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Managing erectile dysfunction

Introduction

Erectile dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. ED is an important worldwide health issue that has a significant negative impact on men’s quality-of-life and relationships as well as their emotional and psychological wellbeing. Its prevalence is set to increase from 152 million in 1995 to 322 million by 2025. Over the past 50 years, treatment of ED has evolved rapidly in both pharmacotherapy as well as surgical techniques. Treatment of ED was revolutionised with the advent of oral phosphodiesterase type 5 inhibitors (PDE5Is), which remain the first-line therapy for treatment. Overall there are four principle options for the treatment of ED – oral therapy, vacuum erectile devices (VEDs), intercavernous injections or intraurethral suppositories, and penile prosthesis.

Epidemiology

 A longitudinal study from the Massachusetts male ageing study demonstrated an ED incidence rate of 26 per 1,000 men aged between 40 and 69 years. The prevalence of sexual dysfunction among men in the US from one study was almost 5 per cent in men aged less than 40 years, 44  per cent of men aged between 60-69 years old and up to 70 per cent in men aged over 70 years. This study also demonstrated a higher incidence rate among men with one or more cardiovascular risk factors, men with hypertension, and men with a history of cardiovascular disease.

Physiology

An erection is a complex physiological process involving hormonal, vascular, and neural systems, as well as psychosexual stimulation. There are four stages of male sexual function: (1) desire, (2) erection, (3) ejaculation, and (4) detumescence. Stimulation of sensory receptors in the penile skin, glans, urethra, and corpus cavernosum or psychosexual arousal stimulate parasympathetic pathways through the sacral portion of the spinal cord to the pelvic nerves to the penis. Activation of parasympathetic pathways prompts release of nitric oxide (NO) from cavernous nerves and endothelial cells. This relaxes the arteries of the penis as well as the trabecular meshwork of smooth muscle fibres in the erectile tissue of the corpora cavernosa and corpus spongiosum in the shaft of the penis. Large cavernous sinusoids become grossly dilated when arterial blood flows rapidly into them under pressure while venous outflow is partially occluded. The erectile bodies, especially the two corpora cavernosa, are surrounded by strong fibrous coats, which facilitates high pressure within the sinusoids causing ballooning of the erectile tissue to such an extent that the penis becomes hard and elongated. This is the phenomenon of an erection.

On a molecular level, NO release activates guanylyl cyclase, catalysing the formation of cyclic guanosine monophosphate (cGMP). cGMP plays a pivotal role in penile arteriolar vasodilatation and relaxation of penile corporeal smooth muscle. Phosphodiesterase-mediated degradation of cGMP to GMP phosphodiesterase type 5 (PDE5) prompts detumescence and it is this degradation process which is targeted by PDE5Is. Detumescence is also mediated by adrenergic nerve terminals whose neurotransmitter, norepinephrine, activates alpha-adrenergic receptors producing vasoconstriction of the penile vasculature and decompression of penile venules.

Risk factors

ED shares common risk-factors for cardiovascular disease (CVD), namely obesity, sedentary lifestyle, and smoking. ED is extremely common in men with chronic coronary artery disease, affecting approximately 75 per cent. Based on a meta-analysis of 45,558 participants from seven cohort studies, the relative risk (RR) of coronary events in men with ED is 1.47 (95 per cent confidence interval (CI) 1.29-1.66). Lifestyle changes in midlife may be too late to reverse the effects of smoking, obesity, and alcohol consumption on ED. Weight reduction as well as increased physical activity, however, may reduce the risk of ED even if initiated in midlife.

There is a strong association between men who have lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and ED independent of other risk-factors.

Radical prostatectomy in any form (open, laparoscopic, or robotic) carries a significant risk of ED due to cavernosal nerve injury, poor oxygenation of the corpora cavernosa, and vascular insufficiency. Some 25-75 per cent of men will suffer with ED post-operatively.

Evaluation

The pathophysiology of ED may be vasculogenic, neurogenic, anatomical, hormonal, drug-induced and/or psychogenic. Vasculogenic ED accounts for 60-80 per cent of all cases and can be further subclassified into arterial insufficiency, corporal veno-occlusion dysfunction (CVOD) or a combination of the two conditions. The evaluation of the male with ED comprises three categories: (1) history and physical exam, (2) lab testing, and (3) adjunctive testing with imaging and related modalities.

History

A social and sexual history including sexual orientation, current and previous relationships, and duration of erectile problems, should be taken as well as a history of previous treatments. Desire, arousal, ejaculation, and orgasm should each be discussed in turn. The International Index for Erectile Dysfunction (IIEF) or the Sexual Health Inventory for Men (SHIM) are validated questionnaires targeting specific sexual functional domains used to supplement the history. The SHIM provides a score to classify a patients ED in to five categories of severity: no ED (SHIM score 22-25), mild (17-21), mild to moderate (12-16), moderate (8-11), and severe (1-7).

