#93772: Male Sexual Dysfunction

Substance effects contribute to a large proportion of sexual dysfunction in men, and certain drug classes are especially prone to inducing sexual dysfunction. These include antidepressants, neuroleptics, 5α-reductase (5α-R) inhibitors, and certain recreational or illicit drugs.

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) account for most antidepressant prescriptions, and primary care providers should have an appreciation of the impact of sexual side effects common to these agents. Antidepressant-induced sexual side effects largely result from increased serotonin (5-HT) neurotransmission via reuptake blockade of serotonin transporters, while antidepressants that primarily increase dopamine and norepinephrine neurotransmission produce markedly fewer sexual side effects.

In patients showing an otherwise positive therapeutic response, switching medications to an antidepressant with fewer sexual side effects is highly undesirable and should be avoided, if possible. Another strategy is antidepressant dose reduction, on the basis of a dose-response relationship in sexual side effects. The incidence of male sexual dysfunction (particularly ejaculatory delay) is much higher with SSRIs and serotonin-norepinephrine reuptake inhibitors, and much lower in antidepressants with primary adrenergic or dopaminergic mechanism. However, this can be a desired instead of adverse effect in men with PE, and the SSRI dapoxetine has been approved as first-line therapy for PE in more than 50 countries, but not in the United States [9,22,23,24]. To date, no drug has been specifically approved by the U.S. Food and Drug Administration (FDA) for the treatment of PE [19]. However, the SSRIs sertraline, paroxetine, fluoxetine, and citalopram are used off-label for PE [24].

Tricyclic antidepressants (TCAs) with SSRI-like activity have a similar effect as SSRIs. The TCA most studied for treatment of PE is clomipramine. Studies suggest that the off-label, on-demand administration of clomipramine is more effective for PE than many SSRIs [19,25,26].

Hyperprolactinemia Secondary to Neuroleptics

Antipsychotic medications, also referred to as neuroleptics, are prescribed for schizophrenia, other psychotic disorders, and bipolar disorder and are widely prescribed off-label for mood and anxiety disorders, insomnia, and other psychiatric conditions. Though often effective for these uses, the prevalence of neuroleptic-induced sexual dysfunction is high [27]. A 12-month comparative trial of neuroleptic therapy for schizophrenia reported sexual dysfunction rates of 29% with olanzapine, 34% with quetiapine, 43% with risperidone, and 45% with haloperidol [28].

Hyperprolactinemia is the underlying factor in almost all neuroleptic-induced sexual dysfunction [27]. Neuroleptics over-ride normal pituitary inhibitory mechanism by facilitating prolactin synthesis and secretion, a mechanism shared by all D2 receptor antagonists. Among D2 antagonists, neuroleptics are the most widely prescribed and show the highest rates of drug-induced hyperprolactinemia [29,30]. Some trials have found 100% hyperprolactinemia rates with risperidone and older first-generation phenothiazine neuroleptics [31,32]. Verapamil induces hyperprolactinemia in 8.5% of patients by blocking hypothalamic dopamine [33]. In addition, opioids and cocaine can induce mild hyperprolactinemia through mu-opioid receptor action. Some patients with hyperprolactinemia remain asymptomatic, but men can develop ED, diminished libido, and hypogonadism [34,35].

In patients with sexual dysfunction complaints while receiving neuroleptics, the Endocrine Society recommends the following [29]:

5α-Reductase Inhibitors

The enzyme 5α-R transforms testosterone into the potent androgen 5α-dihydrotestosterone. The 5α-R inhibitors finasteride and dutasteride were developed to block 5α-R in order to produce an anti-androgenic effect. Both were U.S. Food and Drug Administration (FDA)-approved for treatment of benign prostate hyperplasia and male pattern hair loss[24]. However, 5α-R is broadly distributed in central nervous system tissue, and inhibition blocks synthesis of several key hormones and neuroactive steroids. This effect was later found to result in numerous adverse effects, including impaired or complete loss of libido, erectile, and orgasm function; high Gleason grade prostate cancer; cardiac arrest and cardiovascular events; and depression[24]. In some patients, total sexual dysfunction has been irreversible, with significant emotional toll and impact on quality of life[36,37,38,39,40]. Treatment of 5α-R inhibitor-induced post-treatment enduring sexual dysfunction has focused on endocrine interventions, but no approach has been successful[41,42,43].

In 2013, the Sexual Medicine Society of North America published a comprehensive review that acknowledged a link between 5α-R inhibitors and persistent sexual dysfunction after treatment cessation but stopped short of stating a causal relationship had been established. They concluded more research was needed[44].

Illicit Drugs

There is some evidence that illicit drug use, particularly heroin and cannabis, may cause sexual dysfunction in men [45,46]. In one study, researchers hypothesized that "cannabis may actually have peripheral antagonizing effects on erectile function by stimulating specific receptors in the cavernous tissue" [45]. Use of opioids (such as heroin) and cocaine has been associated with mild hyperprolactinemia, with related impairment in sexual functioning. Although amphetamines are often illicitly used to enhance sexual experience, in one study of 1,159 male amphetamine abusers, the prevalence of ED was higher among the drug users (29.3%) than non-abusing controls (11.9%) [47]. A study of male drug abusers in a drug treatment program found that the participants were more likely than the general public to have ED, decreased sexual desire, and increased ejaculation latency [46].

Cigarette Smoking and Nicotine

Cigarette smoking is an established sexual dysfunction risk factor in both men and women, although the link in men is strengthened by the adverse vascular effect that directly impacts erectile function [48].

The added risk, as odds ratio (OR), of developing ED from smoking was calculated using data from 28,586 study participants. Compared to nonsmokers, the odds of developing ED were 1.51 in current smokers and 1.29 in former smokers. Compared with never-smokers, the odds of developing ED were 1.23 in those who smoke 20 or more cigarettes and 1.60 in those who have smoked for more than 23 years (after correcting for education) [49,50]. Smoking is linked to disrupted signaling and inhibited production of nitric oxide from excess generation of reactive oxygen species. This leads to impaired endothelium-dependent smooth muscle relaxation and the development of ED [51,52].

Dysregulated sympathovagal balance is a reliable acute nicotine effect and is associated with reduced erectile function tumescence. Nicotine may contribute to ED by inducing dysfunctional cardiac autonomic tone [53]. A series of highly controlled trials isolated nicotine effect (using nicotine gum) on sexual function in young, healthy, nonsmoking volunteers. In one study, nicotine reduced erectile response in 16 of 20 men, with a 23% reduction in physiologic sexual arousal. Nicotine did not affect subjective sexual arousal ratings [54].

In a separate four-week smoking cessation study, erectile function did not differ between continued- and quit-smokers at two weeks, likely due to quit-smokers receiving a high-dose nicotine patch. At four weeks, after all nicotine replacement was discontinued, erectile function significantly improved in those who quit smoking [55].

Hypogonadism is characterized by low testosterone levels and may adversely impact libido and erectile function. To some degree, nitric oxide release in the corporal endothelium is androgen dependent, and androgen deficiency decreases nocturnal erections and libido [56]. Hyperprolactinemia can also contribute to male sexual dysfunction, as discussed [56].

Several reports have linked lower urinary tract symptoms with male sexual dysfunction. Ejaculatory dysfunction, higher prevalence of ED, and reduced sexual desire were found in men with lower urinary tract symptoms, with symptom severity correlated with ED severity. Additionally, men with overactive bladder are significantly more likely to have ED than controls [13,57,58]. Any lifetime history of sexually transmitted infection shows an OR of 5.4 for non-pleasurable sex [59].

Acute and chronic lower urogenital infection, prostatodynia, and chronic pelvic pain syndrome are associated with ED, PE, and painful ejaculation. Men with chronic prostatitis or chronic pelvic pain syndrome have a 26% to 77% prevalence of PE [60,61]. Antibiotic treatment of bacterial prostatitis in men with acquired PE led to a 2.6-fold increase in intravaginal ejaculation latency time (IELT) and improved ejaculatory control in 83.9% of subjects [62]. One study suggests that routine screening for chronic prostatitis may be beneficial for men presenting with PE [63].

In most patients, ED and cardiovascular disease are viewed as clinical manifestations of a common pathophysiology. ED may be viewed as a sentinel event for cardiovascular disease; it often develops before cardiovascular disease because the smaller diameter of penile blood vessels creates susceptibility to plaque buildup before larger coronary, internal carotid, and femoral arteries. Coronary artery disease and ED share a generalized arteriopathy that may initially affect arterial inflow to the penile corpus cavernosum [56,76].

The Male Training Center for Family Planning and Reproductive Health asserts that asking males about problems with sexual function is particularly important to identify underlying cardiovascular disease among men who present with symptoms of sexual dysfunction routinely starting at 25 years of age.

(https://rhntc.org/sites/default/files/resources/mtc_male_prevrhc_2014.pdf Last Accessed: February 21, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

The vascular endothelium is essential for regulating normal circulatory function, and the association between ED and vascular disease resides in vascular endothelial dysfunction [56,77]. Endothelial and vascular smooth muscle dysfunction are highly prevalent in patients with ED and represent shared etiologic pathways for other vascular disease states such as cerebral vascular accidents, myocardial infarction, heart disease, hypertension, hyperlipidemia, low high-density lipoprotein (HDL), arteriosclerosis, and peripheral vascular disease [13]. Most risk factors of ED promote endothelial dysfunction, including hypertension, dyslipidemia, diabetes, depression, obesity, cigarette smoking, and metabolic syndrome [52,77,78,79].

ED is predictive of potential future cardiovascular events, and the presence of ED, particularly severe ED, significantly elevates patient risk of hypertension, ischemic heart disease, peripheral arterial disease, and stroke. ED development is a precursor to symptomatic coronary artery disease, with an average 39-month lead-time, and men with ED have a 65% to 85% increased risk of subsequent coronary artery disease. Some have concluded that ED is the most robust predictor of silent coronary artery disease, and the importance of careful cardiovascular risk evaluation in men with ED cannot be overemphasized [80,81,82,83,84].

