Professor Geoffrey Hackett explains why ED is an important marker for men’s health and why prescribing options should be widened

  • All men presenting with ED require a full cardiovascular assessment:
    • ED is an important marker of cardiovascular risk, especially in men aged under 40 years
  • All men with ED require tests for lipid profile, fasting glucose, HbA1c, IFCC, and morning TT
  • Men with ED and TT of less than 8 nmol/l on two separate occasions are candidates for testosterone replacement therapy, before a PDE5 inhibitor is introduced
  • Management of associated co-morbidities is at least as important as managing the ED—medication changes often improve sexual function
  • LUTS/BPH are commonly associated with ED and both should be included in an assessment of men’s health
  • Daily PDE5 inhibitors are an important therapy option for both ED and LUTS/BPH that should be discussed with patients
  • A men’s health check without asking about ED is incomplete
  • The availability of generic PDE5 inhibitor medication makes the 1999 Department of Health guidance on ED outdated and should spell an end to patients seeking counterfeit ED medication
  • Involve the partner wherever possible by explaining the important relationship of ED with medical conditions and stressing the importance of communication and sexual stimulation. Sexual difficulties in the partner will need to be addressed simultaneously.

ED=erectile dysfunction; HbA1c=glycated haemoglobin; IFCC=International Federation of Clinical Chemistry; TT=total testosterone; PDE5=phosphodiesterase type 5; LUTS=lower urinary tract symptoms; BPH=benign prostatic hyperplasia


E rectile dysfunction (ED) has been defined as the persistent inability to attain and/or maintain an erection sufficient for sexual performance.1,2 Although ED is not perceived as a life-threatening condition, it is closely associated with many important physical conditions (e.g. coronary heart disease [CHD]) and may affect psychosocial health. As such, ED has a significant impact on the quality of life of patients and their partners.2

Current guidance

Since the initial publication of the British Society for Sexual Medicine (BSSM) guideline on the management of erectile dysfunction in 2008,2 several updates have been made in the light of recent research and expert opinion. These updates relate predominantly to the recognition of the important predictive value of ED for underlying CHD, and the importance of diagnosing and treating associated hypogonadism.1 The most recent (2013) summary of the guideline can be found at www.bssm.org.uk/downloads/BSSM_ED_Management_Guidelines_2013.pdf.3

Although it is 16 years since phosphodiesterase type 5 (PDE5) inhibitors were first licensed in the UK, there is still no NICE guidance specifically on ED; current NICE guidance on type 2 diabetes and the 2013/14 quality and outcomes framework recommend that all men with diabetes should be asked annually about ED, assessed, and offered oral treatment with the lowest acquisition cost.4,5

Erectile dysfunction and risk factors

The risk factors for ED are very similar to those for cardiovascular disease, which are managed regularly in primary care: 1,2

  • sedentary lifestyle
  • obesity
  • smoking
  • hypercholesterolaemia
  • the metabolic syndrome
  • type 2 diabetes
  • hypogonadism.

A recent publication from the European Male Ageing Study (EMAS) suggested that the presence of ED and a morning total testosterone (TT) of less tha 8 nmol/l increased cardiovascular and all-cause mortality five-fold.6

Several recent expert review papers have confirmed that ED is an important marker for cardiovascular risk and that the detection and modification of risk factors,7 especially in younger men,8 is at least as important as treating the underlying condition. The recent Princeton III guideline suggests that enquiring about ED is an essential component of all medical health assessments for men.1 The recommendations also clarify the assessment of fitness for sexual activity, which is important for all patients, not just those taking oral therapy (see Figure 1).

In addition to the ED risk factors, ED itself is a cardiovascular risk factor conferring a risk equivalent to a current moderate level of smoking.2 It confers a 1.46 increased risk for cardiovascular disease1 especially in younger men (under the age of 40 years), where the magnitude of risk7 may be up to 50-fold (see Table 1).9

Figure 1: Management of all men with erectile dysfunction, especially those with known cardiovascular disease1
Management algorithm according to graded cardiovascular risk
  • * Sexual activity is equivalent to walking 1 mile on the flat in 20 minutes or briskly climbing two flights of stairs in 10 seconds.
  • Sexual activity is equivalent to 4 minutes of the Bruce treadmill protocol.
  • Nehra A, Jackson G, Miner M et al. The Princeton III consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc 2012; 87 (8): 766–778. Reproduced by kind permission.
Table 1: Relative risks for men with erectile dysfunction8
 Relative risk95% confidence intervalP value
Overall 1.48 1.25–1.74 <0.001
Coronary heart disease 1.46 1.31–1.63 <0.001
Stroke 1.35 1.19–1.54 <0.001
All-cause mortality 1.19 1.05–1.34 0.005
  • Adapted from Dong J, Zhang Y, Qin L. Erectile dysfunction and risk of cardiovascular disease meta-analysis of prospective cohort studies.
  • J Am Coll Cardiol 2011; 58 (13): 1378–1385. By kind permission.

