Alprostadil is a synthetic prostaglandin E1 that was discovered to improve sexual dysfunction. It was the first medication approved by the FDA for erectile dysfunction (ED) in 1995, and it is the only approved medication by intra-cavernosal injection. It is also approved as an intraurethral suppository for ED. However, topical alprostadil has been developed and approved in Europe and Canada for ED (Vitaros^®) and for phase III clinical trials for female sexual interest/arousal disorder (Femprox^®).

Alprostadil acts on prostaglandin E receptors leading to an increase in cAMP through membrane-bound adenylyl cyclase as well as a decrease in noradrenaline through alpha-adrenergic receptors. Studies showed the safety and efficacy of intra-cavernosal alprostadil doses from 1 to 40 μg [4]. Intraurethral application using the Medicated Urethral System for Erection (MUSE) has not gained traction partly because of side effects such as local pain/burning as well the significant difference between its effects compared to intra-cavernosal administration where complete penile rigidity has been achieved in only 10% of patients on MUSE (1000 micro-gm) compared to 43% of patients on intra-cavernosal alprostadil (20 μg) [5]. For sexual enhancement, the more exciting topical route is gaining more attention especially because it is combined with a cutaneous permeation enhancer. Phase II and Phase III trials show rapid onset from 10 to 12 min and erections lasting >60 min, with satisfactory erection rates ranging from 74% to 83% at dose of 300 μg every 4–7 days [6]. Although large placebo-controlled trials led to topical alprostadil’s approval in Europe and Canada [7], it is still considered less effective than oral PDE5 inhibitors or alprostadil injection in ED. Nevertheless, the convenience of its administration places it as a combination agent or in mild cases.

Topical alprostadil: 200–300 μg every 4–7 days.

Apomorphine is a dopamine receptor agonist with its effects being mediated by interacting with dopamine D1 and D2 receptors [8]. It also increases growth hormone-releasing hormone, growth hormone, and somatomedin C secretions [9]. By virtue of its central activity, apomorphine is thus able to activate a neuronal cascade, with effects reaching the periphery via natural signal amplification [10]. Classically prescribed as an anti-Parkinson’s agent, apomorphine has been explored for the use both in the treatment of male erectile disorder (ED) as well as in the treatment of female hypoactive sexual desire disorder (HSDD) .

Apomorphine has been found in a small (n = 24) study to produce subjective and objective changes in the sexual arousal phase of women with orgasmic sexual dysfunction. A clitoral hemodynamic measure, known as peak systolic velocity, was found to improve post-stimulus from 72.5% with placebo to 139.14% with apomorphine. Moreover, arousal and lubrication were subjectively found to improve with administration of apomorphine [11]. In a placebo-controlled study of 62 premenopausal women with HSDD, six women benefited from as-needed apomorphine (2–3 mg). With daily 3 mg administration, the effects on arousal and desire were better than with 2 mg. Enjoyment, orgasm, and satisfaction also improved during treatment with daily apomorphine [12]. The effect of treatment with apomorphine in premenopausal women with HSDD merits more investigation.

Apomorphine was studied in 5000 men who participated in phase II/III clinical trials assessing the safety and efficacy of apomorphine. The 3 mg dose has similar efficacy to the 4 mg dose, but with less adverse effects. A positive outcome was defined primarily as attempts resulting in erections firm enough for intercourse, as well as by percentage of attempts resulting in intercourse, and by improvement in erection. From a baseline of 24.4% of erections firm enough for intercourse, apomorphine treatment resulted in 49.4% success. Erections were found to occur between 18 and 19 min after dosing [13]. Another study of 849 men—11.5% with mild, 23.8% with moderate, and 48.1% with severe ED—examined a dose-optimized regimen of sublingual apomorphine. Erections firm enough for intercourse increased from a baseline of 13.1 to 39.4% with apomorphine. Attempts resulting in intercourse rose from a baseline of 12.7 to 38.3% with treatment. Average time to erection was 23 min, while average duration of erection was 13 min [14]. Another study comparing the 3 mg and 4 mg dosing found that a median time to erection was 18.8 min, with efficacy not being greatly impacted by dosing [15]. A double-blind, placebo-controlled multicenter trial over 8 weeks with 569 subjects showed that between 48 and 53% of men, compared to 35% with placebo, reported erections firm enough for intercourse and between 45 and 51% of men, compared with 33% with placebo, reported attempts resulting in intercourse [16].

A European study of 507 patients with varying etiologies and severities of ED, but all with pharmacologically treated comorbidities, such as hypertension, coronary artery disease, diabetes, or benign prostatic hypertrophy, examined safety and tolerability of a forced-dose escalation of 4 mg. Adverse effects were not found to limit treatment [17].

Of note, inhaled apomorphine showed faster onset of action, as a significant number of patients achieved an erection of long enough duration for successful intercourse, within 10 min of dosing [18].

Nausea is a common dose-related effect, but has been found to decrease with treatment duration [16]. Other common ones include sweating, dizziness, and drowsiness [19].

Start with 2 mg subcutaneously and then increase as needed to 4 mg [16].

Inhaled for faster onset of action [18], 0.5 or 0.8 mg [21]. (Inhalational form is not available in the US.)

Avanafil is the newest among the oral phosphodiesterase-5 (PDE5) inhibitors prescribed for the treatment of ED. PDE5 inhibitors’ mechanism of action is depicted in Figure 26-1. It offers enhanced selectivity, faster action of onset, and a lower side effect profile relative to its other drugs in this class [22]. It is a competitive antagonist of cyclic guanosine monophosphate and has a high degree of selectivity for PDE5 compared to other PDE subtypes [23]. Avanafil is rapidly absorbed and has a short time to peak response [24]. It has a plasma half-life comparable to that of sildenafil and vardenafil [25]. Table 26-2 shows the onset of action and duration of action for each of the FDA-approved PDE5 inhibitors. Avanafil’s selectivity for PDE5 over PDE1, PDE6, and PDE1 causes it to produce fewer musculoskeletal, hemodynamic, and vision-related effects compared to less-selective PDE5 inhibitors [26]. Avanafil is effective for patients seeking on-demand treatment of ED [27].

