Therapy for Erectile Dysfunction: Pocketbook

Therapy for Erectile Dysfunction

Therapy for Erectile Dysfunction Ian Eardley MA MChir FRCS(Urol) Consultant Urologist St James University Hospital, Leeds, UK

© 2003 Martin Dunitz, an imprint of Taylor & Francis Group First published in the United Kingdom in 2003 by Martin Dunitz, an imprint of Taylor and Francis Group, 11 New Fetter Lane, London EC4P 4EE Tel.: +44 (0) 20 7583 9855 Fax.: +44 (0) 20 7842 2298 E-mail: [email protected] Website: http://www.dunitz.co.uk This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London WIP 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. A CIP record for this book is available from the British Library. ISBN 0-203-50219-1 Master e-book ISBN

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Contents

Preface 1.

2.

3.

4.

vii

Background

1

Normal erectile function

1

Causes of erectile dysfunction

7

How common is ED?

13

Assessment

18

The philosophy of patient assessment

18

The history

19

Examination

21

Baseline investigation

22

Specialist investigations

24

Treatment

29

A plan of treatment

29

General measures

30

Oral therapy

30

Other physical and pharmacological therapies

37

Psychological therapy

44

Hormone therapy

46

Special problems

50

Erectile dysfunction in men with cardiac disease

50

Other aspects of male sexual dysfunction

53

vi

Further reading

55

Index

57

Preface

Erectile dysfunction (ED) is a common symptom that may result from a number of different medical conditions. Previously, many men with ED did not seek treatment for their problem, but with increasing public awareness, and with the publicity that has surrounded the launch of oral therapies, more and more patients are now visiting their doctors and seeking solutions for their erectile difficulties. It behoves the physician to have a basic understanding of the relevant issues, and this handbook is an attempt to provide the basics required for the assessment and treatment of men with ED, although it does not deal with many of the wider issues of male and female sexual dysfunction. The book is divided into four chapters, the first of which deals with the background to the condition, including a description of normal erectile function, a discussion of the causes of ED, and an outline of what we know about its prevalence. The second chapter deals with patient assessment, and attempts to provide guidance on the appropriate initial assessment of ED, as well as some information on those investigations that are occasionally necessary in particular cases. The third chapter deals with therapy. For most men, treatment is a hierarchical process that does not depend upon the cause of the problem. The least invasive treatments are used as first line, with more invasive treatment being reserved for failures, and surgical therapy only being used when all else has failed. However, it is important to identify those men in whom referral for specific therapy may be appropriate, and this section will aim to provide guidance on this. The fourth chapter deals with two specific areas, erectile dysfunction and cardiovascular disease, and the relation ship between the two, and following this there is a brief outline of a few other male sexual disorders. Clearly such a small handbook cannot hope to be comprehensive and, wherever appropriate, guidance for further reading is given. Ian Eardley 2003

viii

1 Background

Normal erectile function Erections are vascular events. They depend upon the presence of a normal vasculature that is under appropriate neural control, and an understanding of these ‘normal’ physiological mechanisms is helpful in understanding how disease processes can lead to erectile dysfunction. Types of erection Erections occur by one of three mechanisms (Table 1). First, erotic stimuli can lead to an erection. Such stimuli can be visual, auditory, olfactory or imaginative, and they appear to originate in the cerebral cortex before stimulating the hypothalamus, from where descending pathways pass into the spinal cord. A number of neurotransmitters have a role in this process, including dopamine, serotonin, oxytocin and noradrenaline (norepinephrine), and of these, dopamine appears to be particularly important. It is present within the hypothalamus, and when released in response to a sexual stimulus it appears to be proerectile (Figure 1). It is this mechanism that has been exploited by the use of apomorphine, a dopaminergic drug, as an oral therapy for men with ED. From the hypothalamus, the descending oxytocinergic neurons to the spinal cord Table 1 Types of erections. Erotic Occurring in response to an erotic stimulus Nocturnal Night-time erections occurring during REM sleep in normal men Reflex Occurring in response to genital stimulation

2 BACKGROUND

Figure 1 The central position of dopamine in the CNS control of erectile function.

stimulate the parasympathetic proerectile pathways to the penis. The roles of noradrenaline and serotonin within the CNS are more complex, although both are mainly antierectile in action. These central pathways may also be relevant to the second type of penile erection, which normally occurs during sleep. All men will achieve an erection four to six times every night, usually during REM (rapid eye movement) sleep. It has been theorised that these erections serve the physiological purpose of increasing blood flow (and thereby oxygenation) to the penis during the night, thereby keeping the penile smooth muscle healthy.Whatever the reason, the neural mechanisms involved are probably the same as those of the erotic erections described above, although it has been suggested that there may also be a ‘switching off’ of antierectile nervous pathways, which are mediated by the sympathetic nervous system and which emanate from the lower thoracic and upper lumbar segments of the spinal cord. The final way by which erections occur is by a reflex mechanism whereby tactile stimulation of the genitalia leads to reflex stimulation of the parasympathetic nerves to the penis. Peripheral nervous control of erections The parasympathetic nerves that produce an erection arise from the second, third and fourth segments of the sacral spinal cord, and pass forward around the rectum to the pelvic plexus that lies posterior to the bla dder. From there, cavernous nerves pass bilaterally in the groove between the bladder and the prostate before leaving the pelvis beneath

THERAPY FOR ERECTILE DYSFUNCTION 3

Figure 2 Structure of the penis.

the pubic arch. Throughout this pathway the nerves are at risk of damage from trauma (such as pelvic fracture) and from surgery (such as radical prostatectomy and abdominoperineal excision of the rectum). After passing outside the pelvis, they penetrate the corpora cavernosa of the penis, where they spread out to innervate the smooth muscle, blood vessels and endothelium.

4 BACKGROUND

Vascular changes during erection The penis is a vascular organ that consists of three tubes (Figure 2), one (the corpus spongiosum) whose function is to transmit urine, and two (the corpora cavernosa) that have the primary erectile function. They are anchored posteriorly to the pelvis, so that when erect they are stable, and they have a tough fibrous outer layer called the tunica albuginea. They are filled with spongy tissue (Figure 3) within which are vascular spaces surrounded by walls (called trabeculae) containing smooth muscle. The trabecular spaces are lined with endothelium. When the parasympathetic nerves become activated, they release a cocktail of neurotransmitters (see below) that lead to smooth muscle relaxation within the penis. The smooth muscle relaxation results in arterial dilatation, with increased arterial inflow into the penis, and also in relaxation of the vascular sinusoids, with increased pooling of blood within the penis (Figure 4). This results in swelling of the penile spongy tissue and compression of venous sinusoids that lie underneath the tunica albuginea. In turn this leads to reduced venous outflow from the penis, and together these three processes result in a rigid penile erection. Neurochemical control of penile erection The neurotransmitters released from the parasympathetic nerves include acetylcholine, vasoactive intestinal polypeptide (VIP) and nitric oxide (NO), of which the latter is by far the most important. In addition to this neural release of NO, during an erection there is also release of NO from the vascular endothelium surrounding the sinusoidal spaces. The nitric oxide penetrates the smooth muscle cell, where it stimulates the enzyme guanylate cyclase to produce cyclic GMP (cGMP), which is the active second messenger within the cell (Figure 5). cGMP production leads to smooth muscle relaxation via a variety of cellular mechanisms, until its action is terminated by an enzyme called phosphodiesterase type 5 (PDE5). Inhibition of this enzyme results in persistence of the cGMP and consequently in improved smooth muscle relaxation, and this mechanism is exploited by the PDE5 inhibitors silde-nafil, tadalafil and vardenafil as a means of treating erectile dysfunction.

THERAPY FOR ERECTILE DYSFUNCTION 5

Figure 3 Trabecular structure of the spongy tissue at rest. Contracted arteries, contracted sinusoids and open venous drainage.

Summary ■ There are three types of erection: ■ Those that arise following erotic stimulation (psychogenic) ■ Those that accompany genital stimulation (reflex) ■ Those that occur at night (nocturnal) ■ Within the central nervous system the hypothalamus is important in coordinating sensory inputs and initiating the erectile response ■ Within the hypothalamus, dopamine is currently thought to be the most important neurotransmitter ■ The main proerectile peripheral nervous pathways are the parasympathetic nerves that arise from S2, 3 and 4 ■ The main antierectile peripheral neural pathways are the sympathetic nerves that emanate from T10–12 and LI–2 ■ The parasympathetic nerves release a number of neurotransmitters within the penis, the most important of which is nitric oxide

6 BACKGROUND

Figure 4 Trabeculae during erection. Arterial dilatation, with pooling of blood within the sinusoids and venous compression.

Figure 5 The actions of nitric oxide within the penile smooth muscle cell. It stimulates guanylate cyclase to convert GTP (inactive) to cyclic GMP (active). Phosphodiesterase type 5 (PDE5) breaks down the cyclic GMP.

■ During sexual stimulation nitric oxide is also released from the vascular endothelium ■ Nitric oxide release causes vascular smooth muscle relaxation within the penis. This in turn results in:

THERAPY FOR ERECTILE DYSFUNCTION 7

■ Arterial dilatation ■ Relaxation of the trabecular smooth muscle, with swelling of the spongy tissue ■ Compression of the veins that normally drain the penis ■ These vascular changes result in penile erection Causes of erectile dysfunction The mechanism by which a man achieves an erection is complex, commencing with some form of sensory stimulus and then involving both central and peripheral neural pathways that lead to vascular changes that in turn result in an erection. Interference with this process can occur at a number of levels, and accordingly there are a large number of different causes of erectile dysfunction (Table 2). Traditionally, organic causes of erectile dysfunction (ED) were separated from psychogenic causes, but we now recognise that such a separation is artificial, as both processes are present at the same time in most patients. Indeed, it is now recognised that for many men there are multiple pathophysiological factors, both physical and psychogenic, which contribute to the ED (Tables 3 and 4). Table 2Causes of erectile dysfunction. Psychogenic Organic Neurological Vascular Endocrine ED of ageing latrogenic

Psychogenic ED Psychogenic ED can occur in a variety of situations (Table 4), and although the division into predisposing, precipitating and maintaining factors is often inappropriate, it does provide a framework upon which to identify the causes of psychogenic ED, where they exist.

