Guidelines for the Treatment of Erectile Dysfunction and Peyronie’s Disease

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© Springer Nature Switzerland AG 2020
C. R. Chapple et al. (eds.)Urologic Principles and PracticeSpringer Specialist Surgery Serieshttps://doi.org/10.1007/978-3-030-28599-9_21



21. Practical Guidelines for the Treatment of Erectile Dysfunction and Peyronie’s Disease



Julian Marcon1   and Christian G. Stief1


(1)
Urologische Klinik und Poliklinik, Campus Großhadern—Klinikum der Universität München, Munich, Germany

 



 

Julian Marcon

Email: julian.marcon@med.uni-muenchen.de


Keywords

Erectile dysfunctionPeyronie’s diseasePenile prosthesisGraftingPlicationPDE-5 inhibitorsVasoactive agents


Management of Erectile Dysfunction


Male Erection and Erectile Dysfunction


An elaborate interaction of neurological, vascular and psychological factors is necessary for the mechanism of male erection. Sexual arousal, for instance in the form of visual or haptic stimuli, is processed in several parasympathetic loci of the brain, such as the limbic system. Via the mediation of multiple neurotransmitters (e.g. dopamine, oxytocin and serotonin) neural impulses are sent to the parasympathetic erection center (S2–S4). Vegetative nerve fibers run from the spinal erection center through the pelvis and enter, in the form of the cavernous nerves, the penile cavernous bodies. Non-adrenergic non-cholinergic (NANC) synapses release nitric oxide (NO). Additionally, cholinergic signals from nerve fibers stimulate the epithelioid nitric oxide synthase (eNOS) in the corpora, leading to the transformation of l-arginine and oxygen to NO. Consecutively, activation of the guanylyl cyclase by NO causes the enzymatically triggered transformation of 5-guanosine triphosphate (5-GTP) to 3′5′-cyclic guanosine monophosphate (3′5′-cGMP). At the same time, 3′5′-cGMP is cleaved by enzymatic activity of phosphodiesterase-5 (PDE-5). By prostaglandin-mediated activation of the adenylyl cyclase, ATP is converted to cAMP as the other second messenger. Both messengers activate cAMP- and cGMP-dependent protein kinases, which via phosphorylation of target proteins causes cell hyperpolarization, sequestration of intracellular calcium and blockage of calcium influx, leading to a decrease of intracellular calcium. This decrease results in smooth muscle relaxation in the cavernous trabeculae. Arterial blood streams into the cavernous bodies of the penis, causing penile tumescence and an erect state. The increasing corporeal blood volume leads to an occlusion of efferent veins along the tunica albuginea, inducing penile rigidity. In the rigid phase, an intracorporeal pressure of several hundred millimeters of mercury is reached, the ischiocavernosus muscles are synchronously contracted. A continuous transgression of 3′5′-cGMP threshold levels, with simultaneous degradation by PDE-5, supports maintenance of rigidity. Following sexual activity, nerve signaling induces calcium influx into the cell, causing a contraction of smooth muscle tissue, leading to detumescence [1, 2].


Erectile dysfunction (ED) is a functional disorder and is defined as the continuing inability to gain and maintain an erection sufficient for satisfactory sexual activity. Degrees of severity can vary in patients, not least because expectations towards sexuality are individually different. Temporary episodes of ED, often linked to external stress factors and a resulting negative impact of catecholamine secretion appear at least once in a majority of men. While appropriate episodes are commonly self-limited, persevering disorders require medical attention. A primary ED is defined by an occurrence with the beginning of sexual activity, which is usually in early adolescence. Affected men never had normal erections before. A secondary ED is considered a new event at a later time, with normal prior erectile function [3].


Epidemiology and Etiology of ED


In the German Cologne study, ED was prevalent in 19.2% of men between 30 and 80 years. It showed a higher occurrence with increasing age. Affected men often suffered from a greatly decreased quality of life [4]. A multinational study on self-reported ED in 2912 men between 20 and 75 years described an overall prevalence of 16%. ED was associated with other comorbidities such as cardiovascular disease, diabetes, dyslipidemia and depression [5]. Loss of erectile function has both been recognized as an independent risk factor for and an indicator of coronary heart disease [6]. ED can occur in consequence to hormonal disorders (e.g. hypothyroidism or hypogonadism), genital diseases (e.g. Peyronie’s disease), pelvic or penile trauma and psychological reasons. Neurological disorders associated with ED can affect central (e.g. multiple sclerosis) or peripheral nerve structures (e.g. autonomous polyneuropathy). External factors, such as the abuse of drugs, alcohol or tobacco can cause ED. Other etiologies include renal or hepatic impairment and an association with benign prostatic hyperplasia. Iatrogenic causes of ED include a drug-induced etiology and previous pelvic surgery or radiation therapy for malignant tumors. Irritation or damage of the neurovascular bundles along the dorsal capsule of the prostate can subsequently lead to partial or complete ED [1]. More recent data could link ED to chronic prostatitis/chronic pelvic pain syndrome and other comorbidities, such as psoriasis, inflammatory bowel disease and gouty arthritis [3].