Avanafil’s rapid onset of action was demonstrated in a randomized, double-blind, placebo-controlled trial by a 64–71% success rate at successful intercourse within 15 min of dosing in 300 sexual attempts compared with 27% in placebo-treated subjects. Moreover, 59–83% of the sexual attempts of the 80 subjects occurred at more than 6 h after dosing compared to 25% on placebo, indicating continuing effect of avanafil [28]. In a multicenter, randomized, placebo-controlled, double-blind trial, 200 subjects with ED showed significantly improved erectile function on avanafil compared to placebo, and after 12 weeks, the proportions of patients achieving normal Erectile Function Domain (EDF) scores were 39.4% and 45.6% on avanafil 100 mg and 200 mg, respectively, compared to 16.7% in the placebo group [29]. One study even demonstrated that treatment with avanafil could be efficacious in as little as 10 min after dosing. The proportion of successful sexual attempts within 15 min, defined by achievement of erection sufficient for vaginal penetration, as well as by successful completion was shown to improve by 25.9% in the 100 mg group and by 29.1% in the 200 mg group with on-demand avanafil therapy [30].

The fast onset of action of avanafil has made it an attractive option among the PDE5 inhibitors in addition to vardenafil. Using visual sexual stimulation, avanafil showed a peak response of 20–40 min after dosing with tumescence and rigidity standing superior to that associated with placebo. In comparison, sildenafil exhibited peak responses in the 60–80 min and 100–120 min ranges [27].

Avanafil also has been shown to be effective in ED patients with medical comorbidities. For example, the treatment of ED in men with diabetes mellitus (most with type II) was explored in a 12-week study of 390 men. Not only was avanafil (100 mg and 200 mg) found safe and effective as early as 15 min after dosing, but also the study revealed that successful intercourse could be initiated more than 6 h after dosing [31].

Avanafil has been investigated in more difficult-to-treat patient populations. A study to investigate the efficacy and safety of avanafil 100 mg and 200 mg in the treatment of ED after nerve-sparing radical prostatectomy was undertaken with 298 subjects. 16.1% of the men were age 65 years or older, and 71.5% had severe ED. Among the features measured were erectile function and successful vaginal insertion. At 12 weeks, patients on avanafil had 36.4% of sexual attempts that were successful at 15 min (or less), versus 4.5% for placebo [32].

To evaluate the long-term efficacy and tolerability of avanafil, a 52-week extension trial of two 12-week trials with 686 patients measured the percentage of sexual attempts ending in successful vaginal penetration and intercourse, as well as erectile function. Success rates improved from 44 to 83% in vaginal penetration and from 13 to 68% in intercourse after avanafil (100 mg and 200 mg). Moreover, 65% of patients who did not respond to 100 mg of avanafil did respond when the dose was increased to 200 mg [33].

50–200 mg PO 15–30 min before sexual activity

Start: 100 mg PO 15 min before sexual activity; max: 200 mg/dose up to one dose/24 h [35]

Bupropion is an antidepressant in the aminoketone family . It is a weak, dopaminergic reuptake inhibitor [36], and its metabolite, hydroxybupropion [37], is a norepinephrine reuptake inhibitor. It also acts as a noncompetitive antagonist at nicotinic acetylcholine receptors, specifically blocking α3β2 and α4β2 and weakly blocking α7 nicotinic acetylcholine receptors [38]. Bupropion is used to treat depression, attention deficit hyperactivity disorder, and for smoking cessation. It is marketed under the following brand names: Wellbutrin^®/SR/XL/Aplenzin^®/Forfivo™/Zyban^®/Budeprion^® _.

The antidepressant activity of bupropion has been demonstrated in double-blind, placebo-, and drug-controlled studies, with a number of significant advantages over other antidepressants: less weight gain [39], less cardiovascular effects [40], and less cardiotoxicity in cases of overdose [41]. Compared to SSRIs, bupropion has been found not only to have a lower negative impact on sexual function across desire, arousal, and orgasm domains but also to enhance sexual function in both depressed and nondepressed women and men [42, 43]. Among the first placebo-controlled clinical trials demonstrating an improvement in the psychological components of sexual dysfunction (inhibited sexual desire, inhibited sexual arousal, and/or inhibited orgasm), 63% of male and female patients treated for 12 weeks by bupropion exhibited greater improvements in libido and on the global assessment of sexual functioning. Moreover, a trend toward increased sexual activity was observed [44].

Studies comparing sertraline to bupropion showed that while the two agents proved similar over time across rating scales for depression, sertraline was more associated with sexual dysfunction in men and women compared to bupropion [45]. Similar studies comparing the effects between fluoxetine and bupropion sustained-release (bupropion SR) found that significantly more men and women experienced less sexual dysfunction with bupropion than with fluoxetine [46] and sertraline [47]. Before the DSM-V merged both HSDD and female sexual arousal disorder (FSAD) into female sexual interest/arousal disorder, bupropion studies were performed using the DSM-IV criteria for HSDD and FSAD [48, 49]. One 4-week study assessing the effect of bupropion sustained-release (SR) in nondepressed women with HSDD showed that sexual desire and sexual function overall increased in 29% of subjects [50]. Another study examining the effect of bupropion on premenopausal women found it to increase sexual arousal, as well as orgasm completion and sexual satisfaction over a 112-day trial [51]. Sexual thoughts/desire scores more than doubled in patients with regular menstrual cycles suffering from HSDD who were treated for 12 weeks by bupropion [52].

