¹Department of Medical Physiology, University of Copenhagen, Denmark

²Oude Baan 370, Leuven, Belgium

³123 Rue de l'olivette, St Clement de Riveiere, France

⁴Via Verdi 8, Campi Bisenzio, Italy

⁵Nic. Maesstraat 22A, 3601 Dr Maarssen, Holland

⁶Department of Urology, Radbond University Hospital, Nijmegen, Netherlands

⁷Court Gate House, Harbourneford, Devon, UK

⁸Department of Genito-Urinary Medicine, Royal Belfast Hospital, Belfast, UK

⁹University of Dublin, Mater Hospital, Dublin, Ireland

¹⁰Department of Urology, Institute of Urology and Nephrology, London, UK

¹¹Holly Cottage, Fisherwick Road, Lichfield, UK

¹²Department of Urology, Queen's University & Kingston General Hospital, Kingston, Ontario, Canada

¹³77 Mitropoleos Str, Thessaloniki, Greece

¹⁴La Mina Health Centre, Barcelona, Spain

¹⁵University Hospital Nijmegen, Department of Urology, Nijmegen, The Netherlands

¹⁶Urology Department, University 'Frederico II', Naples, Italy

¹⁷Divisione di Urologia, Ospedale S Raffaele, Italy

¹⁸4 Rue du Perigord, Paris, France

¹⁹Department of Urology, Erasme Hospital, University Clinics Brussles, Brussles, Belgium

²⁰Urologisch Klinik der Medzinischen, Hannover, Germany

²¹Krummbogen 15, Marburg, Germany

²²Belmont Surgery, Belmont, Durham, UK

Correspondence to: G Wagner, Department of Medical Physiology, University of Copenhagen, Denmark and Division of Sexual Physiology, Suite 7121, Rigshospital, Blegdamsva 9, Copenhagen, Denmark

Erectile dysfunction (ED) affects men of all ages and results in considerable distress and impact on quality of life for those who suffer from it. As ED is associated with a wide variety of under-lying conditions and cardiovascular co-morbidities, there is a requirement for diversity of treatment options and several factors must be considered to customise and optimise therapy. In the ideal holistic approach to management of the ED patient, both primary care and specialist physicians have an important role to play. This article reports on a sequential approach for the diagnosis and treatment of ED, with an emphasis on 'shared care'. The deliberations are based on a pan-European inter-disciplinary group that met at the Lygon Arms, UK on 22 February 2002.

International Journal of Impotence Research (2002) 14, 189-194. doi:10.1038/sj.ijir.3900882

erectile dysfunction; holistic approach; treatment algorithm; shared care

Introduction

Society's attitude to male sexuality, and in particular, erectile function and dysfunction, is dynamic and has been continuously evolving.^1,2,3,4,5,6 Originally this field was considered to be the exclusive province of psychologists and/or endocrinologists. The arrival of penile prostheses in 1973 and other, non-surgical, therapies such as vacuum constriction devices and local self-injection of therapeutants in the 1980s brought the urologist to the forefront of patient management. Since these early days, from the therapeutic perspective there has been, and continues to be, considerable improvement in the availability of user-friendly, reliable and dependable interventions in the area of male sexual health.

Up to the end of the 20th century fewer than 10% of men sought treatment and even within this apparently well motivated group, a high treatment drop-out rate was routinely observed.^1,2,3,4,5 It was hypothesised that drop-out occurred as the treatment options were relatively invasive/intrusive in nature or artificial, had associated risks, may be irreversible and were expensive. On this basis, it was anticipated that the general availability of the first effective oral therapeutants, sildenafil⁷ and apomorphine sublingual (SL),^8,9 would have had considerable and far-reaching impact on the management of male sexual health issues. In particular, there has been a major change in medical focus. Primary care physicians have increasingly become the front line in the management of patients complaining of sexual disorders. It is worth noting, however, that even now the majority of men experiencing erectile dysfunction (ED) still do not present to discuss the condition with their physician. As previously, there is also perceived to be an unexpectedly high discontinuation rate, at least in Europe. It has been suggested that this, in part, may arise from setting inappropriate expectations in the minds of patient and partner.