Differentiating organic ED from psychogenic ED should be possible through a thorough sexual history encompassing erection quality on awakening, as well as during masturbation, foreplay, and intercourse. Circumstantial variability of erectile function obtained through a history allows psychogenic ED to be accurately diagnosed.

Physical examination

ED can herald an underlying cardiovascular issue such as coronary artery disease. Blood pressure, heart rate, waist circumference, and weight should be recorded. A rectal examination should be performed in every patient older than 40 years. An examination of the external genitalia should be performed looking for signs of hypogonadism and any penile pathology or deformity such as Peyronie’s disease. Examination should also evaluate secondary sex characteristics, peripheral pulses and sensation, abdominal masses, and presence of gynaecomastia.

Laboratory investigations

A fasting blood glucose or haemoglobin a1c and lipid profile should be taken if not assessed in the past year. For testosterone levels > 8nmol/l the relationship between circulating testosterone and sexual function is very low. Further hormonal analysis can be performed in the setting of a low testosterone in order to further evaluate the hypothalamic-pituitary-gonadal axis (free testosterone, prolactin, sex hormone binding globulin, follicle stimulating hormone (FSH), and luteinising hormone (LH)). Serum prostate specific antigen (PSA) should be considered if clinically indicated.

Radiological investigations

Penile duplex ultrasonography can be used to evaluate blood flow direction and velocity. It is the most common and informative method of assessing for both arterial insufficiency and veno-occlusive dysfunction. If normal no further vascular investigations are warranted.

If penile revascularisation surgery is being considered, then arteriography and dynamic infusion cavernosometry or cavernosography (DICC) can be performed. An intercavernous injection test that is positive will confirm that a patient will respond to the intracavernous injection programme, but does not exclude an underlying cardiovascular issue.

A duplex ultrasound of the penis is performed during pharmacological erection. A peak systolic blood flow >30cm per second, an end diastolic value velocity of <3cm per second, and a resistance index of >0.8 are considered normal.

Management

Patient education along with their partner and discussing expectations is an essential part of ED management. Most cases of ED are not curable with the exception of psychogenic ED, post-traumatic arteriogenic ED in young patients, and cases with an underlying hormonal cause.

Modifying reversible risk-factors is the first contributing change advised to ED patients. A stepwise approach to further treatment options should start with the least invasive and progress depending on the risks and likelihood of success. Therapies include oral PDE5Is, intra-urethral alprostadil, intracavernous vasoactive drug injection, vacuum devices, and penile prosthesis implantation.

Psychosexual therapy (first-line)

Psychosexual therapy is considered a first-line therapy for those with psychogenic ED and can be used as an adjunct to treatment for those with organic ED. In a Cochrane Review of 11 trials of psychotherapy alone or psychotherapy and medication or vacuum erection devices in men with ED, men receiving group psychotherapy alone had less ED at six-month follow-up when compared to controls, with up to a 95 per cent success rate, and men concomitantly taking PDE5Is were less likely to drop out of therapy.

Pharmacotherapy (first-line therapy)

PDE5Is are first-line therapy for ED. They cause smooth muscle relaxation in the penis with increased arterial blood flow, leading to compression of the subtunical venous plexus and erection. They depend on the release of NO by parasympathetic nerve endings, which occurs on sexual stimulation, hence all PDE5Is require sexual stimulation for efficacy. There are no significant differences in efficacy, safety, and tolerability among PDE5Is. Sildenafil, tadalafil, vardenafil, and avanafil are the current approved drugs by the European Medicines Agency (EMA). Dose titration of PDE5Is to the maximum tolerated dose is strongly recommended because it increases efficacy and satisfaction from treatment.

PDE5Is are contraindicated with the following:

Myocardial infarction, stroke, or life threatening arrhythmias within the past six months;

Hypotension (blood pressure <90/50mmHg);

Hypertension (blood pressure >170/100mmHg);

Unstable angina or a history of angina on intercourse;

Congestive cardiac failure (New York Heart Association Class II or greater);

Nitrates.

Sildenafil

This was the first PDE5I and comes in doses of 25mg, 50mg, and 100mg. The recommended starting dose is 50mg. It is effective from 30-60 minutes after ingestion and efficacy can be maintained for up to 12 hours. Efficacy can be reduced if taken after a heavy fatty meal. Peripheral vasodilation such as facial flushing, nasal congestion, headache, and dyspepsia are potential side effects.

Tadalafil

Effective from 30 minutes after ingestion and not affected by food. Efficacy can be maintained for up to 36 hours. Starting dose of 10mg is recommended.