Elevated mortality risk is associated with ED. The relationship between ED and increased risk of cardiovascular events and mortality was confirmed by analysis of 14 studies involving more than 90,000 patients. The presence of ED (vs. no ED) increased patient risk of cardiovascular events by 44%, all-cause mortality by 25% (mostly cardiovascular mortality), myocardial infarction by 62%, and cerebral vascular accidents by 39% [85,86].

In 1,402 men followed over 20 years, ED in younger men markedly elevated the risk of future cardiac events, but the prognostic importance of ED substantially diminished in older men. Younger men with ED may be ideal candidates for cardiovascular risk factor screening and intervention [56,82].

A prostate cancer prevention trial followed 9,457 men randomized to placebo over 19 years. New-onset ED was associated with an increased risk for cardiovascular events during follow-up. This elevated risk for cardiovascular events in earlier-onset ED was comparable to risk associated with current smoking or family history of myocardial infarction [56,83].

While evidence stresses the importance of early cardiovascular evaluation in men with ED of unexplained etiology, impaired masturbation-induced erections in younger men are usually presumed psychogenic. To examine this assumption, young men (mean age: 29 years) presenting with weaker masturbatory erections and no sexual intercourse were evaluated for early cardiovascular risks associated with ED [87]. Compared to ED and healthy controls, these men demonstrated higher prevalence of early ED risk factors, including endothelial dysfunction, insulin resistance, elevated glycosylated serum protein, and abnormal nocturnal penile tumescence and rigidity. Endothelial dysfunction was a strong and independent risk factor for sexual dysfunction. In young men with weaker masturbatory erection without history of successful sexual intercourse, ED may be a sign of early cardiovascular risk [87].

Abnormal Cholesterol Levels

Hypercholesterolemia can impair endothelium-mediated smooth muscle relaxation of corpus callosum tissue [52]. A study found ED risk inversely correlated with low HDL cholesterol levels but unrelated to elevated total cholesterol levels in older men, while in younger men ED correlated with abnormal HDL and elevated total cholesterol [88].

Sexual Activity and Cardiovascular Risk Assessment

The Princeton Consensus (Expert Panel) Conference is a multispecialty collaboration dedicated to improving identification of men with ED who may require additional cardiovascular work-up and evaluation of cardiac risk associated with sexual activity in men with documented cardiovascular disease. The most recent Princeton consensus (Princeton III) emphasizes that evaluation of exercise ability and use of stress testing should be conducted before ED treatment to ensure adequacy of patient cardiovascular capacity for the physical demands of sexual activity. Princeton III also emphasizes patient stratification by level of cardiac risk from sexual activity [74,89]:

Chronic periodontitis is a bacterial disease that manifests as inflammation of gingival tissues and possibly of structures that support teeth. There is evidence that chronic periodontitis promotes endothelial dysfunction, which may lead to systemic vascular disease. Chronic periodontitis was found highly prevalent in men with ED; one study found men with severe chronic periodontitis were 3.29 times more likely to have ED than men without chronic periodontitis [90].

Transurethral resection of the prostate for benign prostatic hyperplasia is associated with a 10% to 20% rate of ED from cauterization-induced nerve damage, but newer procedures using microwave, laser, or radiofrequency ablation have reduced ED rates to nearly 0%. Radical prostatectomy treatment of prostate cancer poses a significant risk of ED, but erectile function may be preserved if both nerves that run through the lateral edges of the prostate are saved. Potency preservation is related to surgeon experience and patient age, with baseline erectile function maintained in 75% to 80% of men younger than 60 years of age, and 10% to 15% of men older than 70 years of age. At two-year follow-up of early-stage prostate cancer treatment, patient ability to achieve erection suitable for intercourse was 35% with radical prostatectomy, 37% with external beam radiotherapy, and 43% with brachytherapy [91].

A population-based cohort of 835 men with newly diagnosed prostate cancer was followed prospectively using the validated Prostate Cancer Symptom Indices (PCSI) instrument, which measures likely physical and psychological symptoms and the distress they cause following prostate cancer treatment. Patients were treated with external beam radiotherapy (EBRT), EBRT with androgen deprivation therapy (EBRT/ADT), brachytherapy, nerve-sparing radical prostatectomy, or non-nerve-sparing radical prostatectomy. EBRT and brachytherapy treatment groups resulted in similar PCSI scores through 24 months. Patients treated with EBRT/ADT and radical prostatectomy, with or without nerve sparing, had the lowest PCSI scores at all post-treatment time points. Preservation rates of useful sexual function at 24 months were 14.1% to 70.7% for EBRT; 8.4% to 52.3% for EBRT/ADT; 4.7% to 45.3% for nerve-sparing radical prostatectomy; and 4.8% to 34.5% for non-nerve-sparing radical prostatectomy [92].

ED can also result from trauma to the pelvic blood vessels or nerves. Bicycle riding for long periods is a known causal factor of ED, the result of vascular and nerve injury from direct compression of the perineum by the bicycle seat. However, bicycling for less than three hours per week may be modestly protective against ED, and some newer bicycle seats are designed to reduce perineal pressure [93,94]. There is some evidence that surgical repair may improve ED in patients with a history of pelvic or perineal trauma [95].

Diabetes is a recognized ED risk factor, and decreased sexual desire and orgasmic dysfunction are highly prevalent in men with diabetes [13]. Approximately 50% of patients with diabetes will develop ED, with an earlier onset than in those without diabetes [96]. Contributors to diabetes-induced ED include hyperglycemia and hypogonadism, which facilitate development of impaired vasodilatory signaling, smooth muscle cell hypercontractility, and veno-occlusive disorder [52,97,98]. Obesity and metabolic syndrome also elevate the risk of ED and are common in men with diabetes [13].

Peyronie disease can result in penile curvature and fibrosis. In severe cases of Peyronie disease, extensive scar tissue in the corpora may impede blood flow and result in ED [76].

Exercise and lifestyle modifications may improve erectile function. Weight loss may help by decreasing inflammation, increasing testosterone, and improving self-esteem. Patients should be advised to increase activity, reduce weight, and stop smoking, as these efforts can improve or restore erectile function in men without comorbidities. Optimal glycemic control in patients with diabetes and pharmacologic treatment of hypertension may be important in preventing or reducing sexual dysfunction [99]. A prospective cohort study of 31,742 men 53 to 90 years of age found physical activity associated with a 0.7 relative risk for ED and obesity associated with a 1.3 relative risk for ED [51,75].

Age is strongly linked to ED, due to increased oxidative stress, penile endothelial dysfunction, vascular changes, and decline of circulating steroids [52,100].

Psychological and interpersonal factors may cause or exacerbate acquired PE. Specific factors include the effects of early experience and sexual conditioning, sexual abuse, and attitudes toward sex internalized during childhood. Individual psychological factors may include poor body image, depression, performance anxiety, and alexithymia. Relationship factors include decreased intimacy or partner conflict. Anxiety is thought to activate the sympathetic nervous system and reduce ejaculatory threshold, leading to earlier ejaculation. Hypoactive sexual desire may lead to acquired PE from an unconscious desire to abbreviate the unwanted penetration or, conversely, may develop as a consequence of chronic and frustrating PE. Psychological factors and PE can be bi-directional, with either factor causing or exacerbating the other. An example is performance anxiety leading to PE, which further exacerbates the original performance anxiety [64,105,106,107,108].

Up to 50% of patients with ED also experience PE, and while ED is unlikely to co-occur or cause lifelong PE, evidence confirms the association of acquired PE and ED [101]. These men may experience rapid ejaculation from performance anxiety or, with deliberate intensification of stimulation, complete ejaculation before loss of erection. Men with comorbid ED and PE may manifest a more severe variant of each disorder and experience lower sexual satisfaction and diminished response to treatment of PE [109,110].

The association of PE and intimate relationship distress is bi-directional. Numerous studies show high levels of personal distress in men with PE and in their female partners [64]. Men with PE show low scores on self-esteem and self-confidence, and one-third experience anxiety connected to sexual situations. Men with PE have more interpersonal difficulties than men without PE, feel they are "letting their partner down" with PE, and believe their relationship quality would improve if they did not have PE. The negative impact of PE on single men may be greater, as it can impose a barrier to seeking and becoming involved in new relationships [111,112]. PE can also negatively impact female partner sexuality and is correlated to overall female sexual dysfunction, low sexual satisfaction, and sexual distress [9,107].

Partner inclusion in the treatment process is important, but not mandatory, for PE treatment success. Some patients may not understand the importance for partner involvement, and some partners may be reluctant to participate or to change the sexual interaction. A cooperative partner augments the power of treatment, and this is more likely to improve sexual and broader aspects of their relationship [9,113].

In order to reach a diagnosis of erectile disorder, at least one of the following three symptoms must be present in most or all (75% to 100%) sexual activity [4]:

The severity is classified as mild, moderate, or severe on the basis of patient level of distress over the symptoms.

In men with PE, all or almost all (75% to 100%) sexual activity is marked by a pattern of ejaculation occurring during partnered sexual activity within one minute after penetration and before the individual wishes it [4]. The severity of PE is specified as:

Patients with MHSDD experience low desire for sex and absence of sexual thoughts or fantasies. On most occasions, there is a marked delay, infrequency, or absence of orgasm during sexual activity and/or a tendency to ejaculate after less than one minute of sexual activity. These experiences cause clinically significant distress or interpersonal problems and are usually present (75% to 100% of the time) [4].

Delayed ejaculation is defined as an inability to climax during sex with a partner about 75% to 100% of the time, with either a delay in ejaculation or infrequent or absent ejaculation [4]. The ejaculatory delay is not considered pathologic if it is due to a deliberate effort to prolong sexual activity.

The ISSM PE criteria combine lifelong PE and acquired PE and apply to intravaginal sex only [9,101]:

Subjective PE is characterized by subjective perception of consistent or inconsistent short IELT and at least one of the following [9,101]:

Anteportal ejaculation occurs prior to penetration [9,101]. It is considered the most severe form of PE and affects 5% to 20% of men with lifelong PE.