8 BACKGROUND

Vascular ED The single most common organic cause of ED is vascular disease or atherosclerosis. Just as atherosclerosis affects the myocardial or cerebral vasculature, risk factors for vasculogenic ED include hypertension, diabetes, hyperlipidaemia and smoking.All these factors, both individually and collectively (with the possible exception of smoking), have been associated with the development of ED, and we are increasingly recognising that early diagnosis of ED may help us to identify reversible cardiovascular risk factors that, if treated, might help to reduce serious cardiac morbidity in the future. Diabetic ED Men with diabetes are around three times more likely to develop ED than non-diabetics. The mechanisms underlying this include the autonomic neuropathy that commonly accompanies diabetes, the vascular disease that results from diabetes and, as we are increasingly recognising, the endothelial dysfunction that is associated with diabetes. Endothelial release of nitric oxide is crucial to normal erection.and we now know Table 3 Common organic causes of ED. Vascular disease Atherosclerosis Diabetes mellitus Hypertension Hyperlipidaemia Neurological disease Multiple sclerosis Diabetes mellitus Depression Spinal cord injury Cauda equina lesion Parkinson’s disease Alzheimer’s disease Pelvic fracture injury Endocrine and metabolic disease Hypogonadism Hyperprolactinaemia

THERAPY FOR ERECTILE DYSFUNCTION 9

Renal failure ED of ageing latrogenic ED Pelvic radiotherapy Radical pelvic surgery, e.g. radical prostatectomy, radical cystectomy Drugs

that diabetes results in widespread endothelial damage. There is increasing evidence that, as with other complications of diabetes, better glycaemic control results in fewer men developing ED. Hypertension and hyperlipidaemia As well as being risk factors for atherosclerotic ED, both hypertension and hyperlipidaemia on their own can cause ED. Studies show that ED is Table 4 Causes of psychogenic ED. Predisposing causes Issues that predispose the man to develop psychogenic ED Examples • Traumatic sexual experience, e.g. humiliation by partner in previous relationship • Lifestyle issues, e.g. increased stress from financial, marital or work issues • Educational issues, e.g. unrealistic expectations about sexual intercourse • Cultural issues, e.g. repressed or abnormal sexuality as a result of cultural, religious or parental attitudes Precipitating causes Issues that precipitate loss of normal erectile function Examples • Infidelity can result in ED with either partner • Ageing results in changes in sexual function which may not be expected or recognised • Educational issues can lead to unrealistic expectations about sexual function • Loss of partner by divorce or death may precipitate ED with subsequent partners Maintaining factors Issues that tend to maintain ED when some other cause has precipitated it

10 BACKGROUND

Predisposing causes Examples • Performance-related anxiety, where anxiety leads to increased sympathetic nervous tone and increased smooth muscle contraction in the penis • Poor communication may not allow couples to discuss problems with sexual function • Educational issues can result in perpetuation of so-called ‘sexual myths’ • Fear of intimacy may exacerbate psychosexual problems

present in 17% of untreated hypertensive men, rising to 25% in those on treatment. With respect to dyslipidaemia, it is raised low-density lipoprotein (LDL) that is the major pathogenic risk factor for the ED associated with hyperlipidaemia. Increased levels of HDL (high-density lipoprotein) appear to be relatively protective against ED. ED of ageing There are numerous mechanisms that underlie the ED that develops with ageing, but chief among these is vascular disease (Table 5). We now know that as men get older vascular disease becomes more prevalent, and this is accompanied in the penis by loss of smooth muscle and replacement with collagen. These processes seem to be a direct consequence of the vascular disease and the relative hypoxia that accompanies it. Endocrine ED Hypogonadism may occur as a result of either testicular, pituitary or hypothalamic disease. Although rare, the former is the commonest organ to be diseased; examples include mumps orchitis, bilateral maldescent or torsion, and radiotherapy to the testes. Occasionally testicular (or primary) hypogonadism is congenital, as in Klinefelter’s syndrome. Pituitary or hypothalamic disease is rare, but may occur with pituitary tumours, haemochromatosis or trauma. Hyperprolactinaemia due to a prolactin-secreting tumour of the pituitary can also cause ED. Although rare, it is important to identify because it is one of the few causes of organic ED in young men. Clinical features

THERAPY FOR ERECTILE DYSFUNCTION 11

Table 5 Factors associated with the erectile dysfunction that accompanies ageing. Atherosclerotic vascular disease Loss of smooth muscle within the penis Increased collagen within the cavernosal tissue Gradual diminution of serum testosterone Gradual (relative) denervation of the penis Loss of elastin within the tunica albuginea Other changes in sexual function which can increase ‘worry’ Decreased arousal to erotic stimuli and increased dependence upon tactile stimulation Decreased force and volume of ejaculation Increased (postejaculation) latency between sexual episodes

include gynaecomastia, galactorrhoea and erectile dysfunction. In the later stages of the condition there may be compression of the optic nerves, with visual field defects. There is usually an associated modest reduction in the serum testosterone. Depression and ED Depression is one of the commoner causes of ED, and although it has traditionally been classified as a psychogenic cause it really has much more in common with other organic causes of ED. We are increasingly recognising that there is a very close relationship between depression and ED which may also be exacerbated by the use of antidepressants. Interestingly, there is increasing evidence that if ED is treated effectively, then associated depressive symptoms improve. Iatrogenic ED It is easy to see how radical pelvic surgery can damage the nerve supply of the penis, but it is similar damage that is also probably the mechanism for the ED that occasionally accompanies transurethral resection of the prostate (TURP). It seems likely that during TURP diathermy injury occurs to the cavernous nerves as they run alongside the prostate. The true incidence of ED following TURP is disputed, but it probably occurs in around 10% of men who are potent preoperatively. In around 50% of these men there will be complete recovery within 12 months, suggesting some sort of neuropraxia.

12 BACKGROUND

Pelvic radiotherapy for prostate, bladder or rectal cancers can also cause ED, probably as a result of a vasculopathy affecting the parasympathetic nerves. Perhaps 40% of men undergoing external beam radiotherapy for prostate cancer will develop ED, and it is increasingly clear that similar numbers develop ED following prostatic brachytherapy. A list of the more common drugs that can cause erectile dysfunction is given in Table 6. It is a long list, but it would be wrong to interpret this as meaning that every man on any of the drugs in the list will have ED. The effects of each drug are variable, and will be affected by other coexistent conditions: for instance thiazides are said to have a two to six times greater risk of causing ED than placebo, whereas β-blockers are associ Table 6 Drugs that can cause erectile dysfunction. Antihypertensive medication Thiazide diuretics β-blockers Centrally acting agents, e.g. methyldopa, clonidine NB: ACE inhibitors and α-blockers do not cause ED Psychotropic medication Phenothiazines Butyrophenones Lithium Anxiolytics and hypnotics Antidepressant medication Tricyclic antidepressants Monoamine oxidase inhibitors Drugs used to treat prostate cancer LHRH analogues Steroidal antiandrogens, e.g. cyproterone Oestrogens Other drugs Digoxin Cimetidine Metoclopramide Phenytoin Carbamazepine

THERAPY FOR ERECTILE DYSFUNCTION 13

Anticholinergics Recreational drugs Alcohol Marijuana Opiates Cocaine Anabolic steroids

ated with ED in around 10–15% of men. In clinical practice, if the commencement of a new drug appears to be associated with the onset of ED, then it is reasonable to change the medication (if there is an alternative), but experience shows that return of normal erectile function rarely occurs. This reflects the multifactorial nature of ED in many men, and suggests that the introduction of a new drug has simply proved to be the final precipitating factor. Summary ■ There are a large number of conditions that can lead to erectile dysfunction ■ In many men there may be a number of causative mechanisms working at any time ■ The commonest cause of erectile dysfunction is vascular disease ■ Psychogenic ED is occasionally found in isolation, but may accompany physical causes ■ ED is three times more common in diabetics than in non-diabetics How common is ED? Until the last 10 years we have had little detailed information concerning the prevalence of ED. The first modern study was the Massachusetts Male Aging Study (MMAS), published in 1994, and since then a number of similar epidemiological studies have been undertaken in other countries. Although the methodology has varied a number of common themes have emerged, which are outlined below.

14 BACKGROUND

Figure 6 Proportions of MMAS population with mild, moderate and severe erectile dysfunction.

Erectile dysfunction is common The MMAS study suggested that around 50% of men over the age of 40 suffered from ED (Figure 6). However, it was also clear that many of these cases were not severe, and this has been confirmed in subsequent studies. Overall, in the MMAS 35% of men between the ages of 40 and 70 had moderate or severe ED. The prevalence of erectile dysfunction increases with age The prevalence of ED increases with increasing age (Figure 7), such that, if we restrict ourselves to patients with moderate and severe ED, then around 10% of men in their 40s, around 20% of men in their 50s, around 40% of men in their 60s and 60% of men in their 70s are affected. Similarly, the incidence of newly developing cases of ED also increases with increasing age (Figure 8).

THERAPY FOR ERECTILE DYSFUNCTION 15

Figure 7 International age-related prevalence of ED.

Erectile dysfunction shows some geographical and cultural variation The prevalence of ED is broadly similar across a range of countries with different cultures (Figure 7). However, there is variation, with some countries (such as Turkey) appearing to have a substantially higher incidence, particularly in older men.The possible reasons for these differences are multiple, and include different cultural attitudes towards sexual activity and differing rates of vascular disease. Unfortunately, the methods of assessing ED were not the same in each study, so any comparisons cannot be definitive. Erectile dysfunction is associated with other conditions, including vascular disease and its risk factors (Table 7) Most of the studies looked at risk factors for erectile dysfunction and most found significant associations with a variety of diseases, including: ■ Cardiovascular disease (approximately increased relative risk×2), ■ Diabetes (approximately increased relative risk×3–4)

16 BACKGROUND

Figure 8 Incidence of ED in the Massachusetts Male Aging Study (MMAS).