Diagnostic Work-Up of ED


Patient history is a crucial aspect in the diagnostic process and should include a detailed description of the individual sexual history. The beginning of sexual development and appropriate experiences should be part of the conversation. The start and duration of ED symptoms should be discussed. Further points should address the patient’s sexual orientation, prior and present relationship status and, if applicable, previous treatments of sexual dysfunction. Information on the current status of libido as well as the presence of normal orgasm and ejaculation are ideally provided by the patient. A history of pelvic or genital trauma should be explored, as well. To objectivize symptoms and to determine the grade of ED severity, especially under ongoing therapy, usage of a standardized questionnaire is recommendable. Initially created for the assessment of medical therapy success, the International Index of Erectile Function (IIEF—currently in the fifth edition) is generally used. The IIEF score addresses frequency, maintenance and quality of erections as well as the patient’s libido and general sexual satisfaction. A shorter six-item version (IIEF-EF) covers erectile function only. It distinguishes between normal erectile function (26–30 points) as well as mild (22–25 points), mild-moderate (17–21 points), moderate (11–16 points) and severe ED (6–10 points). A study analyzing 17 randomized-controlled studies calculated minimal clinically important differences (MCID) for the erectile function domain of the IIEF score as ≥4 points [7, 8]. Another abridged five-item version of the IIEF score (IIEF-5), ranging in severity from no ED (22–25 points) to severe ED (5–7 points), has been validated for the evaluation of ED and is widely used [9].


Other commonly used scoring systems include the Erection Quality Score (EQS), the Erection Hardness Score (EHS) and the Sexual Encounter Profile (SEP), the latter being based on patient diary notes. The occurrence and dynamics of nocturnal penile erections should also be addressed, a lack of which is an indicator of advanced vascular dysfunction. Four to five episodes of penile tumescence, each between 10 and 40 minutes, is considered physiological. The patient’s past medical and surgical history should be addressed, including a history of cardiovascular, neurological and metabolic disorders. In terms of past surgery, prior genital and abdominopelvic operations need to be discussed in particular.


Previous or current medications should be covered in the discussion, as well, as there are several substances with a potentially negative impact on sexuality. This is mostly due to a hormonal disequilibrium in testosterone, gonadotropin and prolactin balances. Among the drugs that are known to be associated with ED are:



  • Antihypertensive drugs (ß-blockers and thiazide diuretics) – > influence on testosterone biosynthesis and enhanced zinc excretion (total and free testosterone levels reduced) [10]



  • Statins (atorvastatin, simvastatin) – > inhibition of testosterone biosynthesis (total and free testosterone levels reduced) [11]



  • Psychopharmaceuticals [12]



    • Tricyclic antidepressants (TCA) (imipramine, desimipramine) -> increase of prolactin levels



    • Selective serotonin reuptake inhibitors (SSRI) (fluoxetine, paroxetine) -> increase of prolactin levels



  • Opioids/sedatives (benzodiazepines) -> central inhibition of gonadotropin release (total testosterone, FSH and LH levels reduced)



  • Antimycotics (clotrimazole, ketoconazole) -> inhibition of testosterone biosynthesis



  • 5α-reductase inhibitors (5-ARI) (finasteride, dutasteride) -> decrease of dihydrotestosterone, increase of estradiol [13]


With respect to external noxae, the role of nicotine abuse is unclear. A small study in a small non-smoking cohort found a positive association between acute nicotine application and decreased sexual function [14]. However, a more recent large meta-analysis, including more than 50,000 cases, could not find an appropriate association between tobacco smoking and ED [15]. Yet, cessation of smoking is regarded as beneficial for erectile function [16]. A recent meta-analysis investigated the effect of alcohol consumption on the risk of ED. Light to moderate consumption (less than 21 drinks per week) was hereby inversely associated with ED, high consumption had no impact on prevalence [17]. Studies on the association of ED and recreational drugs are scarce, one trial suggested a negative effect of illicit drugs (heroin, amphetamine and MDMA) on sexual function [18].


Physical examination should contain an assessment of all organ systems involved in erectile function, including a vascular, hormonal, neurological and urological status. If measurement of heart rate and blood pressure was not performed within the past three to six months, it should be done at first presentation. Abnormalities in these parameters or a suspected vasculogenic ED should be followed up with a cardiologist to estimate the patient’s cardiovascular risk. Indicators of hormonal dysfunction, e.g. a gynecomastia, should also be evaluated [19].


A genital examination should include a palpation of the testes for indurations or suspicious masses (e.g. testicular cancer), measurement of testicular volume and assessment of the penis for abnormalities or deformation (e.g. Peyronie’s disease).


Digital-rectal examination can provide information on the presence of prostatic enlargement or suspicious indurations. An association between lower urinary tract symptoms and sexual dysfunction has been described [20].


Sonography should be incorporated in the diagnostic process. Sonography of the testes may reveal suspicious lesions, a varicocele or hydrocele and can support determination of testicular volume.


With regard to laboratory testing, determination of early morning serum total testosterone, prolactin and luteinizing hormone (LH) can reveal hormonal imbalances. A blood lipid profile and, serum glucose and glycosylated hemoglobin, to exclude metabolic disorders or diabetes should also be part of blood testing. Determination of prostate-specific antigen (PSA) is useful in distinct patient groups [21].


There is a variety of specific examinations, which are not part of the standard work-up of ED.