Variable PE is a short ejaculatory latency that occurs irregularly and inconsistently, with some subjective sense of diminished ejaculatory control [9,101]. Variable PE is not considered a sexual dysfunction, but rather a normal variation in sexual performance.

According to the British Association for Sexual Health and HIV, sexual history taking should take place in a confidential, private environment.

(https://www.bashhguidelines.org/media/1241/sh-guidelines-2019-ijsa.pdf Last Accessed: February 21, 2023)

Level of Evidence: 1D (Strong recommendation based on non-analytic evidence, e.g. case reports or series or expert opinion)

The sexual history should include information about previous and current sexual relationships; current emotional status; the onset, duration, and clinical course (stable or worsening) of the current problem and whether the problem is continuous, intermittent, or context-specific; and previous provider contact for sexual function concerns, including any treatments and treatment response. Partner sexual health status (when available) may be useful. A detailed description should be made of the rigidity and duration of both sexually stimulated and morning erections and problems with arousal, ejaculation, and orgasm. In patients with a sexual partner, clinicians should begin developing a sense of patient and partner distress surrounding the sexual dysfunction and whether the sexual dysfunction was antecedent to, or a consequence of, the current relationship. Sexual orientation and gender identity should be noted. Patients should also be asked whether they favor or oppose any specific treatment and the extent they wish to explore the cause of their sex concern [74,119].

ED

With possible ED, determine which sexual response aspect is dysfunctional by exploring whether [9,76]:

PE

In patients with PE, patient and partner estimation of ejaculatory latency should be the measure for determining IELT in clinical practice [9]. To help identify PE, consider asking the following:

Recommended questions to distinguish between ED and PE may include [9,76]:

To assess for lifelong versus acquired PE, ask:

According to the Male Training Center for Family Planning and Reproductive Health, specific questions to include in the sexual history if the patient is experiencing sexual dysfunction such as inability to obtain and maintain an adequate erection for satisfactory sexual activity (e.g., impotence, erectile dysfunction), premature or delayed ejaculation, loss of libido, painful intercourse, and also priapism, a prolonged painful erection not associated with sexual desire.

(https://rhntc.org/sites/default/files/resources/mtc_male_prevrhc_2014.pdf Last Accessed: February 21, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

The following questions can help evaluate relationship impact, previous treatment, and impact on quality of life:

Taking a thorough sexual history also allows the clinician to begin forming an objective opinion regarding the interpersonal relationship between the patient and his sexual partner [120]. In PE, two validated questionnaires with extensive data are the Premature Ejaculation Profile (PEP) and the Index of Premature Ejaculation (IPE). Both may be useful as adjuncts but should not replace a detailed sexual history [9,121,122].

Information should be obtained on general medical status and history and any current or past medical conditions that may affect sexual function. This should encompass details concerning hospitalization, diagnosis, treatment and response, and follow-up with healthcare professionals with positive history in any of the following [17,52,56,74]:

Prescribed and Recreational Drug Use Assessment

A detailed list of all medications taken in the past year should be obtained, including vitamins and supplements. Prescribed and recreational substances associated with male sexual dysfunction can be assessed with inquiry by drug class [17,74]:

Current or past history of psychiatric illness, diagnoses, and treatment should be obtained, as well as current or past contact with counselors, therapists, or other mental health practitioners. The reason for the contact and extent the concern was resolved should also be explored [76].

Significant stressors in the family, relationship, or work environment should be explored to assess patient psychological state, with particular attention to [74,123]:

In patients with clinical depression, a two-question depression scale is recommended [74,123]:

It is especially important to have the patient explain his own interpretation of the problem. To this end, questions such as the following may be asked:

Pure psychogenic ED is uncommon and is characterized objectively by the presence of good nocturnal and morning erections and negative findings on all other tests. However, a psychogenic component is usually present in men with organic ED. A history of highly variable erection function suggests a psychogenic cause.

Studies show that as the severity of depression increases, there is a decrease in libido and sexual satisfaction [124]. Loss of sexual interest and desire is the core feature of MHSDD and a common symptom of major depression. All patients with sexual interest and desire complaints should be screened for depression [4].

Widely used in clinical research and clinical practice, the IIEF is considered the criterion standard assessment instrument for ED [131]. This 15-question instrument evaluates five domains: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and global satisfaction [132,133].

A shorter version of the IIEF, the IIEF-5, was developed as a sexual health inventory for men and is useful for screening patients for ED. The IIEF-5 asks the patient the five questions below, as applied to the previous six months. Answers to the five questions are scored on a 0–5 scale. A score of 25 is typical in healthy men; a score ≤11 indicates moderate-to-severe ED [133,134]:

Commonly used in pharmacotherapy trials for ED, the Sexual Encounter Profile (SEP) is a diary maintained after each sexual attempt. A series of yes/no questions regarding specific aspects of each encounter are asked [133,135]:

The Global Assessment Question (GAQ) also has been used in clinical trials. The GAQ asks the following questions [133,136]:

The Psychological and Interpersonal Relationship Scales (PAIRS) questionnaire measures the broader psychological and interpersonal outcomes concerning sexual dysfunction (specifically ED) and its treatment with three domains: sexual self-confidence, time concerns, and spontaneity. Patients rate their agreement or disagreement with a specific statement on a scale of 1 (strongly disagree) to 4 (strongly agree) [133,137].

The Self-Esteem and Relationship Questionnaire (SEAR) measures psychosocial outcomes in patients with ED by 14 items assessing two domains: sexual relationship and confidence. The confidence domain has two subscales: self-esteem and overall relationship [133,138].

The Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) assesses patient satisfaction with their ED treatment. For each question, satisfaction is rated on a scale of 0 (extremely low treatment satisfaction) to 4 (extremely high treatment satisfaction) [133,139].

Testosterone

Serum testosterone testing can be useful in patients with decreased sexual interest, delayed ejaculation, reduced ejaculate volume, PDE5I failure, or diabetes-related ED [119]. Testosterone level is measured to identify hypogonadism, defined by the American Urological Association (AUA) as biochemically low testosterone levels and the presence of a cluster of symptoms including male sexual dysfunction and impairments in mood, energy, and body composition [140]. The prevalence of biochemical hypogonadism in middle-aged men is 2.1% to 12.8%, and the prevalence of low testosterone and hypogonadism symptoms in men 40 to 79 years of age is 2.1% to 5.7%. Hypogonadism rates are higher in men who are older, who are obese, with medical comorbidities, and/or with poor health status [30].

Serum total testosterone circulates as unbound or free total testosterone (2% to 3%) or bound to sex hormone-binding globulin (SHBG) (44%), albumin (50%), or corticosteroid-binding globulin (CBG) (4%). SHBG-bound testosterone is not bioavailable, but testosterone is weakly bound to CBG and albumin and easily and rapidly dissociates from both [141]. As such, bioavailable total testosterone refers to the sum of total testosterone that is CBG-bound, albumin-bound, and free. This represents the total testosterone fraction that is available to cells, but it should not be confused with cellular and tissue bioavailable total testosterone that bind to androgen receptors to produce androgenic action [141].

Professional organizations and regulatory agencies disagree over the serum testosterone levels that define hypogonadism, low testosterone, or the threshold for testosterone therapy. The FDA uses a cut-off total testosterone value of 300 ng/dL to define hypogonadism for clinical trials and drug development [141]. A consensus statement by several European and North American urology and andrology organizations recommends that treatment is not necessary for total testosterone >350 ng/dL [142]. This group concluded that total testosterone <230 ng/dL (with symptoms) may require testosterone therapy, and that total testosterone levels 230–350 ng/dL require repeat total testosterone measurement, use of SHBG values to calculate free testosterone, or direct measurement of free testosterone by equilibrium dialysis [142].

The AUA stresses that biochemical and clinical parameters are equally important as indicators of hypogonadism and that rigid interpretation of testosterone ranges should not dictate decisions concerning patient care. Rigid adherence to a predetermined cut-off value, such as 300 ng/dL, can lead to unnecessary treatment of asymptomatic men and treatment withheld from persistently symptomatic men. However, they note that free or bioavailable testosterone levels can help diagnose biochemical hypogonadism, especially with equivocal total testosterone values or lack of signs and symptoms. With free testosterone, values <65 ng/mL can support testosterone therapy [141].

A systematic overhaul is underway for analytic methods used in testosterone measurement. Some laboratories now use reliable and valid assays, but many still use older, less reliable assays. Potentially unreliable lab results and fluctuation in serum testosterone levels from diurnal, seasonal, and age-related temporal factors can complicate patient care and impose a risk of non-payment by insurance carriers that often require serum total testosterone <300 ng/dL for reimbursement. The AUA states that no patient should be denied coverage for testosterone treatment based solely on payer-defined cut-offs when clinical need for the treatment is established [141].

Luteinizing Hormone

LH levels vary according to physiologic requirements for testosterone. The hypothalamus regulates testosterone levels by releasing or inhibiting LH-releasing hormone, which activates pituitary production and release of LH. With a high LH level and a low testosterone level, primary testicular (Leydig cell) failure is suggested. Low levels of both LH and testosterone suggest a central defect [74].

Thyroid-Stimulating Hormone

Thyroid-stimulating hormone evaluation is appropriate in selected patients with ED or loss of sexual desire [74].

Psychological assessments can provide important insight into psychosocial contributors to or causation of male sexual dysfunction. Findings may also guide psychological therapy selection and treatment goals, such as reducing performance anxiety, understanding the context in which the patient or couple functions sexually, modification of sexual scripts through psychoeducation, or improving pharmacotherapy adherence [119,143].

Erections normally occur during rapid eye movement sleep. Nocturnal penile tumescence testing is used to measure and record nighttime erectile events to differentiate organic from psychogenic sexual dysfunction. Several bands are placed around the penis and connected to a device (e.g., a RigiScan monitor) and worn by the patient for two to three consecutive nights. With occurrence of an erection, the force and duration are measured. Inadequate or absent nocturnal erections suggest organic dysfunction, and a normal result strongly suggests psychogenic etiology [119].

