg if side effects occur. If, on the other hand, it is well tolerated but the erectile response is not fully satisfactory, the dose can be increased to 100 mg. The duration of action is approximately four hours (table 2A).

Vardenafil — Vardenafil shares a similar structure, onset, and duration of action and side-effect profile with sildenafil [41]. Although there are no direct comparison studies, the efficacy of vardenafil appears to be similar to that of sildenafil, with rates of successful penetration in the 65 to 80 percent range compared with 30 percent for placebo [42-44]. It is also effective for men with ED due to diabetes mellitus [45] or nerve-sparing radical prostatectomy [46]. (See "Radical prostatectomy for localized prostate cancer", section on 'Impotence'.)

Its duration of action, like sildenafil, is approximately four hours (table 2A). Vardenafil is available as a 10 and 20 mg dose, but it has also been released in a new formulation, an orodispersible (ODT; ie, orally disintegrating) tablet, with a potentially more rapid onset than the standard oral formulation. It may be preferable for some patients in that it appears to have a more rapid onset of action and is effective when taken in the fed state [47,48]. High-fat, but not moderate-fat, meals may lower vardenafil's peak serum concentration by approximately 18 percent and delay its absorption by one hour [49].

Tadalafil — Tadalafil has a different chemical structure than sildenafil and vardenafil [50]. Although there are no direct comparison studies, tadalafil appears to be as effective as sildenafil and vardenafil, but it has a longer duration of action [51,52]. Tadalafil has been effective in some men with psychogenic ED [53]. The recommended starting dose for as-needed use is 10 mg, decreasing to 5 mg or increasing to 20 mg if necessary [54].

Lower doses of tadalafil (2.5, 5 mg) are available for once-daily administration [55,56]; this approach appears to be as effective as taking higher doses on an as-needed basis [57]. In one trial of 268 men randomly assigned to tadalafil 5 or 10 mg/day or placebo for 12 weeks, those receiving either dose of tadalafil experienced significantly greater improvement in erectile function than those receiving placebo (successful penetration in 36 to 39 versus 11 percent; successful completion of intercourse in 45 to 50 versus 13 percent; and "no erectile dysfunction" in 50 versus 8 percent) [57].

Daily tadalafil may be particularly effective in men with "complete" ED, defined as having a persistent failure to achieve an erection satisfactory for intercourse. These individuals often do not respond well to intermittent (as-needed) PDE5 inhibitor dosing. In one study, 595 men (mean age 58 years) with "complete" ED, approximately half of whom had hypertension and/or type 2 diabetes, received daily tadalafil (2.5 or 5 mg) or placebo for 12 weeks [58]. At the end of the treatment period, intercourse success rates were 12.5, 32, and 46 percent for placebo, tadalafil 2.5 and 5 mg groups, respectively.

Daily tadalafil also has been approved for treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). Significant improvement in symptoms, but not urodynamic parameters, has been demonstrated in individual trials and a meta-analysis of five randomized trials. Newer trials have found improvements in maximum urine flow rates in addition to symptom scores. Daily dosing of tadalafil should not be prescribed in men with a creatinine clearance <30 mL/min. This issue is reviewed separately. Men presenting with both ED and LUTS may benefit from the convenience of taking one medication to treat both conditions.

Avanafil — Avanafil is a newer PDE5 inhibitor that has been approved in the United States and Europe. It has enhanced PDE5 selectivity compared with the other PDE5 inhibitors, a more rapid onset of action, a plasma half-life that is similar to sildenafil and vardenafil, and it appears to be effective and well tolerated [59-61]. It is taken on an as-needed basis at a starting dose of 50 mg, increasing to 100 and 200 mg as needed. The 50 mg dose should be taken 30 minutes before sexual activity, while the 100 to 200 mg doses can be taken just 15 minutes in advance [62]. Avanafil is the only PDE5 inhibitor approved for 15-minute onset of action.

Avanafil is rapidly absorbed after oral administration (within 30 to 45 minutes), and absorption is not significantly impacted by food. Avanafil, like all other PDE5 inhibitors, is contraindicated with any form of nitrates. Its side-effect profile is similar to other PDE5 inhibitors.

Choice of drug — All four PDE5 inhibitors (avanafil, sildenafil, vardenafil, and tadalafil) work to sustain levels of cyclic GMP within the penile corpora cavernosa to allow men with ED to achieve erections in response to appropriate sexual stimuli. Sildenafil, vardenafil, tadalafil, and avanafil result in similarly high rates of successful sexual intercourse (68 to 69 percent compared with 33 to 35 percent for placebo) and similar side-effect profiles [13]. Therefore, a Clinical Practice Guideline from the American College of Physicians (ACP) recommends that the choice of PDE5 inhibitor be based upon on the patient's preferences, including cost, ease of use, desired duration of action, and adverse effects (table 2A) [5].

Sildenafil has the longest safety record of the four drugs.

Nitrates are contraindicated with all available PDE5 inhibitors.

Onset and duration of action separates one PDE5 inhibitor from another. Sildenafil, vardenafil, and tadalafil should be taken 60 minutes before sexual activity, although the onset of action may sometimes be more rapid than 60 minutes. Avanafil and the ODT vardenafil tablet are more rapid acting and can be taken 30 minutes before sexual activity. The duration of action for sildenafil, vardenafil, and avanafil is up to four to five hours (although some effect may persist for 8 to 12 hours for men with mild to moderate ED) [63]. In contrast, tadalafil is effective for up to 36 hours after dosing (table 2A) [51].

Daily, low-dose tadalafil administration eliminates the concern about onset and duration of action (table 2A).