Healthcare providers, economic planners and the public are concerned about the economic impact of the development of safe and effective therapy for ED. In this context there are four major influences: ED is highly prevalent; its incidence is age related; it is a progressive condition; and it is currently under-treated. The economic impact of a disease or medical condition is not limited to the cost of diagnosis and treatment. Various models have been used to determine the overall socio-economic cost of ED. This includes lost time at work, decreased productivity and effects on wife/partner, family and co-workers. Although the analysis is incomplete, it is obvious that ED presents a considerable indirect cost to society.

Primary care in many ways is the ideal situation for health screening and promotion, as well as for the treatment of most chronic health problems. Family physicians will usually have the detailed knowledge of the physical and psychological health of the individual, his partner and their family, and of their social context. This is unavailable to the secondary care physician. As all of these factors have a particular bearing on sexual health, the family physician is ideally placed to assess and manage the majority of men with ED.

The advent of more widespread disease awareness and the availability of orally active agents have resulted in the requirement for accepted treatment algorithms to be used specifically as the potential basis for patient management in the community setting. The objective is to facilitate dialogue between physicians, patients and increasingly, the initial health care provider in issues relating to male sexual health. One example, based on that developed by the International Consultation on Erectile Dysfunction,¹⁰ is shown in Figure 1.

Penile erection is a complex series of integrated vascular events resulting in accumulation of blood under pressure and end-organ rigidity. Although it relies on the co-ordination of various neural and humoral events at several levels of the neuroaxis, there is an absolute requirement for central neural input to provide normal function. Any imbalance can result in erectile dysfunction. Traditionally, drugs have been developed to act as peripheral vasodilators.^7,11 Another approach involves the production of an erectogenic action within the central nervous system (CNS). Apomorphine SL is the first example of a drug acting exclusively within the CNS to re-dress any imbalance in central processing and thereby providing benefit across a wide range of aetiologies.^8,9

Classification of erectile dysfunction

ED may be classified based on severity, aetiology or onset.

When classified on a severity basis, ED can be stratified as mild, moderate or severe, depending on the ability to attain and/or maintain an erection with either intermittent (mild), infrequent (moderate) or absent (severe) ability for satisfactory sexual performance.

Although the conditions frequently coexist, on the basis of aetiology ED is defined as either psychogenic or organic. The former definition is used when there is no clear-cut evidence of a physical precipitant and/or determinant or if there is a clear psychological basis for ED such as anxiety or stress. Organic ED is considered to be that which occurs as the result of an acute or chronic physiological precipitant and/or determinant, including underlying endocrinological, neurological or vascular aetiologies. There is no reliable way of determining the relative contributions. However, a psychological component is present in almost all cases and may contribute to the worsening of the condition. Recently, Sachs has raised issues relating to the dichotomy psychogenic/organic.¹² He points to the fact that all psychological functions are regulated by the brain and as such involve underlying organic processes.

Using onset as the criterion, ED is classified as either primary or secondary. The former, which is uncommon, is that which occurs in men who have never had the ability to attain and/or maintain an erection. The potential causes include deep-seated psychological conflicts or perineal/pelvic trauma. Secondary ED is that which is acquired following a period of satisfactory sexual performance and is the most common.

It is essential to remember that ED patients may present with many co-morbidities,¹³ (Figure 2), particularly diabetes and hypertension. Frequently these and other co-morbidities are undiagnosed and it is probable that ED may be a sentinel manifestation of these vascular disorders. These can be an important factor in the selection of the most appropriate treatment.

