Summary

Erectile dysfunction and premature ejaculation are common sexual dysfunctions. The primary care physicians should be able to recognize these problems. Effective treatments are available and most patients can be managed by their primary care doctors. The symptomatic treatment of these conditions will improve the quality of life. More importantly, erectile dysfunction may be an indicator of underlying vascular risk factors. Management of erectile dysfunction by reversing such risk factors may help to reduce mortality and morbidity from vascular complications.

摘要

勃起障礙和早泄是常見的性功能障礙。基層醫生應該能夠識別這些問題。多數病人可從基層醫生得到有效治療。有效的針對症狀治療可改善生活素質。更重要的，勃起障礙可能是顯示潛在者有血管病的風險因素。在處理勃起障礙時將這些風險因素矯正或可減少因血管性疾病引起的發病和死亡。

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Introduction

Erectile dysfunction is the persistent and consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for satisfactory sexual performance. A minimum duration of three months is generally accepted as definition. It is a highly prevalent condition in the aged male population. According to an American study, 52% of men above aged 40-70 had some degree of erectile dysfunction and in 10% the loss of erection is complete.¹ In a survey by the Hong Kong Urological Association in 2003, 62% of men aged 40-80 in Hong Kong had erectile dysfunction.² Erectile dysfunction is a symptom based on patient"s complaint. The symptom is a starting point for searching for underlying causes and for initiating symptomatic treatment.

The diagnosis of erectile dysfunction should be distinguished from other sexual dysfunctions. Premature ejaculation may actually be more prevalent than erectile dysfunction. Premature ejaculation means ejaculation occurring sooner than desired either before or shortly after penetration, causing distress to one or both partners.³ Over 90% of premature ejaculation patients have intravaginal ejaculation with latency time of less than 60 seconds.

Premature ejaculation

Patient may have mistaken premature ejaculation as erectile dysfunction. A detail sexual history should be able to identify elements of premature ejaculation or erectile dysfunction in the sexual dysfunction of the patient.

Aetiology of premature ejaculation is unknown. Factors that may be involved include increased sensitivity of the glans penis, hyperexcitable reflex or lack of central inhibition. Hypothalamus exerts tonic inhibition on ejaculation. The inhibition depends on the level of serotonin in the central nervous system. Most cases are primary and start from an early age. Cases that occur late in life are often a consequence of erectile dysfunction. Erectile dysfunction aggravates premature ejaculation because of the associated anxiety and the need for more intense stimulation to attain or maintain an erection. In patients with concomitant premature ejaculation and erectile dysfunction, the erectile dysfunction should be treated first.³ Phosphodiesterase 5 inhibitor is effective for premature ejaculation or increased efficacy of drug treatment used for its management.⁴

Patient and partner satisfaction is the primary target outcome for treatment of premature ejaculation and thus the physician should talk with the patient about the benefit and risks of treatment options. Self-help behavioural measures including more frequent intercourse, use of condoms or distraction during intercourse could be suggested to the patient and may help in mild cases. Other behavioural techniques including stop-start or squeezing techniques could be taught but are more easily said than done. Topical anaesthetics such as EMLA cream (lignocaine 2.5%) could be applied 20-30 minutes before intercourse. The cream must be washed off before intercourse or a condom needs to be used to prevent the anaesthetic effect to the female partner.

Premature ejacualation could be treated effectively with several serontonin reuptake inhibitors,³ even though no approval from FDA is yet available for such off-label use. The drugs clomipramine, sertraline or paroxetine could be given on demand about 4 hours before intercourse. The doses could be titrated up and short courses of 2-4 weeks could be given in cases of failure of on-demand therapy. Continuous dose may also be used. Fluoxetine could be used for short or continuous courses in addition to the three drugs mentioned. The usual dose of serotonin reuptake inhibitors used in premature ejaculation is less than that used in treatment of depression and thus side effects are less severe. Patients, however, still need to be warned of common side effects such as dry mouth, gastrointestinal upset or drowsiness, and about withdrawal symptoms and possible drug interactions. A newer serotonin reuptake inhibitor, dapoxetine, is now in the pipeline. It has faster onset of action and shorter half time and may be a better on-demand drug with less side effects.