Vardenafil

Effective from 30 minutes after ingestion and affected by a heavy, fatty meal if taken as a film coated tablet. An alternative dispersible tablet is available which is not affected by food. Starting dose of 10mg is recommended.

Avanafil

Avanafil is a highly selective PDE5I and thus minimises side effects. The starting dose is 100mg orally 30 minutes before sexual activity. The maximum recommended dosing frequency is once per day.

Vacuum erection devices

Vacuum therapy (VT) utilises negative pressure to distend the corporal sinusoids increasing the blood inflow to the penis allowing passive engorgement of the corpora cavernosa. Once engorged a constricting ring is then placed at the base of the penis. This ring can be removed at climax to facilitate ejaculation. Efficacy for penetrative intercourse is up to 90 per cent with 27-94 per cent satisfaction rates among users. Vacuum devices are a good alternative to those unresponsive to or excluded from pharmacotherapy. They are also used for penile rehabilitation post-radical prostatectomy. Artificial induction of erections after surgery facilitates tissue oxygenation, reducing cavernosal fibrosis in the absence of nocturnal erections, and potentially increases the likelihood of preserving erectile function.

Intercavernous injections (second-line therapy)

Alprostadil is the only approved intercavernous injection for ED. Alprostadil is a synthetic analog of prostaglandin E1 (PGE1). Its mechanism of action involves binding to G-proteins coupled to PGE1 receptors on the surface of smooth muscle cells, activating cyclic adenosine monophosphate (cAMP) pathway and thus inducing vascular smooth muscle relaxation and erection. Alprostadil’s action as a direct agonist means that it can produce erection independent of a stimulus within five-to-15 minutes after injection. Efficacy rates are higher than 70 per cent, with satisfaction rates of 87-93.5 per cent in patients and 86-90 per cent in partners. Despite the high levels of satisfaction, discontinuation rates of 41-68 per cent exist with most patients stopping use within the first two to three months. Side effects include pain, fibrosis, priapism, and prolonged erections.

Intraurethral alprostadil in a pellet form is available, with efficacy rates 0f 30-65.9 per cent. It provides a less invasive alternative to intercavernous injections. The most common adverse effects are pain and dizziness with possible hypotension.

A further alternative with a topical cream or gel is available. Use of the gel led to an erectile response in 67-75 per cent of patients at varying doses. Clinical trials have shown topical alprostadil cream to be effective, increasing a patient’s IIEF score by up to 13 points from baseline. Although marketed as a topical cream, its use involves insertion of an applicator device in to the meatus to deliver the cream intraurethral.

Penile prosthesis (third-line therapy)

History

The first documented attempt to develop a penile prosthesis was in 1936 by a Russian surgeon Nikolaj A Bogoraz who reconstructed an amputated penis using an abdominal tube pedicle graft and a segment of rib cartilage to provide rigidity. Early artificial penile implants using materials such as acrylic, silicone rubber, and silastic were placed beneath the Buck’s fascia but outside the corpora. Extrusion of the implant was a common complication. The placement of polyethylene and acrylic rods into the corpora cavernosa within the tunica albuginea provided more stability, comfort, and better cosmetic results. This would become the basis for further surgical design with malleable and inflatable devices.  

Penile implant devices

Prosthesis implantation has one of the highest satisfaction rates for people with ED (92-100 per cent). Made available more than 40 years ago, implantable penile devices have undergone numerous modifications by manufacturers since their release, increasing their durability and improving patient outcomes and satisfaction. It is reserved for those who fail to respond to pharmacotherapy. There are two types available; an inflatable penile prosthesis (IPP) device with either two or three pieces and a malleable implant. These devices can be inserted via an infrapubic or penoscrotal approach.  AMS (American Medical Systems) and Coloplast Ltd produce the majority of inflatable and malleable devices. Three-piece inflatable penile implants provide a more natural erection allowing for distinctive periods of rigidity and flaccidity (AMS 700CX/CXR and Coloplast Alpha I).

A malleable implant results in a firm penis, which can be placed in to an erect position as required. Several malleable devices are available including the 600M and 650M by AMS. Both have a stainless steel, woven wire centre covered by a trimmable silicone elastomer sheath. Coloplast offer the Genesis, with a single spiral silver wire core with an antibiotic hydrophilic coating and the Acu-Form, which has a helical shape surrounding a central wire core allowing greater flexibility.

The first IPP was introduced in 1973, which consisted of two non-distensible cylinders, two internalised pumps and a fluid reservoir. This resulted in the ability to create a flaccid or erect penis. Since that time multiple improvements have been produced, such as kink-resistant tubing, lockout valves, easy release systems, antibacterial coatings, varied cylinder profiles, and reinforced materials.