Intracavernous injection of vasoactive agents to induce erection, with or without performance of color-coded duplex sonography, can be performed to assess concomitant localized disease (e.g. Peyronie’s disease). It is also used to discern psychogenic from organic ED, although results can be inaccurate. Regarding the interpretation of results, a response to low doses can indicate a psychologically or hormonally caused ED, while a response to only high dosages suggests a vascular etiology. A lack of response to high doses can be interpreted as veno-occlusive dysfunction [22]. Neurophysiological assessment of the bulbocavernosus reflex latency (BCR) or pudendal somatosensory evoked potentials (SSEP) can be used when a neurological etiology is suspected. Performance of invasive cavernosography or cavernosometry can be used to evaluate intracavernous pressure and to visualize vascular anomalies. Nowadays, these invasive examinations only play a role in rare, posttraumatic cases, eligible for vascular surgery [23]. Measurement of nocturnal erections using a special electronic device is positive, if a rigidity of 60% on the tip of the penis is recorded on two separate nights. However, it has poor reliability in terms of a distinction between organic and psychogenic ED and is mostly used for forensic purposes, e.g. in men charged with rape [24].


ED and Cardiovascular Disease


As described above, presence of vasculogenic ED should be followed up with an assessment of the cardiovascular system. In this context, ED can play a role in the early detection of cardiovascular disease, even in the absence of cardiac symptoms at that time. A multidisciplinary consensus panel defined three cardiovascular risk groups for patients with ED. This algorithm can also help to determine whether patients with known cardiovascular disease are safe to perform sexually. A main criterion is the patient’s exercise ability. Benchmarks are the ability to walk one mile in 20 minutes or to climb two flights of stairs in ten seconds [25]. Patients in the low-risk group do not bear a significant cardiac risk for sexual activity, e.g. under the following conditions:



  • Mild valvular disease



  • Left ventricular dysfunction/congestive heart failure (NYHA classes I/II)



  • History of successful cardiovascular revascularization (e.g. by stenting, bypass grafting)



  • Asymptomatic controlled hypertension


Patients in the high-risk group are threatened by significantly increased cardiac risk during sexual performance, e.g. under following conditions:



  • Uncontrolled hypertension



  • Severe congestive heart failure (NYHA class IV)



  • Myocardial infarction within the past two weeks without intervention



  • High-risk arrhythmia (e.g. uncontrolled atrial fibrillation, exercise-induced ventricular tachycardia)



  • Unstable or refractory angina pectoris



  • Severe valvular disease


Patients who do not match low- or high-risk categories, are considered to be of indeterminate risk. An additional stress test, in the form of a four-minute Bruce treadmill protocol, without signs of arrhythmia or symptoms is performed to determine the final risk category (low- or high-risk). Patients in the indeterminate-risk group include those with:



  • Myocardial infarction within the past two to eight weeks without intervention



  • Mild to moderate stable angina pectoris



  • Congestive heart failure (NYHA class III)


Patients in the low-risk group can safely continue with sexual activity and initiate ED therapy.


In high-risk patients, treatment should be postponed until a stable cardiac status has been attained. These patients should be referred to a cardiologist to direct further diagnostic assessment and therapy [3, 25, 26].


Conservative Treatment of ED


General Considerations


A variety of conservative treatment options for ED are available, which can be used separately or as part of combination regimens. A first and essential step should address the adjustment of lifestyle and cardiovascular risk factors, such as weight optimization and regulation of an existing arterial hypertension. Patients with poorly controlled diabetes are more at risk to develop ED, an optimization of glycosylated hemoglobin can improve erectile function [27]. Patients with obstructive sleep apnea can preserve or enhance their sexual function by undergoing long-term continuous positive airway pressure (CPAP) treatment [28]. A healthy diet, e.g. the Mediterranean diet with an emphasis on fruits and vegetables, fish, cheese and yogurt, in combination with regular physical exercise is beneficial for erectile function. Moreover, a termination of exposure to external noxae, such as the cessation of smoking should be aimed for. By an adjustment of these factors an improvement of ED symptoms can be achieved. Further, these measures can lead to an improved response to medical therapy [29]. However, patients should be informed that although a modification of lifestyle factors and therapy regimens can yield partial reversibility and have a positive impact on symptoms, in most cases ED cannot be cured. If curable causes of ED are present, they should be addressed prior to further therapy steps. An algorithm regarding conservative and surgical treatment options is provided in a flow diagram in Fig. 21.1.

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Fig. 21.1

Treatment algorithm for ED (modified after [Trottmann et al. 2018])