Diagnosis and evaluation of the ED patient

The ideal foundation for the management of ED is a careful clinical evaluation. As a minimum, thorough medical and psychological histories, physical examination and focused laboratory testing are recommended. More specialised diagnostic tests (eg nocturnal penile tumescence and rigidity or penile vascular studies) although available may only be justifiable in individual patients rather than used generally. The cornerstone of clinical assessment remains a detailed sexual, medical and psycho-logical history. This accomplishes several goals, including characterisation of the problem and identification of patient and partner needs and priorities, as well as fostering a good relationship between physician and patient. Although this is not always possible, every effort should be made to involve the patients' partner as early as possible.

The first phase of the evaluation is to determine whether the patient meets the consensus definition of ED, ie has a consistent or recurrent inability to attain and/or maintain an erection sufficient for sexual performance. Subsequently other issues can be tackled. These relate to whether intervention is warranted and whether ED is the primary complaint or is associated with, or misinterpreted as, another sexual dysfunction such as premature ejaculation or hypoactive desire.

The next phase of the evaluation, following problem identification, is the obtaining of a comprehensive sexual, medical and psychological history. In addition to the usual concerns in medical history taking, clinicians should pay special attention to the sensitivity of the topic, as well as looking at this as an opportunity to initiate patient and partner education and communication.

Within the scope and capability of the primary care physician is arrangement for supportive laboratory evaluations. Obviously however, there can be issues relating to cost containment within certain healthcare environments that can render such testing impracticable. This may include an evaluation of the hypothalamic-pituitary-gonodal axis via assessment of serum testosterone and prolactin levels. Abnormalities of either may correlate with diminished sexual desire. Also of potential merit are evaluations of serum lipids that can be predictive of vasculogenic ED, assessments relating to diabetic control and other evaluations including prostate-specific antigen.

Specialised diagnostic testing may be indicated in several circumstances, as follows:

• if the initial laboratory assessment reveals abnormalities potentially warranting further evaluation to enable a more precise diagnosis
• if the selected treatment option requires more specialised diagnostic assessment (eg penile ultrasound and angiography prior to penile revascularisation) prior to decision-making
• if the patient would prefer a more comprehensive evaluation and understanding prior to selection of a treatment option
• for medico-legal reasons

Specialised diagnostic tests for ED include a wide range of vascular, neurological and endocrinological studies. Although specialists, often in gaining insight into the underlying pathophysiology, may routinely use these tests, their use should be reserved for selected cases in the primary setting. Although useful knowledge can be gained, their utility may be limited by expense and associated risks. Historically, particularly in the USA, nocturnal penile tumescence and rigidity (NPTR) testing has been relatively widely used and was used in the discrimination of organic and psychogenic dysfunction. NPTR studies can be conducted in a sleep-laboratory or, more commonly, in an ambulatory setting. Overall, however, NPTR is no longer widely used during the initial diagnostic work up. Also of interest, but only really feasible in the office evaluation, is the use of intracavernosal injection of pharmacological agents (such as prostaglandin E1 (PGE1) or 'trimix') to determine functional assessment of penile arterial inflow and veno-occlusive integrity. There is an increasing tendency, however, to use pharmacotesting with apomorphine SL or sildenafil in this form of 'diagnosis'.

It has become obvious with the advent of effective oral agents that an increasing amount of diagnostic evaluation takes place in the primary care environment. In practice this can include giving suitable patients trial doses of either sildenafil or apomorphine SL. It is important however to set appropriate expectations and ensure that the patient realises that several doses may be required to optimise the response before a patient is considered to be a non-responder.^14,15 Ultimately, more complex evaluation particularly of poor or non-responders to therapeutic agents may well be required. This will probably involve dialogue with, and referral to, a specialist to ensure optimal patient management. In many cases, subsequent to referral to a specialist, the responsibility for patient management will be returned to the primary care physician and essentially the patient will be subject to 'shared care'. The concept of shared care is widely and successfully employed across Europe in the management of prostatic disease¹⁶ and in the management of cardiac and diabetic patients.