Sildenafil and vardenafil must be taken on an empty stomach (high-fat meals and alcohol delay absorption). Food does not interfere with the absorption of tadalafil [64], avanafil, or ODT vardenafil (table 2A).

In one crossover comparison trial of sildenafil and tadalafil, 66.3 percent of men expressed a preference for tadalafil and 33.7 percent for sildenafil as a treatment for their ED [65]. The interval between dosing and sexual intercourse differed. On average, sildenafil-treated men had intercourse 2.2 hours after dosing, well within the four-hour window of opportunity stipulated on the label, whereas tadalafil-treated men were able to maintain efficacy but were able to delay sexual intercourse for 5.5 hours after dosing.

Adverse effects and precautions

Cardiovascular — PDE5 inhibitors are associated with a variety of cardiovascular effects. Sildenafil has two important cardiovascular actions in patients with heart disease: It is a vasodilator that can lower the blood pressure, and it can interact with nitrates. The most data are available for sildenafil. Sexual activity in patients with heart disease, including the management of ED, is reviewed in detail separately. (See "Sexual activity in patients with cardiovascular disease", section on 'Treatment of sexual dysfunction'.)

Key points include:

PDE5 inhibitors are contraindicated in patients taking nitrates of any form, regularly or intermittently, as the combination can lead to severe hypotension. (See "Sexual activity in patients with cardiovascular disease", section on 'Adverse interaction with nitrates'.)

Nitrate treatment should be delayed if a man who has taken a PDE5 inhibitor develops chest pain. The delay should be at least 12 hours if he has taken avanafil, 24 hours if he has taken sildenafil or vardenafil and 48 hours if tadalafil; the delay should be longer for each if he has renal or hepatic dysfunction. (See "Sexual activity in patients with cardiovascular disease", section on 'Adverse interaction with nitrates'.)

Myocardial infarction and sudden death have been described with and after intercourse, both in men who have and have not taken a PDE5 inhibitor. Thus, the relation to the drug is uncertain. (See "Sexual activity in patients with cardiovascular disease", section on 'Does sildenafil promote MI?'.)

Higher doses of PDE5 inhibitors are used for patients with pulmonary hypertension as monotherapy or in combination with other agents, such as guanylate cyclase stimulants (eg, riociguat). However, the US Food and Drug Administration (FDA) has issued a warning against this combination because of an excess risk of hypotension.

Common side effects — Side effects associated with sildenafil are related to its vasodilatory properties and are similar to those induced by nitrates. In a meta-analysis of 14 trials, adverse events with sildenafil included flushing, headaches, and dyspepsia in 12, 11, and 5 percent, respectively [33]. Nasal congestion has been described in other reports [66]. Side-effect profiles with vardenafil [44,45], avanafil, and tadalafil [51,67] are similar to sildenafil.

Visual effects — Sildenafil occasionally causes "blue vision" in men. The PDE5 inhibitor in sildenafil crossreacts with the PDE6 inhibitor, which is present in the retina and plays a role in color vision. "Blue vision" has been reported in approximately 3 percent of sildenafil-treated men, lasts two to three hours, and disappears spontaneously. Blue vision has not been reported with vardenafil, tadalafil, or avanafil (table 2A).

Rare cases (n = 23) of nonarteritic anterior ischemic optic neuropathy (NAION) were reported in men taking sildenafil and tadalafil between 1998 and 2005 [68].The estimated annual incidence of NAION in men over age 50 years is 2.5 to 11.8 cases per 100,000; observational data now suggest that recent use of PDE5 inhibitors, as a class, may be associated with a twofold increase in risk of NAION [69].

NAION shares a number of risk factors with ED: age over 50 years, hypertension, dyslipidemia, and diabetes. Therefore, it is unclear whether NAION in these patients is due to their underlying vascular risk factors, anatomic defects, or use of PDE5 inhibitors. However, the FDA has added warnings to labeling of all PDE5 inhibitors to reflect this potential risk. (See "Nonarteritic anterior ischemic optic neuropathy: Epidemiology, pathogenesis, and etiologies", section on 'Phosphodiesterase-5 inhibitors'.)

Although there are no clinical data on the safety and efficacy of sildenafil in men with retinitis pigmentosa (a minority of whom have genetic disorders of retinal PDE), the manufacturer recommends caution in these patients.

The long-term effects of sildenafil on visual function are unknown. At this time, monitoring of visual function does not appear to be necessary in the average man without retinal disease [70].

Hearing loss — Sildenafil, vardenafil, and tadalafil use have been associated with rare reports of sudden hearing loss [71-73]. Although no causal relationship has been demonstrated, the FDA requires that labeling of all PDE5 inhibitors include this potential risk [74]. The hearing loss is usually unilateral, occurs with the first 24 hours of drug administration, and is temporary in approximately one-third of patients [72,73].

Potential risks — PDE5 inhibitors can promote melanin synthesis in vitro [75], and some studies have reported an association between PDE5 use and a small increased risk of malignant melanoma [76,77]. However, a third study concluded that the association was unlikely to be causal, as greater exposure to PDE5 inhibitors was not associated with higher melanoma risk, the association was observed for other sun exposure-related conditions, and patients taking PDE5 inhibitors were more likely to have greater sun exposure [78].

Drug interactions — All PDE5 inhibitors are contraindicated in men taking concurrent nitrates (table 2A). In spite of tadalafil's longer half-life, the duration of its interaction with nitrates does not appear to be prolonged [79]. However, it has been suggested that nitrates should be avoided for at least 48 hours after the last tadalafil dose [80]. Other issues related to sexual activity in men with coronary heart disease are similar to those with sildenafil. (See "Sexual activity in patients with cardiovascular disease".)