Complications

Mechanical failure and infection are the two most common complications with implant devices. In cases of infection, removal of the hardware is required along with antibiotic administration. Rates of infection are <3 per cent and can be lower with devices with antibiotic-impregnated hardware and hydrophilic coatings. Skin flora organisms can be introduced during surgery leading to IPP infections. Staphylococcus epidermis is the most common pathogen in primary and revision surgeries. A ‘no touch technique’, which avoids contact of the implant device with the patient’s skin has been shown to reduce infection rates to 0.48 per cent from 2 per cent with antibacterial devices. Mechanical survival rates for the AMS 700CX/CXR were 97.6 per cent, 93.2 per cent, and 78.2 per cent at three, five, and 10 years after implantation. Overall, IPP have good patient satisfaction rates of 92-100 per cent and rates of 91-95 per cent for partners, while malleable implants have slightly lower overall satisfaction rates of 75-91 per cent, but higher rates of mechanical reliability.

Penile revascularisation and venous ligation surgery

Arterial reconstructive surgery is a treatment option only in healthy individuals with recently acquired ED secondary to a focal arterial occlusion and in the absence of any evidence of generalised vascular disease. Young men under the age of 30 years with isolated arterial stenosis following perineal or pelvic trauma have been shown to have higher success rates. The distal internal pudendal artery, common penile artery, and proximal cavernosal artery are at increased risk of injury due to their fixed anatomical relationship with the ischiopubic ramus as they run through Alcock’s canal. The aim of surgery is to bypass the obstructed distal internal pudendal, common penile, and proximal cavernosal arteries to deliver increased systolic perfusion pressure and blood flow from the donor inferior epigastric artery to the recipient dorsal penile artery. Patients with CVOD identified on Doppler ultrasound are not suitable candidates for microvascular arterial bypass penile revascularisation.

The pathology that causes CVOD is not clearly understood. The presence of large venous channels draining corpora cavernosa and structural alterations in fibroblastic components of trabeculae and cavernous smooth muscles are thought to be underlying causes. Other studies have shown that the tunica albuginea plays a key role in rigidity and atrophy of the tunica can lead to increased venous leakage during erection. A diagnosis of CVOD is by way of Doppler US with end diastolic values >6cm per second, a resistance index of 0.6, and a normal peak systolic flow of >30 cm per second.

The merit for conducting penile venous surgery to treat ED has never been firmly established. Currently, there is no evidence from randomised controlled trials documenting a standardised approach to diagnosis or the efficacy of treatment for veno-occlusive ED. Venous ligation surgery has remained an area of debate with some international guidelines not recommending its use. Other studies have shown that this surgery still plays a role in a select cohort of patients. Either way, venous ligation surgery is making a resurgence as a viable treatment option for men of all ages with ED secondary to CVOD.

Test your knowledge of erectile dysfunction – complete this module on MediLearning and earn 2 CPD credits

The answers to the following True/False and MCQ questions are available on MediLearning.ie

PDE5Is are first-line therapy for most men with ED who do not have a specific contraindication to their use.
True or False?

PDE5Is require sexual stimulation in order to work.
True or False?

Psychogenic ED can only be diagnosed after imaging studies.
True or False?

Intracavernosal injection therapy with alprostadil should be offered to patients as second-line therapy for erectile dysfunction.
True or False?

There are significant differences in efficacy, safety, and tolerability among PDE5 Is.
True or False?

There is a strong association between cardiovascular disease and ED.
True or False?

ED is an uncommon complication after a radical prostatectomy.
True or False?

Penile duplex ultrasound should be performed on all patients with ED.
True or False?

Most cases of ED are curable.
True or False?

Penile implant devices have low patient satisfaction rates True or False?

Q1. Which of the following areas are potential future treatment modalities for ED?

A. Stem cells.

B. Penile vibrators.

C. Tissue engineering.

D. Nanotechnology.

Q2. Which of the following risk factors are NOT associated with erectile dysfunction?

A. Hypertension.

B. Sedentary lifestyle.

C. Smoking.

D. Lower urinary tract symptoms secondary to BPH.

E. Low BMI. 

Q3. Which of the following laboratory tests is used to investigate a patient with ED and suspected hypogonadism?

A. Total testosterone.

B. Sex Hormone Binding Globulin.

C. Albumin.

D. Prolactin.

E.  Oestrogen.

Q4. Which of the following therapies are used as a first-line treatment for penile rehabilitation post radical prostatectomy?

A. PDE5Is.

B. Vacuum devices.

C. Intraurethral alprostadil.

D. Lifestyle modification.

E. Penile implant devices.

Which of the following categories are NOT included in the International Index of Erectile Function (IIEF) questionnaire?

A. Erectile function.

B. Orgasmic function.

C. Sexual desire.

D. Intercourse satisfaction.

E. Overall satisfaction.

F. Partner.

Answers, bibliography, and references available at
www.medilearning.ie 

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