Situations for specialist referral

Theoretically, if operating within the context of a shared care healthcare policy, most patients with ED could be managed within the primary care environment, should such an infrastructure exist. However, the availability and access to primary care physicians who have an interest in and are prepared to treat sexual health will be highly country or even regionally dependent. Even assuming that most cases can be managed by primary care physicians, in specific circumstances referral to a specialist will be required for additional diagnostic testing, patient management or indeed surgery. The need for referral or consultation may arise at any time from initial evaluation, ie prior to or during the course of treatment or follow-up. Care should be taken to ensure that patients are fully informed about the reasons for referral, the evaluations to be undertaken and the potential outcomes. Equally, after referral, results should be carefully reviewed with the patient and when appropriate the partner.

Specific indications for specialist referral include the following:

• where laboratory evaluations are ambiguous or to identify the need for more comprehensive evaluation
• when there is a suspicion of cardiac problems
• when there is primary ED, eg in young patients with a history of pelvic/perineal trauma
• in patients with significant penile curvature (eg Peyronie's disease or congenital deformity)
• a request from the patient or a medico-legal requirement for further evaluation

Specialist referrals will be to urologists, cardiologists, psychiatrists, endocrinologists, sex therapists or vascular-reconstructive or neurosurgeons, as appropriate.

Holistic approach to management of the ED patient

Patient management options can be subdivided into lifestyle modification and treatment interventions. The latter, in turn, can be considered as first-line (primary), second-line (secondary) or third-line (tertiary) options. The treatment algorithm (Figure 1) is based on a stepwise approach to disease management. Treatment should normally follow the above order.

Epidemiological analysis shows that a number of risk factors and lifestyle issues can contribute to the occurrence of ED. In keeping with a step-wise approach, risk-factor modification usually represents the least invasive and therefore the first approach. Good clinical practice mandates that this is the initial focus in the present era of cost containment, although quantification of risk-factor modification on ED is lacking. This may often be attempted, however, in parallel with a more direct (ie therapeutic) intervention. By analogy to the general systemic circulation, as the penis is a modified vascular bed, modification of cardio-vascular risk factors would certainly represent an obvious starting point; these include hyperlipidaemia and hypertension. Environmental factors such as cigarette smoking and alcohol use may also contribute to cardiovascular disease and/or ED. Equally, modification of several other behaviours relating to inter-partner relationships and sexual behaviours and conflicts may be of benefit. Finally, many patients presenting with ED have a history of prescription and non-prescription drug use and abuse. On this basis, in many instances ED may have an iatrogenic origin.¹⁷ One viable treatment option could involve withdrawal or replacement of existing agents. Obviously, however, caution should be exercised to ensure that primary therapeutic activity, eg control of hypertension or depression, is not compromised.

The next level of patient management would involve therapeutic, device or surgical intervention. Three levels of treatment are apparent when stratified on the clinical criteria of: ease of administration, reversibility, invasiveness and cost. Efficacy is an underlying assumption for all treatments designated as first-line (primary), second-line (secondary) and third-line (tertiary).

First-line interventions are primarily oral erectogenic agents,^7,8,11 vacuum erection devices and psychosexual therapy. In addition to meeting the above criteria, they all have relatively low risk profiles that make them particularly suited for empiric therapy given the heterogeneity of patients in the primary care setting. The selection of individual agents or strategies will be dependent on patient profile and need, medical indications, co-morbidities and contraindications, as well as cost and reimbursement and should ultimately be driven by patient preference.¹⁸ In specific instances (eg documented endocrine abnormality), androgen replacement therapy may also be considered as first-line therapy.

In terms of first line drug options both apomorphine SL and sildenafil are available. The response of both drugs would appear to be independent of the baseline severity (mild, moderate or severe), the underlying aetiology or the presence of significant co-morbidites.^7,8,9 Likewise, both drugs afford consistent and predictable responses although several doses may be required to optimise benefit.^14,15 In this context it should be explained to all patients and partners that the early or initial response to any ED therapy will initially be affected by general stress, performance anxiety and other factors that can inhibit erectile function.

