E. Wespes, E. Amar, D. Hatzichristou,
F. Montorsi, J. Pryor, Y. Vardi
TABLE OF CONTENTS
Male erectile dysfunction (ED) (impotence) has been defined as the persistent (lasting for at least 6 months)inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Although ED is abenign disorder, it is related to physical and psychological health, and has a significant impact on the quality oflife of both sufferers and their families. Recent epidemiological data have shown a high prevalence andincidence of ED. The Massachusetts Male Aging Study reported a combined prevalence of 52% for minimal,moderate, and complete ED in non-institutionalized 40–70 year-old men in the Boston area (1). In this study, theindividual prevalences were 17.2%, 25.2% and 9.6% for minimal, moderate and complete ED, respectively (1). The same study found that the incidence of ED was 24 new cases per 1000 men.
Erection is a neurovascular phenomenon under hormonal control, and includes arterial dilatation,
trabecular smooth muscle relaxation and activation of the corporeal veno-occlusive mechanism (2,3). Theadvances in basic and clinical research during the last 15 years have led to the development of several newtreatment options for ED, including new pharmacological agents for intracavernosal, intraurethral and oral use.
The recent advent of medical therapy and the poor results of long-term follow-up in reconstructive vascularsurgery, have significantly modified the medical management of this disorder (4–6).
The current availability of an effective and safe oral therapy for ED and the future availability of other
oral drugs, awaiting final approval, in conjunction with the tremendous media interest in the condition, haveresulted in an increasing number of men seeking help for ED. As a consequence, many physicians withoutbackground knowledge and clinical experience in the diagnosis and treatment of ED are involved in makingdecisions concerning the evaluation and treatment of these men. The result of this is that some men with EDmay undergo little or no evaluation before treatment is initiated, or that men without ED may seek treatment inorder to enhance their sexual performance with anti-ED drugs. In such circumstances, the disease causing thesymptom (ED) may remain untreated. Such observations made the development of guidelines for the diagnosisand treatment of ED a necessity. The European Association of Urology formed an expert panel to address theshortcomings and problems associated with the diagnosis and treatment of ED. The overall objective of theproject was to develop guidelines for clinical evaluation and treatment, based on the evaluation and review ofavailable scientific information, as well as on current research and clinical practice in the field. Moreover, thepanel identified critical problems and knowledge gaps, setting priorities for future clinical research.
During the first visit, the essential step in the management of ED is the taking of a comprehensive medical andpsychological history of the patient and his partner when possible (7,8). A detailed medical history is critical asmany common disorders are associated with ED, including hypertension, diabetes mellitus, myocardialdisease, lipidaemia, hypercholesterolaemia, renal insufficiency, hypogonadism, neurological and psychiatricdisorders, and indeed any chronic illness. Genitourinary and rectal surgery, as well as many drugs, particularlyantihypertensive and psychotropic drugs may cause ED. Other drug groups and substance abuses are well-documented causes of ED. The chronic use of alcohol, marijuana, codeine, meperidine, methadone and heroinis associated with a high incidence of ED (9). The influence of radiation therapy on ED is well known. Evaluationhas revealed vasculogenic alteration to be the most consistent organic erectile abnormality in radiotherapy (10).
The initial enquiry about medical history allows a more relaxing atmosphere to be established and
permits questions about erectile function and other aspects of sexual history to be asked more easily, evenwhen men do not volunteer to describe their problem. The sexual history may include information aboutprevious and current sexual relationships, current emotional status, onset and duration of the erectile problemand possible previous consultations and treatments. Detailed descriptions of the quality of both erotic andmorning erections, in terms of rigidity and duration, as well as arousal, ejaculation and orgasmic problemsshould be discussed. The use of validated questionnaires, such as the International Index for Erectile Function,may be helpful in order to assess objectively not only the present status but also the impact of a specifictreatment (11).
