There are certain groups of men in whom specific therapy is indicated because there is a possibility of cure. Patients in whom cure is possible include:

• Patients with predominantly psychosexual ED
• Patients with endocrine disease
• Patients with localised vascular disease such as those who have developed ED following pelvic or perineal trauma

General measures for the man with ED

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 onset of the ED, then a change of medication to a drug with less risk of causing ED might be beneficial

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 decreased responsibilities.
• 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 for Erectile dysfunction

Phosphodiesterase inhibitors (Sildenafil, Tadalafil, Vardenafil)
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, its’ active second messenger. Cyclic GMP (cGMP) produces smooth muscle relaxation which in turn leads to increased arterial inflow, cavernosal expansion and reduced venous outflow. The action of cyclic GMP is terminated by the enzyme Phosphodiesterase type 5 (PDE5) and inhibition of PDE5 will potentiate the pro-erectile effects of cGMP.

Potency and selectivity

Eleven different groups of phosphodiesterase enzymes have been identified within the body. These are called isoenzymes and are numbered PDE1 to PDE11. An ideal PDE5 inhibitor would inhibit only PDE5 and none of the other isoenzymes.

All three drugs are potent inhibitors of PDE5. None of the three drugs has any significant activity against PDE’s 1, 2, 3 and 4 and PDE’s 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 activity against PDE6 and tadalafil has no significant activity at all.

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 the 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 get 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.

Efficacy

• Treatment of men with 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 men with ED secondary to depression or hypertension.
• Lower efficacy rates are seen in diabetics (when around 50-60% of men get adequate erections) and in men who have undergone radical pelvic surgery for prostate cancer, where response rates as low as 30-40% are seen.

Side effects

• Side effects seen with all drugs include headache, flushing, indigestion and nasal congestion.
• The commonest of these is the headache that is seen in around 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.
• All the side effects are transient and well tolerated.

Safety of the medication

• Although there were initial concerns about the cardiac safety of this class of drugs, these concerns have proven 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 nitrate medication is a contraindication for this class of drugs, since they potentiate the vascular smooth muscle relaxation produced by nitrates, and considerable falls in blood pressure have been seen when both are taken together.

Issues specific to Sildenafil

• In fasted patients, it is effective within 30 minutes, but food delays it’s 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 duration of action of 6-8 hours.
  Side effects are as above, but in addition, occasional visual side effects are seen, such as bluish vision or blurred vision.
• The usual starting dose is 50mg, which can be titrated up to 100mg or down to 25mg. The lower dose is recommended in older patients and in those with renal or hepatic impairment.

Issues specific to Tadalafil

• Following administration, it reaches maximal plasma levels in around 2 hours, but it is active before that time and because of this, there is only marginal food interaction.
  It has a significantly greater half life than sildenafil at around 17 hours, and there is data to confirm it’s 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 sildenafil with a few exceptions. Visual side effects are not seen, the frequency of flushing appears to be reduced and some patients (around 10%) complain of muscular discomfort or backache.
• The usual starting dose is 10mg, which can be increased to 20mg if necessary. The lower dose is recommended for men with hepatic or renal impairment.

Issues specific to Vardenafil

• It reaches maximal plasma levels more rapidly than sildenafil, and may well be more rapidly acting in fasted patients and in patients who have eaten lightly. 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 sildenafil, but there are few (if any) visual side effects, and none of the muscular cramps seen with tadalafil. 
• The usual starting dose is 10mg, which can be raised to 20mg or reduced to 5 mg as required. The lower dose is recommended for men with hepatic or renal impairment.

Comparative trials of PDE5 inhibitors

• While many trials have sought to compare the efficacy and safety of the PDE5 inhibitors, most have suffered from poor design making interpretation of the results impossible. However, more recently, some trials have been published with reasonable (if not perfect design) which suggest the following:
• Efficacy and safety of the PDE5 inhibitors is approximately equal
• Some patients prefer to use one or the other drug, based upon characteristics such as speed of action of the drug, duration of action, and perceived ability to provide a rigid erection.

Using PDE5 inhibitors: practical considerations

When commencing a man on a PDE5 inhibitor, he will take some time to become adjusted to the use of 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 carefully 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.  Co-administration 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 which metabolise these drugs. In the 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.

Treatment of non responders to PDE5 Inhibitors

When a patient apparently fails to respond to a PDE5 inhibitor a number of approaches are possible to “rescue” the situation;

• Issues such as the need for appropriate sexual stimulation, awareness of the appropriate time window for the medication, and avoidance of any food interactions are vitally important to maximise success.
• An adequate trial of therapy must include at least 6-8 attempts with the top dose of the drug used since it has been clearly shown that that several attempts are required to maximise the response rate to PDE5 inhibitors.
• Continuous dosing of the PDE5 inhibitor may be helpful. The mechanism whereby regular dosing with a PDE5 inhibitor can be effective, when intermittent use has been ineffective is that there may be some more generalised improvement in endothelial function that is modulating this improved response
• It has been demonstrated that testosterone levels may modulate PDE5 expression and activity and there is a suggestion that in men whose testosterone levels are low or even in the lower end of the “normal” range, that testosterone supplementation might be effective as a means of salvaging men who have failed to respond to a PDE5 inhibitor.