Along with primary sexual dysfunction, bupropion SR has been investigated as an adjunctive agent to reverse selective serotonin reuptake inhibitor (SSRI) -induced sexual dysfunction in menstruating women. Although improvements in scores for desire, arousal, lubrication, orgasm, and satisfaction were significantly higher in a bupropion SR for SSRI-induced female sexual dysfunction, the desire domain increased most after treatment [53, 54]. It also seems that higher doses are most efficacious for treatment with bupropion SR of SSRI-induced sexual dysfunction [55]. Two studies comparing the effects of escitalopram and bupropion extended-release (bupropion XL) on sexual functioning and depression showed a significantly decreased percentage of orgasm dysfunction and decreased “worsened sexual functioning” in women treated with bupropion XL compared to escitalopram [56]. In a 43-person study, desire and frequency of sex increased most significantly after treatment of men with SSRI-induced sexual dysfunction after bupropion SR was added [54].

The use of bupropion in the treatment of delayed ejaculation has been investigated, with mixed outcomes. Although 70% of men and women reported improvement in libido, arousal, and orgasmic function during bupropion treatment of ejaculation/orgasmic delays [57], bupropion 150 mg daily showed limited benefit as an agent in the treatment of lifelong delayed ejaculation [58].

75–450 mg PO per day (BID or TID).

Bupropion regular-release: 75 mg and 100 mg tablets.

Bupropion SR/Zyban: 100 mg, 150 mg, and 200 mg tablets.

Bupropion XL: 150 mg and 300 mg tablets.

Aplenzin: 174 mg, 348 mg, and 522 mg extended-release tablets.

Buspirone is FDA approved for the management of anxiety disorders . Its mechanism of action suggests activity in a wide variety of neuronal systems [59]. It is a presynaptic and postsynaptic partial agonist selectively at the 5-hydroxytryptamine-1A (5-HT1A) receptor , lending to its antianxiety and antidepression properties [60]. Among anxiolytics, it is an azaspirodecanedione and does not interact with gamma-aminobutyric (GABA) receptors [61]. It is used for longer-term treatment of anxiety, because compared to the benzodiazepine-type anxiolytics, it is not associated with dependence, and there are no additive effects when taken with ethanol or benzodiazepines [62].

An HSDD study in women posited that although testosterone increases sensitivity to sexual cues, it might increase sexual inhibitory mechanisms in women predisposed to sexual inhibition by 5-HT1A-mediated mechanisms in the prefrontal cortex. The study found that a single dose of buspirone in combination with testosterone enhanced sexual responsiveness in women with high sexual inhibition with HSDD [63]. The same combination of testosterone and buspirone also worked for the treatment of low desire in women with SSRI-induced sexual dysfunction [64]. Moreover, buspirone alone was shown to be effective in the reversal of SSRI-induced sexual dysfunction [65].

Available in 5, 7.5, 10, 15, and 30 mg in divided doses

For treatment of anxiety/sexual dysfunction: 20–30 mg/day PO divided BID-TID

Clomiphene citrate is a nonsteroidal, ovulatory stimulant indicated for female infertility. It binds to estrogen receptors in the hypothalamus and pituitary where it has both estrogenic and antiestrogenic effects, leading to increases in GnRH, LH, and FSH release [67]. Increasing LH levels in men leads to a rise in testosterone levels, justifying its use for treating males with low testosterone. With fewer side effects than clomiphene, enclomiphene citrate—the trans-stereoisomer of clomiphene citrate—is becoming an alternative to testosterone replacement therapy.

For the past three decades, multiple studies showed that clomiphene citrate consistently increases serum testosterone levels in men. For instance, a study of 25 mg daily of clomiphene citrate increased testosterone levels and the testosterone/estradiol ratio in men with hypogonadism [68]. Enclomiphene citrate 25 mg daily increased levels of total testosterone in men within 2 weeks into the normal range, and the effects persisted for at least 1 week of treatment discontinuation [69].

Clomiphene citrate in men: 25–50 mg daily and then increase to 50 mg PO BID

Enclomiphene citrate in men: 12.5–25 mg daily

Dapoxetine, a potent SSRI that is similar to fluoxetine in structure, was specifically developed for premature ejaculation (PE) . Despite its approval in Europe, the Middle East, and Mexico, it has not yet been approved in the United States [70]. Dapoxetine has a rapid onset and is administered 1–3 h before intercourse or on a daily basis [71].

Dapoxetine has been evaluated using randomized, double-blind, placebo-controlled studies. Five industry sponsored of 6081 men showed that the geometric mean average stopwatch-measured intravaginal ejaculatory latency time (IELT) increased from 0.8 min at baseline to 2 min on dapoxetine 30 mg and 2.3 min on dapoxetine 60 mg versus 1.3 min on placebo (p for both comparisons <0.001) [72].

Start with 30 mg 1–3 h before intercourse or daily and could be increased to 60 mg.

Flibanserin is a novel multifunctional serotonin agonist and antagonist. Its mechanism of action is as a 5-HT1A agonist and secondarily a 5-HT2A antagonist. Additional action includes weaker antagonism at 5-HT2C and 5-HT2B and partial agonist activity at D4-dopamine receptors [74]. A centrally acting agent, it preferentially activates mesolimbic, dopaminergic, and hypothalamic structures involved in response to sexual stimuli [75]. Flibanserin is used to treat premenopausal women with acquired HSSD [76]. Thus, flibanserin offers a new direction in the treatment of HSDD [77].

Flibanserin increases the number of reported satisfying sexual events and general sexual function and decreases sexual distress. In terms of experiencing meaningful benefits, women taking flibanserin (37.6%) reported to have benefited compared to placebo (28.0%) [78]. Flibanserin clinical trials are named after a series of flowers.