Assessment and investigations—the key role of GPs

All men with ED should receive a full cardiovascular risk assessment, even if there seems to be an obvious cause for
the problem.2 This should involve:

  • measurement of blood pressure
  • assessment for lower urinary tract symptoms (LUTS)
  • laboratory testing for:
    • serum lipids
    • fasting glucose and glycated haemoglobin (HbA1c) or International Federation of Clinical Chemistry
    • morning serum TT and ideally sex hormone-binding globulin and free testosterone.

Healthcare professionals should take a thorough history and perform a focused medical examination. Simple questionnaires, such as the Sexual Health Inventory for Men (see www.njurology.com/_forms/shim.pdf), International Prostate Symptom Score (see www.urospec.com/uro/Forms/ipss.pdf), and Aging Males Symptoms Scale (see www.aging-males-symptoms-scale.info/documents/question.pdf), can be very helpful. 2,10

Many men presenting with ED are diagnosed and treated by physicians who have limited background knowledge and clinical experience of ED. This can be a problem because the proper assessment of men presenting with ED can:2

  • uncover diabetes (as ED may be
    the first symptom in up to 20%
    of cases)
  • detect dyslipidaemia, which might not otherwise dictate treatment according to primary heart disease prevention guidelines, but may be the major reversible component of the patient’s ED
  • reveal the presence of hypogonadism, a reversible cause of ED, which can sometimes be managed without the need for specific ED therapy, and which has other long-term health implications (e.g. obesity, depression, and osteoporosis)
  • identify:
    • occult cardiac disease—ED may be a marker for underlying coronary artery disease in an otherwise asymptomatic man
    • partner and relationship issues, which may need to be addressed alongside any medical management.

Despite the likelihood of them having some of the above underlying conditions, many men with ED may undergo little or no evaluation before treatment, particularly if they seek help from sources such as the internet.6 Men with medical problems do not readily visit their GP, and a consultation for ED may represent a vital opportunity for health interventions. Currently, GPs receive extra remuneration for addressing female-related health issues; health assessment for men with ED, in the author’s opinion, would also be an ideal topic for enhanced payment.2

Referral and specialist investigations

Most patients do not need referral for further investigations2 unless specifically indicated (see Table 2). However, some patients may wish to know the aetiology of their ED and should be investigated appropriately.

Other indications for specialist investigations include patients who:2

  • are young (<40 years), especially men who have always had difficulty in obtaining and/or sustaining an erection
  • have a history of trauma, including possible cycling-related ED
  • on examination, have an abnormality of the testes or penis
  • are unresponsive to medical therapies and who may desire surgical treatment for ED.

Specialist laboratory investigation is rarely required, unless surgical intervention is contemplated.

Effects on erectile dysfunction of drugs prescribed for other conditions

 

Hypertension and cardiovascular disease

Around 65% of men with hypertension will have ED, and those taking thiazide-type diuretics or beta blockers are at increased risk. Angiotensin-converting-enzyme (ACE) inhibitors and calcium-channel blockers probably have a neutral effect, but there is now considerable evidence that angiotensin-receptor blockers (ARB) can significantly improve erections.2,11 If men with hypertension are routinely asked about ED and problems are detected early, changing to an ARB may resolve the issue.11 Recent evidence suggests that statins,12 when prescribed early, improve erections but may have adverse effects on erections in patients with established CHD.2

Depression and psychosis

Selective serotonin reuptake inhibitor (SSRI) antidepressants cause ED, desire and ejaculatory disorders, and many prescriptions can be reduced or stopped if the ED is treated.2 Patients often complain that their treatment for ED might not be working when, in effect, the problem could be related to a recent prescription for an SSRI.

Psychotropic medications may cause hyperprolactinaemia and low testosterone with a reduced response to ED therapies.

Lower urinary tract symptoms/benign prostatic hyperplasia

Alpha-blockers, particularly tamsulosin, cause ejaculatory problems in over 30% of men,13 which can be extremely important in view of the strong association between LUTS/benign prostatic hyperplasia (BPH) and ED.2

Table 2: Further investigations
InvestigationRationaleIndication
Intracavernous injection test Assessment of penile deformities
Colour Doppler ultrasound Assesses vascular integrity Young patients being considered for surgical intervention
Phalloarteriography Clarifies vascular abnormality Arterial abnormality fo Doppler ultrasound
Cavernosometry/cavernosography Assesses venous occlusive mechanism When primary venous leakage suspected in a young man
Nocturnal penile tumescence Assesses nocturnal erections when smooth muscle is relaxed. Reduces false positive investigation rate When other investigations are inconclusive, or prior to surgery

Current prescribing issues in erectile dysfunction

First-line therapies

There are currently three PDE5 inhibitors available:

  • sildenafil
  • tadalafil
  • vardenafil.