Alpha-adrenergic antagonists, which are commonly used for the treatment of BPH, may cause symptomatic hypotension when taken in combination with PDE5 inhibitors (table 2A) [81]. These drugs include terazosin, doxazosin, tamsulosin, alfuzosin, and silodosin [82]. Tamsulosin and silodosin are better choices (ie, less or no hypotension) than doxazosin or terazosin [83,84].

Current labeling for all four PDE5 inhibitors recommends that a patient who is taking an alpha-blocker should be on a stable dose prior to initiating the PDE5 inhibitor (which should then be started at the lowest recommended dose). Conversely, in patients already taking a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose (table 2A). The use of PDE5 inhibitors for BPH is discussed separately. (See "Medical treatment of benign prostatic hyperplasia", section on 'Phosphodiesterase type 5 inhibitors'.)

PDE5 inhibitors should also be avoided in patients taking drugs that can prolong the half-life of sildenafil by blocking CYP3A4 (table 7) (if used, the potential adverse effects should be stressed with the patient and the PDE5 starting dose should be decreased).

Role of testosterone — Testosterone is an important regulator of sexual desire and sexual function in men. ED and low testosterone levels often coexist in middle-aged and older men. Measurement of serum testosterone is recommended for men with ED [3,7], and testosterone replacement has been shown to improve libido, sexual activity, and erectile function in hypogonadal men [85-87]. As a result, combination therapy with a PDE5 inhibitor and testosterone has become increasingly common [3]. Data on the impact of testosterone on ED, either alone or combined with PDE5 inhibitors, have been conflicting [5,7,13,88-91], but there is emerging evidence that combination therapy may be useful for hypogonadal men who do not initially respond to PDE5 therapy alone [88,89].

A 2017 meta-analysis of 14 trials in 2298 patients assessed the effects of testosterone replacement therapy on sexual function [92]. Testosterone therapy was associated with an improvement in erectile function (as measured by IIEF) when compared with placebo. Men with more severe hypogonadism (serum testosterone level less than 8 nmol/L [231 ng/dL]) experienced the greatest improvement in erectile function.

Previous data on the impact of adding testosterone therapy to PDE5 inhibitors have been conflicting [7]. In a trial of 140 men with both ED and low serum testosterone levels (<330 ng/dL [11.45 nmol/L]) or free testosterone <50 pg/mL, sildenafil dose was first optimized, and then subjects (sildenafil responders only) were randomized to receive additional therapy with either testosterone gel or placebo [91]. At the end of 14 weeks, erectile dysfunction domain (EFD) scores were no better in the testosterone group than the placebo group, in spite of significantly higher serum testosterone concentrations in the intervention group (mean 649 ng/dL [22.5 nmol/L]) than placebo (347 ng/dL [12 nmol/L]). One possible explanation for the lack of effect is that sildenafil use alone increased serum testosterone by approximately 100 ng/dL (from approximately 250 ng/dL at baseline to 350 ng/dL in both groups [8.7 to 12.1 nmol/L]), and perhaps higher serum testosterone concentrations do not provide additional benefit.

Of note, this study did not evaluate nonresponders to PDE5 inhibitors. The TADTEST study, published after the meta-analysis described above, did evaluate subjects (n = 173) who had not responded to tadalafil (10 mg/day for four weeks) and who had serum testosterone <400 ng/dL (13.9 nmol/L) who were then randomized to testosterone or placebo therapy for 12 weeks [88]. Erectile function improved in both the placebo and testosterone groups, but in a subgroup analysis, there was greater improvement with the addition of testosterone to tadalafil in men with baseline testosterone ≤300 ng/dL (10.4 nmol/L) versus no added benefit in men with baseline testosterone level >300 ng/dL (10.4 nmol/L). These findings suggest that maximal benefit of tadalafil may require longer than four weeks of treatment, and the addition of testosterone may only be beneficial in hypogonadal men (serum testosterone <300 ng/dL [10.4 nmol/L]) ng/mL. Similar results were reported in a second trial, where hypogonadal men who previously did not respond to PDE5 inhibitors had an improvement in erectile function with combined testosterone and tadalafil therapy [89].

Other issues

Men with diabetes — Men with diabetes are at very high risk for developing ED. Intensive glycemic control may reduce the development of ED [93,94]. However, there are no data to suggest intensive therapy can reverse or improve ED once it has developed. The management of ED in men with diabetes is essentially the same as that for men without diabetes [95]. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Glycemic control and vascular complications in type 2 diabetes mellitus".)

Recreational use — Because sildenafil treatment is associated with a marked reduction in the postejaculatory refractory time [96], men are capable of having a second erection in a shorter time frame than was possible without this therapy. As a result, recreational use of sildenafil is common. However, although not a well-established risk, there are case reports of stroke in men taking high-dose sildenafil [97,98]. In a systematic review of published studies, sildenafil use among gay men was associated with sexual risk behavior and risk of sexually transmitted diseases, including human immunodeficiency virus (HIV) infection [99].

Dietary supplements and counterfeit medications — The FDA has issued a warning to consumers not to purchase or consume dietary supplements that claim to increase sexual stamina, confidence, and performance and/or claim to contain prescription-strength doses of sildenafil or tadalafil [100,101]. Current studies suggest that one-third to one-half of supplements claiming to be "natural" products for sexual enhancement contain synthetic chemicals, most commonly, PDE5 inhibitors or analogs of PDE5 inhibitors [102-105]. The concern is that patients who take nitrates for cardiovascular disease may experience a drastic lowering of blood pressure if these supplements are consumed.