Hormonal therapy for erectile dysfunction

• Testosterone is vital for normal sexual functioning in man. 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, testosterone replacement is usually beneficial.
• Options for therapeutic replacement include oral, transdermal (patches and gels), intramuscular or implanted testosterone.
• Side effects of testosterone treatment in general include oedema, raised haematocrit, gynaecomastia, acne, hirsutism. Hepatotoxicity has been reported especially with oral preparations.
• Patients on testosterone therapy need regular monitoring of lipid levels and PSA

References

1. Eardley et al, JSM, Pharmacotherapy for Erectile dysfunction, J Sex Med, 2010, 7: 524-540
2. Eardley I.  Optimisation of PDE5 Inhibitor Therapy in Men with Erectile Dysfunction: Converting 'Non-Responders' into 'Responders'.  European Urology. Vol. 50(1)(pp 31-33), 2006. 
3. Eardley I.  Mirone V.  Montorsi F.  Ralph D.  Kell P.  Warner MR.  Zhao Y.  Beardsworth A.  An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naive to phosphodiesterase 5 inhibitor therapy.  BJU International. Vol. 96(9)(pp 1323-1332), 2005. 
4. Hatzimouratidis K. Hatzichristou D.G.  Looking to the future for erectile dysfunction therapies.  Drugs. 68(2)(pp 231-250), 2008.

• The first objective is to confirm the diagnosis.
• This is best done by means of a sexual history.
• The second objective is to ascertain the severity of the problem.
• This can be performed objectively with questionnaires (e.g. IIEF) or 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 while all others will require special investigations.  
• The fourth objective is to identify patients who have causes of ED which might be amenable to specific treatment
• Eg vascular anomalies amenable to reconstructive surgery
• Eg endocrine abnormalities amenable to therapy
• Eg A psychogenic component amenable to therapy

Given these objectives, there is a basic assessment that should be applied for every patient and specialist investigation is appropriate in selected cases only 

Basic assessment

The fundamentals of assessment for any patient are the history, the physical examination and special investigations.

The basic elements of the sexual history are as follows:

b)  Medical History
In addition to the sexual history a full medical history is important.  Some of the known risk factors for organic erectile dysfunction are as follows:

• Ageing
• Hypertension
• Arteriosclerosis
• Diabetes mellitus
• Smoking
• Depression
• Dyslipidaemia
• Pelvic/Perineal/penile trauma or surgery
• Neurological illness
• Endocrine disease
• Prescription and recreational drugs

c) Psychogenic versus Organic ED
It is often helpful to try and differentiate those patients with primarily organic erectile dysfunction from those patients with primarily psychogenic erectile dysfunction (although it is well recognised that both aetiologies play a significant part in the majority of patients).

• Erectile dysfunction of organic origin usually has a gradual onset, is usually constant, usually affects non-coital erections and may occur under all circumstances. 
• Erectile dysfunction of a primarily psychogenic origin often is sudden in onset and may be situational with varying degrees of ED under different circumstances.  For instance it is not unusual in men with primarily psychogenic ED for them to be able to achieve a fully rigid non-coital erection.
• Another useful point in history, is the presence or otherwise of nocturnal or early morning erections. If these are present and of normal strength then a primary diagnosis of psychogenic erectile dysfunction is more likely. 

d) Physical examination
Physical examination does usually not need to be complete.  The most important aspects of the physical examination are listed below:

• Complete genital examination
• Examination for secondary sexual characteristics (gynaecomastia, body hair distribution, fat distribution)
• Blood pressure measurement.

The value of rectal examination, peripheral vascular examination and neurological examination is controversial. In the majority of patients they are unnecessary. However if there are other symptoms within the history that suggest a problem either with the urinary tract, the neurological system or with the vascular system, then an appropriate focused examination is appropriate.

e) Investigation
Most authorities agree that the following investigations should be performed in all patients:

These investigations will be discussed in detail below:
Fasting blood glucose

• Diabetes mellitus is one of the commonest causes of ED and it is important to identify when present. 
• In some patients diabetes is unrecognised prior to the diagnosis of ED.
• It is now clear that urinalysis is inadequate as a screening test for diabetes
• The appropriate diagnostic test for diabetes in 2003 is a fasting blood sugar.

Fasting lipid profile

• It is now clear that ED is often a marker for atherosclerosis.
• Risk factors for atherosclerosis include diabetes, hypertension, smoking and hyperlipidaemia. 
• Is in increasingly clear that in a proportion of men with ED there is previously unrecognised hyperlipidaemia. 
• 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 while high levels of LDL promote a risk of atherosclerosis. 