In 2010 the DAISY study initiated a series of 24-week studies on the effects of flibanserin on premenopausal women with HSDD. This study sets out to assess efficacy and tolerability of flibanserin, revealing a direct relationship between optimal dosing (100 mg at bedtime) of flibanserin and improvements in satisfying sexual events, sexual desire, sexual function, and sexual distress. Still, improvements in female sexual distress and female sexual function were reported with all dosage (25 mg twice daily and 50 mg twice daily) regimens [79]. The VIOLET study aimed to evaluate efficacy and safety of flibanserin. It revealed at 50 mg and 100 mg once daily at bedtime that flibanserin was well tolerated and associated with similar results to the DAISY study [80]. This helped establish the safety of optimal dosing of flibanserin.

The 24-week trial standard was extended to one of 52 weeks in the SUNFLOWER study . Women participating in this trial were not only premenopausal as in the other studies, but they had already completed a trial of flibanserin or placebo. By study end, 42% of those with active HSDD showed improvement of sexual distress to remission level, and the percentage of those in remission rose from 83 to 90% [81].

The 24-week BEGONIA trial sets out to assess the efficacy and safety of flibanserin in premenopausal women with HSDD. This randomized, placebo-controlled trial was geared toward optimal dosing of 100 mg at night. A significant number of women reported reductions in distress associated with sexual dysfunction, as well as reductions in distress associated with low sexual desire [82]. The SNOWDROP trial reaffirmed that flibanserin, compared with placebo, is associated with improvement in sexual desire, increased number of satisfying sexual events, and reduced distress secondary to low sexual desire [78]. Prior to the August 2015 FDA approval of flibanserin for women experiencing HSDD, there had been two prior failed FDA reviews, mainly due to concerns for flibanserin’s efficacy and the product’s risk/benefit profile [83]. A systematic review and meta-analysis of randomized clinical trials assessing the safety of flibanserin for the treatment of HSDD in women revealed that treatment with flibanserin, on average, resulted in only one-half additional satisfying sexual event per month while statistically and clinically significantly increasing the risk of dizziness, somnolence, nausea, and fatigue [84]. To limit risk, it is encouraged that flibanserin be taken at bedtime, and the concomitant use of alcohol with flibanserin should be discouraged [83].

For the treatment of HSDD, acquire 100 mg PO QHS; for premenopausal female patient, discontinue after 8 weeks if no improvement is noted [86].

Melanocortins constitute a group of peptide hormones, which include adrenocorticotropic hormone and melanocyte-stimulating hormones, and are derived from the proopiomelanocortin , which is made in the pituitary gland. By binding to one of five melanocortin receptors, melanocortins influence a variety of functions, including pigmentation, inflammation, energy homeostasis, and sexual function [87, 88]. Melanocortins play a role in the central pathways involved in mediating arousal and orgasm in females, as well as in erection in males [89]. Successful efficacy in preclinical treatment studies of ED using centrally acting melanocortin receptor agonists was limited by side effects such as nausea, severe enough to warrant discontinuation [90]. The melanocortin agonist available on the market is called Melanotan II, available in subcutaneously injectable form.

A study to investigate the effect of a selective melanocortin analog known as bremelanotide on 18 premenopausal women diagnosed with female sexual arousal disorder revealed that even upon exposure to sexually explicit visual stimuli, it improved subjective sexual desire and more positive feelings of genital arousal. This change occurred within 24 h of treatment with nasal bremelanotide [91]. Another study of 80 married, premenopausal women, average age 31, showed that intranasal bremelanotide was associated with improvements in arousal, as well as with significant gains in intercourse satisfaction [92].

The use of a nonselective melanocortin analog, known as Melanotan II, was investigated on 20 men with psychogenic and organic ED. Without sexual stimulation, Melanotan II led to penile erection in 17 out of 20 men. Moreover, participants reported 68% increased sexual desire, as opposed to 19% in placebo [93]. The melanocortin 4 receptor, specifically, has been found to be of interest, as its agonists in both oral and in sublingual form have been shown to be safe and effective at 200 mg in the treatment of ED up to a similar efficacy level as that exhibited by sildenafil [94], as well as in those who fail sildenafil therapy [95]. Likewise with another study of healthy patients and of patients who had failed sildenafil therapy, in doses of 0.3–10 mg, a cyclic heptapeptide melanocortin analog offered statistically significant erection improvement in patients who had not responded to phosphodiesterase-5 (PDE5) inhibitor therapy [96].

Nausea, stretching, yawning, spontaneous penile erection, and increased pigmentation [97]

Healthy patients: 1.0 mg SC

Erectile dysfunction: 4 or 6 mg SC [96] or up to 200 mg PO or up to 200 mg sublingual [95]

Oxytocin (OT) is a neuropeptide made of nine amino acids naturally produced by the paraventricular and supraoptic nuclei of the hypothalamus and then stored in the posterior pituitary where it could be released to the bloodstream or is secreted from the paraventricular nuclei projections into brain structures such as the amygdala, hypothalamus, and hippocampus and nucleus accumbens [98]. OT is responsible for contractility and social bonding. Synthetic OT has been prescribed to induce labor (IV form) and mild ejection (intranasal form) and experimentally to improve social skills in autism [99] and schizophrenia [100].

Using a continuous blood sampling technique and anal electromyography, Carmichael et al. reported in 1994 a positive correlation between oxytocin levels and the intensity, but not duration, of orgasmic contractions in males and females [101]. IsHak et al. in 2008 used intranasal oxytocin successfully in treatment refractory anorgasmia [102]. Oxytocin is administered intranasally during intercourse (due to its half-life of 2–3 min), at the point when ejaculation is sought. For multiorgasmic women, the amount of oxytocin level increase was positively correlated with subjective reports of orgasm intensity [103]. A number of case reports have documented the role of oxytocin in producing remarkable improvement in sexual function [104] and improving orgasmic difficulties [105]. In a 2013 review of oxytocin, Wudarczyk et al. proposed the use of oxytocin for enhancement of romantic/sexual relationships [106].