■ Hypertension (approximately increased relative risk×1.5–2) ■ Depression (approximately increased relative risk×2–3.5) ■ Lower urinary tract symptoms (approximately increased relative risk×1.5–2). Erectile function is associated with a number of lifestyle issues (Table 7) There is increasing evidence that exercise is beneficial for sexual function, as is modest alcohol consumption, whereas increasing body mass index (BMI) and excessive alcohol consumption lead to increased erectile dysfunction. Although intuitively we would expect to find that ED is associated with cigarette smoking, the data are inconclusive in this respect. Table 7 Factors associated with ED from epidemiological studies. Medical conditions

Risk factors

Protective factors

Diabetes Hypertension Cardiovascular disease Depression

High levels of HDL

THERAPY FOR ERECTILE DYSFUNCTION 17

Risk factors Lower urinary tract symptoms Raised LDL Lifestyle issues Raised BMI Excessive alcohol consumption Psychosocial issues Unemployment

Protective factors

Exercise Modest alcohol consumption Better education

Summary ■ Significant erectile dysfunction is present in around a third of men over 40 years of age ■ The prevalence of ED: ■ ■ ■ ■

Increases with age Is strongly associated with vascular risk factors Is also associated with psychosocial issues Is broadly similar in different races and cultures

■ Normal erectile function is associated with ‘healthy’ living

2 Assessment

Philosophy of patient assessment Before considering the appropriate assessment of a man who presents with ED it is important to consider what the objectives of that assessment are, and this is particularly relevant in an era where oral therapy is effective for the majority of sufferers, regardless of the aetiology. In the past extensive investigations were undertaken, partly to identify the cause of the ED, as this often dictated therapy. Such extensive investigation is now considered unnecessary for the majority of patients, and a ‘goal-orientated’ approach is usually taken. With this in mind, the objectives of therapy are asa follows : ■ The first objective of patient assessment is to confirm the diagnosis. This is best done by means of a detailed sexual history. ■ The second objective is to ascertain the severity of the problem.This can be performed objectively with questionnaires (e.g. International Index of Erectile Function, IIEF), or it can be ascertained from the history. ■ The third objective is to identify treatable conditions that may be relevant to the aetiology of the ED. Such conditions might include diabetes, hyperlipidaemia, depression, hypertension or hypogonadism. Some of these conditions will be identified during history and examination, whereas all others will require special investigations. ■ The fourth objective is to identify patients who have causes of ED that might be amenable to specific treatment, such as vascular anomalies amenable to reconstructive surgery, endocrine abnormalities amenable to therapy, or a significant psychogenic component where psychosexual therapy might be appropriate.

THERAPY FOR ERECTILE DYSFUNCTION 19

Given these objectives, two things are clear: ■ There is a basic assessment that should be applied to every patient. ■ In some patients additional specialist investigations are appropriate. The history The history is central to the assessment of a man with sexual difficulties. This may take time, and in the context of a busy clinic there may not be enough time at the initial assessment. Under these circumstances a further consultation might be necessary. Standardised questionnaires can be of value, although they are usually reserved for screening or for assessment under trial situations. For the purposes of description the history can be divided into three sections: ■ The sexual history ■ The medical history ■ The psychosocial history. Sexual history It is important to take time with the sexual history. The basic elements are as below, with some potentially useful questions highlighted: What is the nature of the problem? ■ It is important to clarify exactly what the patient’s symptoms are, as some men confuse disorders of erection with disorders of ejaculation, orgasm or desire. ■ Are erections affected under all circumstances? For instance, are satisfactory erections achieved during masturbation? Are nighttime erections normal? Is the erectile problem intermittent? What is the chronology of the problem? ■ When did it start? ■ What were the circumstances? ■ Has there been a sudden or a gradual deterioration in erectile function? How severe is the problem?

20 ASSESSMENT

■ Is there a problem with achieving or maintaining erections, or is there a complete loss of erections? ■ Is penetrative sexual intercourse possible? Are there other sexual problems? ■ Are there problems with sexual drive, desire, ejaculation or orgasm? Definition of patient’s needs and expectations ■ What does the patient want to achieve from the consultation and from treatment? It is often helpful to try and differentiate patients with primarily organic ED from those with primarily psychogenic ED (although it is well recognised that both aetiologies play a significant part in the majority of patients). Some pointers as to whether the ED is mainly psychogenic or organic in nature can usually be obtained from the history, and are shown in Table 8. Medical history Table 8 Features that help to differentiate between psychogenic and organic ED. Feature psychogenic ED Onset of the problem

Nocturnal or early morning erections Circumstances of ED

Non-coital erections

Features which suggest organic ED Sudden, sometimes associated with a specific event. Present

Features which suggest

ED occurs under some, but not all, circumstances Often normal

ED occurs under all circumstances

Gradual

Absent

Absent

In addition to the sexual history a full medical history is important. Conditions that are known to cause ED should be identified, if present. A checklist of some of the more important conditions is shown in Table 9. A list of drugs that may be associated with ED was given earlier (see Table 6).

THERAPY FOR ERECTILE DYSFUNCTION 21

Table 9 Checklist of conditions that can be associated with or cause ED. • • • • • • •

Diabetes Hypertension Hyperlipidaemia Cardiovascular disease Atherosclerosis Depression Liver disease

• • • • • •

Renal disease Pelvic surgery Pelvic radiotherapy Lower urinary tract symptoms Neurological disease Hypogonadism

Psychosocial history Sexual difficulties can disrupt relationships and affect other aspects of a man’s life, and so, although it is sometimes embarrassing for both patient and physician, this is an important aspect of the history. Sensitive enquiries about the patient’s partner (or partners) are relevant, together with the partner’s attitudes to the sexual difficulties. In addition, issues in everyday life may be impinging upon a man’s sexual function. Worries about work or money can result in a reduced interest in sex that may become apparent as ED. Where this is a feature, it is not uncommon for the man to admit to a better sexual life while on holiday. Examination The physical examination usually does not need to be comprehensive. However, a basic, focused examination is necessary in all patients, including a complete genital examination, examination for secondary sexual characteristics and blood pressure measurement.A range of abnormalities may be apparent (Table 10). The value of rectal examination, peripheral vascular examination and neurological examination is controversial, but in the majority of patients they are probably unnecessary. However, if there are other symptoms in the history that suggest a problem either with the urinary tract, the neurological system or the vascular system, then examination of the relevant systems is appropriate. Table 10 Abnormalities to look for on physical examination. Features Genital examination

Absent or small testes

22 ASSESSMENT

Features

Secondary sexual characteristics

Phimosis Size and shape of penis Penile lumps Body habitus Gynaecomastia Abnormal body hair distribution Abnormal stature

Baseline investigation In line with the philosophy of assessment outlined above, a number of investigations are indicated in all patients, in order to identify important treatable conditions. These are: ■ Fasting blood glucose ■ Fasting lipid profile. In addition, most authorities also recommend a baseline endocrine assessment in all patients. A minority reserve these tests for those patients in whom an endocrine abnormality is suspected from the history or examination. A standard screening assessment would be: ■ Serum testosterone ■ Serum prolactin. Fasting blood glucose Diabetes mellitus is one of the commonest causes of ED and is important to identify when it is present. In some patients diabetes is unrecognised prior to the diagnosis of ED, and it is now clear that urinalysis is inadequate as a screening test for diabetes. Currently, the appropriate diagnostic test is a fasting blood sugar. Fasting lipid profile It is now clear that ED is often a marker for atherosclerosis, the risk factors for which include diabetes, hypertension, smoking and hyperlipidaemia. There is increasing evidence that in a proportion of

THERAPY FOR ERECTILE DYSFUNCTION 23

men presenting with ED there is previously unrecognised hyperlipidaemia, and therefore a fasting lipid screen should be performed. The most important features of this are the ratio of HDL to LDL. In short, high levels of HDL are good but high levels of LDL promote a risk of atherosclerosis. Testosterone Testosterone is secreted in a pulsatile fashion by the testicular Leydig’s cells in response to stimulation by luteinising hormone (LH), which in turn is secreted by the pituitary gland. Most (98%) testosterone is bound to plasma proteins, with most of the binding being to either albumin or sex hormone-binding globulin (SHBG). Only 2% of the total testosterone is unbound or free. So-called bioavailable testosterone includes both the free and the albumin-bound testosterone, but excludes the proportion that is bound to SHBG. A testosterone assay will therefore assess the hypothalamic-pituitarygonadal axis. It is important that the testosterone assay is undertaken in the morning, as there is diurnal variation in the level of testosterone in the serum. Levels of testosterone may fall by up to 40% in the afternoon. There is controversy as to the most appropriate testosterone assay (total, free or bioavailable), with the former (i.e. total testosterone) being most usually available. The relative value of these three assays is unclear. Although the pickup rate for hypogonadism is relatively low, the test is justified in that testosterone replacement represents a potentially reversible form of erectile dysfunction. Prolactin Although hyperprolactinaemia is a rare cause of male ED it is an important diagnosis to make. It is usually due to a prolactin-secreting tumour of the anterior pituitary gland, and the classic clinical features are gynaecomastia, galactorrhoea and erectile dysfunction. In most cases the serum testosterone is slightly low, although this is not invariably the case. A number of conditions that cause marginal rises in the serum prolactin are not thought to be pathogenic in terms of erectile function. Such conditions include hyperthyroidism, stress. chronic renal failure, liver disease and a variety of drugs, including methyldopa, opiates and metoclo-pramide.

24 ASSESSMENT

Specialised investigations Under certain circumstances further investigation is appropriate and such tests are usually performed in specialist centres. They are indicated when baseline assessment has either suggested a cause that is potentially amenable to specific curative therapy, or has raised the possibility of a serious condition that merits further investigation in its own right, or at the request of the patient himself. Specific indications for particular investigation are listed in Table 11. Some patients request investigation, often because they are convinced that there is an organic cause for their problem. Such tests cannot conclusively prove this one way or another: normal tests can be very reassuring for them, but abnormalities suggest therapeutic approaches. Table 11 Indications for specialist investigation. Specialist assessment

Indications

General indications for specialised assessment Detailed endocrine screen

Patient request Medicolegal cases Clinical suspicion of hypogonadism Clinical suspicion of hyperprolactinaemia Clinical suspicion of thyroid disease Suspicion of vascular disease amenable to surgical treatment e.g. ED following pelvic fracture Patient request Medicolegal cases

Vascular assessment

Rigiscan studies

Endocrine evaluation If the serum testosterone and prolactin are normal then further endocrinological evaluation is usually unnecessary. If either of these tests is abnormal they should both be repeated. At the same time a serum FSH (follicle-stimulating hormone) and LH should also be performed. If the total testosterone has been used as a screening test (usually because it is easiest to obtain), then the free serum testosterone, with or without an SHBG estimation, is a valuable follow-up investigation.