Testosterone

• A serum testosterone will assess the hypothalamic/pituitary/gonadal axis. 
• It is important that the testosterone assay is undertaken in the morning since there is diurnal variation in the level of testosterone within the serum. 
• There is controversy as to the most appropriate testosterone assay (total testosterone, free testosterone or bioavailable testosterone) but a consensus does exist that at least one of these assays should be performed. 
• 98% of testosterone is bound to plasma proteins with the majority of binding being either to albumin or to sex hormone binding globulins. 
• Only 2% of the total testosterone is unbound or free. 
• Bioavailable testosterone includes both the free and the albumin bound serum testosterone.
• It is possible to measure either the total testosterone or the free testosterone or the bioavailable testosterone
• Can calculate the free Testosterone on the website www.issam.ch
• While the pickup rate for hypogonadism is relatively low, the test is justified in that testosterone replacement represents a potentially reversible form of erectile dysfunction.
• NB Some believe that serum testosterone should be reserved for those men with reduced libido, or with testicular abnormalities.

Specialised Investigation

A. Endocrine Evaluation

• For the specialist, if a man is referred having “failed” oral therapy, then a full endocrine evaluation is mandatory
• If the serum testosterone is normal then further endocrinological evaluation is usually unnecessary. 
• If it is abnormal then it should be repeated. At the same time the serum Prolactin, FSH and LH should also be performed.
• Low serum LH suggests hypothalamic or pituitary disease
• Raised serum LH suggests testicular disease

(a) Prolactin assessment

• Prolactin should be assessed when the Testosterone is reduced or if there is clinical suggestion of hypothalamic or pituitary disease eg gynaecomastia, reduced libido
• Hyperprolactinaemia is usually due to a prolactin secreting tumour of the anterior pituitary gland. 
• Clinical features suggesting hyperprolactinaemia are gynaecomastia, galactorrhoea and erectile dysfunction.
• In some cases of hyperprolactinaemia the serum testosterone is slightly low but this is not invariable.
• A number of conditions cause marginal rises in the serum prolactin that 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 Metoclopramide.

(b) Thyroid disease

• ED can occasionally be due to thyroid disease.  If there is clinical suspicion of this then a thyroid hormone and serum TSH are appropriate.

(c) Pituitary and hypothalamic disease

• If the serum prolactin is significantly raised or if there is a reduced serum LH/FSH then a CT or MR scan of the pituitary gland is appropriate.

B. Vascular testing

• In the late 1980’s and early 1990’s vascular testing was undertaken in all patients.  It is now clear that this is unnecessary for the vast majority. 
• The following would be (current) usual indications for vascular testing:
• Selection of patients for reconstructive penile vascular surgery
• Medico-legal reasons
• Patient request

(a) Colour Doppler Scanning of the penile vasculature

• The usual first line investigation is colour Doppler scanning of the penile arteries
• The following methodology is usually used:
• The test should be performed following an injection of a smooth muscle relaxant such as prostaglandin E1. 
• High frequency linear array transducers (5-10 MHz) provide the best images
• The examination should be performed in a warm and darkened room.  
• A challenge of 10mcg of Prostaglandin E1 with genital stimulation and visual erotic stimulation is considered to be the best initial challenge. 
• Measurements are usually made around 10 minutes following injection of the Prostaglandin E1.
• Interpretation of results
• A peak systolic velocity (PSV) of less than 25cms/sec suggests penile artery insufficiency
• PSV more than 35cms/sec is considered normal.
• The diagnosis of penile veno-occlusive dysfunction should be considered when the PSV is greater than 30cms/sec and the end diastolic velocity is more than 3-5cms/sec.

(b) Dynamic infusion pharmacocavernosometry and cavernosography (DICC)

• This is a test designed to assess veno-occlusive function.
• It is now only indicated in patients who are suspected as having a site specific venous leak where vascular surgery is considered a treatment option. 
• Such cases might include patients with 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 injection of a smooth muscle relaxation such as prostaglandin E1 10mcg. 

(c) Penile arteriography

• Selective pudendal arteriography is reserved for those cases who are being considered for vascular reconstruction in whom colour Doppler scanning has demonstrated arterial insufficiency.
• These are usually young men with a history of pelvic or perineal trauma
• Arteriography should be performed following intracavernosal PGE1

C. Other tests
(a) Neurological Testing

• There is no good neurophysiological test that assesses autonomic innervation of the penis.
• Corpus cavernosal smooth muscle EMG is of questionable validity and currently should only be considered an investigational tool

(b) Nocturnal Penile Tumescence Testing

• Most men achieve an full and rigid erection four to five times during the night. The presence of normal nocturnal erections is strongly suggestive of a psychogenic aetiology. Historically, nocturnal penile tumescence studies were undertaken to make this diagnosis but they are rarely indicated in 2003.
• In 2003, almost the only indication for NPT studies is in medico-legal cases (e.g. suspected rape cases). 
• In 2003, the device most commonly used for NPT studies is the Rigiscan device that measures tumescence and rigidity at both the base and the tip of the penis.
• In research studies, Rigiscan monitoring is widely used to assess the efficacy of oral therapy during visual sexual stimulation
• The normal measurement that is used under these circumstances is the period of time during which the base rigidity exceeds 60%. 

Conclusion

With the advent of effective oral therapy for the treatment of most men with erectile dysfunction the assessment of these patients has moved to a goal directed approach.  Extensive investigation is therefore not indicated for most men.  However baseline investigations are important to identify potential treatable underlying diseases.