Off-label use for delayed orgasm: 24 IU intranasally [108]

Dopamine agonists—ropinirole originally novel—were first used in patients diagnosed with moderate to advanced Parkinson’s disease (PD) , as they allowed for reduction in dosing and hence decreased adverse motor response reactions to levodopa [109, 110]. Ropinirole is a potent and selective D2-dopaminergic agonist [111, 112]. In contrast to pramipexole, a D2-agonist ergot ropinirole is a non-ergoline [113], centrally acting agent, which was also employed to alleviate restless legs syndrome [114]. It also came to be explored as an agent to combat sexual dysfunction, a common side effect of antidepressants [115]. Ropinirole has a half-life of about 6 h and has approximately 50% bioavailability , with low plasma protein binding [116]. Although not classically offered for the treatment of sexual dysfunction, ropinirole merits attention as a dopaminergic agent with potential for the treatment of sexual dysfunction.

Dopaminergic agents have gained attention in the treatment of antidepressant-induced sexual dysfunction. An early report of 13 patients, 10 of whom were men, indicated that over 4 weeks of daily treatment, 54% of patients reported improvement in sexual function, suggesting that ropinirole may be part of the arsenal in the strategy against antidepressant-induced sexual dysfunction [115].

A case report of a 45-year-old man with 20 years of PD, medicated with a high dose of ropinirole, indicates that this patient displayed hypersexuality and exhibitionism. The account urges caution as to sexual impulses and reduced control of behavior in the face of dopaminergic agents [117]. Moreover, pathological hypersexuality is documented to have developed in 13 patients with PD, with hypersexuality exhibited in 14 out of 15 cases beginning within 8 months after onset of treatment with ropinirole [118].

An analysis of 1580 adverse drug events from the United States and 21 other countries suggesting impulse control disorders (pathological gambling, hypersexuality , and compulsive shopping) revealed that 710 cases had involved in them patients taking dopaminergic agents, with 188 of these patients on ropinirole [119]. Further, a screening interview of 272 patients with idiopathic PD revealed that, in fact, 4% of them suffered from an impulse control disorder [120, 121]. Further exploration into the use of dopaminergic agents for the treatment of sexual dysfunction is warranted.

Start at 0.25 mg PO daily and titrate up to 2–4 mg PO daily over 4 weeks, as tolerated [115].

Sildenafil is the first in its class of vasoactive drugs developed for the oral treatment of ED. It is a peripherally acting agent that inhibits cyclic guanosine monophosphate (cGMP) -specific PDE5 from the corpus cavernosa. PDE5 is the chief PDE type in the corpus cavernosum and plays a key role in penile erection [123]. Erection is dependent on NO and on its second messenger, cGMP [124]. Sildenafil potentiates the NO-stimulated cGMP signal that mediates relaxation of penile cavernosal smooth muscle during sexual stimulation [125]. Sildenafil has also been shown to successfully treat female sexual arousal disorder in hormonally replete women without contributing psychosocial stressors [126, 127], likely clarified by NO-mediated relaxation of clitoral and vaginal smooth muscle [128]. PDE5 contains two N-terminal domains (GAF A and GAF B) and is activated upon cGMP binding to the GAF A domain. Moreover, activated PDE5 demonstrates higher sensitivity toward sildenafil than does nonactivated PDE5 . In fact, PDE5 is activated directly upon cGMP binding to the GAF A domain, without the need for PDE5 phosphorylation [129]. Sildenafil also has direct muscle relaxant potential, likely inhibiting Ca²⁺ influx through both receptor-mediated and voltage-dependent Ca²⁺ channels [130]. PDE6 is also inactivated by sildenafil, explanatory for adverse visual disorders [131]. Cyclic adenosine monophosphate (cAMP)-dependent signaling mechanisms also interplay with cGMP-dependent signaling mechanisms in human cavernous arteries [132]. By nature of being a PDE5 inhibitor, sildenafil may have an effect on adrenal steroidogenesis , as its administration has been shown to be associated with an increase in testosterone levels, likely secondary to a direct effect on the testis [133]. Employed classically for the treatment of ED, sildenafil affects the domains of desire and of orgasm less so than it does arousal [134], with a duration of approximately 4 h [135]. Table 26-2 shows the onset of action and duration of action for each of the FDA-approved PDE5 inhibitors.

A direct relationship between sildenafil dosing and efficacy is documented. The first published large-scale clinical trial for sildenafil included a 24-week-dose-response study of 532 men and a 12-week, flexible dose-escalation study of 329 men, followed by a 32-week, open-label extension study of 225 of the 329 men. The dose-response study showed a direct relationship between dosage and erectile function (achieving and maintaining erection); a 100% increase in the number of men achieving erections was observed for men receiving 100 mg of sildenafil. During the final 4 weeks of the dose-escalation study, there was a 69% success rate at sexual intercourse, compared to 22% for those receiving placebo. There was a staggering near 400% increase in attempts at sexual intercourse for these men [136]. Men with ED treated with 100 mg compared to 50 mg sildenafil have also been shown to attain greater gains in erectile function and, even within the first 2 weeks of treatment, have experienced completely hard and rigid erections [137]. The dose-response relationship was poignantly evinced in a study of 54 men with refractory ED, who had failed treatment with 100 mg sildenafil, with 37%, 46.3%, and 68% of these patients experiencing improved erections using 100 mg, 150 mg, and 200 mg sildenafil, respectively [138].

