Fig. 13.1
a, b Anatomy of the penis. © CCF 2003, 2005. Reprinted with permission
The International Society of Impotence Research has classified ED broadly into organic and psychogenic ED [9] (Table 13.1). Organic ED can be the result of vascular, neurologic, or endocrinologic ailments. Arterial insufficiency and/or veno-occlusive dysfunction are the major components of vascular ED. Common risk factors associated with arterial insufficiency include hypertension, dyslipidemia, smoking, diabetes mellitus (DM), perineal or pelvic trauma, and pelvic irradiation [10]. The overlap in risk factors between ED and CVD, together with a higher incidence of elsewhere arterial lesions in impotent men than the general population, has led researchers to consider ED to be a manifestation of generalized or focal arterial disease [11]. Failure of adequate venous occlusion can be seen in patients with Peyronie’s disease, DM, or in patients with a traumatic history to the tunica albuginea such as penile fracture.
Table 13.1
Classification of male ED
Organic | Psychogenic |
|---|---|
Vascular Arterial Venous Mixed Neurogenic Endocrinologic | Generalized Absence/decline in sexual reusability Chronic disorder of sexual intimacy Situational Partner-related Performance-related Psychological distress- or adjustment-related |
A neurologic origin is encountered in about 10–19% of ED cases [12]. It commonly results from iatrogenic nerve injury that occurs with pelvic and retroperitoneal surgeries. Other traumatic and medical conditions such as pelvic fractures, spinal cord injuries, Parkinson’s disease, stroke, spina bifida, disc herniation, syringomyelia, transverse myelitis, and multiple sclerosis are also associated with neurogenic ED. Hypogonadism is the most recognized endocrine condition related to ED. Testosterone increases sexual desire, frequency of sexual acts, and occurrence of nocturnal erections [13]. Despite this, treatment of hypogonadal impotent men with exogenous testosterone reportedly improved their libido with little effect on potency [14]. Previously, about 90% of impotent men were thought to suffer from psychogenic ED [15]. Such belief has been replaced by an understanding that ED originates from either functional or physical circumstances. Psychogenic ED may be from an exaggerated sympathetic outflow as few clinical studies have demonstrated higher levels of serum norepinephrine in patients with psychogenic ED than in normal controls or patients with vascular ED [16].
Case Scenario
A 47-year-old gentleman presents to a men’s health clinic complaining of erectile dysfunction that he has been noticing over the past 3 months. He reports weak erections, early detumescence, and much lower frequency of weaker morning erections. He was diagnosed with DM 4 years earlier and is on oral hypoglycemic agents with suboptimal control in his blood sugar as evidenced from a recent HbA1c of 8.3%. He also has had hypertension for 8 years. Five months ago, his primary care physician added a beta-blocker (atenolol) to his antihypertensive regimen. He denies any issues with ejaculation or with sexual desire. He is a non-smoker. On physical examination, his body mass index (BMI) is 27 kg/m2. He has normal secondary sexual characteristics. His abdomen is soft and lax with no palpable masses and intact hernia orifices. His genital examination reveals a normal penis and urethral orifice with no palpable penile plaques. Both testes are of normal size and consistency. No other scrotal abnormalities have been detected. Peripheral pulses are symmetrically palpable.
Initial evaluation of a patient complaining of ED should entail a sexual, medical, and psychosocial history together with a focused physical examination of the abdomen, genitalia, and lower extremity pulsations [1]. Details such as onset, duration, progression, and sustainability of symptoms with different sexual stimulants are very important. Additionally, the frequency and strength of morning erections and the patient’s ability to ejaculate during sexual encounters would help the clinician differentiate an organic from a psychogenic origin of symptoms (Table 13.2). The nature of symptoms has to be explored such as whether the patient experiences weak erections from the start, or whether he is not able to maintain an erection. Such info would help differentiate between an arterial or venous etiology. Presence or absence of reported penile pain or deviation during intercourse would suggest the presence of Peyronie’s disease. Hypogonadism is also suspected when symptoms of decreased sexual desire, generalized fatigability, sleepiness, and lack of concentration exist. The patient’s past medical, surgical, medication, social, and habitual history should be collected in detail searching for risk factors for the development of ED. This permits an understanding of the circumstances leading to ED but more importantly allows for the identification of modifiable risk factors, such as the use of medications known to alter erection (as in our clinical scenario). A complete list of risk factors is presented in Table 13.3.