Determination of penile duplex cavernous artery flow after corporal vasoactive injection is commonly used with ultrasound to localize and measure blood flow through the cavernous vessels for assessment of penile circulation. A peak systolic blood flow more than 30 cm/second and a resistance index >0.8 represent normal results and additional vascular investigation is unnecessary. With abnormal findings, further testing involves arteriography and dynamic infusion cavernosometry and cavernosography (DICC), but only in appropriate candidates for vascular reconstructive surgery [144].

DICC is used for assessment of veno-occlusive mechanism function. Penile dye and fluid delivery induce an erection. The rise and fall of intra-penile pressure is measured and visualized to determine if the veno-occlusive mechanism is intact [145].

Arteriography, the most invasive diagnostic test, is usually reserved for high-flow priapism or planned vascular bypass. Penile angiogram visualizes the penile circulation to guide embolization in penile injury [146].

Prostaglandin E1 (PGE1) may be injected into the corpus cavernosum to evaluate penile function. An erection developing within minutes indicates adequate penile vasculature and, depending on quality of the erection, establishes PGE1 injection as a therapeutic option [74].

Many healthcare professionals are uncomfortable initiating discussion of patient sexual functioning, in many cases due to inadequate education, training, knowledge, skills, and confidence. A 2010 study showed that fewer than 50% of U.S. medical schools offer sexual health curricula [147]. A 2018 study sought to quantify the sexual health knowledge of undergraduate medical students. A 32-question survey evaluated six areas of knowledge: sexual function and dysfunction; fertility and reproduction; sexuality across the lifespan; sexual minority health; society, culture, and behavior; and safety and prevention [148]. The 1,014 survey respondents scored an average of 66% correct, with the lowest scores (49% correct) on questions regarding safety and prevention and the highest scores (75% correct) on questions regarding sexuality across the lifespan [148]. Primary care providers understand the importance of sexual health but may avoid initiating discussion due to limited time, expertise, comfort, compensation, or litigation concerns. Men with sexual dysfunction are frequently reluctant to discuss their sexual problems and must be specifically asked. When clinicians fail to open the dialogue, sexual dysfunction remains unaddressed [119,149].

Clinician awareness of patient comfort level is vital, given the highly sensitive nature of the presenting problem. Patient history-taking gives clinicians the opportunity to provide education about the sexual dysfunction and its treatment to patients and their partners, facilitate communication, and establish rapport. Validated psychometric questionnaires can be valuable for obtaining information that patients may be reticent in disclosing [119].

Phosphodiesterase inhibitors act through cGMP-specific PDE type 5 inhibition. PDE5 degrades cGMP in the corpus cavernosum, and the rates of PDE synthesis and degradation regulate tissue concentrations of cGMP. In the corpus cavernosum, PDE5 is the most prevalent cGMP-specific PDE, and PDE5Is enhance erectile function by increasing cGMP [52].

Sildenafil, vardenafil, tadalafil, and avanafil are PDE5Is FDA-approved for treating ED, and their safety and efficacy is established. All have efficacy rates around 60% to 70%, with lower rates in patients with severe neurologic damage, post-radical prostatectomy ED, diabetes, and severe vascular disease [151]. PDE5I selection is guided by intercourse frequency and patient preference [52,74,152].

Initially, PDE5Is were approved for on-demand use. Tadalafil is also approved for daily use of 2.5–5 mg in patients anticipating sexual activity more than twice per week [24]. This regimen may be more cost-effective in this context, and a marked reduction in adverse events has been suggested [76].

Vardenafil and sildenafil are also available in orodispersible tablet formulation, which offers improved convenience that patients may prefer over the oral tablet. Absorption of the agents in orodispersible tablet form is unaffected by food ingestion, and the bioavailability is improved relative to oral tablets. Safety and efficacy are equivalent between the vardenafil and sildenafil formulations [24,153,154,155].

Efficacy and side effect differences between PDE5Is reflect the varying enzymatic selectivity and pharmacokinetic properties. Sildenafil and vardenafil are cross-reactive for PDE6, and dominant PDE6 expression in the retina helps account for side effects of visual disturbance (<2% of patients) with both drugs. Tadalafil cross-reacts with PDE11; while expressed in cardiac tissue, the testes, and the anterior pituitary, complications from PDE11 inhibition are unknown [52]. Possible long-term consequences of visual disturbance side effects are concerning and were evaluated in 277 patients with pulmonary arterial hypertension associated with connective tissue disease or following congenital heart disease repair. Sildenafil up to 80 mg three times per day for ≥18 months was not associated with visual change and did not show adverse effects on best corrected visual acuity, contrast sensitivity, color vision, visual field, slit lamp examinations, funduscopy, or intraocular pressure during the study period [156].

Pharmacokinetic Differences

The clinical effect of PDE5Is is influenced by pharmacokinetic properties that include bioavailability, maximum plasma concentration (Cmax), time duration to reach Cmax (Tmax), and time required to eliminate half the drug from plasma (t1/2) (Table 2) [157]. Sildenafil, vardenafil, and avanafil have broadly similar Tmax, which predicts a similar time of onset of action. The t1/2 value of tadalafil is longer than other PDE5Is, possibly from slower intestinal absorption and/or hepatic degradation. The extended t1/2 of tadalafil provides a longer therapeutic effect. The Cmax of vardenafil is significantly lower than with sildenafil and tadalafil, likely from lower bioavailability [157]. PDE5Is are degraded in the liver, and interactions with the CYP3A4 inhibitor ketoconazole, for example, may prolong their effect duration. PDE5I duration of effect is inconsistently associated with elimination rate from plasma. Molecular mechanisms that can contribute to this have been suggested [158]. Thus, there may be a persistence of biochemical effects after the inhibitor is cleared from cells (i.e., memory effect). Because inhibitors bind tightly to PDE5 in muscle cells, for example, this could significantly retard their exit from these cells and prolong their effects[52,158].

Tolerability and Safety

Adverse events common to PDE5Is include headache, flushing, dyspepsia, nasal congestion, and dizziness (Table 3) [74,160,161]. Tadalafil may cause back pain/myalgia in up to 6% of patients. Adverse events are generally mild in nature, usually resolve with continuous use, and resulted in few dropouts in clinical trials. PDE5Is are considered safe in patients with cardiovascular disease, and PDE5Is do not adversely affect total exercise time or time to ischemia during exercise testing in men with stable angina [162]. PDE5Is may even be beneficial in cardiovascular disease, and sildenafil has been approved for treatment of pulmonary arterial hypertension [52,163].

Clinical trial results and post-marketing data of sildenafil, tadalafil, and vardenafil have demonstrated no increase in myocardial infarction rates in patients receiving PDE5Is compared to expected rates in age-matched male populations [74]. Sildenafil does not alter cardiac contractility, cardiac output, or myocardial oxygen consumption according to available evidence. Chronic or on-demand use is well-tolerated, with a similar safety profile [74]. Single-dose avanafil 100 mg and 800 mg in healthy male subjects did not cause significant changes in QTc interval or ventricular repolarization [160].

Drug-Drug Interactions

Use of nitrates are absolutely contraindicated in all patients taking PDE5Is due to potentially severe hypotension resulting from cGMP accumulation. Organic nitrates include nitroglycerine, isosorbide mononitrate, isosorbide dinitrate, and other nitrate preparations used to treat angina[24]. Amyl nitrite or butyl nitrate ("poppers") used recreationally are also dangerous[74].

Duration of interaction between organic nitrates and PDE inhibitors varies according to the specific agents involved. If a patient develops angina while using a PDE inhibitor, other anti-angina agents should be used instead of nitroglycerin until at least 24 hours after the last dose of sildenafil or vardenafil, at least 48 hours after the last dose of tadalafil, and at least 12 hours after the last dose of avanafil[24,74,162].

In general, the adverse effect profiles of PDE5Is are not amplified by antihypertensive medications, even in patients taking several antihypertensive agents[74]. However, all PDE5Is interact to some degree withα-blockers, possibly resulting in orthostatic hypotension under certain conditions[164,165]. Sildenafil should be used cautiously in patients prescribedα-blockers (especially doxazosin). Hypotension is most likely to occur within four hours ofα-blocker use. The recommended sildenafil starting dose is 25 mg in these patients[24]. Vardenafil should be initiated only when the patient has reached dose stabilization onα-blocker therapy. Concurrent vardenafil and tamsulosin therapy is not associated with significant hypotensive effect. Tadalafil amplifies the hypotensive properties of doxazosin but not tamsulosin 0.4 mg. Single-dose avanafil 200 mg combined with stable-dose doxazosin or tamsulosin lacks appreciable effect[160].

Alcohol and PDE5Is both act as mild vasodilators, and the blood pressure-lowering effects of each compound may be synergistic with concurrent ingestion. Significant alcohol consumption (more than three standard drinks) combined with PDE5Is can increase the potential of orthostatic signs and symptoms, including increased heart rate, decreased standing blood pressure, dizziness, and headache[24,160].

PDE5Is are substrates of, and predominantly metabolized by, CYP3A4, and drugs that inhibit the CYP3A4 pathway will inhibit the metabolic breakdown of PDE5Is[160]. Strong CYP3A4 inhibitors can substantially increase systemic exposure, maximum blood concentration, and half-life of single-dose PDE5Is. As such, PDE5Is should not be used in patients taking strong CYP3A4 inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin[24,160].

Moderate CYP3A4 inhibitors are likely to increase PDE5I exposure, and patients taking concomitant moderate CYP3A4 inhibitors should only be prescribed lowest-dose PDE5Is no more than once every 24 hours. Moderate CYP3A4 inhibitors include erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil. Other CYP3A4 inhibitors, such as grapefruit juice, are likely to increase avanafil exposure[160].

Drugs that act as CYP3A4 inducers, including rifampin, phenobarbital, phenytoin, and carbamazepine, can accelerate PDE5I metabolism and elimination. In patients taking these medications, higher doses of PDE5Is may be required[160].