Relative safety was shown in a 1998 data analysis of 2722 sildenafil patients and 1552 placebo patients, who collectively had undergone double-blind, placebo-controlled, and ten open-label extension studies of sildenafil . Adverse effects, such as headache, flushing, and dyspepsia, were transient, mild, or moderate. Discontinuation secondary to side effects nearly matched that of placebo [139]. Successful ongoing improvement of ED has been shown to be dependent upon continued treatment with sildenafil [140].

Different types of ED have been successfully treated with sildenafil therapy. One double-blind, placebo-controlled study of 329 patients suffering from ED of organic, psychogenic, or mixed etiology revealed that 74% of patients receiving sildenafil versus 16% for placebo had improved erections and that 65% of patients receiving sildenafil versus 20% for placebo reported successful attempts at sexual intercourse [141]. A study of 514 men with a mean age of 56 years, with 32% diagnosed with organic ED, 25% with psychogenic ED, and 43% with mixed ED, showed between 67 and 86% relative to placebo improved erections, helping to establish sildenafil as well tolerated and efficacious among ED of various etiologies [142]. Likewise, with age matching to healthy subjects across broad-spectrum ED etiologies, one study demonstrated that sildenafil is associated with near normalization of ED [143].

Sleep-related erectile activity, especially tip rigidity, was shown to be enhanced in 77% of the 30 patients tested, 23 of whom experienced ED due to established medical or biological “organic” reasons [144]. Another study of organic impotence demonstrated that sildenafil improves nocturnal penile activity (rigidity and tumescence) in organic ED. Moreover, ED due to psychogenic etiology in the same study was shown to benefit rigidity, as opposed to tumescence [145]. Even men without ED, who in fact were potent, demonstrated improved nocturnal erections with sildenafil [146]. Refractory time was cut from 10.8±0.9 min to 2.6±0.7 min in a study of 20 healthy men in stable relationships with proven fertility [147].

Investigation of the treatment of ED in men with diabetes is important because diabetes is a common comorbidity in ED. A randomized, double-blind, placebo-controlled, flexible dose-escalation clinical trial over 7 months of 268 men with a diagnosis of diabetes (mean = 12 years) and with a diagnosis of ED (mean = 5.6 years), showed improved erections in 56% of patients receiving sildenafil versus 10% on placebo. The proportion of men with a minimum of one successful attempt at sexual intercourse was 61%, compared to 22% for the placebo group [148]. This study, as well as another to investigate sildenafil’s efficacy in diabetes mellitus, hypertension, history of pelvic surgery, and ischemic heart disease, helped establish sildenafil as an effective treatment of ED in men with these common comorbidities [149]. Men with moderately severe congestive heart failure also exhibited good tolerance, improved erectile function, and relief of depressive symptoms with low-dose (50 mg) sildenafil [150].

Sildenafil has gained notice as a well-tolerated and efficacious pharmacological treatment of ED in men with spinal cord injuries. One analysis of a two-part pilot study to assess the efficacy of sildenafil in the treatment of ED was conducted on patients with spinal cord injury. Results revealed that 65% of patients receiving sildenafil versus 8% for placebo had erections of at least 60% rigidity. Moreover, 67% of these men wanted to continue treatment with sildenafil. None of the subjects discontinued due to adverse effects [151]. Another study of spinal cord injury patients showed similar results to the pilot study; [152] while another study elucidated that the efficacy of sildenafil depends on sparing of sacral (S2–S4) or thoracolumbar (T10–L2) spinal segments, which help mediate psychogenic erections in males with spinal cord injuries [153].

The studies of ED and comorbidities using sildenafil treatment called for the need to study its effects on medication treatment. In a study of 1685 men with at least 6 months of ED, who were taking antihypertensive medication, sildenafil was found not to have clinically significant effects on blood pressure and heart rate in the acute, short-term treatment of ED [154]. One study of men with ED and taking two or more antihypertensive medications likewise revealed similar efficacy and tolerability [155].

Psychiatric symptoms are commonly encountered in ED, especially depressive symptoms. “Positive affect” was a change of particular note in one of the early sildenafil studies [156]. Another study showed that Hamilton depression scale scores were lower in 76% of patients treated by sildenafil, while 14% of patients did not exhibit a significant decrease in depressive symptoms. Improvement of ED was shown to reduce depressive symptoms and improve quality of life in mild to moderate depressive disorder [157]. Ten post-traumatic stress disorder (PTSD) patients with ED taking antidepressants demonstrated significant improvements in all sexual domains (particularly arousal), following treatment with sildenafil 50 mg daily as needed [158].

About 81% of patients with antidepressant-associated ED who did not respond to treatment responded fully to open-label sildenafil [159]. As antipsychotic use is associated with ED and remains a common reason for poor compliance, sildenafil has been studied in patients with ED on antipsychotics. While one study showed that ED decreased significantly after treatment with sildenafil of ED in patients with schizophrenia on risperidone [160], another study revealed an odds ratio with sildenafil of 4.07 for adequate erections [161].

As the first approved agent, sildenafil is often compared to other agents. A pilot study of 10,750 ED patients was conducted prior to the release of vardenafil and tadalafil, comparing sildenafil, apomorphine, yohimbine, and alprostadil. The results showed that 81% were satisfied with the treatment outcome with all the interventions; however, 85% reported particularly satisfaction with sildenafil’s onset of action, duration of action, efficacy, and tolerability [162].

Additional effects were detected with sildenafil. Ejaculatory latency secondary to treatment by serotonin reuptake inhibitors was decreased in nine out of ten men in remission from MDD by treatment with 150–200 mg sildenafil [163]. Conversely, sildenafil was found more efficacious relative to paroxetine and the squeeze method in the treatment of premature ejaculation [164]. Adding sildenafil to a fluoxetine regimen also significantly improved rates of premature ejaculation when compared to fluoxetine by itself [165]. Similarly, adding sildenafil to talk therapy in the treatment of ED proved more efficacious than the former alone [166].