THERAPY FOR ERECTILE DYSFUNCTION 25

ED can occasionally be due to thyroid disease (both hyper- and hypothyroidism). If there is clinical suspicion then thyroid hormone and serum TSH tests are appropriate. If the serum prolactin is significantly raised then a CT or MRI scan of the pituitary gland is appropriate. Vascular testing In the late 1980s and early 1990s vascular testing was undertaken in all patients. It is now considered unnecessary for the vast majority. The following would be usual indications for vascular testing: ■ Selection of patients for reconstructive penile vascular surgery ■ Medicolegal reasons ■ Patient request. The usual first-line investigation is colour Doppler scanning of the penile arteries. The test should be performed with a high-frequency linear-array transducer (5–10 MHz) following an injection of a smooth muscle relaxant such as prostaglandin E1 and measurements are usually made around 10 minutes after injection. The main penile arteries are scanned, with the intention of ascertaining the flow within them, under circumstances of maximal smooth muscle relaxation (Figure 9). Under normal circumstances this would be achieved during sexual intercourse, but in an X-ray department relaxation is achieved with the prostaglandin E1. A peak systolic velocity (PSV) in the main penile artery of less than 25 cm/s suggests penile artery insufficiency, whereas a PSV more than 35 cm/s is considered normal. The range 25–35 cm/s is an intermediate equivocal range. Abnormal venous function is considered when the PSV is greater than 30 cm/s and the end-diastolic velocity is more than 3–5cm/s. Dynamic infusion pharmacocavernosometry and cavernosography (DICC) is a test designed to assess the integrity of the veins of the penis. During erection there should be no flow in the veins draining the penis, and if there is evidence that flow is maintained this suggests abnormal smooth muscle function within the penis. Under these circumstances abnormal venous channels or ‘Venous leakage’ is seen (Figure 10). This investigation is only indicated in patients suspected as having a site-specific venous leak, in whom vascular surgery is considered a treatment option. Such cases might include patients with

26 ASSESSMENT

Figure 9 Colour Doppler scan of penile arteries. The upper part shows how the vessels are highlighted as blue (veins) or red (arteries), and the lower part shows the waveform from which flow velocity calculations are made.

primary (congenital) erectile dysfunction, a history of penile fracture, perineal or pelvic trauma, or Peyronie’s disease. Again, it is usual to perform the study following the injection of a smooth muscle relaxant such as 10 µg prostaglandin E1. Selective pudendal arteriography is reserved for patients being considered for vascular reconstruction in whom colour Doppler scanning has demonstrated arterial insufficiency. Again, it is usually performed following the injection of a smooth muscle relaxant such as 10 µg prostaglandin E1. Nocturnal penile tumescence testing (NPT) Most normal men achieve an erection four to five times during the night. The presence of normal nocturnal erections is strongly suggestive of a psychogenic aetiology for ED, whereas their loss suggests an organic cause. Historically, nocturnal penile tumescence studies were undertaken to explore this issue, but they are currently performed infrequently. One of the rare indications for a study is in medicolegal or rape cases, where it is valuable to know whether a man is able to achieve erections during the night. Otherwise it is largely used as a research tool.

THERAPY FOR ERECTILE DYSFUNCTION 27

Figure 10 Abnormal venous channels seen during cavernosography.

The device most commonly used for NPT studies is the Rigiscan device, which measures tumescence and rigidity at both the base and the tip of the penis. Recording bands are placed around both the base and the tip of the penis and connected to a small portable recorder. At the end of the recording period the recorder downloads data into a computer for analysis. A variety of parameters can be recorded and analysed, but the most important in clinical terms appears to the period of time during which the base rigidity exceeds 60% of maximum (Figure 11). Summary ■ Assessment of the man with ED is goal orientated, as most men are treated with oral therapy regardless of the aetiology ■ Assessment is directed at: ■ Confirming the nature of the problem ■ Assessing the severity of the problem ■ Identifying significant causative conditions such as diabetes and hypertension ■ Identifying those cases amenable to specific treatment

28 ASSESSMENT

Figure 11 A Rigiscan trace. Note that measurements of tumescence and rigidity are made at both the base and the tip of the penis.

■ Examination of the genitalia, secondary sexual characteristics and blood pressure is essential in all men with ED ■ Measurement of fasting blood sugar and fasting lipids is essential in all men with ED ■ A baseline endocrine evaluation is valuable in all men with ED ■ Specialist investigations are clinically indicated: ■ If there is clinical suspicion of endocrine disease ■ If there is the possibility of specific vascular surgical treatment

3 Treatment

A plan of treatment Regardless of the aetiology of the ED, most men will benefit from oral therapy. If this fails then more invasive options are indicated, progressing if necessary to penile implants for severe cases, provided the patient is willing to have them inserted. Indeed, it is important not to forget these other options for those men who do not respond to tablets. In addition to oral therapy, it is clear that more general therapy must be directed at the control and treatment of risk factors such as diabetes, depression and hypertension. Not only will treatment of these conditions help the ED but also it may prevent further clinically related problems arising in the future. In a similar way, alteration of a patient’s medication may be helpful in some cases. There are certain groups of men in whom specific therapy is indicated because there is a possibility of cure. Most treatments for ED do not cure the underlying problem, but only treat the symptom. Therefore, whenever cure is possible it should be pursued. Patients in whom cure is possible include: ■ Those with predominantly psychosexual ED ■ Those with endocrine disease ■ Those with localised vascular disease, such as those who have developed ED following pelvic or perineal trauma. In these patients specialised investigation may be indicated, and referral for specialist treatment almost always is.

30 TREATMENT

General measures General measures that are valuable in all men with ED include: ■ Control of concurrent risk factors. This includes control of diabetes, hypertension and hyperlipidaemia. Better control often helps the ED, and may resolve the problem altogether. Similarly, treatment of depression often results in improved sexual function. ■ Change of medication. If the onset of the ED appears to be related to the commencement of the drug then a change of medication to one with less risk of causing ED might be beneficial. However, this approach is not as successful as one might wish. It is often the case that the medication was the final precipitating factor, but that there are a number of other pre-existing contributory issues. ■ Change of lifestyle: ■ For the middle-aged man with undue stress, at home, at work or with respect to money, sexual function may be improved by a change in lifestyle, with more exercise, more relaxation and fewer responsibilities. Although this may not always be possible, if it can be achieved it may prove extremely beneficial ■ Advice to reduce any excessive alcohol intake, together with cessation of smoking, is helpful. Although the evidence that stopping smoking actually helps is somewhat limited, prevention of subsequent cardiovascular and cerebrovascular disease is important. Other recreational drugs can also affect sexual function, and advice in this respect is also helpful, where relevant. Oral therapy Oral therapy is the mainstay of treatment for most men with ED. Currently there are four licensed drugs used to treat ED, including three (sildenafil, tadalafil and vardenafil) that inhibit the enzyme phosphodiesterase type 5 (PDE5), and a further drug (apomorphine) that acts centrally.

THERAPY FOR ERECTILE DYSFUNCTION 31

Figure 12 Mechanism of action of the PDE5 inhibitors. Inhibition of PDE5, in the presence of sexual stimulation, leads to increased levels of cGMP within the penile smooth muscle cell, which in turn results in smooth muscle relaxation.

Phosphodiesterase inhibitors Mechanism of action Nitric oxide is released within the corpus cavernosum by parasympathetic nerve endings and by the vascular endothelium.When it enters the smooth muscle cell it stimulates the enzyme guanylate cyclase to produce cyclic GMP (cGMP), its active second messenger. Cyclic GMP produces smooth muscle relaxation, which in turn leads to increased arterial inflow, cavernosal expansion and reduced venous outflow.The action of cGMP is terminated by PDE5, and inhibition of PDE5 will potentiate the proerectile effects of cGMP. Sildenafil, tadalafil and vardenafil all act by inhibiting PDE5 (Figure 12). Sildenafil (Viagra) was the first of these drugs to be launched worldwide, in 1998, and tadalafil (Cialis) and vardenafil (Levitra) were launched in Europe in 2003. All three have many features in common. For instance, all are dependent upon the presence of a sexual stimulus in order for them to work, and when that stimulus disappears so will the erection. However there are some differences between these compounds (Table 12), although at the time of writing there are no comparative clinical studies.

32 TREATMENT

Potency and selectivity ■ Currently 11 different groups of phosphodiesterase enzymes have been identified in the body. These are called isoenzymes and are numbered PDEI to PDEI 1. An ideal PDE5 inhibitor would inhibit only PDE5 and none of the others. ■ All three drugs are potent inhibitors of PDE5. There are slight differences in potency, but these differences are unlikely to have any significant clinical effect. None of the three drugs has any significant Table 12 Differences between the PDE5 inhibitors. Selectivity

Time to peak plasma levels

Duration of activity

Side effects

Sildenafil inhibits PDE6 at high doses, whereas vardenafil does so to a lesser extent Tadalafil has no clinically relevant effect upon PDE6 Tadalafil inhibits PDE II at high doses, Sildenafil and vardenafil have no clinically relevant effects upon PDE II Vardenafil reaches peak plasma levels in around 35–40 minutes in fasted patients. Sildenafil reaches peak plasma levels at around 60 minutes, and tadalafil reaches peak plasma levels at around 2 hours Sildenafil and vardenafil have clinical activity for around 6–8 hours Tadalafil has clinical activity for at least 24 hours All can lead to headache, flushing, indigestion and nasal congestion Sildenafil can lead to visual side effects, usually at higher doses (around 5% patients) Tadalafil can cause myalgia and back pain at clinical doses

activity against PDEs 1, 2, 3, 4, 7, 8, 9 and 10, and the only differences in selectivity is in their activity against PDE6 and PDE11. ■ PDE6 is found in the retina and is involved in phototransduction.At high doses sildenafil inhibits it, resulting in the occasional transient visual changes seen with sildenafil treatment. There is no evidence that there are any permanent visual changes. Vardenafil has less

THERAPY FOR ERECTILE DYSFUNCTION 33

activity against PDE6 and tadalafil has no significant activity at all, so they might be expected to have fewer visual side effects. ■ PDE11 is the newest isoenzyme to be identified and is found in a number of tissues, including the testis and the heart. Its physiological function is as yet unknown. Sildenafil and vardenafil have no significant activity against it, but at high doses tadalafil does. At present there is no evidence of any deleterious effect due to this inhibition. Clinical results of PDE5 inhibitors PDE5 inhibitors need to be taken in conjunction with sexual stimulation, when they will facilitate a return to normal erectile function. In responders, upon sexual stimulation the man will have a normal erection that usually persists until orgasm and ejaculation, following which detumescence will occur. Repeated sexual activity is possible while the drug is still present in the body. Treatment of ED of mixed aetiology results in around 70–75% of men achieving normal erections, with rigidity adequate for penetration and which is maintained to ejaculation. The aetiology of the ED has an effect on the outcome of therapy, with particularly high response rates in men with psychogenic ED and in those with ED secondary to depression or hypertension. Lower efficacy rates are seen in diabetics (when around 50–60% of men achieve adequate erections) and in men who have undergone radical pelvic surgery for prostate cancer, where response rates as low as 30–40% are seen. These latter response rates reflect the relative denervation that occurs in these cases. When there are no nerves there is no nitric oxide release, and so PDE5 inhibitors cannot work. Side effects seen with all drugs include headache, flushing, indigestion and nasal congestion. The commonest of these is the headache that is seen in up to 15% of patients. The side effects become more frequent with increasing doses of the drugs, and reflect inhibition of PDE5 in other tissues within the body. Most of the side effects are transient and well tolerated. It is also clear that the frequency with which patients experience side effects diminishes with repeated doses of the drug. Although there were initial concerns about the cardiac safety of this class of drugs, these concerns have proved unfounded. There is no evidence of any increased risk of either sudden death or myocardial infarction when these drugs are used in men with ED. Concurrent use of