For the past decade, international regulatory agencies have taken yearly action against websites that illegally sell potentially dangerous, unapproved prescription drugs. In 2016, 1283 packages were seized in Canada that contained counterfeit or unlicensed health products; 98 percent of these were sexual enhancement products that were either fake or unauthorized [106]. The ingredients in the health products were not reported.

The World Health Organization (WHO) reported in 2008 that 37 percent of the counterfeit medication involved the genitourinary therapeutic area [107]. Over the past decade, the number of drug fraud cases investigated by the FDA for has increased 10-fold in the United States [108]. In 2006, it was estimated that between 0.6 and 2.5 million European men were possibly exposed to illicit sildenafil compared with 2.5 million men using legal sildenafil [109].

Additional options — If PDE5 inhibitors are ineffective, we recommend vacuum erection devices, penile injections with vasodilating agents, or intraurethral alprostadil as second-line therapy. We often suggest trying a vacuum device first because it is noninvasive and less expensive than the other options.

Vacuum-assisted erection devices — Several mechanical devices have been developed that utilize vacuum pressure to encourage increases in arterial inflow and occlusive rings to limit venous egress from the penile corpora cavernosa (figure 3 and table 2B). A certain amount of mechanical dexterity is required to use these devices effectively, but once men become comfortable with using the vacuum and restraining rings many men can create an erection sufficient for vaginal penetration and sexual intercourse. The men may have difficulty ejaculating externally, however, because the occlusive rings that prevent venous drainage also compress the penile urethra sufficiently to prevent seminal fluid from reaching and traversing the urethral meatus. A number of devices are available for purchase over the counter. Although the initial dropout rate may be as high as 50 percent, long-term satisfaction of patients and partners has been reported by several groups [110]. This is especially true in patients who do not respond to penile injections.

The vacuum erection device may be used with oral PDE5 inhibitors to augment an insufficiently rigid erection post-ingestion of the PDE5 inhibitor [111]. Vacuum erection devices should only be applied for a maximum of 30 minutes. These devices can also be used in patients taking blood thinners, albeit with caution. Clinical experience has suggested that these devices are most often used by couples in stable relationships.

Vacuum devices successfully create erections in as many as 60 to 70 percent of patients [112]. Satisfaction with vacuum-assisted erections has varied between 25 and 49 percent. As an example, one prospective study evaluated 18 men by questionnaire at six months: 16 (89 percent) were able to attain satisfactory erections, and the overall satisfaction rate was 83 percent [113]. Sixteen of the 18 men found the device easy to use.

Penile self-injection — Intracavernosal injection therapy with alprostadil (prostaglandin E1) and papaverine have been used for purposes of inducing erection (figure 4 and table 2B). In the United States, prostaglandin E1 is the only FDA-approved drug for penile self-injection. The drug has vasodilatory properties and is also used in infants to maintain the patency of the ductus arteriosus before definitive cardiac surgery can be performed.

In other countries, a combination of vasointestinal peptide (VIP) and phentolamine are marketed as Invicorp (table 2B). Some clinicians prefer compounded mixtures of phentolamine and papaverine (Bimix); prostaglandin E1 is sometimes added as a third component (Trimix). Compounded penile injections of Trimix are commonly utilized penile injections mainly due to excellent efficacy, cost, and finer ability to titrate the dose. It should be noted that compounded penile injections are considered off-label use. All penile injections, whether compounded or commercially available, increase the risk for penile plaque development, and patients should be counseled about this potential risk.

The sympathetic nervous system normally maintains the penis in a flaccid or non-erect state. Vasodilator drugs, when injected into the corpora cavernosa, inhibit or override sympathetic vasoconstriction and act as direct smooth muscle vasodilators. The relaxation of the smooth muscle trabeculae within the penile erectile bodies leads to an increase in blood flow to the penis. The increased inflow of blood engorges the penile corpora cavernosa sinusoidal spaces with sufficient pressure to compress the emissary veins that normally drain blood from the penis. The combination of accelerated arterial inflow and impeded venous outflow from the corpora cavernosa creates an erection (figure 5).

Considerable education is required for men to become facile with penile self-injection. Men are trained in sterile methods and the proper technique for inserting an insulin syringe with a 26- to 30-gauge one-half-inch needle through the shaft of the penis and injecting the vasoactive agent into one corporeal body (figure 4). The cross circulation of the penile corpora allows medication injected into one penile corporeal body to diffuse over to the contralateral side, so that a full, firm erection can be expected within a few minutes after intrapenile installation of the drug [114,115].

In a study of 683 men using alprostadil penile self-injections over a six-month period, 87 percent of subjects of the 471 who completed the study were satisfied with results (as were 86 percent of their partners) [116]. Penile pain, which occurred in 50 percent of subjects, was the side effect most often cited by men who discontinued therapy.

Priapism — Priapism, or a prolonged erection lasting more than four to six hours, is a medical emergency often requiring immediate urologic attention to evacuate blood clogged within the corpora cavernosa [117]. Prolonged erections occur in 6 percent of men who use intrapenile alprostadil and approximately 11 percent of those who use intrapenile papaverine. Priapism should be reversed as quickly as possible; long durations of priapism may result in permanent corporal fibrosis and ED. The management of priapism is reviewed separately. (See "Priapism", section on 'Ischemic priapism'.)

Lower doses of intracavernosal injections should be used in men with neuropathic ED (due to spinal cord injury or multiple sclerosis), due to their risk of priapism.

One study evaluated the effects of prolonged priapism [118]:

Most priapism that lasted 36 hours could be treated successfully by puncture and alpha-adrenergic drugs, without any fibrosis of the corpora cavernosa.