Erectile dysfunction: 50 mg PO ×1; start 0.5–4 h prior to intercourse; maximum 100 mg/dose up to 1 dose/day; consider starting at 25 mg PO × 1 in patients above 65 years old [168].

Range of onset to erection 12–30 min, mean time 27 min, duration of action at least 4 h [169].

Remains clinically active 12 h after administration in patients with ED at 100 mg [170, 171].

No significant loss of efficacy occurs when sildenafil is taken shortly before or with a meal [172].

Tadalafil is among the PDE5 inhibitors class of vasoactive drugs developed for the oral treatment of ED. Erection is dependent on nitric oxide and on its second messenger, cGMP [124]. The long-acting active inhibition by tadalafil of PDE5 lends to increased cGMP and hence smooth muscle relaxation in the penis for up to 36 h [135, 173], with the longest plasma presence among the PDE5 inhibitors [174]. It is also the only PDE5 inhibitor whose pharmacokinetic profile is not affected by fatty food [175]. Table 26-2 shows the onset of action and duration of action for each of the FDA-approved PDE5 inhibitors. Tadalafil exhibits peripheral action by inhibiting cGMP-specific PDE5 from the corpus cavernosum [123]. PDE6 is not inhibited by tadalafil, explaining its nearly nonexistent visual side effect profile [131]. Tadalafil is unique among the PDE inhibitors in that it also inhibits PDE11, an effect that does not have any known clinical implications [176]. Another set of distinctions it holds among PDE5 inhibitors is that it lacks significant effect on noradrenaline [130].

By virtue of a longer half-life, tadalafil conceivably offers a specific advantage over sildenafil, as patients might less closely link dosing with planning of sexual intercourse. In a multicenter study of 207 men, it was found that 82.8% of those treated with tadalafil experienced improved erections, versus 19.6% taking placebo. Of note, the higher rate of successful intercourse attempts occurred between 4 and 36 h after dosing [177]. The length of time that tadalafil works has proven favorable and gained significant patient satisfaction [178]. Sexual partner satisfaction has mirrored that of patients in the treatment of ED by tadalafil [179, 180].

The versatility in dosing of tadalafil is also noteworthy. One large (n = 4262), multicenter study looking at male preference for on-demand tadalafil treatment versus three times weekly tadalafil treatment found that although 57.8% of men preferred the on-demand regimen of tadalafil 20 mg, a considerable 42.2% of men preferred the three times weekly treatment [181], especially that tadalafil proved efficacious up to 36 h. Moreover, men of different age groups demonstrated significantly changed sexual behavior on the three-time weekly dosing [182]. These men engaged in having sex distributed over a wider period of time, having sex beyond the 4-h window, and having sex during the morning and the evening hours [183]. In fact, in one study of 367 PDE5 inhibitor-naïve men with ED, 71% preferred tadalafil and 29% chose sildenafil as their preference [184].

As ED is increasingly common with advancing age, a study of 188 men with a mean age of 71.6 years without depression and without diabetes mellitus demonstrated 81% improved erections and 56% successful completion of sexual encounters up to 36 h after tadalafil 20 mg dosing. Moreover, only 5% of patients discontinued treatment due to adverse effects [185]. Long-term treatment with tadalafil 5 mg once daily has also been shown to be well tolerated and effective in a 472-patient study [186]. Moreover, 46.3% of patients in one trial continued to show normal erectile function after 4 weeks of no treatment, following a period of 1 year of tadalafil therapy [187].

In order to understand the effect of tadalafil over time on men with ED with medical comorbidities and their medication treatment, a multicenter, open-label study of 1173 men with ED who were taking concomitant medications for such conditions as diabetes (30.5%) and hypertension (29.5%) was conducted. The study demonstrated the overall safety and tolerability for tadalafil at doses of 5, 10, or 20 mg taken once daily for 18–24 months [188]. A larger study (n = 1911) showed adequate tolerance and efficacy for tadalafil 20 mg for men with ED who had comorbid diabetes mellitus, cardiovascular disease including hypertension and hyperlipidemia, and depression and with men with two or more comorbidities [189]. Moreover, men with ED secondary to traumatic spinal cord injury showed improved erectile function and good tolerance to treatment with tadalafil [190]. One study revealed that patients with ED due to treatment by SSRIs, who were treated with tadalafil 20 mg, demonstrated significantly improved sexual function [191]. The effect of tadalafil versus fluoxetine versus the combination of tadalafil and fluoxetine versus placebo on PE was investigated, with results indicating statistically significant increase in intravaginal ejaculatory latency time by 49.57±25.87 to 336.13±224.77 s [192].

The treatment of ED is typically ongoing and success depends on compliance. In five double-blind, placebo-controlled 12-week studies, 308 men were randomized to placebo, 321 to tadalafil 10 mg, and 258 to tadalafil 20 mg. Dose-dependent success was demonstrated [193]. Tadalafil has shown efficacy within 3 days at 2.5 mg and 5 mg once-daily dosing [194]. Dose-dependent success, beyond first-time success, has been demonstrated by improved erections in 79% of tadalafil 20 mg patients, 67% of tadalafil 10 mg patients, and 22% of placebo patients. Successful completion of sexual intercourse was achieved in 62% of tadalafil 20 mg patients, 50% of tadalafil 10 mg patients, and 31% of placebo patients [195].

As ED presents in various severities, a study of 443 men—47% with mild, 30% with moderate, and 23% with severe ED—was undertaken. Erectile function improved to normal in 64% of patients treated with tadalafil, as opposed to 16% in the placebo group [196]. Tadalafil 20 mg has also proven as efficacious in Hispanic and in African-American groups as in the Caucasian reference group [197]. Similarly, tadalafil has been shown to be effective in Egyptian and Turkish men with ED [198] and as effective and well tolerated for the treatment of ED in East Asian, Southeast Asian [199], and Japanese men [200].