A focused physical examination must be performed on every patient, with particular emphasis on the
genito-urinary, endocrine, vascular and neurological systems (7). The physical examination may revealunsuspected findings, such as Peyronie’s disease, small testes and prostatic cancer. A rectal examinationshould be performed in every patient older than 50 years.
Laboratory testing (blood glucose and testosterone) should be carried out in the majority of the patients
and selectively in other patients when lipid profile, prolactin and prostate-specific antigen (PSA) assessmentshould be considered (12–14).
It is important that the physician facilitates communication with the patient and his partner, and explains
the strategy behind the diagnostic and therapeutic approach. It may not often be possible to involve thepartner on the first visit, but an effort should be made to involve the partner during the second visit. On thatoccasion the physician examines the results of the blood tests. If any abnormality is observed, furtherinvestigation by referral to another specialist may be necessary.
The discussion considers patient’s expectations and needs, and should involve the physician, the
patient and their partner. It should cover the understanding of the disorder, interpretation of the diagnostic testsand rational selection of treatment options. Patient and partner education are essential components in themanagement of ED (15).
While the majority of patients with ED can be managed within the sexual care setting, some
circumstances may dictate the need for specific diagnostic testing:•
The patient with primary erectile disorder because, beside psychogenic causes, it is mandatory toexclude organic disease
Young patients with a history of pelvic or perineal trauma who could benefit from potentially curativevascular surgery
Specific tests may also be indicated at the request of the patient or his partner
Among the specific tests used are: assessment of nocturnal penile tumescence and rigidity using
Rigiscan-NPTR; vascular studies, such as intracavernous vasoactive drug injection and duplex ultrasoundcompleted with arteriography or cavernosometry; neurological studies, such as bulbocavernous reflex latencyand nerve conduction; endocrinological studies and specialized psychodiagnostic evaluation. The NPTRshould take place for at least two nights. The presence of an erectile event of at least 60% rigidity recorded onthe tip of the penis, lasting for 10 min or more, should be considered as indicative of a functional erectilemechanism (16).
The intracavernosal injection test offers limited information regarding vascular status. A positive test is
defined as a rigid erectile response (unable to bend the penis) that appears within 10 min after theintracavernosal injection and lasts for 30 min. Such a response may be considered to be associated withnormal arterial and veno-occlusive haemodynamics (16). In all other cases, the test is inconclusive, and aduplex ultrasound of the penile arteries should be requested. A peak systolic blood flow higher than 30 cm/sec.
and a resistance index higher than 0.8 are generally considered as normal (16). If the result of the duplexexamination is normal, the vascular investigation stops. When it is abnormal, arteriography andcavernosometry should be performed only for patients who are considered potential candidates for vascularreconstructive surgery. Patients with psychiatric disorders will be sent to a psychiatrist particularly interested inED. Patients with penile abnormalities, such as hypospadias, congenital curvature or Peyronie’s disease withpreserved rigidity, may require surgical correction with very good success.
The first objective of every doctor is to cure the medical condition. Therefore, the primary goal in themanagement strategy for a patient with ED is to determine the aetiology of the disease and treat it whenpossible, and not to treat the symptom alone. It is clear that ED may be associated with modifiable or reversiblefactors, including lifestyle or drug-related factors, that may be modified prior to or in conjunction with theemployment of specific therapeutic operations.
Testosterone deficiency is potentially reversible and is a result of primary testicular failure or secondary
to pituitary/hypothalamic causes (12). Patients with hormone abnormalities need to take the advice of anendocrinologist. Testosterone replacement therapy is effective, but can only be used when other possibleendocrinological causes for the testicular failure have been excluded. Testosterone replacement therapy iscontraindicated in men with a history of prostate carcinoma or with symptoms of prostatism. Prior to initiatingtestosterone replacement, a digital rectal examination and serum PSA test should be performed. Patientsreceiving androgen therapy should be monitored for clinical response as well as the development of hepatic orprostatic disease (12). However, it should be mentioned that this treatment is not always effective in themanagement of ED associated with hypogonadism.