After 48 hours, glandulocavernosal shunts were required to achieve detumescence. All the men developed fibrosis of the corpora cavernosa, and all but one were unable to continue with the injections of vasoactive drugs.

Intraurethral alprostadil — Intraurethral administration of alprostadil (prostaglandin E1) provides a less invasive alternative to intrapenile injection (table 2B). Administration of alprostadil cream into the urethral meatus is more effective than application to the glans penis [119]. After insertion of the alprostadil into the urethra, the penis is massaged for up to one minute to ensure equal distribution in the corpora cavernosa. Doses include 125, 250, 500, and 1000 mcg. Although this option is less invasive than penile injections, it appears to be less effective than penile injections; it also causes penile pain and bleeding in many men. The main limiting factor to the use of intraurethral alprostadil is cost, with most insurance plans not offering coverage for this medication.

The efficacy of intraurethral alprostadil was evaluated in a double-blind, placebo-controlled trial in 1511 men with chronic ED from a variety of organic causes [120]. Two-thirds of these men responded to intraurethral alprostadil with an erection sufficient for intercourse; these men were then randomly assigned to therapy with either alprostadil or placebo. Successful intercourse on at least one occasion was much more likely with alprostadil (65 versus 19 percent with placebo). Among the men who responded to alprostadil, 7 of 10 applications were followed by successful intercourse.

Systemic effects were uncommon, but some men experienced penile pain. No subject experienced priapism or penile fibrosis (unlike what is seen when alprostadil is given by penile injection) (see 'Penile self-injection' above). The 19 percent response rate in the placebo group suggests that psychogenic factors were responsible for the sexual dysfunction in some men, since placebo injections do not induce erections in solely organic causes of impotence. A systematic review of three studies of intraurethral alprostadil reported similar efficacy [121].

Intraurethral administration of alprostadil should not be used in sickle cell anemia or sickle cell trait, leukemia, bone marrow problems (eg, multiple myeloma), or other conditions that may increase risk for a prolonged, painful erection (priapism). It also should not be used in men who have a deformed penis or certain other penile problems (eg, Peyronie's disease, fibrosis of the penis). One expert group suggests that men with ED considering the use of intraurethral alprostadil should first undergo an in-office test.

Surgical options

Penile prostheses — Surgical management of ED should be reserved for men who cannot use, or who have not responded to, first- and second-line therapies [122]. (See 'General principles' above and "Surgical treatment of erectile dysfunction", section on 'Penile prostheses'.)

Patients with curvature abnormalities (ie, Peyronie's disease) with ED or significant risk factors for future ED are candidates for the placement of a penile prosthesis at the time of their reconstructive surgery. (See "Surgical management of Peyronie's disease".)

Penile revascularization — For most men with vascular ED, we do not suggest arterial revascularization, as success rates are low. However, reasonable success rates may be achieved in young, nonsmoking, otherwise healthy men with recently acquired ED due to a focal arterial occlusion. Only 6 to 7 percent of men with vascular ED are candidates for penile revascularization using these restricted criteria; long-term success rates are in the 50 to 65 percent range. The Clinical Guidelines Panel of the AUA suggested that venous and arterial surgery was no longer justified for routine use, especially in patients with arteriosclerosis. This topic is reviewed in detail separately. (See "Surgical treatment of erectile dysfunction", section on 'Penile revascularization'.)

Therapies for psychogenic ED

Psychotherapy Psychological factors can play a role in the etiology of ED, alone or in combination with organic causes. ED is a common symptom of depression, and erectile function may be restored as psychotherapy or antidepressant drugs alleviate the depression.

However, some of the most effective antidepressant drugs of the SSRI class (eg, fluoxetine, sertraline, paroxetine) decrease both libido and erectile function [123]. However, SSRIs can cause delayed ejaculation, an effect that is beneficial for men with premature ejaculation (PE). (See "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Management" and 'Premature ejaculation' below.)

Psychological counseling, including the use of sensate focus exercises by both partners, can be helpful for men with performance anxiety. This is usually best accomplished by referral to a certified sexual therapy counselor. A meta-analysis of psychotherapy interventions suggests that psychotherapy, in particular group psychotherapy, is beneficial [124].

Yohimbine Yohimbine, a drug that blocks presynaptic alpha-2-adrenergic receptors, resulting in increased cholinergic and decreased adrenergic tone, has also been used for the management of psychogenic ED. It may be more effective than placebo in men with psychogenic ED, but data are limited [125-127]. We suggest not using yohimbine, given the limited data for efficacy and the availability of effective alternatives (PDE5 inhibitors).

Regenerative and restorative therapies — Experimental therapies for ED are currently in development [3]. These treatment options are known as regenerative or restorative therapies and include:

Stem cell therapy The use of stem cells to treat erectile dysfunction is being actively investigated [128]. The majority of studies have used adipose-derived stem cells (ADSCs) with transplantation performed via intracavernous injection. Others use alternative strategies such as periprostatic application (linked or not linked to a scaffold) and intravenous injection. This approach appears promising for the treatment of ED, but it is not currently FDA approved in the United States. The stem cells are thought to exert their effect through a paracrine action.

Another emerging technology to treat ED is low-intensity shock therapy (LIST), the delivery of several thousand low-intensity shocks to the penis over several weeks [129]. LIST has been reported to induce angiogenesis, stimulate neovascularization in the penile tissue, improve penile blood flow and endothelial function, and convert PDE5 inhibitor nonresponders to responders. However, it has not been shown to be effective in clinical trials [130].

Hyperbaric oxygen therapy has also been investigated as a potential therapy for ED. While some data suggest potential improvement in erectile function [1], no benefit was observed in men with ED post-radical prostatectomy [131].