One study investigated the effect of tadalafil on ED by examining 1112 men (age range 22–82, mean age = 59), suffering with mild to severe ED of various etiologies. They were randomized to placebo or tadalafil in five randomized, double-blind trials of 12-week duration. Tadalafil exhibited significant improvements in erectile function from baseline, intercourse attempts, and successful completion. Moreover, the tadalafil group showed 81% improved erections at endpoint, compared with 35% in the control group [201].

Another study looked at the effect of tadalafil at 24 and 36 h after dosing. It stratified patients by baseline severity of ED and then randomized within the severity group to tadalafil 20 mg or placebo. Patients were asked to attempt sexual intercourse at approximately these time marks, with success being defined as completion to ejaculation. Not only was tadalafil well tolerated by patients at both time points, but also the 36-h group exhibited 59.2% success relative to placebo, whereas the 24-h group showed 52.9% success [202].

Erectile dysfunction: [PRN dosing regimen] 5–20 mg PO × 1 prior to sexual activity; start at 10 mg PO × 1 and adjust based on individual response; maximum 20 mg/dose, 1 dose/24 h; 10 mg/dose, 1 dose/72 h if strong CYP3A4 inhibitor use; effects may last for 36 h [204].

Testosterone is generally considered the chief male sex hormone, playing a pivotal role in the development of male reproductive tissues , such as the testes and the prostate, as well as in formation of secondary sex characteristics, such as growth and pattern of body hair, muscle mass, and bone mass. Despite the inverse relationship between testosterone levels and time, the decline in testosterone levels in men that comes with age is not mutually exclusive with acquisition of erectile dysfunction (ED) [205] nor is the relationship between age and ED firm and fixed. Nonetheless, sexual function is revived in severely hypogonadal men who receive androgen replacement therapy [206, 207]. It has been demonstrated that testosterone treatment in men with lower levels increases the number of nocturnal erections, the frequency of sexual thoughts, and the rate of successful intercourse and improves erectile function and overall sexual satisfaction scores. The effects of testosterone on eugonadal men, however, are not significant [208]. Although much attention has been paid to the treatment of ED, testosterone therapy has also been explored for women for the treatment of HSDD symptoms related to menopause and of decreased sexual desire secondary to medication. Testosterone plays a vital role for both sexes in the treatment of sexual dysfunction.

The use of testosterone therapy for the treatment of HSDD after oophorectomy in menopausal women was explored in a 24-week, randomized, double-blind, placebo-controlled trial of 87 people. Transdermal testosterone therapy was shown to improve sexual desire, as well as other domains of sexual function. The testosterone-treated group showed a significantly greater change from baseline in sexual desire, compared with placebo. Arousal, orgasm, sexual concerns, responsiveness, and self-image also significantly improved with testosterone therapy [209]. A larger study of 132 surgically postmenopausal women with HSDD looked at the effect of testosterone treatment on frequency of sexual activity and sexual desire. The study showed that 52% of the women who received testosterone therapy reported a “meaningful treatment benefit” or desire progressing from “seldom” to “sometimes,” compared with 31% who received placebo [210].

The use of estrogen as hormonal treatment for the symptoms of menopause is common. The addition of testosterone to this regimen has been explored. A 52-week trial in which 814 women with HSDD were assigned testosterone or placebo showed benefits with testosterone treatment. These postmenopausal women had not received estrogen therapy prior to treatment with testosterone. The effects of testosterone without estrogen on sexual function, specifically satisfying sexual episodes, were modest, though significant [211].

A 3-month assessment of the effect of testosterone cream on 36 women who had undergone hysterectomy and were taking transdermal estrogen revealed that testosterone cream significantly improved sexual desire and frequency of sex [212]. Testosterone undecanoate added twice weekly to an already in-place hormonal regimen was also noted to improve sexual function among postmenopausal women, more so than the estrogen treatment alone [213].

A study to assess naturally occurring menopause in 277 women with HSDD both with and without conventional hormone therapy to treat the menopause revealed that a transdermal testosterone patch over 6 months was associated with significant improvements in sexual desire versus placebo [214].

The effect of testosterone treatment on antidepressant-induced female sexual dysfunction, focusing on the facet of emergent loss of libido, was not published until 2014. What was discovered was that transdermal testosterone therapy resulted in a significant increase in the number of satisfying sexual events, compared to placebo in women with SSRI-/serotonin-norepinephrine reuptake inhibitor (SNRI)-emergent loss of libido, suggesting that transdermal testosterone therapy might be a smart option for SSRI-/SNRI-emergent loss of libido in patients who need to remain on antidepressant therapy [215].

The use of testosterone injection in hypogonadal men for the treatment of low sexual desire has been long-standing. It is common for ED to be comorbid with low testosterone levels [216]. Studies of men without hypogonadism have been found, though to a much lesser extent, and merit investigation. An early double-blind crossover comparison of testosterone and placebo injection in two groups of men with normal testosterone levels—ten with loss of sexual interest and ten with erectile failure—suggested a “significant increase in sexual interest” in the former group. These results pointed to the notion that testosterone influences sexual interest, even in men with normal levels [217].

As comorbid depression and antidepressant side effects typically include sexual dysfunction, a test involving men with major depressive disorder (MDD) who were taking an SSRI and exhibited low or low-normal testosterone level was conducted. Ejaculatory ability was improved by testosterone. In this 6-week, double-blind, placebo-controlled trial of testosterone gel versus placebo in 100 men, it was found that the subgroup of men with the higher baseline testosterone levels showed nearly the same improvement in ejaculatory ability than those with the lower baseline testosterone levels. This implies that the improved ejaculatory ability was unlikely to be secondary to correction of hypogonadism [218].