PDE5I Non-Response

Guidelines recommend at least six maximum-dose PDE5I trials with sexual stimulation before classifying a patient as a non-responder [74]. The most common reasons for PDE5I nonresponse are incorrect drug use (e.g., failure to take an adequate dose, failure to engage in sexual stimulation) or lack of efficacy. Non-response management depends on identifying the underlying cause [74]. Inadequate counseling is a common cause of incorrect PDE5I use, and patient education may salvage apparent non-response by addressing dose, timing, and need for sexual stimulation. It is also important for patients to be aware of the window of efficacy after ingestion and initiation of sex. For sufficient effect, most patients need to wait 60 minutes after taking sildenafil and vardenafil and 120 minutes after tadalafil. Sildenafil absorption is delayed by a meal, and vardenafil absorption may be delayed by a fatty meal. The normal efficacy window is 6 to 8 hours for sildenafil and vardenafil and up to 36 hours for tadalafil [74].

In patients using PDE5Is correctly, switching agents may lead to patient response. While not approved for daily use independent of regular on-demand use, daily sildenafil or vardenafil dosing may salvage some non-responders to intermittent dosing [74,76]. In patients with hypogonadism, normalizing testosterone may improve PDE5I response. Patients should also be questioned regarding where they obtain their medications, as illicitly obtained PDE5Is may differ in purity or dose [74].

Adequate sexual stimulation is necessary for PDE5I efficacy because the drugs' action is dependent on release of nitric oxide by parasympathetic nerve endings in penile erectile tissue. The usual trigger for nitric oxide release is sexual stimulation, but some patients may incorrectly believe that the drugs act independent of any stimulation [74].

Some patients preferentially respond to specific PDE5Is. A randomized controlled trial of sildenafil and tadalafil non-responders found 17% and 14% response rates, respectively, after switching to the alternate PDE5I [166]. This may be due to pharmacokinetic variation between the two drugs, but with identical mechanism of action, the possibility is raised of an unidentified mechanism that contributes to preferential PDE5I response [74].

Another option, cabergoline, was evaluated in 402 patients with ED (21 to 59 years of age) who were not responding to sildenafil. Following weekly dosing at 0 mg or 0.5–1 mg for six months (92% study completion rate), mean improvements from baseline included weekly intercourse episodes (45.5% cabergoline, 15% placebo), IIEF intercourse satisfaction domain scores (+50% cabergoline, -9% placebo), and IELT (51.4% cabergoline, 16% placebo). Adverse events (12.2% versus 2.0%) and withdrawals due to adverse events (5.9% versus 1.01%) were more frequent with cabergoline [167]. In the United States, cabergoline is approved for use in the treatment of hyperprolactinemia [24].

Efficacy of PDE5Is in Subpopulations

Clinical trials have further evaluated efficacy, safety, or tolerability with PDE5Is in general ED populations or in subgroups with comorbid medical or psychiatric conditions. PDE5Is are effective in men with ED and untreated depression and in antidepressant-induced ED. Sildenafil efficacy (0 mg or 25–100 mg for six weeks) was assessed in 202 men with ED and mild-to-moderate untreated depressive symptoms (not major depressive disorder). At baseline screening, men with ED were more likely to have depression compared with men without ED, and ED severity was a predictor of depression. Compared with placebo, sildenafil led to significantly greater changes from baseline in Beck Depression Inventory-II scores and significant improvement in all IIEF domains and Sex Effects Questionnaire components. Adverse events were mild and consistent with PDE5I therapy [126].

ED is associated with significant loss in quality of life and self-esteem. In one study, 841 patients with ED received sildenafil (0, 25, 50, or 100 mg) for 14 weeks to assess self-esteem changes and their causality during sildenafil therapy. Patients receiving sildenafil showed significantly greater changes (versus placebo) in all SEAR component and IIEF domain scores. This finding was maintained in all subgroups with ED comorbidities of hypertension, hyperlipidemia, benign prostatic hypertrophy, or depression. In patients receiving sildenafil, a highly significant correlation was found between improvements in self-esteem subscale scores and erectile function domain scores. The physiologic and emotional benefits of sildenafil treatment of ED were confirmed overall and in men with common ED comorbidities [127].

Partner Effect

Initiation of sildenafil at 50 mg or 100 mg was assessed for effects on the sexual experience and anxiety level anticipating the next intercourse attempt. After 12 weeks, 56% receiving 100 mg and 39% receiving 50 mg reported no anxiety concerning the next intercourse attempt. Changes in functional scores from baseline were comparable. Measures of treatment satisfaction and sexual experience significantly favored those receiving 100 mg, and adverse events were not increased with the higher dose. The authors conclude that sildenafil 100 mg can be initiated instead of titrated, based on anxiety-reduction benefits and tolerability [128].

Partners' quality of sexual life is strongly impaired by ED, and their involvement in ED treatment is important for adherence and long-term efficacy but remains difficult. Without concurrent sex therapy, open-label sildenafil treatment of ED was assessed using the Index of Sexual Life (ISL) for impact on female partners in 67 couples. After 14 weeks, women showed a 79.0% positive response rate. Mean sex life satisfaction scores increased 40% from baseline, and a significant correlation was found between final scores on ISL sex life satisfaction, IIEF erectile function, and SEAR confidence domain. Both partners reported high levels of treatment satisfaction [129].

Early trials of phentolamine showed some success in patients with nonspecific ED, and it became viewed as a promising oral "on-demand" approach for ED treatment. A review of randomized, double-blind, placebo-controlled trials of oral phentolamine in ED found the mean change in erectile function was significantly higher with active drug (40 mg and 80 mg) than placebo, with three to four times as many patients on phentolamine reporting being satisfied or very satisfied (versus placebo). At 40-mg and 80-mg doses, 55% to 59% of men achieved vaginal penetration. ED was resolved or improved in 53% of men with 80 mg and 40% with 40 mg. All responses were consistent regardless of concomitant medication, and there were no severe adverse events. The most common side effects were nasal congestion (10%), headache (3%), dizziness (3%), and tachycardia (3%). Although phentolamine is concluded to be safe, well-tolerated, and efficacious as ED treatment, it has not yet received FDA approval for this indication [24,52,64,168,169]. Intracavernous injections of phentolamine are a mainstay of the second-line treatment of neurogenic sexual dysfunction and have been found to be highly successful in the spinal cord injury population [76,170].

Yohimbine, a bark extract, is a selectiveα2-blocker with central and peripheral effects and has been used as ED treatment for more than a century. In studies, yohimbine was found modestly more effective than placebo[171]. Orally administered yohimbine may benefit some patients with ED, and there has been renewed interest in this agent, particularly when combined with an oral PDE5I. Yohimbine is considered safe with few known adverse effects, and typical dosing is one tablet (5.4 mg) taken three times per day[52].

Apomorphine (APO) is a dopamine D1- and D2-receptor agonist with higher affinity for D2 and is absorbed through the oral mucosa to produce erection [52]. The overall results of five clinical trials with sublingual APO 2 mg and 3 mg showed statistically significant improvements (versus placebo) in erectile function. Sublingual APO efficacy is weakly dose-related, and limited efficacy in patients with organic ED has led to suggestions that APO was best suited for mild ED [172,173]. Subsequent comparisons between sublingual APO and sildenafil found sildenafil more effective and preferred by patients.

Significant tolerability or safety issues seem lacking. Adverse events of nausea, headache, dizziness, and yawning are more frequent with sublingual APO than placebo. Two trials suggested that APO did not differ from placebo in serious adverse events [172,173]. Because of sildenafil's superiority, sublingual APO never reached broad acceptance and is not FDA-approved for treatment of ED [24,52].

Trazodone is an antidepressant drug that selectively inhibits central 5-HT uptake and increases central dopamine transmission without peripheral norepinephrine reuptake inhibition. Positive clinical results have been reported but have not been replicated in controlled trials [52]. However, trazodone may have some efficacy in men with ED who are anxious or depressed. Pilot studies found trazodone beneficial in SSRI-induced sexual dysfunction and in psychogenic ED when combined with sildenafil [52,174,175]. The most frequent side effects are sedation and headache [17].

A four-month study of cabergoline (0.5 mg/day) in 50 men with psychogenic ED found the drug to be well tolerated. With cabergoline (but not placebo), hormone levels normalized in most patients; significant interactions were observed between serum prolactin and testosterone levels and improvements in erectile function, sexual desire, and orgasmic function. Patient and partner sexual satisfaction were also enhanced. Mean improvement from baseline in IIEF erectile function domain score was 41% higher with cabergoline than with placebo [176]. A 2015 survey of sexual health providers demonstrated an overall treatment success of 40%, with most providers commonly using cabergoline, bupropion, or oxytocin [177]. However, this survey measured only anecdotal results; there was no proven efficacy or superiority of any drug due to a lack of placebo-controlled, randomised, blinded, comparative trials [72].

Bremelanotide is a synthetic heptapeptide with strong binding affinity and agonist action with melanocortin receptor 4, and several trials have evaluated intranasal bremelanotide in the treatment of ED [178]. In healthy volunteers without use of visual sexual stimulation (erotic films), significantly increased erectile activity was found, with duration of erections with rigidity approximately 140 minutes with 20 mg bremelanotide versus 21 minutes with placebo [179]. In men with mild-to-moderate ED, bremelanotide 20 mg with visual sexual stimulation increased erectile activity three-fold and significantly increased duration of erection and penile rigidity [179]. In patients with ED, comparison of sildenafil 25 mg alone versus sildenafil 25 mg plus bremelanotide 7.5 mg found the combination resulted in significantly prolonged time of increased base rigidity (>60%) over the 2.5 hour trial. The combination was well tolerated, without significantly increased side effects over sildenafil or bremelanotide alone [180,181]. No serious side effects have been reported in healthy or ED subjects [52].

It is important to note that these studies involved no more than 32 subjects. Bremelanotide may have clinical efficacy in ED, but larger trials are required to determine efficacy and adverse events before regulatory approval and possible clinical introduction is possible [52]. Bremelanotide is not currently approved for the treatment of MHSDD [24].