In young patients with pelvic or perineal trauma, a surgical penile revascularization erection procedure is
often associated with good results; there is a 60–70% long-term success rate (5). The lesion must bedemonstrated by duplex sound and confirmed by penile pharmaco-arteriography. A corporeal veno-occlusivedysfunction must be excluded by pharmaco-cavernosometry.
When no specific therapies for ED are required, a strategic approach should be followed. Again the
patient and his partner, when possible, must be informed on the route of administration, the invasiveness, the
cost and the reversibility of the treatment. In other cases, such as older patients without traumatic lesions or inpatients with secondary cavernovenous leakage, vascular surgery is no longer recommended due to poorresults at long-term follow-up.
Sildenafil citrate (Viagra) and Apomorphine (Uprima) are currently the only oral drugs available on the marketwith proven efficacy and safety for the treatment of ED.
Sildenafil is an oral drug, effective after 60 min. in the presence of sexual stimulation. The most
common side effects include headaches, flushing, dyspepsia and nasal congestion. It causes small decreasesin systolic and diastolic blood pressure, although clinically significant hypotension is rare. For that reason, it isformally contraindicated in patients who take long-acting nitrates or who use short-acting, nitrate-containingmedications (17). It may be hazardous to prescribe Sildenafil in patients with:•
Congestive heart failure and borderline low blood pressure
A complicated multi-drug antihypertensive programme
Drug therapy that can prolong the half-life of Sildenafil
The dosages are 25, 50 and 100 mg. The starting dose should be 50 mg regardless of the aetiology of
ED and adapted according to the success and side-effects; however, patients with liver/renal failure and thoseaged over 65 years should be given 25 mg. After 24 weeks of treatment in a dose–response study, improvederections were reported by 56%, 77% and 84% of the men taking 25, 50 and 100 mg of Sildenafil, respectively,compared with 25% by those taking placebo (4).
Sildenafil is a potent and selective inhibitor of cyclic GMP (cGMP), specifically phosphodiesterase type 5, thepredominant isoform of the enzyme found in the human penis, resulting in smooth muscle relaxation,vasodilatation and penile erection (4).
Apomorphine sublingual (18) is a dopamine agonist that acts through enhancing pre-erectile stimuli
through the hypothalamic neural pathways. The sublingual formula produces a fast acting circulating plasmaconcentration resulting in the quick onset of action; producing an erection in a median response time of 18-19minutes. The dosages are 2 and 3 mg.
Uprima 2 mg resulted in a 1,66 fold increase and 3 mg resulted in a 2,2 fold increase in the percentage
of attempts presenting an erection firm enough for intercourse from baseline. It is well-tolerated and thereseems to be no interaction with other medications, food and alcohol.
Oral phentolamine (19) and other phosphodiesterase inhibitors, are under investigation.
It must be emphasized that the physician should warn the patient that sexual intercourse is considered
to be a vigorous physical activity, which increases heart rate as well as cardiac work. Physicians should assessthe cardiac fitness of patients prior to treating ED.
A vacuum device could be used in patients in stable relationships in whom the mechanism of ED is easilyunderstood (20). It is also better accepted in older patients. The device applies a negative pressure to thepenis, thus drawing venous blood into the penis, which is then retained by the application of a visibleconstricting band at the base of the penis. The adverse effects associated with vacuum therapy are penile pain,numbness and delayed ejaculation.
For patients with a significant psychological problem, psychosexual therapy may be given either alone or incombination with another therapeutic approach. Psychosexual therapy takes time and has been associatedwith variable results (21).
Intracavernosal injection or intraurethral therapy can be used according to the patient’s wishes.
Several drugs have been proposed for intracavernosal injection, alone or in combination (prostaglandin E1,phentolamine–vasointestinal polypeptide, phentolamine–papaverine, maxislititrimx); however, only two areapproved by the FDA – alprostadil sterile powder and alprostadil alfadex (22). Patient comfort and educationare essential elements of the practice of intracavernosal injection therapy. The use of an automatic special pen
that avoids the needle view can resolve the fear of penile puncture.