34 TREATMENT

nitrate medication is a contraindication for this class of drugs, as they potentiate the vascular smooth muscle relaxation produced by nitrates, and considerable falls in blood pressure have been seen when both are taken together. It is not possible to directly compare the efficacies of sildenafil, vardenafil and tadalafil until appropriate comparative randomised trials have taken place. However, there are some clinical differences between the three drugs that are summarised above (Table 12). Sildenafil Sildenafil (Viagra) was launched in Europe in 1998 and was the first truly effective oral treatment for erectile dysfunction. It currently has the greatest body of evidence relating to its use. In fasted patients it is effective within 30 minutes, but food delays its absorption, and it is usually best to tell patients to leave an hour after dosing before attempting sexual intercourse. The half-life of the drug is around 4 hours, giving a useful duration of action of around 6–8 hours. Side effects are as above, but in addition occasional visual side effects are seen, such as bluish vision or blurred vision. This reflects the inhibition of PDE6 that occurs with higher doses. The usual starting dose is 50 mg, which can be titrated up to 100 mg or down to 25 mg. The lower dose is recommended in older patients and in those with renal or hepatic impairment. Tadalafil Tadalafil (Cialis) was launched in Europe in 2003. At the time of writing the published data suggest that it has similar efficacy to sildenafil. Following administration it reaches maximal plasma levels in around 2 hours, but it is clinically active in advance of that time, and because of this there is only marginal food interaction. It has a significantly longer half-life than sildenafil, at around 17 hours, and although it is only licensed for efficacy over 24 hours, there are data to confirm its efficacy at 36 hours. Accordingly, it is probably best administered several hours before sex is attempted, thereby reducing any anxiety that might be associated with using a drug to treat ED. The side-effect profile is broadly similar to that of sildenafil, with a few exceptions. Visual side effects are rarely seen, the frequency of flushing appears to be reduced, and some patients (around 10%) complain of muscular discomfort or backache.The cause of this is unclear, but it may

THERAPY FOR ERECTILE DYSFUNCTION 35

be related to the half-life of the drug.The usual starting dose is 10 mg, which can be increased to 20 mg if necessary. The lower dose is recommended for men with hepatic or renal impairment. Vardenafil Vardenafil (Levitra) was launched in Europe in 2003. Again, its efficacy appears to be similar to that of sildenafil. It reaches maximal plasma levels more rapidly than does sildenafil, and may well be more rapidly acting in fasted patients and in those who have eaten lightly. However, absorption is delayed by heavy meals containing fatty food, and again it is sensible to allow around an hour between dosing and attempting sexual activity. Its half-life is around 4 hours, giving 6–8 hours of clinical benefit. Side effects are similar to those of sildenafil, but there are few (if any) visual side effects, and none of the muscular cramps seen with tadalafil. The usual starting dose is 10 mg, which can be raised to 20 mg or reduced to 5 mg as required. The lower dose is recommended for men with hepatic or renal impairment. Using PDE5 inhibitors There are a few golden rules relating to the use of PDE5 inhibitors in men with ED.These are outlined in the Table 13.When starting on a PDE5 inhibitor the patient will take some time to adjust to using a tablet to treat his erectile dysfunction.There may well be anxiety, both on his part and on the part of his partner. Accordingly, it is important to care Table 13 Golden rules for the use of PDE5 inhibitors. Sexual stimulation is essential for the drugs to be effective When starting medication, men should allow adequate time for the drug to be absorbed Dose titration is usually advised for most men For men with severe ED (such as diabetes) it is reasonable to start with the top dose The starting dose should be the lowest available in men with renal or hepatic impairment The starting dose should be the lowest available in men taking the following drugs: Ketoconazole Erythromycin

36 TREATMENT

Protease inhibitors Before labelling a man as being unresponsive an adequate course (i.e. at least four doses) of an adequate dose (i.e. the maximum dose) is essential to assess response Control of associated medical conditions improves the response to PDE5 inhibitors Contraindications to the use of PDE5 include: Concurrent use of nitrates Retinitis pigmentosa Recent MI or CVA (within 90 days) Patients with uncontrolled cardiac disease (angina, arrhythmias, heart failure)

fully explain the importance of sexual stimulation and of leaving an adequate period between taking the drug and attempting sex. In addition, it is important to provide the patient with an adequate number of tablets (usually four at least), and to be prepared to increase dosage up to the maximum, again providing tablets for at least four attempts. The use of nitrates for angina is a contraindication to the use of any PDE5 inhibitor. in addition, the use of the recreational drug amyl nitrate (‘popper’) is also a contraindication. Coadministration can lead to significant hypotension. Other drugs that interfere with the metabolism of these drugs include ketoconazole, erythromycin, and the protease inhibitors used in AIDS patients, which inhibit the hepatic enzymes that metabolise these drugs. In these patients the lowest starting dose of the drug should be used. On the other hand, in patients taking rifampicin, which stimulates the metabolism of these drugs, the maximal dose is advisable. Apomorphine During the 1980s and 1990s considerable evidence accumulated confirming the importance of the hypothalamus in erectile function, and demonstrating the role of dopamine as a proerectile neurotransmitter within the hypothalamus. Apomorphine is a dopaminergic drug which is active in the treatment of erectile dysfunction. When taken sublingually it seems to be preferentially concentrated within the central nervous system, where it

THERAPY FOR ERECTILE DYSFUNCTION 37

acts primarily on the dopaminergic D1 and D2 receptors, although it has a degree of selectivity for the latter. It was licensed in Europe in 2001 for use in the treatment of men with ED, and there are considerable data supporting its efficacy and safety. It provides erections adequate for penetration in around 50% of men with ED of mixed aetiology, although it is clearly most effective in men with mild ED (i.e. those with some degree of residual erectile activity, or those with predominantly psychogenic ED). In comparative studies with sildenafil the efficacy of sildenafil has proved superior, with most patients preferring the PDE5 inhibitor. When taken sublingually it has a rapid onset of action, being effective within around 10–15 minutes of dosing. The most frequent side effects are nausea, headache and dizziness, and their incidence appears to be dose related; the frequency with which patients experience side effects diminishes with repeated doses of the drug. In those patients experiencing nausea the severity is usually mild, with only a few feeling the need to use antiemetics. Syncope is a potential serious adverse event that is occasionally seen. When it does occur it is usually preceded by prodromal autonomic symptoms, including sweating and a feeling of faintness. Patients should be warned to lie down if they experience syncope. The usual starting dose is 2 mg, increasing to 3 mg. Higher doses were used in clinical trials, but have not been licensed because of the significantly increased risk of side effects. In practice, the role of apomorphine is limited by its lower efficacy compared to the PDE5 inhibitors. It is of value in men with mild ED who are anxious to achieve an erection quickly. Other physical and pharmacological treatments Intracavernosal injection Prior to the advent of oral therapy the mainstay of treatment for men with ED was self-injection of alprostadil (prostaglandin E1, or Caverject) into the penis prior to sexual activity. Alprostadil is a smooth muscle relaxant which, when injected, produces an erection within around 10–15 minutes, even in the absence of sexual stimulation. This erection is maintained for between 30 minutes and a few hours. Other agents have been used in this way, including papaverine and phentolamine, but alprostadil is the only licensed preparation. Its main

38 TREATMENT

use nowadays is in patients in whom oral therapy has proved ineffective, or in whom it is contraindicated, and intracavernosal injection is effective in producing an erection in around 60% of the former group. Patients are taught to self-inject into the side of the penis (Figure 13), thereby missing the neurovascular bundle which is sited dorsally. The technique can be difficult to learn, but with care and attention, in a patient who is motivated, it is usually possible to master it. In men who have failed PDE5 inhibitors the usual starting dose is 10–20 µg, although up to 40 µg may be necessary in some patients. Problems with intracavernosal self-injection include: ■ Pain at the injection site. This occurs in around 20–30% of patients and may be severe. It only occurs with alprostadil, and not with other agents. ■ Prolonged erections. These rarely occur when alprostadil is used (around 1% of men, and around 0.06% of injections). Patients should be warned to seek medical attention urgently if the erection lasts longer than 4 hours. Aspiration may suffice to resolve the situation, but occasionally intracavernosal injection of small doses of an α-adrenoceptor agonist such as phenylephrine is necessary. Great care is needed with this, as severe systemic hypertension can be associated. ■ Penile fibrosis with penile deformity. This occurs in around 2–5% of men using self-injection therapy. The risk appears to be related to the frequency of injection and the dose of the drug used. ■ Urethral bleeding. This is usually related to injection into the urethra. ■ Drop-out from treatment. The process of self-injection is not easy. There is a loss of spontaneity, and around 40–60% of men who commence self-injection stop within 2 years. Intraurethal therapy Alprostadil can also be applied intraurethrally (Figure 14). It is absorbed through the urethral mucosa and passes from there, via retrograde flow, into the spongy tissue of the penis, where an erection may ensue.The doses used are much higher than with intracavernosal therapy (250– 1000 µg) and the efficacy is somewhat lower. In fact, there is good evidenc e that the oral PDE5 inhibitors are more effective as a treatment for men with ED than intraurethral alprostadil. Despite this, some patients do respond to intraurethral therapy and prefer it to other treatments. Side effects include urethral pain (in around 10–20%) and dizziness (rarely).

THERAPY FOR ERECTILE DYSFUNCTION 39

Figure 13 Optimal site for injection of alprostadil is into the side of the penis, away from the dorsally placed neurovascular bundle and the ventrally placed urethra.