Table 13.2
Factors differentiating between organic and pyscogenic ED
Organic ED | Psychogenic ED | |
|---|---|---|
Onset | Gradual | Sudden |
Duration | Long | Short |
Progression | Progressive | Intermittent |
Reaction to different sexual stimuli | Persistent | Inconsistent |
Morning erections | Weak, less frequent | Normal |
Ejaculation | Normal | Difficult/absent |
Psychosocial problems | Secondary to ED | Long history |
Anxiety | Secondary to ED | Primary |
Table 13.3
Risk factors for erectile dysfunction
Risk factors for erectile dysfunction |
|---|
Medical history: Diabetes Mellitus Hypertension Coronary artery disease Cerebrovascular disease Obesity Hypogonadism Parkinson’s disease Multiple sclerosis Pelvic/spinal cord injury |
Surgical history: Radical pelvic surgery (prostatectomy, cystectomy, low anterior resection) Retroperitoneal surgery (lymph node dissection, aortic aneurysm, resections) Orchiectomy |
Medications/treatments: Diuretics (Hydrochlorothiazide, Furosemide) Antihypertensives (Propranolol, Atenolol, Metoprolol, labetalol, Enalapril, Captopril, Methyldopa, Verapamil, Nifedipine, Hydralazine) Antihistamines (Dimenhydrinate, Diphenhydramine, Hydroxyzine, Meclizine, Promethazine) Antidepressants (Fluoxetine, Sertraline, Amitriptyline, Clomipramine, Buspirone, Diazepam, Imipramine, Lorazepam) Parkinson’s disease drugs (Bromocriptine, Levodopa, Benztropine) Antiarrhythmics (Disopyramide) Muscle relaxants (Cyclobenzaprine, Orphenadrine) Nonsteroidal anti-inflammatory drugs Histamine H2-receptor antagonists (Cimetidine, Nizatidine, Ranitidine) Chemotherapy medications (Busulfan, Cyclophosphamide) Prostate cancer drugs (Flutamide, Leuprolide) Pelvic and retroperitoneal radiotherapy |
Habitual use of the following substances: Amphetamines Barbiturates Cocaine Marijuana Methadone Nicotine Opiates |
Aiming to collect more objective information, a number of questionnaires have been developed to assist clinicians in their evaluation of patients. The most commonly used questionnaires include the International Index of Erectile Function (IIEF) and the Sexual Encounter Profile (SEP).
The IIEF is a 15-question tool that evaluates five domains of a sexual encounter: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and global satisfaction [17]. It has been standardized and validated in several languages [17] and is commonly used to monitor the degree of satisfaction to different therapeutic agents. A shorter version of the IIEF, termed the IIEF-5, has been developed as a more efficient sexual health inventory for men [18]. SEP, on the other hand, is a simpler method commonly used in clinical trials involving pharmacologic therapies for ED. It mimics a diary where men respond to a series of yes or no questions after each sexual attempt [19]. Specifically, the questions are as follows: Q1—Were you able to insert your penis into your partner’s vagina? and Q2—Did your erection last long enough for you to have successful intercourse?
Physical examination is initiated with an assessment of body habitus and secondary sexual characteristics. Obesity is a well-known risk factor for ED and has been significantly linked to hypogonadism. Blood pressure and heart rate should be measured in every patient. Abdominal examination then follows in the standard manner with special attention on scars of prior surgeries on inspection, presence of masses or hernias on palpation, and an audible bruit on auscultation. Penile anatomy is fully considered during genital examination. Circumcision status, urethral orifice location, and presence of penile plaques during palpation should be noted. If penile deviation is reported, the patient should be asked to take pictures of his erect penis to estimate the angle of deviation. Scrotal examination for assessment of testicular size and consistency and presence of other scrotal pathology is then performed. A rectal examination should be performed in every patient older than 40 years. Finally, lower extremity examination looking for lower limb edema and abnormal peripheral pulses is important as it would suggest cardiac and vascular disease.