Potentially Curable Conditions in ED


Hormonal Disorders: Hypogonadism and Hyperprolactinemia


Testosterone is an essential hormone regarding male sexual and reproductive function. Biosynthesis in testicular Leydig cells (95%) and the adrenal cortex (5%) is centrally regulated by a secretion of luteinizing hormone (LH) in the pituitary gland. A negative feedback mechanism prevents overstimulation. As an anabolic steroid testosterone plays an important role in muscle and bone metabolism. It promotes body hair growth and the development of secondary sexual organs. Several steps in erectile physiology are testosterone-dependent: Neural processes on the spinal level, parasympathetic signal transfer in the cavernous bodies and smooth muscle relaxation require sufficient testosterone levels. Insufficiency, present in up to 40% of men above 40 years, can therefore lead to ED and to an apoptosis of smooth muscle cells [30]. Relevant threshold levels of testosterone are reported to range between 2.3 and 3 ng/mL (8–10.4 nmol/l). Testosterone substitution (TS) has been shown to significantly improve PDE-5 inhibitor response in men with ED and testosterone levels lower than 3 ng/mL [31]. Several application forms are available, such as topically applicable gels and intramuscular injections of depot preparations (e.g. testosterone undecanoate every 10–14 weeks). Before treatment is started, patients should undergo a blood test, including determination of PSA, hematocrit, liver function and a lipid profile. Patients should be informed about an elevated cardiovascular risk under TS, high risk patients should be referred to a cardiologist before therapy start. In adult men with late-onset hypogonadism, TS is only to be carried out after failure of conservative lifestyle adjustments. Testosterone-related, inhibitory effects on spermatogenesis should be addressed and therapy held in couples trying to conceive. A digital-rectal examination of the prostate should be performed to rule out irregularities. TS is contraindicated in patients with untreated prostate cancer. Men with a history of the disease, and low risk of tumor recurrence (Gleason score < 8, PSA < 10 ng/mL, pathological stage pT1–2), may be substituted under close-meshed surveillance. TS in prostate cancer patients is regarded as controversial, due to the unclear role of externally applied testosterone as a promoter in prostate cancer. Generally, a follow-up of patients receiving TS at 3, 6 and 12 months should include determination of hematocrit, PSA and testosterone levels, further controls thereafter should be performed annually. If the hematocrit exceeds 50%, substitution should be held until further clarification of etiology. Discontinuation or a dose-reduction should be performed if the hematocrit under therapy reaches levels of 54% or more. Due to the variety of underlying causes of hypogonadism, consultation of an endocrinologist in complex cases can be helpful prior to initiation of TS [32, 33]. In men, prolactin is being excessively secreted before sexual climax, although its exact function remains unknown. Hyperprolactinemia has a negative effect on male sexuality and can either be drug-induced or the result of a prolactinoma. A prolactinoma, either occurring as a micro- (size: <1 cm) or macroprolactinoma (size: >1 cm) is a tumor of the pituitary gland, which produces large amounts of prolactin. Diagnosis is established by measurement of prolactin levels and consecutive magnetic resonance imaging (MRI) of the brain. Treatment consists mostly of medication with dopamine agonists (e.g. 20–40 mg bromocriptine per day). Microsurgery is necessary only in large tumors and has to be followed with life-long medication, as drug discontinuation results in recurrence in a majority of patients [34].



  • In men with testosterone levels lower than 3 ng/mL substitution of testosterone can benefit sexual function and PDE-5i response



  • Careful evaluation of etiology and necessary laboratory testing should be performed prior to substitution



  • In prolactinoma, usually life-long therapy with dopamine agonists is indicated


Psychogenic ED


Numerous psychological factors have to be considered when counseling patients with ED. For one, perception of sexuality is influenced by individual preferences, cultural background and upbringing. Previous negative or unfulfilling sexual experiences, abusive or dysfunctional sexual relationships, can contribute to a negative self-image and result in low sexual confidence. A resulting anxiety with regard to sexual performance is commonly found in men with long-term erectile disorder. Sexual therapy, such as psychodynamic approaches, couple counselling or behavioral therapy, can benefit the treatment of both patients with psychogenic ED and, as an additional supportive component, those with ED of mixed etiology. Regular follow-up with the sexual therapist is important for treatment success. Early involvement of the partner has also been shown to be advantageous. Medical therapy with phosphodiesterase-5-inhibitors (described in detail below) can support psychological counseling. The combination of both approaches has been demonstrated to be superior to medical therapy only in terms of treatment discontinuation [35, 36]. A recent large study found a strong association between major depressive disorder and ED, with the highest risk for untreated patients [37]. However, medical therapy for depression can cause sexual dysfunction, as well [38].



  • Psychological counseling is indicated in patients with psychogenic ED with associated anxiety, depression or self-esteem issues



  • PDE-5i treatment can accompany and support psychological therapy



  • Psychopharmaceuticals can be the cause of sexual dysfunction


Pharmacological Therapy of ED


Phosphodiesterase-5 Inhibitors (PDE-5i)