Platelet-rich plasma (PRP) – Although there are little data to support its efficacy [132], some centers are offering platelet-rich plasma (PRP) injections to men with ED as a form of autologous cell therapy. Further studies are needed before suggesting this approach.

Ineffective or no longer used — Other therapies that are ineffective or have been tried in the past include:

Melanocortin receptor agonists Preliminary data suggest that melanocortin receptor agonists, which act on the central nervous system rather than the vascular system, may be effective for ED [133]. However, there are currently no approved or commercially available compounds.

Apomorphine – Apomorphine has been shown to be inferior to sildenafil in treating men with ED [134]. The drug was approved for ED in some countries, but commercially available products were discontinued because of its poor efficacy [135].

EJACULATORY DISORDERS

Premature ejaculation — Premature ejaculation (PE) is also referred to as rapid or early ejaculation and is defined according to three essential criteria: (1) brief ejaculatory latency; (2) loss of control; and (3) psychological distress in the patient and/or partner.

Ejaculatory latency time (ELT) of approximately one minute or less may qualify a man for the diagnosis, which should include consistent inability to delay or control ejaculation, and marked distress about the condition. All three components should be present to qualify for the diagnosis. One study suggests that clinicians should consider ELTs up to two minutes for a PE diagnosis [136].

Subtypes of the disorder are symptom based, including lifelong versus acquired, global versus situational PE, and the co-occurrence of other sexual problems, particularly erectile dysfunction (ED). (See "Epidemiology and etiologies of male sexual dysfunction", section on 'Premature ejaculation'.)

Management depends upon the etiology, but the mainstays of therapy [137] include selective serotonin reuptake inhibitors (SSRIs) [138], topical anesthetics [139], and psychotherapy when psychogenic and/or relationship factors are present [140].

We consider SSRIs to be first-line treatment. Available agents and dosages include paroxetine (10 to 40 mg/day), sertraline (50 to 200 mg/day), fluoxetine (20 to 40 mg/day), citalopram (20 to 40 mg/day), and escitalopram (10 to 20 mg/day) [141,142]. SSRIs should be started at the lowest dose and titrated up as needed at three- to four-week intervals.

A meta-analysis of available trials suggests that paroxetine may be the most effective (nine-minute ejaculation delay over baseline) [143]. The full therapeutic effect of SSRIs is typically not seen until after two to three weeks of therapy, and symptoms return if treatment is stopped.

If SSRIs are ineffective or not tolerated, we consider the serotonergic tricyclic clomipramine (12.5 to 50 mg/day) to be second-line therapy [141].

An additional SSRI, dapoxetine, also appears to be effective, based upon five trials of over 6000 men with PE who were randomly assigned to receive placebo or dapoxetine (30 mg or 60 mg/day) [144]. Unlike other SSRIs, which are most effective when taken daily, dapoxetine is taken on-demand one to three hours before intercourse. Dapoxetine is not commercially available in all countries, including the United States.

Phosphodiesterase (PDE) inhibitors may also be effective for the treatment of PE, but mainly in men with PE and coexisting ED [141,145]. Two meta-analyses have assessed the efficacy of PDE5 inhibitors for PE [146,147]. The main findings were: Both SSRIs and PDE5 inhibitors are more effective than placebo, PDE5 inhibitors are either as effective as SSRIs [146] or slightly more effective [147], and combined therapy is more effective than either therapy alone.

For men with both ED and PE, we suggest starting a PDE5 inhibitor first to treat the ED. If the patient still has PE, we then add an SSRI.

Tramadol, an analgesic that has some activity at opioid receptors but also inhibits reuptake of serotonin and norepinephrine, may also be effective [148,149]. Tramadol is sometimes used as a third-line agent if SSRIs and clomipramine are ineffective or not tolerated. However, it should be used with extreme caution, given the potential risk of addiction and side effects associated with opioids. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Opioids'.)

Topical anesthetics are also more effective than placebo. Multicenter trials with an aerosolized, lidocaine-prilocaine spray have been reported to improve ejaculatory latency, ejaculatory control, and sexual satisfaction when applied topically to the glans penis five minutes before intercourse [150,151]. In a meta-analysis of eight trials, topical anesthetic agents were more effective than placebo and were well tolerated by patients and their partners. [139].

Topical administration of alprostadil cream (200 to 300 mcg) to the penile meatus prior to intercourse may also be beneficial [152]. In one study, common side effects included burning or erythema (12 percent) at the application site, meatal or glandular pain (4 percent), or prolonged or painful erection (1.3 percent). Vaginal burning or itching was noted in 2 percent of the partners.

Behavioral and psychological therapies are effective in some men [141]. These interventions are designed to achieve a number of goals: improve self-confidence and communication in the relationship and, ultimately, increase the ejaculation latency.

Combined pharmacologic and behavioral treatment appears to be more effective than pharmacotherapy alone [141]. We suggest this approach in men with PE who have a clear psychosocial precipitant or in those with individual or couple issues that could impact the success of pharmacotherapy alone.

Other — Ejaculatory dysfunction includes a spectrum of disorders in men ranging from delayed ejaculation to a complete inability to ejaculate, anejaculation, and retrograde ejaculation. Men with delayed ejaculation, anejaculation, and anorgasmia may have an organic and/or psychogenic etiology. This topic and the management of ejaculatory disorders due to antidepressant drugs are discussed in detail separately. (See "Epidemiology and etiologies of male sexual dysfunction", section on 'Other ejaculatory disorders' and "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Management".)