Management of Patients with Erectile Dysfunction
Workup
Information gathered during the initial encounter should provide insight on the type and extent of laboratory and radiologic investigations to be ordered. The International Society for Sexual Medicine recommends a fasting glucose, lipid profile, and, in select cases, a hormone profile in patients presenting with ED [20]. Men reporting a hypoactive desire or who are known to have DM should be tested and potentially treated for low testosterone levels [21]. When low serum testosterone is detected initially, a complete hormonal evaluation is warranted to differentiate between primary and secondary hypogonadism. The third Princeton Consensus Conference on sexual dysfunction and cardiac risk recommends evaluation of cardiovascular risk in men with ED and no known CVD. The aim is to assess patients’ exercise ability to ensure a cardiovascular health that is consistent with the physical demands of sexual activity before prescribing treatment for ED. Moreover, the consensus highlights the value of early detection of cardiovascular risk in an asymptomatic patient who would benefit from cardiovascular risk reduction [22] (Fig. 13.2).
Fig. 13.2
Algorithm for evaluation of cardiovascular risk in patients with ED and no known history of CVD. LVD left ventricular dilatation, CHF congestive heart failure; NYHA New York Heart Association; CAD coronary artery disease; MI myocardial infarction
Specialized Diagnostic Tests
The intracavernous injection test is seldom performed alone as it provides limited information about the penile vascular status. A rigid erectile response occurring about 10 min after an intracavernosal injection of a vasodilator substance and lasting for 30 min generally indicates a functional, but not necessarily normal, erection. It serves, however, as a prognostic tool that would advocate patients who will respond to an intracavernous injection program. Moreover, it helps in the assessment of the angle of penile curvature in patients with Peyronie’s disease.
Penile duplex ultrasonography is indicated in patients who fail in oral therapy, or who have a history of penile or pelvic trauma, Peyronie’s disease or other suspected vascular causes for their ED. During this procedure, the penis is assessed songraphically looking for echogenic areas that would represent penile fibrosis. Blood flow inside the corpora cavernosa is then measured before and after the instillation of a vasodilator, allowing the differentiation between arterial and venous insufficiency. A peak systolic velocity lower than 25 cm/s is a generally agreed upon value indicating arterial insufficiency. End-diastolic velocity serves as a reflection of venous outflow; venous leakage is ruled out when the velocity is <5 cm/s.
Nocturnal penile tumescence testing is less commonly performed to differentiate between organic and psychogenic ED. It involves placing several bands around the penis, which are connected to a device capable of sensing and measuring the change in compression pressure that occurs with erection. Inadequate or absent nocturnal erections suggest organic dysfunction, whereas a normal result indicates a high likelihood of a psychogenic etiology [23].
Angiography was earlier utilized in the evaluation of patients with ED. Currently, it is rarely performed and its role is limited to patients with traumatic vascular injuries resulting in ED who are candidates for vascular reconstruction [24].
Treatment
Management of ED is primarily aimed at identification and treatment of its etiologic factors rather than treating its symptoms alone. Modifiable risk factors such as lifestyle habits or medication use should be reversed, when possible, either before or at the same time as specific therapy is initiated. A systematized treatment strategy is instituted that depends on efficacy, safety, and invasiveness, as well as cost and patient preference. As such, a thorough discussion about the different available options is necessary.
First-Line Therapy
Oral Pharmacotherapy
PDE5 inhibitors (PDE5i) are the most common form of treatment used in patients with ED. Their concept is simple: inhibit the catalytic activity of PDE5 enzyme thereby maintaining the cGMP-mediated smooth muscle relaxation and increase in penile blood flow [25]. Several potent PDE5i exist, namely sildenafil, tadalafil, vardenafil, and avanafil.