The gold standard and first-line option in medical treatment of ED is the oral therapy with inhibitors of phosphodiesterase-5 (PDE-5i), an enzyme found in the cavernous smooth muscle tissue [3, 26]. PDE-5 catalyzes the degradation of the neurotransmitter 3′5′-cyclic guanosine monophosphate (3′5′-cGMP). Sexual stimulation results in cavernous NO production and the formation of 3′5′-cGMP, an essential neurotransmitter in erectile physiology. Persistently high levels of 3′5′-cGMP allow for continuous penile rigidity during sexual activity. Reduced 3′5′-cGMP levels can be found both in organic and psychogenic ED. A complete absence of the neurotransmitter can occur after pelvic surgery with bilateral nerve injury or in other cases of neurogenic ED, e.g. autonomous neuropathy in patients with diabetes. When sexual arousal occurs in these men, production of NO is not triggered by cholinergic stimulation and in consequence activation of the guanylate cyclase is missing. As a result, 3′5′-cGMP is not formed, leaving no actionable target for PDE-5i [2]. The introduction of oral PDE-5i substances in the late 1990s has revolutionized ED treatment. Up to that point, ED was mainly treated with intracavernous injections [13]. Sildenafil was the first PDE-5i to be approved in 1998, followed by tadalafil, vardenafil and most recently avanafil. These four main substances have been investigated in large randomized, placebo-controlled trials and were all associated with highly significant increase of erectile function and rates of successful intercourse, measured by commonly used scoring systems (SEP, IIEF). All four substances were shown to have a good long-term efficacy and high patient satisfaction rates [39–42]. All agents have also shown favorable results in distinct populations with ED, e.g. patients with diabetes or with a history of prostatectomy. Other PDE-5i agents were approved in Brazil/Argentina (Lodenafil), South Korea/Russia (Udenafil) and South Korea (Mirodenafil). They all showed significant improvement of erectile function in placebo-controlled trials, however, due to their limitation to these countries, they are not further explored in this chapter [43–45]. PDE-5i have been demonstrated to have similar safety profiles [46]. However, there are some differences regarding bioavailability, enzymatic affinity to PDE-5 and adverse treatment effects. Table 21.1 provides an overview of substances and their pharmacological characteristics. Table 21.2 lists frequent side effects of all PDE-5i. With respect to pharmacokinetics, there are differences in the time to achieve maximum plasma concentrations as well as in their half-life time. Maximum concentrations of PDE-5i are achieved after 30–120 min, with wider ranges for tadalafil [47, 48]. The onset of effect varies between different PDE-5i. The time interval, after which more than half of the patients report an effect, ranges between 10 and 30 min. The earliest response was hereby reported for avanafil. There is also variation in the duration of effect, with sildenafil and vardenafil lasting shorter (both about 8 h) than avanafil (up to 17 h). Tadalafil outlasts all other PDE-5i regarding effect duration with up to 36 h of response. Due to an alimentary influence in terms of reabsorption and a potential delay in the onset of effect, sildenafil should not be taken with meals. While there is no comparable influence on the metabolization of tadalafil, the effect of vardenafil and avanafil may be delayed or decreased, through reduced intestinal absorption, by fat-rich food [49, 50]. With regard to pharmacodynamics, the diverse affinity to the target enzyme is responsible for the different dosages and the varying onset and duration of effect. Inhibition of other PDE enzymes can lead to, usually self-limited, side effects, such as the impairment of color vision by PDE-6 inhibition caused by sildenafil. Hypotension can occur by inhibition of PDE-1 after vardenafil administration. Besides cardiovascular illness (described below), contraindications to PDE-5i comprise existing ophthalmological conditions like a retinitis pigmentosa or a non-arteritic anterior ischemic optic neuropathy (NAION). With respect to drug interactions, combination with α-blockers, e.g. in patients with male lower urinary tract symptoms (LUTS) should be carefully pondered, as hypotensive episodes may occur. As described below, due to the risk of hypotensive crisis, simultaneous use of nitroglycerines is contraindicated. Caution must be taken in patients with hematologic diseases, such as sickle cell anemia or leukemia, as there is an elevated risk of priapism. There is currently no evidence of a tolerance effect to PDE-5i. A gradual loss of effect during treatment may be due to progression or emergence of causal conditions, like vascular disease or diabetes. Regardless of the high long-term efficacy of PDE-5i, more than half of responding patients eventually drop out of therapy [51]. Reasons for PDE-5i discontinuation include “drug-dependent sexuality” (31%) or financial aspects (approximately 30%). In about 27% of cases, unassisted intercourse was possible with time [52]. PDE-5i are mostly used in an on-demand setting, with an intake before planned sexual activity. Tadalafil is the only substance approved for administration in a low daily dosage (2.5–5 mg per day). It has been associated with higher IIEF scores compared to an on-demand regimen [53]. Daily dosing benefits patients in terms of sexual spontaneity, while a permanent improvement of the cavernous bodies could not be shown [54].



  • PDE-5i are established as a first-line therapy in patients with ED of different etiologies



  • Long-term results and patient satisfaction rates are high



  • A high percentage of patients discontinues PDE-5i due to an unwillingness towards medication, spontaneous cure or financial reasons



  • Oral PDE-5i therapy requires functioning parasympathetic nerve fiber signaling in the cavernous tissue and intracavernosal presence of 3′5′-cGMP



  • Differences in pharmacokinetics/pharmacodynamics and the side effect profile of substances should be minded before treatment start




Table 21.1

Pharmacological properties of the four main PDE-5i (modified after [55])














































 

Sildenafil

Tadalafil

Vardenafil

Avanafil

Dosage

25/50/100 mg

5/10/20 mg

5/10/20 mg

50/100/200 mg


Tmax

30–120 min

120 min

30–120 min

15–30 min


Half-life time

3–5 h

17.5 h

4–6 h

6–17 h


Recommended administration before sexual activity

60 min

>30 min

25–60 min

15–30 min


Nutritional impact

Yes

No

Yes (fatty meals)

Yes (fatty meals)




Table 21.2

Adverse event profile of PDE-5i (modified after [55])
































































 