Approach to the patient with erectile dysfunction
The issues to be addressed in assessing a patient with erectile dysfunction include5: Are there any other sexual problems? How severe is the erectile dysfunction? Is the heart of the patient fit for sex? Are there risk factors for the cardiovascular system? Are there specific organic causes for the erectile dysfunction? Are there serious psychological factors for the erectile dysfunction? The steps to be taken during the initial evaluation include6:
1.	Sexual history:
	Duration of the problem and the ability to achieve and maintain erection should be defined. A sudden onset, the presence of erections on awakening or during masturbation and the variation of erection with different partners may point to psychological factors for the erectile dysfunction. Other sexual problems associated with libido, orgasm and ejaculation should be asked about. The "International Instrument for Erectile Function (5 Questions)" should be used to gauge the severity of the erectile dysfunction.
2.	Medical history:
	The medical history will help to identify factors causing the erectile dysfunction: vascular risk factors: diabetes mellitus, hypertension, hyperlipidaemia, history of cardiovascular diseases, smoking, obesity and sedentary life. local vascular - vascular trauma: fractured pelvis, perineal injury. neurological factors: spinal cord injury, pelvic operations (e.g. Radical prostatectomy), stroke, myelitis or neuropathy. penile factor: Peyronie"s disease, history of fracture of the erect penis. hormonal factors: loss of libido, history of hypogonadism or other endocrine disorders. drug factors: antihypertensive medications (especially diuretics),7 barbiturates, cimetidine, antidepressant, etc. Alcohol abuse should be noted. Prostate symptoms: there is an emerging link between lower urinary tract symptoms and erectile dysfunction even though the general perception is that benign prostatic hyperplasia per se does not cause erectile dysfunction.8 Treatment of patients with lower urinary tract symptoms using alpha blocker may improve erectile function as well as urinary tract function.9 There may be a point to ask for lower urinary tract symptoms in patients with erectile dysfunction and vice versa. The medical history also helps to assess whether the cardiac status of the patient is fit for sex. Sexual intercourse involves energy expenditure of just 3-4 Mets, which corresponds to golfing. Exercise tolerance of over 2 flights of stairs or 15 minutes walk should enable a patient to engage in sexual activity. Absolute risk that sexual intercourse can trigger myocardial infarct is 1-2 per million. In a patient with cardiac problem, the risk with sex could be stratified with the "Princeton Consensus Panel Classification"10 into "low", "medium" and "high" risk groups. The low risk group is safe for sex and treatment for erectile dysfunction. The high risk patients need stabilization before treatment for erectile dysfunction. The medium risk group need re-evaluation.
3.	Psychological assessment:
	A brief psychological assessment should look for features of depression including feeling hopeless and loss of interest. Important life events, difficulty in work or relationship with partner or family, stresses, and consultation of psychiatrist should be noted.
4.	Focused examination:
	Physical examination will help to confirm impressions derived from the medical history: features of hypogonadism or other endocrinopathy peripheral pulses and blood pressure penile problem e.g. Peyronie"s disease with plaque neurological features: anal tone, perineal sensation and bulbocavernous reflex prostate enlargement
5.	Laboratory tests:
	Fasting blood sugar and lipid profile should be routine. Patients with undiagnosed diabetes may have erectile dysfunction as their presenting symptom. Routine testosterone measurement is more controversial. Hypotestosteronaemia is a rare cause of erectile dysfunction. There is progressive decline of testosterone with age and bioavailable testosterone at aged 75 is only 40% that of at aged 25. Low end of normal range of testosterone is sufficient for erection. There is no difference of testosterone leve between men with or without erectile dyfunction. Testosterone should be measured in men with erectile dysfunction over the age of 50 if they present also with libido problem or features suggestive of androgen deficiency. Androgen deficiency could be evaluated using the "Androgen Deficiency in Aging Male" (ADAM) Questionnaire devised by the St Louis University.11 Testosterone replacement therapy is indicated only when hypogonadism is documented.

Making referral

After the initial assessment, the following categories of patients should be referred:

• Patient with penile disorder such as Peyronie"s disease or patients with vascular problems who may be amenable to surgical treatment by urologist.
• Patient with cardiovascular, endocrine, neurological problems requiring referral to physician.
• Patients with severe, complicated psychiatric problem requiring referral to psychiatrist.
• Patient requiring special testing for medico legal purposes.