The Medicated Urethral System for Erections (MUSE) involves urethral insertion of a small intraurethral alprostadil suppository [74]. The vasodilator alprostadil is absorbed through the urethral mucosa and into the corpus spongiosum. The drug is then transferred to the corpus callosum to produce retrograde filling of the cavernosal bodies through the deep dorsal vein and its circumflex branches, producing erection [182].

Alprostadil and alprostadil/prazosin combination produce erections in the majority of patients with chronic organic ED [183]. Intraurethral alprostadil has been found to produce full penile enlargement in 75.4% and intercourse success in 63.6% of men with chronic ED [184]. A trial of 1,511 men with chronic ED of diverse organic etiology found successful intercourse in 64.9% with alprostadil versus 18.6% with placebo. Painful erection and urethral burning occur in <10% [185].

Intraurethral alprostadil is a reasonable option when PDE5I are contraindicated or in PDE5I failure, particularly for men with post-prostatectomy ED [120]. Ease of administration makes it preferred in men experiencing difficulty with intracavernosal injections or wishing to avoid self-injections [120]. Intraurethral alprostadil has been successfully used with sildenafil when each agent alone failed [52].

Patients lacking oral therapy response may benefit from intracavernosal injection of the vasodilators papaverine, phentolamine, PGE1 (alprostadil), or vasoactive intestinal polypeptide (VIP), alone or in combination [120]. Intracavernosal vasodilator injection directly into the penis relaxes corpus cavernosum smooth muscle to facilitate erection. Optimal dose and combination are tailored, and patients should be instructed in proper technique [52].

Papaverine

The introduction of intracavernosal papaverine to the U.S. market in 1993 marked the modern era of clinically effective ED pharmacotherapy. While effective in inducing erections, papaverine is no longer used as monotherapy due to the risks of fibrosis and priapism, but it is highly effective and safer in intracavernosal combination therapy [52,120].

Phentolamine

Intracavernosal phentolamine alone seldom produces a satisfactory erectile response, but is widely used in combination with papaverine or with VIP [52,74,120].

PGE1

PGE1 is the most widely used agent for intracavernosal delivery and is second-line therapy for PDE5I failure [64,120]. The optimal dose and combination should be tailored to reach the target of an adequately rigid erection for less than 30 minutes. These medications can be obtained in standard formulation or from a compounding pharmacy with dose and combination specified by the prescribing physician [186].

High efficacy rates are reported, with one study finding 94% of men with ED achieved erections suitable for penetration after PGE1 injection [187]. Sparse data indicate that the rate of improved erections with PGE1 is greater than with papaverine, moxisylyte, linsidomine, sodium nitroprusside, or combined linsidomine plus urapidil, and comparable to papaverine plus phentolamine [74]. PGE1 plus papaverine is superior to PGE1 alone [17].

The rates of penile pain (>10%) with PGE1 are higher than with moxisylyte or papaverine plus phentolamine. Pain is significantly less frequent with slower PGE1 injection and when PGE1 is combined with lidocaine or procaine (but not sodium bicarbonate) [17].

PGE1 is highly effective with normal corpus cavernosum vasculature, but some trials have found high nonresponse rates. The exact cause is unclear, but it is probably due to the increased prevalence of compromised but asymptomatic vascular function in men with ED [52].

Vasoactive Intestinal Polypeptide

VIP is a potent vasodilator that inhibits contractile activity in many types of smooth muscle and stimulates adenylyl cyclase and cAMP formation. Intracavernosal injection of VIP alone does not induce erections, but VIP combined with intracavernosal papaverine or phentolamine has produced full erections in men lacking response to intracavernosal papaverine or papaverine plus phentolamine. Positive findings with VIP plus papaverine with or without phentolamine have been repeated in several trials, including a study of 304 patients with psychogenic ED [188]. VIP plus phentolamine is approved by several European countries for use in ED, but it is not approved in the United States [24,52].

Underlying hormonal abnormalities substantially elevate the risk of male sexual dysfunction and, if undetected, can result in patient non-response to first-line therapies. Common endocrine system abnormalities include hypogonadism and hyperprolactinemia.

Testosterone Therapy

Hypogonadism causation should be determined before testosterone is initiated, with baseline assessment and safety monitoring performed in accordance with current authoritative guidelines[29,30,150,189]. Testosterone levels peak around 8:00 a.m., and testosterone measurements should be obtained in the morning, when possible. Elevated serum androgen levels can potentially stimulate prostate growth and increase the risk of activating latent cancer, so all patients receiving testosterone should receive periodic prostate examinations that include digital rectal examination, prostate-specific antigen level, and complete blood count[76].

PDE5Is do not address hypogonadism symptoms (e.g., fatigue, loss of libido) that impair erectile function[190]. In one study, poor PDE5I response was associated with serum testosterone <300 ng/dL; serum testosterone normalization in PDE5I non-responders resulted in improved erectile function and normal PDE5I response[191]. Despite these data, salvaging PDE5I failure with testosterone is controversial[190].

Younger patients with significantly depressed serum testosterone levels should receive testosterone as first-line treatment. Restoration of nocturnal erection should be monitored and, if needed, a PDE5I added at a second stage. In older men with late-onset hypogonadism or borderline testosterone deficiency and chronic ED, PDE5Is should be able to restore sexual function, but any medications affecting testosterone levels should be discontinued and any underlying conditions treated. In these patients, testosterone therapy should be added if testosterone levels remain low, PDE5Is fail to alleviate ED, or signs and symptoms of hypogonadism are evident[10].

Efficacy comparison of different testosterone formulations for improving sexual dysfunction found intramuscular injection to be the least effective for improved erectile function. Transdermal testosterone is more effective in intercourse success and satisfaction when combined with PDE5Is. Testosterone 100 mg gel is more effective than testosterone transdermal in intercourse frequency, and combined testosterone, co-dergocrine, and isosorbide dinitrate cream is more effective than testosterone alone for improved erections and successful intercourse[17]. Side effect comparison found application site skin reactions with transdermal but not gel testosterone, and greater frequency of mild headache with combination testosterone, co-dergocrine, and isosorbide dinitrate cream than cream testosterone[17].

As noted, up to 75% of men with type 2 diabetes experience male sexual dysfunction, particularly ED, and hypogonadism is highly prevalent in men with type 2 diabetes[130]. In the primary care setting, long-acting testosterone undecanoate (0 mg or 1,000 mg) was evaluated in 199 men with hypogonadism (total testosterone ≤12 nmol/L, free testosterone ≤250 pmol/L) and type 2 diabetes for a total of 82 weeks. At 30 weeks, IIEF erectile function, intercourse satisfaction, sexual desire, overall satisfaction, and orgasm domain scores significantly improved from baseline with testosterone undecanoate. Benefit began at six weeks, and all IIEF sexual function measures continued to improve significantly up to 18 months. At 30 weeks, 46% of patients receiving testosterone undecanoate (compared with 17% of those receiving placebo) felt treatment had improved their health, which increased to 70% after 52-week open-label therapy. Depression at baseline was associated with markedly lower sexual function and psychological response. Erectile function scores were unchanged at 30 weeks in a subgroup taking PDE5I therapy, but substantially improved after 52-week open-label. Improvement was greatest in less obese, older, and non-depressed patients. There were no significant adverse events. Results suggest that men with type 2 diabetes may require substantially longer testosterone undecanoate trials than the guideline recommendations of three to six months[130].

A separate study found that adding testosterone to sildenafil showed no added benefit beyond sildenafil alone in men without diabetes[192]. Men 40 to 70 years of age with ED and low testosterone (total testosterone <330 ng/dL or free testosterone <50 pg/mL) received daily transdermal gel containing 0 g or 10 g testosterone for 14 weeks. Treatment with testosterone alone was not studied. Divergent findings may have reflected younger age, shorter trial duration, or less stringent inclusion criteria.

A gradual, age-related decline in total serum testosterone levels begins in men in their mid-30s and continues at an average rate of 1.6% per year[142,193]. The incidence of low testosterone in the United States is approximately 20% in men 60 years of age and older, 30% in men 70 years of age and older, and 50% in men 80 years of age and older[194].

In January 2020, the American College of Physicians (ACP) published guideline recommendations for testosterone treatment of men with age-related low testosterone (Table 4) [189]. The recommendations are based on an evidence review of 38 randomized controlled trials [195]. The average of age of participants was 66 years; the average baseline total testosterone level was ≤300 ng/dL. Participants were followed for 6 to 36 months.

The role of testosterone therapy for the management of age-related low testosterone remains controversial. The FDA requires all testosterone medications labeling to clearly state that the products are approved for use only in persons with low testosterone levels due to known causes [196].

Cabergoline

In one small study, men with hyperprolactinemia were evaluated for treatment response to six months of cabergoline 0.5–1.5 mg per week or bromocriptine 5–15 mg per day. Baseline characteristics included libido impairment (100%), ED (59%), infertility (35%), and bilateral galactorrhea (29%). After six months, sperm parameters, RigiScan-measured erectile frequency, and mean serum prolactin were normalized in both groups. The cabergoline group showed more rapid and evident improvement in sexual function. Significant increases in serum testosterone and dihydrotestosterone levels occurred with cabergoline only. Side effects were mild with cabergoline and mild-to-moderate with bromocriptine [197]. One single-center study retrospectively analyzed the records of 498 patients with hyperprolactinemia. The cabergoline group received an average dose of 1.5 mg/week. The bromocriptine group received an average of 3.8 mg/day. Treatment durations were similar. Baseline prolactin levels, frequency of galactorrhea, amenorrhea, oligomenorrhea, erectile dysfunction, infertility, and visual impairment were similar between the two groups. Cabergoline was found to be more effective than bromocriptine in controlling symptoms, normalizing serum prolactin levels, and shrinking prolactinomas [198].