Sildenafil
Launched in 1998, sildenafil was the first PDE5i available in the market. It is effective 30–60 min after administration, and its efficacy lasts for up to 12 h. Its absorption is prolonged with heavy, fatty meals and is hence recommended to be taken on an empty stomach. It is available in doses of 25, 50, and 100 mg, however, a starting dose of 50 mg is recommended, which can be modified according to the patient’s response and side effects. The efficacy of sildenafil has been initially reported in a dose–response study where improved erections were detected in 56, 77, and 84% of patients with ED taking 25, 50, and 100 mg, respectively [26]. These results were later reproduced in several studies utilizing various patient sexual function questionnaires [27, 28].
The efficacy of sildenafil in almost every subgroup of patients with ED has been successfully established. Patients with diabetes reported a 66.6% improvement in erections compared to 28.6% of men taking placebo [29]. Furthermore, 71% of patients with concomitant CVD reported improved erections when taking Sildenafil compared with 24% taking placebo [30].
Tadalafil
Tadalafil was approved as a treatment alternative for ED in 2003. It has a 30-min onset of action while its efficacy is maintained for up to 36 h [31]. Its absorption is not affected by food intake. Tadalafil is available in 10 and 20 mg on-demand doses and 5 mg once-daily dose.
Again, dose–response premarketing studies confirmed the efficacy of tadalafil, where after 12 weeks of treatment, improved erections were reported by 67% of patients taking a 10 mg dose and 81% of patients taking a 20 mg dose in comparison with 35% of men receiving placebo [31]. Postmarketing studies confirmed and reproduced this efficacy with an improvement in scores of IIEF, SEP2, and SEP3 [32]. Recent interest in the chronic use of once-daily dose of tadalafil emerged after reports showing comparable efficacy to on-demand regimens were released. One randomized study (n = 145) has even reported a significantly higher IIEF score in patients receiving daily compared to on-demand tadalafil [33]. Another randomized double-blind clinical trial, using five and 10 mg/day tadalafil for 12 weeks (n = 268) have shown that daily dosing was well tolerated and significantly improved erectile function. These results make tadalafil 5 mg once-daily dose a reasonable alternative to men concerned about spontaneity in sexual activity. Furthermore, tadalafil 5 mg has been recently approved by the US Food and Drug Administration (FDA) as a treatment alternative for men with benign prostatic hyperplasia based on meaningful improvement in obstructive lower urinary tract symptoms [34–36].
Vardenafil
Vardenafil became commercially available in 2003. Its efficacy is initiated 30 min from administration, after which it remains effective for about 8 h. Like sildenafil, vardenafil has to be taken on an empty stomach as its absorption is reduced by heavy, fatty meals. 5, 10, and 20 mg doses have been approved for on-demand treatment of ED. Animal studies have reported a tenfold more potent efficacy in PDE5i inhibition for vardenafil in comparison with sildenafil [37, 38]; this, however, was not translated into clinical efficacy in human trials [39].
Of men with ED, 66, 76, and 80% reported an improvement in erectile function after the administration of 5, 10, and 20 mg vardenafil, respectively, compared with 30% of men receiving placebo [40]. Recently, an orodispersible (ODT) form of vardenafil has been released, offering a convenient alternative that can be taken irrespective of food intake and exhibiting better bioavailability over film-coated tablets [41]. The efficacy of vardenafil ODT did not seem to differ from the regular formulation as demonstrated by several randomized controlled clinical trials [41–44].
Avanafil
Avanafil, the more recent member of the PDE5i group, has been FDA approved since 2012. Its very fast onset of action compared with the other PDE5i proves advantageous. After ingestion, avanafil reaches its maximum concentration in about 30–45 min, providing the ability to engage in sexual activity within 15 min of consumption [45]. Available doses are 100 and 200 mg, taken irrespective of food intake. A meta-analysis of four randomized clinical trials, involving a total of 1381 patients revealed a greater efficacy to avanafil 100 mg over placebo for successful vaginal penetration and intercourse and a less likelihood of dropout due to an adverse event [46].