Vacuum erection devices Vacuum erection devices have been around for almost a century. They work on the principle that if a vacuum is created around the penis, then

40 TREATMENT

Figure 14 Intraurethral application of alprostadil with the MUSE device.

blood can be sucked into it to create an erection. This erection is then maintained with a band placed around the base of the penis. Modern devices are cylindrical and achieve the vacuum with a pump that is either worked by hand or which is motorised, and the band is slipped over the cylinder to the base of the penis (Figure 15). The vacuum is then released and the cylinder removed. When intercourse is over, the band is removed. There are a number of potential problems with vacu um erection devices (Table 14), but despite these issues they continue to be used by some men who have failed oral therapy and who find intracavernosal injection ineffective or impossible. Penile prostheses The principle of inserting a rigid implant into the penis of the impotent man was first used in the 1940s, when rib cartilage was used. The first commercially available penile implants were manufactured in the 1970s, and there is now a range of devices available for those who need them. The main indication for penile implantation is failure of other, less invasive therapies. Some men with severe vascular disease, and some with significant fibrosis of the spongy tissue of the penis, do not respond to medical therapy, and if they find that vacuum pumps are not to their liking then implants are their only solution. Other indications are men with Peyronie’s disease who also have significant ED, and

THERAPY FOR ERECTILE DYSFUNCTION 41

Figure 15 Application of a vacuum erection device.The cylinder is placed over the penis and the air is sucked out, thereby drawing blood into the penis. When the penis is erect, a band is placed around the base.

occasionally some men choose them in preference to other less invasive treatments. The principle of penile implantation is the insertion of two cylindrical prostheses within the penis, one in each corporal body. The prostheses are either ‘semirigid’ or ‘inflatable’. The former (Figure 16) are made of silicone rubber and are reasonably rigid in their own right, but malleable because of silver wires within them. Their main advantage is the simplici Table 14 Problems with vacuum erection devices. •

• • • •

Quality of the erection:the erection is usually cooler and more cyanotic than a normal erection, because the blood drawn into it is venous and because arterial inflow is impeded Pivoting of the erection around the band:the erection does not extend backwards beyond the band, so there is pivoting at the base of the penis Interference with ejaculation:the band compresses the urethra and obstructs ejaculation Spontaneity:application of the pump requires manual dexterity, and inevitably lacks spontaneity Bruising:bruising can occur, especially in men taking anticoagulants

42 TREATMENT

Figure 16 Semirigid penile prostheses.

ty of insertion, and the main disadvantage is the rigidity itself, which makes concealment an issue. Inflatable prostheses (Figure 17) consist of two hollow silicone cylinders connected to a reservoir containing saline, which is placed intra-abdominally, and a pump which is placed within the scrotum. ‘When the man wants to have sexual intercourse he pumps the fluid from the reservoir into the penile cylinders, and when he has finished a release valve allows the fluid to return to the reservoir. The results of surgical implantation are usually excellent, providing that the patient (and his partner) is motivated and has appropriate expectations (Table 15). Contrary to many patients’ expectations, the erections that can be obtained with an implant are not larger than normal, but they do provide good penile rigidity.The glans penis cannot be made rigid (although concurrent use of urethral alprostadil may help this). Complications include infection, erosion of the implant and mechanical failure. The former occurs in around 2–4% of cases, but the risk is increased in men with diabetes and in those undergoing revisional surgery. Vascular surgery As ED is commonly a consequence of vascular disease, it might seem reasonable to attempt vascular surgery to correct it. Indeed, this philosophy was explored quite extensively in the 1980s, but the results of sur gery have proved disappointing and patients suitable for vascular reconstructive surgery are now seen infrequently. Arterial surgery may be of value in young men who have developed ED following trauma, either to the perineum or to the pelvis. Under

THERAPY FOR ERECTILE DYSFUNCTION 43

Figure 17 An inflatable penile prosthesis.

these circumstances the arterial supply to the penis is sometimes disrupted, and an extra arterial input into the penis may be beneficial. Patients are identified by colour Doppler scanning of the penile arteries and by selective pudendal arteriography, and the surgical technique involves connecting an additional arterial source (usually the inferior epigastric artery) to one of the penile vessels. Table 15Results of penile implantation Patient satisfaction Around 80–90% of men are satisfied with the results of penile prostheses Around 60–80% of partners are satisfied with the results of penile prosthesis Quality of the erection Good shaft rigidity Poor glans rigidity No increase in length

44 TREATMENT

Moderate increase in girth with inflatable prostheses Infection Infection rates of around 2–4% are typical Risk is increased in diabetes and revision surgery Other complications Erosion is rare Mechanical failure is approximately 2% per year

Venous surgery has all but disappeared. It was a popular treatment for so-called venous leakage in the 1980s, but we now know that venous leakage is a radiological phenomenon, which really reflects diseased smooth muscle within the penis. If the penile smooth muscle is malfunctioning, then the spongy tissue does not expand appropriately and the venous drainage is not closed off. Hence the abnormal veins are seen on cavernosography. Given what we now know about the pathophysiology of the condition we might not expect surgical procedures to tie off the leaking veins to be helpful, and indeed, time and experience have confirmed this. Psychological therapy There is a psychogenic component in almost all men with ED. However, in most it is not the dominant feature and primary psychotherapy is inappropriate, although these men do need support during assessment and treatment. Appropriate advice, time and empathy can only help to make physical treatments more successful in this group of patients. For those in whom the aetiology of the erectile dysfunction is primarily psychogenic, psychosexual counselling offers an opportunity of cure. If one accepts this premise then a number of issues follow on. How do we identify those men with primarily psychogenic ED? As was outlined in the section dealing with patient assessment, there are a few features in the patient history that suggest a primarily psychogenic aetiology. These are reiterated below (Table 16). Studies have suggested that, of the factors listed, the presence or absence of nocturnal erections is the single most important discriminating factor The issue of age is a complex one. Most young men will have a largely psychogenic problem, but the assessing clinician must be aware

THERAPY FOR ERECTILE DYSFUNCTION 45

of other possible physical causes that can affect this age group, such as neurological disease. trauma, endocrine disease, or some abnormality related to drug use. In older men the cause is usually organic, but again the clinician should not lose sight of possible psychogenic factors. Table 16 Features that help to identify men with predominantly psychogenic ED. Onset Tends to be sudden in onset, often with a specific precipitating event Patient age Most young men will have a significant psychogenic component Older men (>40 years) will more commonly have mainly organic problems Cincumstances of the ED Erectile difficulties can be variable (e.g. with specific partner) Non-coital erections may be normal Night-time and morning erections are normal Other aspects of sexual function The patient may have reduced libido or sexual drive

What format does psychological treatment take? There are a number of approaches to psychological treatment in men with ED, the details of which are beyond the scope of this handbook. However, in general terms the behavioural methods of Masters and Johnson in the 1970s have largely been superseded by more cognitive approaches. This has made it easier to treat single men, in contrast to the behavioural approach, where treatment of couples was the norm. Multiple visits are necessary, and the impatient patient needs reassurance and encouragement to complete the course of treatment, rather than resorting to ‘quick-fix’ medical and physical therapies. What is the place of medical treatment? When faced with a young man in whom there is clear evidence of psychogenic ED, there is a practical problem. Oral therapy may well be effective (the results are excellent in this group of patients), but will fail to deal with the underlying issues. However, psychological therapy is time consuming and there is no guarantee of a rapid outcome, even if

46 TREATMENT

the results of such approaches are reasonably good (see below). Given this dilemma, many specialists now use combination treatment, i.e. they start the patient on oral medication while referring him for formal psychosexual therapy.There are clear risks with this approach, including the possibility that the patient may find the tablets so effective that he will fail to attend for the counselling.The counter argument is that oral therapy, if successful, might provide confidence and a spontaneous resolution of the problem. In theory, combination treatment might give better results than either treatment alone, and trials are under way to test this hypothesis. What are the results of psychological therapy? The results of psychosexual therapy for ED are quite poorly documented. Early behavioural approaches suggested improvement in over 70%, and more recent publications have supported this. However, there are problems with patient drop-out from treatment, and in the era of oral therapy there is always the temptation for the patient and the physician to seek a ‘quick-fix’. It is important to emphasise to the patient the potential benefits of specific therapy. Hormone therapy Testosterone is vital for normal sexual functioning in men. Reduced levels of testosterone affect sexual function significantly, with changes in sexual drive and erectile function. For men with ED who have clear evidence of reduced testosterone levels, replacement therapy is usually beneficial. Diagnosis is as outlined earlier (see Chapter 2), with at least two morning testosterone samples being necessary to confirm the diagnosis. Serum LH and prolactin are necessary to assess pituitary function, as is SHBG if the total testosterone has been measured. Options for therapeutic replacement include oral, transdermal, intramuscular or implanted testosterone (Table 17). For most men, testosterone patches are probably the first-choice replacement option, but skin irritation can be a problem, and if this proves insurmountable then intramuscular injections are probably the next best option. Side effects of testosterone treatment in general include oedema, raised haematocrit, gynaecomastia, acne and hirsutism. Hepatotoxicity has been reported, especially with oral preparations. It is important to monitor the PSA, LFTs and serum lipids of anyone receiving testosterone therapy.

THERAPY FOR ERECTILE DYSFUNCTION 47

The male menopause Total and free testosterone levels gradually fall with increasing age, whereas SHBG, the protein that binds most of the testosterone, rises (Figures 18a-c). These gradual changes have been contrasted with the sudden hormonal changes that accompany the female menopause, and which are known to cause a variety of symptoms and physiological changes in women. The question has arisen as to whether the more gradual hormone changes seen in men produce any comparable symptomatic or physiological changes. In the context of this handbook, the question that arises from this is whether these changes have any effect on erectile function. At present the evidence demonstrating significant physiological or symptomatic consequences of ageing in men is inconclusive, and in particular the effect of these hormone changes on erectile function is unclear. Table 17 Options for testosterone replacement. Mode of administration Oral

Frequency of administration 2–4 times/day

Topical

Daily

Intramuscular

Every 2–3 weeks

Implanted pellet

Every 3–6 months

Features Easy to administer But: • Serum levels less predictable • Hepatotoxicity with some preparations in some men Provide physiological levels of testosterone with diurnal variations But: • Skin irritation in some men • Some patches need scrotal application Inexpensive But: • High levels immediately after injection, which gradually fall to relatively low levels Inexpensive

48 TREATMENT

But: • Require minor surgical procedure to insert • Produce initially high, but gradually falling levels

Furthermore, there are worries relating to the theoretical risks of testosterone supplementation (as opposed to replacement), which include cardiovascular disease, lipid abnormalities and prostate disease. Currently, neither the benefits nor the risks of therapy have been fully elucidated. and supplementation in older men with testosterone values at the lower end of the normal range cannot be recommended. Summary ■ Treatment of the man with ED takes a hierarchical approach, with the least invasive, most acceptable treatment being used initially ■ Oral therapy is first-line therapy for most men ■ The most successful and effective class of oral medications are the PDE5 inhibitors sildenafil, tadalafil and vardenafil: ■ All the PDE5 inhibitors appear to have equal efficacy ■ There are differences in the selectivity, time course and side effects of these drugs ■ Sublingual apomorphine may be of value in men with mild ED who require a drug with a rapid onset of action ■ If oral therapy fails, then patients can choose between intraurethral alprostadil, intracavernosal alprostadil and vacuum erection devices ■ Penile prostheses are reserved for men in whom all else has failed ■ Vascular surgery is rarely indicated ■ Testosterone replacement is of value in men with demonstrable hypogonadism ■ Testosterone supplementation is unproven in the older man with low to normal levels of testosterone

THERAPY FOR ERECTILE DYSFUNCTION 49

Figure 18 Endocrine changes in the ageing male. A gradual fall in total (a) and free testosterone (b), combined with a gradual rise In the SHBG (c).