Injection therapy is effective in most cases of ED, but it is contraindicated in men with a history of
hypersensitivity to the drug employed and in men at risk of priapism. It is not advised in men with limitedmanual dexterity but their partners may be taught the technique. Intracavernosal therapy is effective in 60–90%of cases. The erection appears after 5–15 min and lasts according to the dose injected. Side-effects includeprolonged erections or priapism, penile pain and fibrosis.
After 4 hrs of erection, patients are advised to consult the doctor to avoid any damage to the
intracavernous muscle, which would provoke permanent impotence. A 19-gauge needle is used to aspirateblood and therefore to decrease the intracavernous pressure. This simple method is usually sufficient to makethe penis flaccid. However, if the penis becomes rigid again after this, phenylephrine intracavernous injection ata dose starting at 200 µg every 5 minutes and increasing to 500 µg if necessary is required. The risk of having aprolonged erection during following subsequent injections cannot be predicted. When this problem occurs, thedose is usually reduced for the next injection. The patient must be carefully observed for systemic effects of thetreatment used.
Prostaglandin E1 may be administered intraurethrally in the form of a semi-solid pellet. A band placed at thebase of the penis seems to improve the resulting rigidity. About 70% of patients have been satisfied or verysatisfied. Even the administrated route seems to be less invasive (23). Side-effects include penile pain andhypotension, and the clinical success rate is lower than that achieved with intracavernosal therapy (23).
For patients who fail pharmacological therapy or who prefer a permanent solution to their problem, surgicalimplantation of a prosthesis may be considered. Two types of prosthesis exist: malleable and inflatable. Theinflatable penile prosthesis provides not only a more cosmetic erection but also a more satisfying one. Penilegrowth is usually better with an inflatable rather than a semi-rigid erection, although the former is associatedwith an increased rate of mechanical failure and complications. There is also a difference in price; the inflatableprosthesis is much more expensive. In several countries, patients are reimbursed for the cost of the prosthesis,but an organic cause has to be determined for the ED and the patient has to undergo a complete impotenceassessment.
Prosthetic infection is the most problematic complication following surgery as the combination of
infection and a foreign body requires removal of the prosthesis. The patients most commonly affected byinfection problems are diabetics (24).
Exact intra-operative length measurement is mandatory. If the device is too long, post-operative pain
and eventually prosthesis erosion may result. If too short a device is used, the ‘concorde’ deformity withleaking of the glans during intercourse may occur, and lateral perforation may result.
A great deal of progress has been made in the pharmacological treatment of ED. In the past, the mosteffective therapy required intracavernosal injections, but an increasing number of oral agents have beenintroduced with very good success rates. Any successful pharmacological treatment for erectile failuredemands a degree of integrity of the penile mechanisms of erection. Further studies of individual agents andsynergistic activity of available substances are underway. The search for the ideal pharmacological therapy forerectile failure aims at fulfilling the following characteristics: good efficacy, easy administration, freedom fromtoxicity and side-effects, with a rapid onset and a possible long-acting effect.
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5. ABBREVIATIONS USED IN TEXT
$660m drug plant, 550 jobs for Mass. Deal at Devens site caps an 8-month state effort By Stephen Heuser, Globe Staff | June 2, 2006 Global drug maker Bristol-Myers Squibb Co. has decided to build a $660 million manufacturing plant on the former Fort Devens US Army base, the company said yesterday, bringing as many as 550 jobs to Massachusetts and marking a milestone in the state's effort
Press release issued by SCHMOLZ+BICKENBACH AG, 14 May 2013 Further proposals submitted by the Schmolz+Bickenbach KG / Renova shareholder group to the 2013 Annual General Meeting of SCHMOLZ+BICKENBACH AG Emmenbrücke, 14 May 2013 – The subsidiary of Schmolz+Bickenbach GmbH & Co. KG, Schmolz+Bickenbach Beteiligungs GmbH has written in conjunction with Renova Holding Ltd. to the Board