Vacuum devices are plastic cylinders that draw blood into the penis to induce erection. The cylinder is placed over the penis, air is pumped out to cause a partial vacuum, and a constricting band is placed at the base of the penis when erection is produced. The erection is maintained until the constricting band is released, recommended to not exceed 30 minutes. Vacuum devices are effective in 60% to 90% of patients, are inexpensive and generally safe, and work better with practice. However, many patients lose interest due to assembly, transportation, and spontaneity difficulties [76,199,200]. The use of PDE5Is has eclipsed the use of vacuum devices for the treatment of ED [201].

The American Urological Association asserts that clinicians may offer penile prosthesis surgery to patients with Peyronie disease with erectile dysfunction and/or penile deformity sufficient to prevent coitus despite pharmacotherapy and/or vacuum device therapy.

(https://www.auanet.org/guidelines-and-quality/guidelines/peyronies-disease-guideline Last Accessed: February 21, 2023)

Level of Evidence: C (Randomized controlled trials with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data)

Penile implants involve the placement of semirigid or inflatable prosthetic devices within the corpora and are the last recommended option for ED when less invasive approaches fail, when penile reconstruction is required, or following radical prostatectomy when a nerve-sparing procedure was unsuccessful or not performed [200]. Men treated with radiation therapy are also good candidates for penile implants [202,203].

Semirigid implants involve implantation of two matching cylinders into the corpus cavernosum to provide rigidity sufficient for penetration. Primary drawbacks include cosmetic and concealment concerns from the penis remaining semi-erect and destruction of the natural erectile mechanism during implantation [202,203].

Inflatable implants consist of two cylinders inserted into the corpus cavernosum, a pump placed in the scrotum to inflate the cylinders, and a reservoir within the cylinders or placed beneath the lower abdomen fascia. They usually remain functional for 7 to 10 years before needing replacement. With improvements in these devices, failure occurs in less than 10% of patients [202,203].

One analysis compared the cost of penile implantation following failed first-line PDE5I treatment with alternate PDE5Is, intracorporal injections with alprostadil or trimix, and inflatable penile prosthesis placement [204]. Over a 10-year period, penile implants were more cost effective ($22,009) compared with alprostadil ($62,890), trimix ($48,617), and alternate PDE5I ($52,883).

Patient acceptance is very high and nearly 100% express satisfaction, partially from failure of prior therapies and the high motivation level in these patients [200]. Some evidence suggests additional benefit with PDE5Is following implantation, with enhanced sexual stimulation and sensation [205]. Possible complications include infections (2%), device erosion through the urethra or skin (2%), and painful erections (1%). The development of an antibiotic-coated device has further reduced the infection rate. Pre-implantation education should advise patients that implants do not lengthen the penis as much as normal erections [206,207].

Normal erectile function depends on adequate arterial inflow and venous outflow occlusion. Following normal filling of corporal sinusoids, suprasystolic intracavernosal pressure is required for erection. This filling and required pressure are compromised by impaired cavernosal smooth muscle relaxation and also by compromised arterial inflow or venous leakage, termed vasculogenic ED [149].

With vasculogenic ED, PDE5I failure can occur despite sufficient endothelial and smooth muscle relaxation. Several novel endovascular treatments have been developed, including a drug-eluting stent utilizing zotarolimus; endovascular venous embolization therapy with histoacryl-lipiodol for venous leak involvement; and percutaneous angioplasty of distal penile vasculogenic lesions microsurgical arterial reconstruction. Surgical revascularization procedures for ED secondary to pelvic artery trauma include microsurgical penile artery bypass for focal stenosis secondary to blunt pelvic trauma [74,149]. Vasculogenic ED etiology is complex and multifactorial. These interventions are generally reserved for men with a focal arterial lesion or pelvic arterial trauma and are considered inappropriate in the presence of generalized vascular disease [149].

Myo-Inositol/Folic Acid Combination

As many as 70% of men with type 2 diabetes develop ED, the result of neuropathic, vascular, smooth muscle, and fibrous tissue damage. Myo-inositol can prevent or reverse vascular endothelial dysfunction, reduce endothelial elevations in reactive oxygen species, potentiate nitrergic or vasculo-myogenic relaxation, and preserve nitric oxide signaling through metabolic, superoxide scavenging, and nitric oxide signaling preservation actions [208,209]. In addition, folic acid may reverse nitric oxide synthase uncoupling to improve endothelial dysfunction in patients with type 2 diabetes independent of effect on homocysteine [210].

Myo-inositol/folic acid (myo-inositol 4 g/folic acid 400 mcg) was evaluated in 176 men with type 2 diabetes (50 to 70 years of age) who received active drug or placebo daily. After three months, mean IIEF-5 scores improved 40%, from 12 to 20 (out of 25), with myo-inositol/folic acid but slightly worsened with placebo. Sexual function scores improved 27% with myo-inositol/folic acid and were unchanged with placebo. Diary entries of sexual activity were 50% greater with myo-inositol/folic acid than with placebo. Both groups were unchanged from baseline in bulbocavernosus reflex and all penile hemodynamic variables. The authors conclude that myo-inositol/folic acid deserves consideration as a therapeutic agent in men with diabetes-related ED [211].

Tradamix

Reactive oxygen species are vital signaling molecules in cardiovascular cells, but enhanced production increases nitric oxide inactivation. Reactive oxygen species importantly contribute to endothelial dysfunction that often underlies ED. Tradamix is an herbal supplement developed for use in older men with sexual dysfunction. The three constituents (Ecklonia bicyclis, Tribulus terrestris, and glucosamine oligosaccharide) have activity as reactive oxygen species scavengers, androgen receptor agonists, and nitric oxide modulators [212,213]. Two trials have evaluated Tradamix efficacy. Doses of the constituents E. bicyclis, T. terrestris, and glucosamine oligosaccharide were 300, 450, 250 mg, respectively, in the ED trial, and 150, 396, 144 mg, respectively, in the low libido trial [212,213].

The ED trial enrolled 177 men (average age: 64 years) with IIEF erectile function scores less than 26 (indicating at least mild dysfunction). After three months of treatment, significantly greater improvement was found with Tradamix than placebo on measures of intercourse satisfaction, orgasmic function, sexual desire, overall satisfaction, ejaculation control, and sexual quality of life. In patients with moderate arterial dysfunction, Tradamix resulted in significantly greater improvement (vs. placebo) in peak systolic velocity, erectile function, ejaculation control, and sexual quality of life [212].

In another study, 70 men (mean age: 67.3 years) with low libido with or without ED were randomized to daily Tradamix (group A) or tadalafil 5 mg (group B) treatment. After two months of treatment, group A experienced significant increases in mean total (671 ng/dL vs. 230 ng/dL) and free (120 pg/mL vs. 56 pg/mL) testosterone, while group B remained unchanged from baseline. Normal erectile function significantly increased in both groups, with higher rates in group B, and IIEF total scores significantly increased in both groups, as did sexual quality of life scores. Side effects with tadalafil (occurring in less than 15% of treated patients) included headache, nasopharyngitis, back pain, dizziness, and dyspepsia. No side effects were reported with Tradamix [213].

Both trials used highly restrictive enrollment criteria to exclude medications, medical conditions, past treatment, or anatomical causation of ED or low libido. It is also important to note that this product is patented, and some investigators are financial stakeholders. In addition, the herbal and dietary supplement industry is unregulated in the United States, and this has led to quality and purity concerns. Because Tradamix is produced in Italy, safety concerns surrounding similar domestic products may not be fully applicable.

Extracorporeal Shockwave Therapy

Low-intensity extracorporeal shockwave therapy is a novel, non-invasive approach to the treatment of erectile dysfunction that involves the application of acoustic waves applied to the corpora cavernosa, with the goal of revascularizing the area and improving the blood supply [214]. As such, shockwave therapy is the only modality that aims to cure erectile dysfunction. According to one review, several preliminary trials showed benefit on patient-reported erectile function scores, but results of randomized trials are conflicting [214]. More information is necessary before this approach can be incorporated into routine practice.

Some treatments for ED are either ineffective, not safe, or lack sufficient evidence, and their use may preclude other treatments known to be effective. These include trazodone, oral apomorphine, statins as ED monotherapy, l-arginine alone or combined with other agents, yohimbine, ginseng, and various types of topical treatments [264].

Dapoxetine is a rapid-acting, short half-life SSRI with a pharmacokinetic profile supporting use as on-demand treatment for PE. Dapoxetine has received regulatory approval for PE treatment in more than 50 countries, but not yet in the United States. This drug is considered the best option in PE treatment and has received the highest ratings on efficacy and safety evidence [9,215].

The exact neurologic circuitry target of SSRIs in PE is unknown. Aside from dapoxetine, paroxetine seems more effective for ejaculatory delay than other SSRIs. Daily treatment with doses of paroxetine 10–40 mg, clomipramine 12.5–50 mg, sertraline 50–200 mg, fluoxetine 20–40 mg, or citalopram 20–40 mg is often effective in delaying ejaculation. On-demand treatment is also available with clomipramine, paroxetine, sertraline, and fluoxetine. On-demand dosing three to six hours before intercourse is modestly effective and well tolerated but is substantially less effective than daily treatment. On-demand treatment can be combined with an initial trial of daily treatment or continuous low-dose daily treatment [9].

With daily treatment, the onset of ejaculation delay is usually 5 to 10 days. Full therapeutic effect requires two to three weeks of treatment but is usually sustained with long-term use. Adverse effects start in the first week and may disappear within two to three weeks; they include fatigue, yawning, mild nausea, diarrhea, or perspiration. SSRI side effects of decreased libido and ED may be less common in non-depressed patients with PE (versus depressed men) taking SSRIs. SSRIs are contraindicated in men with history of bipolar depression or bipolar disorder [9,218,219].

The ISSM practice guideline states that, aside from acquired PE secondary to comorbid ED, use of PDE5Is as PE treatment is not supported [9]. Vardenafil is probably an exception, showing particular benefit in PE and significant improvement in IELT among treated patients. Vardenafil is highest in PDE5 specificity among PDE5Is, and PDE5 is expressed in male genital tract regions directly involving the ejaculatory mechanism. In addition, a subgroup of patients with PE exhibits high levels of chronic anxiety, particularly men with lifelong PE. Adrenergic hyperactivity is associated with chronic anxiety, and vardenafil decreases peripheral adrenergic tone, which improves ejaculatory function [10,220,221].