These specialists will provide definitive treatment for curable causes of erectile dysfunction including:

• Penile revascularization for post-traumatic vascular cases or surgery for Peyronie's disease by urologists.
• Psychosexual and psychiatric therapy for complicated psychiatric cases by psychiatrists.
• Treatment for hyperprolactinaemia or hypogonadism by endocrinologists.

Treatment by the primary care physician

Treatment by the primary care physician includes:

• Removal of risk factors for vascular disease and other reversible factors.
• . Symptomatic treatment.

Removal of risk factors for vascular disease and other reversible factors

It is good opportunity when treating a patient with erectile dysfunction to give education about risk factors for cardiovascular disease. The patient should be counselled that erectile dysfunction is associated with the same risk factors for other vascular disorder. The penile artery, being smaller than coronary artery, would be affected earlier. Erectile dysfunction is therefore a warning sign for cardiac ischaemia.¹²

Smoking must be stopped. Patient should have weight reduction and exercises. Hyperlipidaemia should be controlled and compliance with cardiovascular and diabetes medication should be improved. Increased exercise to 200kcal/day (walking one hour) and weight reduction improve IIEF by 30% over two years.¹³

Alcoholism and other substance abuse are advised against. Drugs that may affect erectile functioning should be reviewed and substituted if possible. In case of hypertension, diuretics or beta blockers may be substituted by drugs that less affect erectile function, such as calcium channel blockers, angiotensinogen convertase enzyme inhibitors or alpha blockers.⁷ Co-existing benign prostatic hyperplasia should be treated with alpha blockers. Stress reduction and treatment of depression may help to remove their adversary effect on the erectile function.

Symptomatic treatment

The need and expectation of the patient and his partner has to be clearly discussed. They should participate in the decision making process in selecting treatment. The first line treatment would be the oral agents. Sublingual apomorphine (uprima) is no longer marketed in Hong Kong. The only oral agents are the phosphodiesterase 5 Inhibitors (PDE5I).

Phosphodiesterase 5 Inhibitors (PDE5I)

PDE5Is are the preferred first line treatment by most patients. Currently 3 drugs are available. Sildenafil (viagra), tadalafil (cialis) and vardenafil (levitra) were marketed in Hong Kong in 1998, 2003 and 2004 respectively. There are no direct head to head comparison between these drugs on efficacy and their efficacy are probably similar. There is difference in pharmacokinetics, though. High fat meal intake influence the absorption of both sildenafil and vardenafil but not tadalafil. Both sildenafil and vardenafil have half life of about 4-5 hours, whereas tadalafil has a half life of 17.5 hours, consistent with its longer window for responsiveness. Tadalafil has a higher selectivity ratio for PDE5:PDE6 than sildenafil and vardenafil and thus has lower visual side effect. The significance of the lower PDE5:PDE11 selectivity ratio of tadalafil compared to sildenafil and vardenafil is not clear. PDE11 occurs in pituitary and testis and so far no alteration of reproductive hormone or spermatogenesis have been reported with the use of tadalfil.¹⁴

Preference studies had been conducted demonstrating patient preference of one PDE5I to another.¹⁵ However, there were intrinsic limitations in the design of these studies and the preference should not be construed as a comparison of clinical efficacy. Nevertheless, patient preference and prescriber experience are important determinants of choice of agent used.

General precautions with PDE5Is

Since the PDE5Is potentiates the hypotensive effect of nitrates, the American Heart Association/American College of Cardiology Consensus Panel recommended that nitrates should not be administered within 24 hours of dosing of sildenafil. Tadalafil 20mg can potentiate the hypotensive effect of sublingual nitrate for 24 hours after dosing but not at 48 hours.

Sildenafil can produce acute postural hypotensive symptoms when administered together with alpha blockers and information that the drug over 25mg should not be administered within 4 hours after taking alpha blockers had been added to prescription information in 2002. Only tamsolusin is listed as safe to be administered to patients taking tadalafil. Alpha blockers had been listed as a precaution for vardenafil but recently the prescription information had been updated to allow administration of vardenafil 4 hours after taking tamsulosin.

None of the three drugs had been demonstrated to potentiate the hypotensive effects of ethanol at usual levels of consumption.