Sildenafil

Tadalafil

Vardenafil

Avanafil

Flushing

10–19%

1–3%

8–11%

3–10%


Headache

16–28%

3–15%

16%

9.3%


Dyspepsia

3–17%

1–10%

3–4%

≥1%


Rhinitis

–

–

9%

–


Myalgia

<2–4%

1–4%

<2%

<1%


Impaired color vision

1–11%

<0.1%

<2%

–


Back pain

2–4%

1%

2%

1–3%


Dizziness

2–4%

1%

2%

≥1–2%


Non-Responders to PDE-5i


Approximately 30–40% of all patients fail to show adequate response to PDE-5i treatment. Real non-response is hereby characterized by severe impairment of cavernous smooth muscle tissue, either caused by damage of neural structures or veno-occlusive dysfunction. Non-response to PDE-5i can also be the result of insufficient patient education. Patients should be informed on the necessity of sexual arousal in order for the substances to take effect. The release of pro-erectile NO from parasympathetic nerve fibers in the cavernous bodies requires an according stimulus. Among all PDE-5i agents, sildenafil is the most sensitive substance to simultaneous food intake, while metabolization of vardenafil and avanafil are mostly influenced by grassy foods. Tadalafil is the most resistant PDE-5i regarding effect delay by food. The nutritional effect on gastrointestinal reabsorption should be communicated with the patient in order to choose the right drug. Appropriate scheduling of food intake is key [49, 50]. Selection of an adequate dose is also important for therapy success. Frustration with treatment can be a consequence of a time interval either too short or too long between oral intake and attempts of sexual activity. Most substances require an onset of effect of 15–30 min and, due to the different half-life kinetics of PDE-5i, not all substances are effective for the same periods of time. Patients may benefit from a “trial session”, taking the drug once or multiple times before masturbation attempts thus allowing evaluation of the effect and potential adverse events. This is often regarded as less stressful, compared to sexual activity with a partner. Furthermore, an optimization of comorbidities, such as treatment of a relevant hypogonadism, diabetes or hypertension, should always be performed. Administration of statins in PDE-5i non-responders showed favorable results regarding sexual function [56]. If multiple drug intakes under optimized conditions failed to show adequate results, switching to a different substance may be helpful [57]. Doubling the maximum dose of sildenafil (200 mg) in a salvage setting was successful in approximately every fourth patient with ED in a non-responder cohort [58]. Switching to a daily dosing regimen, as opposed to an on-demand strategy, was demonstrated to be beneficial in non-responders to several PDE-5i substances. In a group of hypertensive patients with ED, more than a third could be rescued with daily dosing of vardenafil [59, 60].



  • Real non-response to PDE-5i can indicate severe vascular and/or nerve damage



  • Thorough patient counseling before PDE-5i treatment is important and can prevent frustrating experiences



  • Statins have shown beneficial effect in PDE-5i non-responders



  • Comorbidities should be sufficiently treated



  • Daily dosing, doubling the maximum dose and substance switching are possible salvage strategies in non-responders


PDE5-i in Patients with Male LUTS


In the recent years, PDE-5i gained significance in the treatment of BPH/male LUTS. The usage of daily tadalafil was demonstrated to have a favorable effect on sexuality, storage and voiding LUTS. In this context, the effect of tadalafil is comparable to α-blockers. A combination of α-blockers with PDE-5i seems to be even more beneficial, without elevated risk of side effects [61]. A pooled data analysis investigated multiple placebo-controlled, randomized studies including over 1000 patients with simultaneous ED and LUTS. Significant improvement of both International Prostate Symptom Score (IPSS), objectivizing irritative and obstructive voiding symptoms, and IIEF-EF was shown. Daily dosage of tadalafil for LUTS is 5 mg [62].



  • Daily application of tadalafil 5 mg is beneficial for both ED and LUTS


PDE-5i in Cardiovascular Risk Patients


Use of PDE-5i is not associated with an elevated risk of myocardial infarction. However, PDE-5i must not be administered in patients with a history of myocardial infarction, apoplexy or severe arrhythmia within the past 6 months. Other contraindications include unstable angina pectoris, a severe congestive heart failure (NYHA class IV), as well as significant hypo- (<90/50 mmHg) or hypertension (>170/100 mmHg). Due to the risk of life-threatening hypotension, the use of organic nitrates (e.g. nitroglycerine, isosorbide mononitrate) is strictly contraindicated. If chest pain occurs in patients after oral ingestion of PDE-5i, nitroglycerine has to be deferred for at least 12 (Avanafil), 24 (Sildenafil) or 48 h (Tadalafil). The concomitant use of antihypertensive drugs is regarded as safe [3].



  • Absolute contraindications to PDE-5i (Nitroglycerines!) must be excluded before application


ED Following Pelvic Surgery


Pelvic surgeries make up an essential part of the management of patients with genitourinary or colorectal neoplasms. This includes procedures such as radical prostatectomy (RP) for prostate cancer, radical cystoprostatectomy for urothelial carcinoma of the bladder and anterior rectal resection for colorectal carcinoma. A common adverse effect of pelvic surgery is the irritation or injury of the cavernous nerves, resulting in neurapraxia and the loss of nocturnal and sexually caused erections. This leads to a hypoxic environment within the cavernous bodies, causing an accumulation of transforming growth factor ß1 (TGF-ß1) and endothelin 1 as well as a reduction of intracavernous PGE1. These changes eventually cause a fibrotic transformation of the cavernous bodies, resulting in an apoptosis of smooth muscle tissue. In urologic oncology, RP is the most commonly performed pelvic surgery. Postoperative potency rates after radical prostatectomy for prostate cancer are approximately 20–30% [63]. For one thing, the grade of deterioration in terms of erectile function after RP is determined by the extent of intraoperative nerve sparing, with the best outcomes observed in bilateral nerve-sparing approaches. Furthermore, patient age and comorbidities (e.g. arterial hypertension, diabetes) have an effect on the postoperative functional outcome, whereas the best results could be demonstrated for healthy patients under the age of 65. Penile rehabilitation is reported to be most common in the first 18 months after surgery, but can be observed up to four years postoperatively. There are several medical regimens for penile rehabilitation after pelvic surgery: Oral PDE-5i medication, local PGE1 therapy and combination treatments of both approaches are used, a decisive factor for therapy success is an early start of rehabilitation after, or even before, surgery. A study comparing early (two months) versus delayed (seven months) penile rehabilitation after RP could show significantly better erectile function in terms of IIEF score (22 vs. 16) and attained erections in the early rehabilitation group, both with (86% vs. 45%) and without (58% vs. 30%) medical PDE-5i support [64]. A recent meta-analysis including seven randomized-controlled trials could confirm an improvement of drug-assisted sexual performance for PDE-5i treatment (daily and on-demand). It could not find a benefit for unassisted erectile function following PDE-5i therapy and a wash-out period. A delay of treatment by six months does not seem to have a negative effect on assisted erectile function [65]. An improved preservation of cavernous tissue, i.e. penile length, was reported after nine months of daily therapy with tadalafil [66].