4 Special problems

Erectile dysfunction in men with cardiac disease The cardiac effects of sexual intercourse Sexual activity involves physical exercise, which in turn causes an alteration in cardiac function. There is a rise in pulse rate to around 120 beats/min and a modest rise in systolic blood pressure to around 160 mmHg. The changes are maximal at orgasm and the usual duration of sexual activity is between 5 and 20 minutes. The work that this involves for the man is around 3–5 MET (Metabolic Equivalent of the Task), and this compares with expenditure involved in playing golf (around 4–5 METs) and gardening (3–5 METs) (Table 18). Table 18 Energy requirements of various daily activities. Daily activity

MET score rating

Sexual intercourse with established partner: Lower range (‘normal’) Upper range (vigorous activity) Lifting and carrying objects (9–20 kg) Walking 1 mile in 20 minutes on the level Golf Gardening (digging) DIY, wallpapering, etc. Light housework, e.g. ironing, polishing Heavy housework, e.g. making beds, scrubbing floors

2–3 5–6 4–5 3–4 4–5 3–5 4–5 2–4 3–6

THERAPY FOR ERECTILE DYSFUNCTION 51

A question that is commonly asked is whether this degree of activity can precipitate myocardial ischaemia and a heart attack? Well, occasionally it can, but the risk is a very small one. For instance, the baseline relative risk of a man without known cardiac disease having a heart attack is around 1 in a million per hour, and this increases to 2.5 in a million per hour in the 2 hours after sexual intercourse. For the patient with cardiovascular disease these risks are higher, but are still only 10 in a million per hour baseline and 30 in a million per hour after sexual intercourse. Accordingly, sexual activity has a very low absolute risk of leading to a heart attack, and it has been estimated that it is a likely contributor in no more than 1 % of heart attacks. Cardiac risk factors in men with ED It is becoming increasingly clear that in many men ED is an early marker for atherosclerosis, and therefore for cardiovascular disease.The main risk factors, namely hypertension, hyperlipidaemia (possibly smoking) and diabetes, are the same, and studies are increasingly showing that in apparently healthy middle-aged men who present with ED, if one looks closely then evidence of cardiovascular risk factors abnormalities can be identified. Modification of these risk factors at presentation might be expected to confer significant benefits on the general health of the man. Erectile dysfunction in men with cardiac disease Erectile dysfunction is commoner in men with cardiovascular disease. In men with untreated hypertension the prevalence is reported as 17%, rising to 25% in treated hypertensive men. The prevalence in men who have previously had a myocardial infarction has been variously quoted as between 44 and 64%. Further, many of the drugs used to treat cardiovascular disease will exacerbate any sexual difficulties. The question therefore arises: in the man with cardiovascular disease who presents with ED, what should the physician do? Certainly there should be a thorough assessment of the cardiac status of the patient and any uncontrolled risk factors should be addressed. With respect to treatment for the ED, a number of consensus groups have published guidelines for this situation, grading men into high, intermediate and low risk (Table 19). The management of such men is summarised below:

52 SPECIAL PROBLEMS

■ Men with low-risk cardiac status can be managed in the primary care setting and treatment options can be reviewed with the patient. ■ Men with intermediate risk should undergo specialist evaluation prior to categorisation into the high- or low-risk categories. ■ Men in the high-risk group need specialised cardiac evaluation, and treatment for the ED should be deferred until the cardiac status is stabilised. Table 19 Grading of cordiovascular risk. Grading of risk Low risk

Cardiovascular status upon presentation Controlled hypertension Asymptomatic ≤3 risk factors for coronary artery disease, excluding age and gender Mild valvular disease Minimal/mild stable angina Post successful revascularisation Mild congestive heart failure Intermediate risk Recent MI or CVA (i.e. within last 6 weeks) Asymptomatic but >3 risk factors for coronary artery disease—excluding age and gender Left ventricular dysfunction or moderate congestive heart failure Murmur of unknown cause Moderate stable angina Heart transplant Recurrent TIA High risk Severe or unstable or refractory angina Uncontrolled hypertension (SBP>180 mmHg) CHF (severe) Recent Ml or CVA (i.e. within last 14 days) High-risk arrhythmias Hypertrophic cardiomyopathy Moderate/severe valve disease

As to what treatment the patient should receive, the algorithm of management is similar to that in a non-cardiac patient. There is no evidence that any particular therapeutic modality has any increased cardiac risk, although it is worth emphasising that if the patient is

THERAPY FOR ERECTILE DYSFUNCTION 53

already taking contraindicated.

nitrate

medication

then

PDE5

inhibitors

are

Other aspects of male sexual dysfunction Peyronie’s disease Peyronie’s disease is a condition of unknown aetiology which can affect adult men of all ages, and which is characterised by penile deformity, fibrotic lumps within the tunica albuginea, painful erections in some men, and erectile dysfunction in some men. It typically progresses over a 12–24-month period before stabilising. There is no proven and effective medical therapy, and in men with a stable deformity that interferes with sexual activity the treatment is surgical. Surgery seeks to abolish any deformity, thereby restoring the ability to undertake sexual intercourse. Premature ejaculation There is no universally accepted definition of premature ejaculation, and a careful history is required to assess whether the problem is genuine. The pathophysiology is unclear at present, although in many there is a significant psychosexual component. Treatment may involve behavioural sex therapy, or the use of drugs such as topical anaesthetic creams or oral antidepressant drugs, of which the selective serotonin reuptake inhibitors (SSRIs) are the most effective. Retrograde ejaculation Retrograde ejaculation occurs when the bladder neck fails to contract during ejaculation. The commonest cause is following bladder neck surgery, such as transurethral prostatectomy, but it can also occur in patients taking α–blocking medication and in patients with autonomic neuropathy secondary to conditions such as diabetes. Treatment involves the removal of any causative factor, and in diabetics α– agonists have some efficacy.

54 SPECIAL PROBLEMS

Anorgasmia Failure to orgasm is unusual, poorly defined, and often psychogenic in origin. It can occasionally occur in neurological disease.

Further reading

Andersson KE, Wagner G. Physiology of erection. Physiol Rev 1995;75:727– 736. Braun M,Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann U. Epidemiology of erectile dysfunction: results of the ‘Cologne Male Survey’. Int J Impotence Res 2000; 12:305–311. Brock GB, MacMahon CG, Chen KK et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 2002; 168:1332–1336. Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Russell RO Jr, Zusman RM. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease.J Am Coll Cardiol 1999;33:273–282. Christ GJ. The penis as a vascular organ. Urol Clin North Am 1995;22:727– 745. Daines B, Barnes T. Psychotherapy in the treatment of erectile dysfunction. In: Carson C, Kirby R, Goldstein I, eds. In: Textbook of Erectile Dysfunction. Oxford: Isis Medical Media, 1999. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151:54–61. Gingell C,Wright P, Barnes T et al. Guidance on the management of erectile dysfunction in primary care. Prescriber 1999; Supplement 5th June: 1–16. Hellmstrom WJG, Gittelman M, Karlin G et al.Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomised double-blind placebo controlled trial. J Androl 2002;25:763–771. Jackson G, Betteridge J, Dean J et al. A systematic approach to erectile dysfunction in the cardiovascular patient: a consensus treatment—update 2002. Int J Clin Pract; 2002 56:663–671. Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts Male Aging Study. J Urol 2000; 163:460–463. Langtry HD, Markham A. Sildenafil: review of its use in erectile dysfunction. Drugs 1999; 57:967–989. Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. N Engl J Med 1996;334:873–877.

56 FURTHER READING

Padma-Nathan H, Hellstrom WJ, Kaiser FE et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997;336:l–7.