Lack of ejaculation is common in men with mild, moderate, or severe lower urinary tract symptoms (LUTS) and in men who are treated for these symptoms with tamsulosin [153]. Treatment of LUTS with alfuzosin has been shown to reduce ejaculatory dysfunction [154]. As previously noted, forward ejaculation is not possible in men whose ED is treated with a vacuum constrictor device. (See 'Vacuum-assisted erection devices' above.)

Low serum testosterone concentrations have also been associated with ejaculatory dysfunction (see "Epidemiology and etiologies of male sexual dysfunction", section on 'Other ejaculatory disorders'). However, testosterone therapy is not effective for ejaculatory disorders, suggesting that the relationship is not causal. This was illustrated in a trial of 76 men with one or more ejaculatory symptoms (delayed ejaculation, anejaculation, low ejaculate volume, and/or decreased force of ejaculation) and low serum testosterone concentrations (<300 ng/dL [<10.41 nmol/L] on two occasions), randomly assigned to testosterone solution (2%, 60 mg) or placebo for 16 weeks [155]. Although testosterone therapy increased mean serum testosterone concentrations to the normal male range (214 to 488 ng/dL [7.4 to 16.9 nmol/L]), there were no improvements in parameters of ejaculatory function.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Male sexual dysfunction".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Sex problems in men (The Basics)")

Beyond the Basics topics (see "Patient education: Sexual problems in men (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — Therapy of men with sexual dysfunction is aimed at improving libido and addressing the two vital sexual functions: the capacity to acquire and sustain penile erections and treating premature ejaculation (PE). Optimal treatment varies, depending upon the factor(s) that have reduced libido or caused erectile or ejaculatory dysfunction.

For men with erectile dysfunction (ED), initial steps include (figure 2) (see 'Overview of management approach' above):

Identifying the underlying etiology, including drugs such as antidepressants or antihypertensive agents that may be causing or contributing to the ED.

Identifying and treating cardiovascular risk factors, such as smoking, obesity, hypertension, and dyslipidemia, as both lifestyle measures and pharmacotherapy for risk factor reduction may be effective for prevention and treatment of ED (table 1 and table 4 and algorithm 1).

We recommend initial use of the phosphodiesterase-5 (PDE5) inhibitors because of their efficacy, ease of use, and favorable side-effect profile (Grade 1A). Sildenafil, vardenafil, tadalafil, and avanafil appear to be equally effective, but tadalafil has a longer duration of action (table 2A) (see 'Phosphodiesterase-5 inhibitors' above). Current practice guidelines suggest that the choice of PDE5 inhibitor should be based upon on the patient's preferences, including cost, ease of use, and adverse effects. (See 'Choice of drug' above.)

One expert group suggests that men can also choose a different option for their initial therapy (after careful counseling and shared-decision making). (See 'Overview of management approach' above.)

PDE inhibitors are contraindicated in men taking nitrates. (See 'Adverse effects and precautions' above.)

Alpha-adrenergic antagonists, which are commonly used for the treatment of benign prostatic hyperplasia (BPH), may cause symptomatic hypotension when taken in combination with PDE5 inhibitors. These drugs include terazosin, doxazosin, tamsulosin, alfuzosin, and silodosin. If the clinician and patient choose to use alpha blockers with PDE5 inhibitors, tamsulosin and silodosin are better choices (little or no hypotension) than doxazosin or terazosin.

When the combination is going to be used, PDE5 inhibitors should be initiated at the lowest possible dose in patients on stable alpha blocker therapy. In patients already taking an optimized dose of PDE5 inhibitor, alpha blocker therapy should be initiated at the lowest possible dose. (See 'Drug interactions' above.)

Other therapies that have been shown to be effective: penile self-injectable drugs (figure 4), intraurethral alprostadil, and vacuum devices (figure 2 and figure 3 and table 2B). We suggest choosing among these options based upon patient preference (Grade 2B). We often suggest that men start with vacuum devices. (See 'Penile self-injection' above and 'Vacuum-assisted erection devices' above.)

We suggest that surgical implantation of a penile prosthesis be reserved for men who cannot use or who have not responded to less invasive therapies (figure 2) (Grade 2B). (See 'Penile prostheses' above.)

We recommend testosterone replacement therapy only in men with documented hypogonadism (Grade 1B). (See 'Role of testosterone' above.)

We suggest referral to a certified sexual therapy counselor or a psychologist for men with psychogenic ED (Grade 2B).

We suggest selective serotonin reuptake inhibitors (SSRIs) as first-line therapy and clomipramine as second-line therapy for men with PE (Grade 2B). (See 'Premature ejaculation' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Glenn R Cunningham, MD, who contributed to earlier versions of this topic review.

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Topic 7469 Version 38.0

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86 : Effects of Testosterone Treatment in Older Men.

87 : Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels.

88 : Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study).

89 : Combination therapy of testosterone enanthate and tadalafil on PDE5 inhibitor non-reponders with severe and intermediate testosterone deficiency.

90 : Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials.

91 : Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial.

92 : Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile Function Scores.

93 : Effect of intensive glycemic therapy on erectile function in men with type 1 diabetes.

94 : Prevalence and associations of erectile dysfunction in a sample of Italian males with type 2 diabetes.

95 : Male and female sexual dysfunction in diabetic subjects: Focus on new antihyperglycemic drugs.

96 : Effects of sildenafil (Viagra) administration on seminal parameters and post-ejaculatory refractory time in normal males.

97 : Bilateral cerebral hemispheric infarction associated with sildenafil citrate (Viagra) use.

98 : Intracerebral hemorrhage associated with sildenafil use: a case report.

99 : Sildenafil use, sexual risk behavior, and risk for sexually transmitted diseases, including HIV infection.

100 : Sildenafil use, sexual risk behavior, and risk for sexually transmitted diseases, including HIV infection.