  • A possible advantage of on-demand versus daily treatment regimens is indicated for different PDE-5i in the post-RP setting



  • There is no conclusive evidence that a delay of postoperative PDE-5i medication negatively impacts the rate of drug-assisted erectile function



  • Results on the recovery of unassisted erectile function remain controversial



  • Daily tadalafil intake after prostatectomy may benefit penile tissue preservation


Alternative Oral Substances


Yohimbine


The alkaloid yohimbine has long been used in patients with psychogenic ED. It is derived from the bark of Pausinystalia yohimbe , a tree found in Central Africa. It is available as tablets, containing the active compound yohimbine hydrochloride. Yohimbine is declared to be an α2-antagonist and is further reported to interact with vasointestinal polypeptide, dopamine and choline receptors, yet, the exact mechanism of action remains unknown. Given functional erectile mechanics, a positive effect on erectile function, through an influence on central mechanisms, has been described [67, 68]. A placebo-controlled study on 48 patients with ED showed a satisfactory improvement in 31% of cases after ten weeks of treatment with yohimbine [69]. Adverse events comprise fluctuations in blood pressure, increased sweating, episodes of anxiety and mania as well as headaches. In patients undergoing treatment with psychopharmaceutic agents or stimulants of the central nervous system, it is contraindicated. Most regimens use oral doses of 5–10 mg, taken three times per day. Due to the various side effects and unclear mode of action, treatment with yohimbine is reserved for selected patients, especially younger patients with psychogenic ED.


Red Korean Ginseng


Panax ginseng is a plant associated with positive effects on male sexuality in traditional Asian medicine [70]. A high concentration of the postulated active ingredients, called saponins, is especially found in red Korean ginseng (KRG). The mode of action is presumably associated with an antioxidant effect as well as an increase of endothelial NO synthesis. A study treated 90 patients with psychogenic ED with 1800 mg of KRG per day versus placebo. Results, based on interviews of patients and their partners, showed an increase of patient satisfaction and rigidity with comparison to the placebo group [71]. Another double-blind study examined the therapeutic effect of daily 2700 mg KRG in a cohort of 45 patients with ED of different etiologies over a period of eight weeks. Results showed significantly higher IIEF scores and higher rates of patient satisfaction in the treatment group [72]. Reported adverse events included dyspepsia, headaches and insomnia. Caution is advised regarding usage of KRG in diabetic patients, due to possible events of hypoglycemia. Regardless of a missing guideline recommendation, usage of KRG seems to be a safe additional treatment option in mild to moderate ED.


L-Arginine and L-Citrulline


L-arginine is an essential amino acid and a donor of NO. Several studies have investigated its beneficial role in ED treatment. In a prospective, randomized and double-blind study 50 patients with organic and complete ED were treated with 5 g of daily l-arginine for a total period of six weeks. The intervention group hereby showed a significantly higher percentage of patients able to perform sexual intercourse (31% vs. 12% in the placebo group) [73]. A newer study examined the use of a substance compound of l-arginine and pine bark extract in 124 patients with moderate ED over a surveillance period of six months. The authors reported a highly significant improvement in erectile function, with an increase of IIEF-EF of nearly 12 points (versus 4 points in the placebo group) after six months. The believability of these findings, however, remains questionable, as this increase would exceed high-dose PDE-5i treatment [74]. L-citrulline is a precursor amino acid of l-arginine in the urea cycle. In the cavernous bodies, it is a by-product in the reaction of l-arginine and oxygen to nitric oxide. It has been evaluated for its potential pro-erectile effect. A single-blind study including men with mild ED receiving 1.5 g of l-citrulline per day, over a period of one month, showed significantly improved erectile function in 50% of the men (versus roughly 8% in the placebo group) and a significantly superior percentage of men able to perform sexually [75].


Apart from mild, asymptomatic hypotensive changes of blood pressure, there were no reported side effects.



  • Yohimbine can be considered in selected cases of psychogenic ED, however, the side effect profile has to be kept in mind (e.g. anxiety, blood pressure fluctuations)



  • Red Korean ginseng has been reported to show favorable effects on rigidity and can be used as a supplementary medication in ED, however, with caution in diabetic patients



  • Doses of 3–5 g per day for l-arginine and 1.5 g per day for l-citrulline remain possible supplementary therapy options in men with mild to moderate ED.