Side Effects and Safety Precautions
Adverse event profiles of PDE5i are generally similar and include headache, flushing, nasal congestion, dyspepsia, and myalgia, which result from capillary smooth muscle dilatation in other parts of the body. More formula-specific side effects stem from individual drug cross-reactivity with other phosphodiesterases. Eleven PDE isoenzymes have been identified in the human body. PDE6, located in the retina, plays an important role in the transfer of light into nerve impulses. Inhibition of this enzyme, seen principally with sildenafil and vardenafil causes disturbances in color perception [26]. Tadalafil, on the other hand, cross-reacts with PDE11, an enzyme expressed in the heart, liver, pituitary, and prostate with physiological functions that are still not clarified [47]. A comparison of pharmacologic properties and side effect profile between the different PDE5 inhibitors is depicted in Table 13.4.
Table 13.4
Comparison of different PDE5 inhibitors
Sildenafil (100 mg) | Tadalafil (20 mg) | Vardenafil (20 mg) | Avanafil (200 mg) | |
|---|---|---|---|---|
Pharmacokinetics | ||||
T max (h) | 0.8–1 | 2 | 0.9 | 0.5 |
T 1/2 (h) | 2.6–3.7 | 17.5 | 3.9 | 10.6 |
Duration (h) | 0.5–4 | 1–36 | 0.5–5 | 6 |
C max (μ[mu]g/L) | 560 | 378 | 18.7 | 5161 |
AUC (μ[mu]g/h/L) | 1685 | 8066 | 56.8 | 10867 |
Side effects | ||||
Bioavailability | 41 | NA | 15 | NA |
Headache | 14 | 15 | 10 | 10.5 |
Flushing | 12 | 3 | 11 | 4 |
Dyspepsia | 7.1 | 15 | 3 | 1 |
Abnormal vision | 4.3 | – | <2 | 1–2 |
Myalgia | – | 5 | – | 1.1 |
Cardiovascular Safety
All clinical trials demonstrated a fairly safe impact for PDE5i on cardiovascular health. No increase in myocardial infarction rates in patients receiving PDE5i has been reported. Moreover, exercise testing in men with stable angina receiving PDE5i did not show an adverse effect on total exercise time or time to ischemia [48, 49]. Cardiac contractility and output as well as myocardial oxygen consumption were not influenced by either on-demand or chronic use of PDE5i.
Nitrate Use
Organic nitrates such as nitroglycerine and isosorbide mono/dinitrate, commonly used to treat angina can amplify cGMP accumulation resulting in life-threatening hypotension. As a result, they are considered an absolute contraindication for the use of PDE5 inhibitors. The duration of interaction depends on the pharmacokinetics of the PDE5i and nitrate used.
Nitroglycerine should be withheld for at least 24 h after the last dose of sildenafil or vardenafil and for at least 48 h after the last tadalafil dose in patients developing chest pain.
Alpha Blockers
Co-administration of PDE5 inhibitors and alpha blockers may result in a small additive effect on blood pressure reduction manifested as orthostatic hypotension. This effect appears to be more prominent within 4 h of alpha blocker treatment. Generally, PDE5i should be administered only after the patient has been stabilized on alpha blocker therapy. Such observations were more documented with less selective alpha blockers (doxazocin) compared to more selective drugs (tamsulosin) [50, 51].
Dosage Adjustment
PDE5 inhibitors are primarily metabolized by the cytochrome P450 enzyme CYP3A4. Therefore, drugs inhibiting the CYP3A4 pathway will reduce the metabolic breakdown consequently resulting in higher serum concentrations of PDE5i. Examples include antifungal agents such as ketoconazole and itraconazole, macrolide antibiotics such as erythromycin and clarithromycin, and human immunodeficiency virus (HIV) protease inhibitors such as ritonavir and saquinavir. Hence, the dose of the PDE5i should be reduced in patients receiving such medications. On the other hand, drugs inducing CYP3A4 activity, such as rifampin, phenobarbital, phenytoin, and carbamazepine, would enhance the breakdown of PDE5i, necessitating higher doses with such medications.
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