Index

Acetylcholine, 3 Age causes of ED, 10, 44 hormonal changes, 46, 48 prevalence and incidence of ED, 13–14, 15 Alcohol intake, 16, 29 α-adrenoceptor agonists, 39, 52 Alprostadil intracavernosal injection, 37–2 intraurethral injection, 39–3 Amyl nitrate, 35 Anorgansmia, 53 Antidepressant drugs, 11, 12, 52 Antierectile nervous pathways, 1 Antihypertensive drugs, 11–12 Anxieties, 9, 22 Apomorphine, viii, 36–37 Arteries anatomy, 2 assessment, 24–7 surgery, 42 Arteriography, pudendal, 26, 42 Assessment, see Patient assessment Atherosclerosis, 7, 21–4

Body mass index (BMI), 16 Brachytherapy, 11 Buck’s fascia, 2 Cardiac risk oral therapies, 33 sexual activity, 48–6 Cardiovascular disease ED in, 16, 50–8 risk factors for, 7, 50 Causes of ED, 6–7 ageing, 10, 44 depression, 11 differentiating psychogenic and organic, 20 iatrogenic, 11–13 organic, 7–13 and outcome of therapy, 32 psychogenic, 7, 9 Cavernosography, 25, 26 Cavernous artery, 2 Cavernous nerves, 2–3, 11 Central nervous system, viii, 1 Cialis, see Tadalafil Cigarette smoking, 7, 16, 29 Circumflex veins, 2 Cognitive therapies, 45 Colour Doppler scanning, 24–7 Combination treatment, 45 Corpora cavernosa alprostadil injections, 37–2 anatomy, 2, 3

Backache, 34 Behavioural therapies, 45 β–blockers, 11–12 Blood pressure raised (hypertension), 9, 16 sexual activity, 48 57

58 INDEX

Corpus spongiosum, 2, 3 Cultural factors, 14–15 Cure, possible, 28 Cyclic GMP, 4, 5, 30 Dartos fascia, 2 Deep dorsal vein, 2 Depression, 11, 16 Diabetes, 7–8, 52 as cause of ED, 7–8 diagnosis, 21 risk of ED, 7, 16 treatment of ED, 32 DICC (dynamic infusion pharmacocavernosometry and cavernsography), 25, 26 Diuretics, thiazide, 11 Dizziness, 36 Dopamine, viii, 1 Dopaminergic drugs, viii, 36–37 Doppler scanning, colour, 1–6 Dorsal artery, 2 Dorsal nerve, 2 Drugs causing ED, 11–13 changes to 29 interfering with PDE5 inhibitor metabolism, 35–9 recreational, 12, 29 see also Oral therapy Dynamic infusion pharmacocaversometry and cavernosography (DICC), 25, 26 Dyslipidaemia, 8–9, 22 Ejaculation disorders, 52 Endocrine system assessment, 21, 22–5, 24 changes in ageing, 46, 48 disorders causing ED, 10–11 Endocrine therapy, 46–2 Energy requirement daily activities, 48 sexual intercourse, 48

Epidemiology, 13–16, 50 Erectile dysfunction (ED) causes, see Causes of ED prevalence, see Prevalence treatment, see Treatment Erections normal function/control, viii–6 prolonged, 37, 39 results of oral therapy, 32 results of penile implants, 43 types of, viii–1 Erotic stimuli, viii Erythromycin, 36 Examination, physical, 20–3 Exercise, 16 External beam radiotherapy, 11 Fasting blood glucose, 21 Fasting lipid profile, 21–4 Fibrosis, penile, 39, 52 Flushing, 32, 34 Follicle stimulating hormone (FSH), 24 Genital examination, 20, 21 Geographical factors, 14–15 Glucose, fasting blood, 21 Guanylate cyclase, 4, 5, 30 Headache, 32–6, 36 Heart attack previous/recent, 50, 51 risk of with sexual activity, 48–6 High density lipoprotein (HDL), 22 History, 18 medical, 20–2 psychosocial, 20 sexual, 18–l Hormones changes with ageing, 46, 48 disorders of, 10–11 replacement/supplementation therapy, 46–1 Hyperlipidaemia, 8–9, 22

THERAPY FOR ERECTILE DYSFUNCTION 59

Hyperprolactinaemia, 10–11, 22–5, 46 Hypertension, 8–9, 16 drug treatments, 11–12 Hypogonadism, 10 causes, 10 diagnosis, 22 hormone therapy, 46–1 Hypothalamus, viii, 1, 10, 36 Iatrogenic causes, 11–13 Implants, penile, 41–5, 42 Incidence, 14, 15 Injections intracavernosal, 37–2 intraurethral, 39–3 Intracavernosal injection, 37–2 Intraurethral therapy, 39–3 Investigations baseline, 21–5 specialised, 23–9 Ketoconazole, 36 Klinefelter’s syndrome, 10 LDLs (low-density lipoproteins), 9, 22 Levitra, see Vardenafil LH (luteinizing hormone), 24, 46 Lifestyle making changes to, 29 risk factors for ED, 16 Lipids, blood, 8–9, 21–4 Low-density lipoprotein (LDL), 9, 22 Luteinizing hormone (LH), 24, 46 Male menopause, 46, 48 Massachusetts Male Aging Study (MMAS), 13–15 Medical conditions, 16, 20 Medicolegal cases, 26 Menopause, male, 46, 48 Metabolic Equivalent of the Task (MET) score, 48

MMAS (Massachusetts Male Aging Study), 13–15 Muscular discomfort, 34 MUSE device, 39–3 Myocardial infarction previous/recent, 50, 51 risk of with sexual activity, 48–6 Nervous system, viii, 1, 2–3 disease/damage to, 3, 7, 8, 11, 32 Neurological examination, 20 Neurotransmitters, viii, 1, 3–4, 5, 32 Nitrate drugs, 33, 35, 52 Nitric oxide (NO), 3–4, 56, 8, 30 Nocturnal erections causes, 1 testing, 26–9 Nocturnal penile tumescence test-ing (NPT), 26–9 Noradrenaline (norepinephrine), viii, 1 NPT (Nocturnal penile tumes-cence testing), 26–9 Older men, 44 Oral therapy, 29–37 apomorphine, 36–37

Oral therapy (contd) cardiac safety, 33 phosphodiesterase inhibitors, 30–9 in psychogenic ED, 45 testosterone, 47 Organic ED, 6–13, 1 differentiating from psychogenic ED, 20 Orgasm, failure, 53 Oxytocin, viii Partner, 9, 20 Patient assessment baseline investigations, 21–5 examination, 20–3 history, 18–2 objectives, 17–18

60 INDEX

specialized investigations, 23–9 Peak systolic velocity (PSV), 24–7 Pelvic injury, 3 Pelvic plexus, 2–3 Pelvic radiotherapy, 11 Pelvic surgery, 3, 11, 32 Penile arteries anatomy 2 assessment, 24–7 Penile deformity/fibrosis, 39, 52 Penile prostheses, 28, 41–5 results of, 43 types of, 41–5, 42 Penis, anatomy, 2, 3, 4 Peripheral nervous system, 2–3 disease/damage, 3, 7, 8, 11, 32 Peyronie’s disease, 25, 41, 52 treatment, 52 Phenylephrine, 39 Phosphodiesterases type 5 (PDE5), 4 type 6 (PDE6), 32, 33 type 11 (PDE11), 32 Phosphodiesterase inhibitors, 30–9 clinical results, 31, 32 contraindications and interaction, 35–9, 52 differences between agents, 31 mechanism of action, 4, 30–4 potency and selectivity, 31–5 rule of use, 34–8 side effects, 31, 32–6 Physical examination, 20–3 Pituitary gland, 10, 11, 22, 24 ‘Poppers’ (amyl nitrate), 35 Premature ejaculation, 52 Prevalence, 13–16, 50 Prolactin, serum, 10–11, 22–5, 46 Prostaglandin E1, 24, 25, 26 Prostate cancer, treatment, 11, 12, 32, 52 Prostatectomy, transurethral, 11, 52 Prostheses, see Penile prostheses Protease inhibitors, 36

Protective factors, 16 Psychogenic ED, 7, 20 causes, 7, 9 differentiating from organic ED, 20 identifying patients, 3, 26

Psychogenic ED (contd) oral therapy, 45 psychological therapy, 43–9 Psychological therapy, 43–9 Psychosocial factors, 16, 20 Psychotropic drugs, 12 Pudendal arteriography, 26, 42 Questionnaires, 17, 18 Radiotherapy, pelvic, 11 Rape cases, 26 Rapid eye movement (REM) sleep, 1 Recreational drugs, 12, 29 Reflex erections, 1 Relationships, 9, 20 Retrograde ejaculation, 52 Rifampicin, 36 Rigiscan studies, 26–9 Risk factors, 16 cardiovascular disease, 7, 50 control and treatment, 28, 29 lifestyle, 16, 29 medical disorders, 16, 20 Selective serotonin reuptake inhibitors (SSRIs), 52 Self-injection, 37–3 Serotonin, viii, 1 Serotonin uptake inhibitors, selective (SSIRs), 52 Sex hormone-binding globulin (SHBG), 22 changes with age, 46, 48 Sexual anxieties, 9, 20 Sexual characteristics, secondary, 21 Sexual history, 18–1 Sexual intercourse

THERAPY FOR ERECTILE DYSFUNCTION 61

cardiac effects, 48–6 energy requirement, 48 SHBG, see Sex hormone-binding globulin Side effects hormonal therapy, 46 phosphodiesterase inhibitors, 31, 32–6, 34 Sildenafil, 33 clinical results, 31, 32 comparison with apomorphine, 36 dosage, 33 mechanism of action, 4, 30–4 potency and selectivity, 31–5 rules for use, 34–8 side effects, 31, 32–6 Sinusoids, 2, 3, 4, 5 Sleep, erections during, see Noctural erections Smoking, 7, 16, 29 Smooth muscle relaxation, 3, 4, 30, 43 Spongy tissue, penile, 3, 4, 43 SSRIs (selective serotonin reup-take inhibitors), 52 Stress, 20, 29 Surgery causing pelvic nerve damage, 3, 11, 32

Surgery (contd) Peyronie’s disease, 52 treatment of ED, 41–7 Surgical implants, 41–5, 42 Syncope, 36 Tadalafil, 33–7 clinical results, 31, 32 dosage, 34 mechanism of action, 4, 30–4 potency and selectivity, 31–5 rules for use, 34–8 side effects, 31, 32–6, 34 Testosterone assay, 22

changes with age, 46, 48 diurnal variation, 22 replacement/supplementation therapy, 46–1 Thiazide diuretics, 11 Thyroid disease, 24 Trabeculae, 3, 4, 5 Transurethral resection of the prostate (TURP), 11, 52 Trauma, 3 Treatment, 49 cardiac risk, 50–8 combination, 45 general measures, 29 hormonal, 46–2 intracavernosal injection, 37–2 intraurethral injection, 39–3 oral therapy, 29–37, 45 plan of, 28 psychological, 43–9

Treatment (contd) surgical, 41–7 vacuum devices, 40–4 Tumours, pituitary gland, 10, 11, 22 Tunica albuginea, 3, 4, 52 TURP (transurethral resection of the prostate), 11, 52 Uretheral bleeding, 39 Urethral injection, 39–3 Urinary tract disorders, 16 Vacuum erection devices, 40–4 Vardenafil, 34 clinical effects, 31, 32 dosage, 34 mechanism of action, 4, 30–4 potency and selectivity, 31–5 rules for use, 34–8 side effects, 31, 32–6 Vascular endothelium, 4, 7–8 Vascular system anatomy and function, 2–3, 4, 5 assessment, 24–8

62 INDEX

disorders, 7–8 surgery, 41–7 Vasoactive intestinal polypeptide (VIP), 3 ‘Venous leakage’, 43 Venous system anatomy and function, 2, 3–4, 5 assessment, 25, 26 surgery, 43 Viagra, see Sildenafil Visual side effects, 32, 33 Worries, 9, 20 Young men, 44