Grapefruit juice inhibits first past cytochrome metabolism and increase bioavailability of PDE5I in a variable manner and should be avoided at the time of dosing. Antifungals and erythromycin are also inhibitors of cytochrome and concurrent administration with PDE5I should be made with caution. Levels of PDE5I may be increased in patients with renal or hepatic impairment and lower doses may have to be used.

Flushing was more common in patients taking sildenafil and vardenafil. Muscle pain and back pain were more common in patients taking tadalafil. These side effects were usually mild, decreased with further doses, and seldom caused withdrawal from treatment.

PDE5I did not adversely affect haemodynamic variables, exercise tolerance and time to cardiac ischaemia on treadmill tests.¹⁶ The reported incidence of myocardial infarct after PDE5I was similar to that of placebo.

NAION (Non-arteritic ischaemic optic neuropathy)

In 2005 FDA issued an alert that small number of men had loss of eyesight after taking PDE5I, including all three drugs. These cases were due to blocking of blood flow to the optic nerve. It is not known whether PDE5I actually causes NAION, as the condition also occurs in men not taking such medication. Patients at high risk of developing NAION are men over fifty, smokers, with history of diabetes, hypertension or hypercholesterolaemia, or having pre-existing eye problems.¹⁷ A fair discussion of this rare condition could be made with the patient at risk.

Follow up

After the first line treatment, the patient should be evaluated for erectile response, side effects and satisfaction with treatment.

Poor response

The physician should ensure that the patient is obtaining medication from reliable sources. Fake drugs with no active components may be the cause of failure. Effect of food, especially a fatty meal, on absorption of sildenafil and vardenafil should be excluded. Patient should have adequate sexual stimulation to initiate the erection.

Patient should be warned that a PDE5I should be tried several times, and up to maximum tolerable dose, before being considered ineffective. The probability of success of PDE5I increases with subsequent attempts up to 9-10 attempts.¹⁸

For patients with poor response or intolerance to sildenafil, vardenafil may be helpful.¹⁹ Non-responding patients may be checked for co-existing low testosterone level. In the presence of low testosterone level, addition of a daily testosterone gel to PDE5I treatment had been demonstrated to be more effective than PDE5I alone.²⁰ Prostate cancer must be excluded before prescription of any testosterone.

Second line treatments

Second line treatments include:

• Intraurethral alprostadil
• Intracavernosal injection of alprostadil
• Vacuum erection device

Intraurethral alprostadil

Intraurethral alprostadil (Muse) is no longer marketed in Hong Kong. Topical gel of prostaglandin for dropping into urethral opening and application on glans penis (Befar) can be used instead. There may be burning sensation and irritation to partner. Precaution must be taken if partner is pregnant as the prostaglandin may trigger uterine contraction. The drug also needs cold storage to preserve the potency of the prostaglandin.

Other second line measures

For the trial of intracavernosal injection or vacuum erection device, the patient may more appropriately be referred to an urologist.

Conclusion

Erectile dysfunction is a common problem. The attending doctor should look out for other co-existing sexual problem, particularly premature ejaculation. These sexual problems affect quality of life. Erectile function commonly indicates vascular risk factors as well. It would be a good chance to advise the patient to adopt a healthier lifestyle. Underlying diseases should be treated. These measures, together with effective symptomatic treatments now available for erectile dysfunction, would help the patient to restore sex life and attain a better health. The primary physician would be able to help the majority of patients with these sexual problems. For more complicated and refractory cases, patients could be referred to specialist for further investigations and treatments.

Key messages

1. In patients with concomitant premature ejaculation and erectile dysfunction (ED), the erectile dysfunction should be treated first with PDE5 inhibitors.
2. Serotonin reuptake inhibitors are useful in the treatment of premature ejaculation and a new drug (Dapoxetine) is now in the pipeline.
3. There is an emerging link between lower urinary tract symptoms (LUTS) and ED. There may be a point to ask for LUTS in patients with ED and vice versa.
4. ED is a warning sign of cardiac ischaemia. Patient need to have work up for and be educated about cardiovascular risk factors.
5. It is not known whether PDE5 inhibitors actually cause non-arteritic ischaemic optic neuropathy (NAION). A fair discussion of this rare condition could be made with patient at risk.
6. Patients not responding to PDE5 inhibitors may be checked for low testosterone level. In such cases addition of testosterone gel may be helpful.

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References