Tramadol is a mild mu-opioid receptor agonist, and its action as a norepinephrine and 5-HT transporter reuptake inhibitor distinguishes it from other opioids and may account for its efficacy in the treatment of PE. Overall, tramadol is moderately effective in lifelong and acquired PE, with efficacy similar to dapoxetine, but high-level studies have not been conducted [222]. Tramadol has abuse potential, and serotonin syndrome may result from concurrent use of SSRIs or other serotonergic agents. Tramadol may be considered when other therapies have failed, especially in countries where dapoxetine is not available [9,215].

Topical local anesthetics, including lidocaine and/or prilocaine cream, gel, or spray formulations, are moderately effective as PE treatment. Topical local anesthetics may induce ejaculatory delay by diminishing glans sensitivity and inhibiting the spinal reflex arc responsible for ejaculation [223].

In one study, a lidocaine-prilocaine spray under development applied to the penis five or more minutes before intercourse produced a 6.3-fold increase in IELT and associated improvements in measures of ejaculatory control and sexual satisfaction [224]. These results were replicated in a larger trial [225]. Reports of penile hypoesthesia and transfer to the partner were minimal and primarily attributed to aspects of the formulation [224]. Significant penile hypoesthesia and possible transvaginal absorption, vaginal numbness, and female anorgasmia are associated with other topical local anesthetics unless a condom is used [226,227]. In all, the evidence supports use of topical local anesthetics for PE [9].

Botulinum toxin A may be a safe and effective means to prolong ejaculatory latency without affecting other aspects of sexual behavior, but dose-ranging Phase II clinical trials were discontinued due to lack of efficacy in interim analysis. Until efficacy data become available, botulinum toxin A should not be considered standard care in PE [265].

Modafinil is a wake-promoting agent used for the treatment of narcolepsy. Several preclinical studies support modafinil as a potential treatment for PE. An uncontrolled trial of on-demand modafinil in men with lifelong PE reported a significant two-fold change in IELT. The short-acting modafinil d-isomer is in pre-clinical trials as an investigational drug for "on demand" treatment of PE [265].

Risks of psychosis exacerbation with cabergoline can be mitigated by close initial monitoring, restricting use to patients stabilized on their neuroleptic, and tailoring cabergoline dose to hyperprolactinemia severity. A trial using terguride, a dopamine agonist similar to cabergoline, for neuroleptic-induced hyperprolactinemia in patients with schizophrenia found unacceptably high rates of insomnia, agitation, and aggravation of hallucinations during the initial two to four weeks of therapy. While terguride is contraindicated for neuroleptic-induced hyperprolactinemia, these findings show the early onset of psychosis exacerbation with dopamine agonist treatment [229].

A successful risk mitigation approach was confirmed in a trial involving 80 patients with schizophrenia and hyperprolactinemia stabilized on neuroleptics. Measures used to assess the participants were the Positive and Negative Syndrome Scale (PANSS) for psychopathology and the Arizona Sexual Experiences (ASEX) Scale for sexual dysfunction. Daily cabergoline 0.25 mg, 0.5 mg, or 1 mg was matched to baseline prolactin <50, 50–99, or >100 ng/mL, respectively. At six-month follow-up, mean prolactin reduction was comparable in all dose groups. Combining all subjects showed significant reductions in prolactin (73.3 to 27.1 ng/mL), ASEX scores (19.1 to 15.0), and PANSS scores from baseline. No psychosis exacerbation was observed. With stabilized neuroleptic dose and cabergoline matched to hyperprolactinemia severity, cabergoline may improve sexual functioning without psychotic exacerbation in patients with schizophrenia and hyperprolactinemia-induced sexual dysfunction [230].

Cabergoline efficacy in sexual dysfunction due to hyperprolactinemia is widely recognized, and increasing evidence suggests efficacy in male sexual dysfunction without hyperprolactinemia causation. However, endorsement of cabergoline for sexual dysfunction treatment was curtailed by reports of heart valve abnormalities from cabergoline use and by FDA warnings of this serious adverse risk [231]. There is some controversy regarding the magnitude of this risk, but steps can be taken to mitigate it.

Cabergoline is an ergot alkaloid used in the treatment of Parkinson disease and Cushing (off-label) disease (in addition to hyperprolactinemia) [24]. Cabergoline lowers prolactin levels through binding pituitary gland D2 receptors and inhibiting prolactin synthesis. It is a D4 and 5-HT1A receptor agonist; both receptors play important roles in regulating male sexual functioning [24,232].

Cabergoline is also a 5-HT2B receptor agonist, and other 5-HT2B agonists have been associated with cardiac-valve regurgitation [24]. In 2011, the FDA required changes to safety labeling warning that cabergoline was associated with fibrotic complications and cardiac valvulopathy; and that valvulopathy screening with echocardiogram (ECG) should be performed before and every 6 to 12 months after starting cabergoline [231]. This FDA action was based on retrospective data from patients with Parkinson disease associating high-dose cabergoline (3–6 mg/day) with a risk of valvular abnormalities [231].

However, it is not possible to determine a causal relationship between cabergoline and valvulopathy from retrospective data. This requires pre-treatment patient evaluation for pre-existing cardiac valvulopathy; assessment of risk factors for developing valvulopathy (e.g., altered cardiovascular system mechanical environments from hypertension or functional cardiac disease); and use of an untreated comparison group to control for high population rates of valvular abnormalities [233,234,235,236].

In a study of 11 men and 29 women (mean age: 38.7 years) with hyperprolactinemia treated with cabergoline for 60 months, baseline ECG found trace mitral, aortic, pulmonic, and tricuspid regurgitations in 20%, 2.5%, 10%, and 40% of patients, respectively, and none with clinically relevant valvulopathy. A 24-month ECG found no changes from baseline, and with 60-month ECG, none had developed significant valvulopathy. No correlation was found between cumulative dose (median: 149 mg) and valve regurgitation prevalence or grade. Cabergoline use for five years did not increase risk of significant cardiac valve regurgitation in patients with hyperprolactinemia [237].

The AACE/ACE investigated valve disease cabergoline treatment of hyperprolactinemia [238]. While the Parkinson disease data suggest cumulative cabergoline exposure is important and minimizing exposure may be appropriate in some contexts, they concluded there is no conclusive evidence that cabergoline causes clinically significant cardiac valve disease at usual hyperprolactinemia doses and that similar regulatory agency directives in the future should use an evidence basis [238].

A separate investigation of valvular abnormalities with cabergoline for hyperprolactinemia reviewed 21 studies and confirmed cabergoline-associated valvulopathy in 3 of 1,812 patients (0.17%). The authors concluded the probability of clinically significant valvular heart disease was very low in the absence of a murmur [239]. A 2014 guideline for clinical endocrinologists stated pre-cabergoline ECG should be reserved for patients with heart disease history or cardiovascular screening exam findings (e.g., heart murmur), with annual ECG limited to patients requiring cabergoline ≥3 mg/week [234].

The Endocrine Society conducted a literature review to clarify the risk of valvular abnormalities with cabergoline. They concluded that patients needing long-term, very high-dose cabergoline may require periodic ECG to assess valvular abnormalities, and patients receiving typical cabergoline doses (1–2 mg/week) will probably not require regular ECG screening [29].

Sex Education

Providers should identify and dispel myths about sex that can negatively influence sexual behavior and contribute to or maintain sexual dysfunction, and the value of basic sex education for this goal should not be overlooked. Many men lack knowledge of basic sexual and reproductive anatomy and physiology. Education should address the diverse range of "normal" sexual function and distorted sexual beliefs or misinformation propagated by popular media and society [7].

Lifestyle Modification

Lifestyle and behavior change should be emphasized to all patients with sexual dysfunction to help optimize sexual functioning. Simple suggestions can be highly beneficial. Reminding patients that changing lifestyle to health-promoting behaviors through diet, exercise, smoking cessation, and stress reduction can improve physical well-being and self-esteem, which may improve physiologic and psychological aspects of sexual desire and response [7].

This is especially true in men with ED. Every modifiable risk factor of ED (e.g., smoking, excessive alcohol, physical inactivity, abdominal obesity, metabolic syndrome, diabetes, hypertension) promotes metabolic conditions strongly linked with a pro-inflammatory state. This can lead to endothelial dysfunction and ED from decreasing nitric oxide availability. Lifestyle and nutrition strongly influence vascular nitric oxide production, testosterone levels, and erectile function. Lifestyle modification that reduces clinical inflammation may help improve erectile function and may potentially decrease ED or even restore absent erectile function in men with obesity or metabolic syndrome [250,251,252].

Sex therapy and cognitive-behavioral therapy are the major psychological treatment approaches for sexual dysfunction in the empirical literature. Traditional sex therapy aims to improve an individual's or couple's erotic experiences while reducing anxiety and self-consciousness about sexual activity [7]. Cognitive-behavioral sex therapy includes emphasis on modifying thought patterns or beliefs that interfere with intimacy and sexual pleasure [253].

In PE, psychological interventions can help men develop sexual skills that promote ejaculatory delay, broaden the sexual script of the couple, increase sexual self-confidence, and reduce performance anxiety. Psychotherapy is also used in resolving psychological and interpersonal issues for the man, partner, or couple that were antecedent to or consequence of the PE [106,254]. Current approaches integrate psychodynamic, systems, behavioral, and cognitive approaches within a short-term psychotherapy model, delivered in an individual, couples, or group format [9]. The squeeze and stop-start techniques are the most common behavioral strategies for PE. Both are designed to help men recognize mid-level ranges of excitement. Men with variable PE should receive education and reassurance, while men with subjective PE may require psychotherapy referral [255].

Performance anxiety can interfere with sexual functioning by diverting focus from erotic input to performance-related concerns, embarrassment, or guilt. Cognitive-behavioral therapy may improve ability and satisfaction by diminishing sex-associated anxiety and cognitive distortions [256].