Mechanical Treatments


Vacuum Erection Devices (VED) and Constriction Rings


VEDs are plastic cylinders, which are placed over the penis and pressed onto the pubic bone, with the application of lubricant on the cylinder rim causing an airtight seal. The creation of a vacuum by an internal or connected pump leads to a passive blood influx into the cavernous bodies of the penis. Simultaneous use of a constriction ring at the penile basis prevents an immediate venous drain of the corpora. VEDs can both be used in patients with contraindications to medical or operative therapy of ED and as part of combination regimens, e.g. with PDE-5i. The latter have shown superiority compared to VED usage only in terms of higher rates of successful intercourse (70 vs. 46.6%). Application of a VED can help to achieve satisfactory intercourse in up to 90% of all ED cases, with patient satisfaction ranging between 27 and 94%. The majority of patients discontinues VED treatment at some point, mostly due to the feeling of a passively induced erection. Because of the corpora filling with venous, deoxygenated blood, erections may feel cooler, the penis can even appear cyanotic. Also, the penile base often lacks rigidity and therefore stability. Other adverse events of VEDs may include dysesthesia, pain, petechiae and hematoma as well as ejaculation disorders due to the constriction ring. The latter makes VEDs an improper option for couples trying to conceive. By removing the penis ring shortly after sexual activity, serious side effects such as skin necrosis can be prevented. Altogether, use of VEDs should not exceed half an hour. Patients with bleeding disorders or those receiving anticoagulation should refrain from usage of VEDs [76, 77].



  • VEDs and constriction rings are a helpful mechanical addition to pharmacological treatment regimens



  • High discontinuation rates are mostly due to uncomfortable, not fully rigid, erections


Low-Intensity Extracorporeal Shock Wave Therapy


The application of low-intensity extracorporeal shock wave therapy (LI-ESWT) is proposed to have a positive impact on neoangiogenesis, Schwann cell activation and stem cell recruitment. The mechanism of action is an induction of shear stress and damage to the endothelium by incoming shock waves. A neoangiogenic effect of shock wave therapy could be demonstrated in preclinical studies [78, 79]. LI-ESWT has previously been used in the treatment of bone fractures and cardiovascular disease [80]. The underlying technology differs between available devices. Its application on the cavernous bodies has been shown to yield short-term effect in PDE-5i responders in first studies [81, 82]. Moreover, evidence suggests that LI-ESWT may trigger therapy response in prior PDE-5i non-responders [80, 83]. Two recently published meta-analyses described increases of IIEF scores (one of them a significant increase) overall for treatment groups in included studies [84, 85]. However, due to limitations in the methodology of both analyses, these results have to be viewed with caution. Possible adverse effects have yet to be evaluated in further studies. Reported shock wave intensities range between 0.09 and 0.25 mJ/mm2, the number of applied pulses per treatment ranges from 1500 to 5000. Application to multiple sites may be favorable, but results remain inconclusive [85].



  • The hypothesized triggering of nerve regeneration deems LI-ESWT an innovative and potentially curable treatment option



  • Heterogeneity in technology and study design make it difficult to determine the role of LI-ESWT in ED treatment



  • Further long-term results from randomized, sham-controlled trials, using consistent study protocols, are warranted


Secondary Treatment Options


Prostaglandin E1 Analogues


In PDE-5i non-responders or in patients undergoing treatment with NO donors for cardiovascular conditions application of locally vasoactive agents remains an established second-line therapy option [3, 26]. Alprostadil is an analogue of prostaglandin E1 (PGE1). It can cause cavernous smooth muscle relaxation independently from PDE-5 inhibition and presence of NO, by activating the adenylyl cyclase, leading to an increase of cAMP and to an outward transfer of intracellular calcium. The fact, that sexual arousal is not necessary for a PGE1-induced erection, allows the application in a diagnostic setting to objectively evaluate erectile function, in order to discriminate between neurogenic and vascular ED.


Intraurethral and Topical Application of PGE1 Analogues


Alprostadil can be introduced in the form of a pellet into the urethra using a special applicator (Medicated Urethral System for Erection, MUSE™). Urethral suppository doses range from 125 to 1000 μg. Onset of effect can be expected after 5–10 min, while the effect usually lasts for up to an hour. Therapy efficacy, in terms of at least one reported successful intercourse, could be registered in about 65% of patients vs. 19% receiving placebo in an initial study [86]. Transurethral alprostadil application has been shown to be significantly less efficacious compared to intracavernous injection. Local pain and hypotensive symptoms, such as headache and dizziness, are possible adverse events of PGE1 analogues and may occur in about 29–42% and 2–14%, respectively. Local application can furthermore cause urethral bleeding or urinary tract infections in 5% and under 1%, respectively [87]. Application can be supported by using a constriction ring around the penile basis. A cream containing alprostadil (brand name Vitaros®) can be used for topical application on the glans penis at doses of 200–300 μg. A double-blind study could demonstrate significant superiority of topical alprostadil compared to placebo in men with ED of all severity grades. With only rare systemic events, the most common side effects are local erythema and pain [88]. Both topical and transurethral application forms are an alternative to patients refusing more invasive intracavernous injections. Patient counseling should, however, mention the inferior efficacy of these less invasive options compared to injection therapy. Also, the option to combine these treatments with oral PDE-5i therapy or mechanical devices, should be discussed.



  • Topical and intraurethral alprostadil are suitable options for patients unwilling to perform injection therapy



  • Compared to PGE1 injection, topical and intraurethral application forms are less effective



  • Combination with mechanical or oral treatment strategies should be discussed

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Mar 7, 2021 | Posted by in UROLOGY | Comments Off on Guidelines for the Treatment of Erectile Dysfunction and Peyronie’s Disease

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