Some couples habitually prefer sexual spontaneity and immediacy and value the opportunity to engage in sexual behaviour as soon as possible. These couples may well prefer apomorphine SL that affords a more rapid onset of action than sildenafil. Other couples practice certain 'ritual' behaviours with sex being more pre-meditated or planned. Both apomorphine SL and sildenafil are likely to be suitable under such circumstances.

Based on the clinical trials databases but in the absence of comparative studies it is not unreasonable to assume that apomorphine SL and sildenafil have equivalent efficacy. Patient preference may be dependent on other factors eg rapidity of onset and 'naturalness' of the erection or the relatively small incidence of colour vision distortion or mild nausea seen with sildenafil and apomophine SL, respectively. However, the co-morbidities of the ED patient (Figure 2), in particular the cardio-vascular status, may also have to be factored into the therapy offered. Although the long-term safety of sildenafil is well documented⁷ the nitrate contra-indication⁷ results in exclusion of a sub-group of ED patients. The absence of a nitrate interaction and the benign cardiovascular profile of apomorphine SL,^19,20 could make it the drug of choice for a broader spectrum of ED patients given their underlying cardiovascular co-morbidities. The post marketing experience with apomorphine SL, showing that there have been no drug associated deaths or myocardial infarctions, would be consistent with the drug's cardiovascular profile and the low mortality could represent a point of differentiation from sildenafil.²¹

Second-line treatment interventions are selected on the basis of: (1) failure or insufficient response or adverse effects associated with one or more of the above primary therapies; and (2) patient preference. These interventions are based on local (intra-urethral or intracavernosal) delivery of pharmacological agents. In general, vasoactive agents and other agents such as PGE1 are most commonly employed as monotherapy. Although widely used, drug administration by these routes is subject to high patient discontinuation rates, side effects (local and systemic), concerns regarding long-term safety and trauma.

Although historically offered as the first option, surgical implantation of semi-rigid or inflatable penis prostheses is now considered tertiary intervention. The surgery is highly invasive and is associated with potential complications; it is essentially irreversible and as such is now reserved for select cases of severe, treatment-refractory ED. However, despite these concerns and the high cost, penile prostheses have been claimed to be associated with a high rate of patient satisfaction.

Summary

In summary, prior to the advent of apomophine SL and sildenafil, there were several advantages and disadvantages associated with all available treatments of ED. The options varied widely in the degree of invasiveness, level of efficacy and side effects, patient acceptability and compliance and cost. Patient satisfaction and quality of life have improved dramatically with the arrival of orally active agents. Paramount in the selection of treatment modality must be patient and partner preference. This represents a major paradigm shift from the traditional physician-directed strategy employed in most other diseases. Ultimately, the long-term success of any therapy is intimately associated with appropriate patient use and compliance and requires sustained monitoring and follow-up by the physician. A pre-requisite may be additional education of not only the patient but also the physician to ensure that appropriate expectations are set.

The availability of effective orally active agents has had a major impact on the treatment of erectile dysfunction. However, in this post sildenafil and apomorphine SL era, still only a minority of the ED population present to their doctors. Of these, the primary care physician treats the majority. The field of male sexual health is, however, still dynamic and continuously undergoing change. In an attempt to cope with increased demand for diagnosis and management of erectile dysfunction within the context of a 'shared care' environment it is essential that both specialist and primary care physician continue to refine treatment algorithms for patient management.

Sexual function consists of a complex series of interacting behavioural, emotional and physio-logical processes and ED can arise from minor perturbations at several loci. The response to a drug is likely to be situational and highly dependent on the nature of the imbalance. Thus the patient perception of clinical efficacy is likely to be highly dependent on the sexual milieu of the patient.¹⁴ This along with patient preference, associated cardiovascular co-morbidities and drug profile should be the major determinant in the choice of therapy.

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21 Cohen JS. Comparison of FDA reports of patient deaths associated with sildenafil and with injectable alprostadil. Ann Pharmacother 2001; 35: 285-288. MEDLINE

Figure 1 Treatment algorithm for management of ED patients (adapted from reference 10).

Figure 2 Prevalence of common co-morbidities and associated risk factors in ED patients.