101 : FDA issues warning on "all-natural" herbal product found to contain viagra.

102 : Designer drugs in herbal aphrodisiacs.

103 : Screening of Indian aphrodisiac ayurvedic/herbal healthcare products for adulteration with sildenafil, tadalafil and/or vardenafil using LC/PDA and extracted ion LC-MS/TOF.

104 : Adulterated and Counterfeit Male Enhancement Nutraceuticals and Dietary Supplements Pose a Real Threat to the Management of Erectile Dysfunction: A Global Perspective.

105 : Efficacy of Tongkat Ali (Eurycoma longifolia) on erectile function improvement: systematic review and meta-analysis of randomized controlled trials.

106 : Efficacy of Tongkat Ali (Eurycoma longifolia) on erectile function improvement: systematic review and meta-analysis of randomized controlled trials.

107 : Efficacy of Tongkat Ali (Eurycoma longifolia) on erectile function improvement: systematic review and meta-analysis of randomized controlled trials.

108 : The growing concerns regarding counterfeit medications.

109 : Counterfeit phosphodiesterase type 5 inhibitors pose significant safety risks.

110 : Treatment of erectile dysfunction with external vacuum devices.

111 : Combination of vacuum erection device and PDE5 inhibitors as salvage therapy in PDE5 inhibitor nonresponders with erectile dysfunction.

112 : Vacuum constriction devices in erectile dysfunction: acceptance and effectiveness in patients with impotence of organic or mixed aetiology.

113 : A prospective trial with vacuum-assisted erection devices.

114 : Experience with triple-drug therapy in a pharmacological erection program.

115 : Papaverine-phentolamine and prostaglandin E1 versus papaverine-phentolamine alone for intracorporeal injection therapy: a clinical double-blind study.

116 : Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group.

117 : Priapism associated with trazodone therapy.

118 : Effects of priapism lasting 24 hours or longer caused by intracavernosal injection of vasoactive drugs.

119 : The intra-meatal application of alprostadil cream (Vitaros®) improves drug efficacy and patient's satisfaction: results from a randomized, two-administration route, cross-over clinical trial.

120 : Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group.

121 : Prostaglandin E1 for treatment of erectile dysfunction.

122 : Clinical guidelines on erectile dysfunction surgery: EAU-AUA perspectives.

123 : Fluoxetine-induced sexual dysfunction.

124 : Psychosocial interventions for erectile dysfunction.

125 : Double blind trial of yohombine hydrochloride in the treatment of erection inadequacy

126 : Effect of yohimbine-trazodone on psychogenic impotence: a randomized, double-blind, placebo-controlled study.

127 : Yohimbine for erectile dysfunction: a systematic review and meta-analysis of randomized clinical trials.

128 : Mesenchymal stem cell therapy for the treatment of erectile dysfunction.

129 : Penile low-intensity shock wave therapy: a promising novel modality for erectile dysfunction.

130 : Effect of Low-Energy Linear Shockwave Therapy on Erectile Dysfunction-A Double-Blinded, Sham-Controlled, Randomized Clinical Trial.

131 : A Double-Blind, Randomized Trial on the Efficacy and Safety of Hyperbaric Oxygenation Therapy in the Preservation of Erectile Function after Radical Prostatectomy.

132 : Platelet-Rich Plasma and Treatment of Erectile Dysfunction: Critical Review of Literature and Global Trends in Platelet-Rich Plasma Clinics.

133 : Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans.

134 : Comparative cross-over study of sildenafil and apomorphine for treating erectile dysfunction.

135 : Examination of the safety and use of apomorphine prescribed in general practice in England as a treatment for erectile dysfunction.

136 : Understanding the effects of establishing various cutoff criteria in the definition of men with premature ejaculation.

137 : Standard operating procedures in the disorders of orgasm and ejaculation.

138 : Oral agents for the treatment of premature ejaculation: review of efficacy and safety in the context of the recent International Society for Sexual Medicine criteria for lifelong premature ejaculation.

139 : Topical anesthetic agents for premature ejaculation: a systematic review and meta-analysis.

140 : Psychosocial interventions for premature ejaculation.

141 : International Society for Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation.

142 : The efficacy of fluoxetine in the treatment of premature ejaculation: a double-blind placebo controlled study.

143 : Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis.

144 : Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials.

145 : Does current scientific and clinical evidence support the use of phosphodiesterase type 5 inhibitors for the treatment of premature ejaculation? a systematic review and meta-analysis.

146 : Phosphodiesterase-5 inhibitors for premature ejaculation: a systematic review and meta-analysis.

147 : Efficacy of PDE5Is and SSRIs in men with premature ejaculation: a new systematic review and five meta-analyses.

148 : Efficacy and safety of tramadol for premature ejaculation: a systematic review and meta-analysis.

149 : Tramadol for premature ejaculation: a systematic review and meta-analysis.

150 : PSD502 improves ejaculatory latency, control and sexual satisfaction when applied topically 5 min before intercourse in men with premature ejaculation: results of a phase III, multicentre, double-blind, placebo-controlled study.

151 : Improved ejaculatory latency, control and sexual satisfaction when PSD502 is applied topically in men with premature ejaculation: results of a phase III, double-blind, placebo-controlled study.

152 : Long-term, multicenter study of the safety and efficacy of topical alprostadil cream in male patients with erectile dysfunction.

153 : Association of sexual dysfunction with lower urinary tract symptoms of BPH and BPH medical therapies: results from the BPH Registry.

154 : Ejaculatory dysfunction in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

155 : Testosterone Replacement in Androgen-Deficient Men With Ejaculatory Dysfunction: A Randomized Controlled Trial.