Frequent exposure to the full dose of PDE5 inhibitor therapy on at least eight occasions is required, accompanied by direct stimulation.2

Sildenafil

The patent on sildenafil expired in June 2013, and its cost has fallen to less than £1 per tablet.14,15 On this basis, there is little reason for restricting the quantity of medication, especially when provided by private prescription. Many patients previously obtaining medication from hospital on a ‘severe distress’ basis 16 should be re-evaluated, as a private prescription may be a better option for them financially, particularly when travel and parking costs are considered. There would also be a huge saving to the NHS on unnecessary referrals. This is also a ‘safer’ practice in view of the possibility that the man could be prescribed contraindicated medication from different sources. The patent expiry of sildenafil is an excellent opportunity to defeat the internet counterfeiters and to treat men with cardiovascular risk factors in the appropriate primary care setting. The 1999 Department of Health guidance on ED,16 based on cost implications, would now appear to be outdated and potentially a waste of secondary care resources.17

Tadalafil and treatment of LUTS associated with benign prostatic hyperplasia

Since October 2012, tadalafil 5 mg daily, having already proved a popular option to treat ED without the need for therapy before planned sexual activity, has been licensed to treat the signs and symptoms (LUTS) of benign prostatic hyperplasia (BPH) in adult men.18,19 Current theories suggest that LUTS are related to pelvic vascular disease, insulin resistance, and sympathetic over-activity rather than simply to prostate size. Alpha-blockers (a treatment option for BPH with LUTS) do not influence disease progression and therefore long-term studies of PDE5 inhibitors will be of interest.

Data suggest that the efficacy of tadalafil in LUTS/BPH is similar to that of tamsulosin. As both ED and LUTS occur together in around 70% of cases,13 it would be logical to use one drug to treat both conditions, especially as tamsulosin causes sexual adverse events (absent or retrograde ejaculation and ED) in over 30% of men,20 and product labelling still suggests ‘caution’ in using the two drugs together.21 A man with bothersome LUTS funding his own ED therapy might well appreciate a consultation facilitating a switch to daily therapy that might treat both problems.

If the man has ED and a small prostate, and an alpha-blocker is ineffective, then the next option might be transurethral resection of the prostate (TURP), which would then qualify him for NHS ED therapy.16 The substitution or addition of tadalafil 5 mg daily might manage both issues and avoid surgery. These issues raise ethical concerns as to whether a GP’s role is primarily to advise what might be in the best interest of the patient, or to consider local prescribing issues.

Second-line therapies
Intracavernosal injection and intraurethral therapy with alprostadil is safe, well established and well within the scope of a motivated primary care team. Two new therapies are expected to be licensed for ED in 2014:

  • topical alprostadil, taken with a substance that enhances skin penetration, which can be applied to the tip of the penis
  • a new form of intracavernosal injection containing vasointestinal polypeptide and phentolamine, claimed to be associated with less pain and lower rates of prolonged erection.

Testosterone replacement therapy

The BSSM2 and Endocrine Society 22 guidelines recommend TT measurement in all men with ED, and treatment of low testosterone (8 nmol/l or less) before prescribing a PDE5 inhibitor.3,23 Clearly, if the patient also has established CVD risk factors, then a PDE5 inhibitor will also be required. Recent long-term studies have shown considerable sexual and metabolic benefits associated with testosterone replacement therapy.24,25 Therapy is usually lifelong unless profound weight loss is achieved (weight loss may be associated with an elevation of natural testosterone levels). There are considerable funding and long-term monitoring issues associated with this approach and these need to be integrated into models of diabetes and cardiovascular care.

Conclusion

The BSSM ED guideline has been reviewed in 2013 in light of recently published evidence. It is firmly established that ED is an important marker for CVD and should be included routinely in men’s health assessments. The management of associated cardiovascular risk is at least as important as the management of the erection problem itself. The availability of low-cost generic sildenafil should render the 1999 Department of Health ED regulations obsolete and remove the need for men with cardiovascular disease to risk their health by seeking counterfeit internet medication.

GP commissioning take home messages for England

written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead

  • Erectile dysfunction is a distressing symptom in itself but is also an important risk factor for coronary vascular disease
  • Commissioners, including public health departments, should include a question about ED in NHS health checks commissioned from primary care providers
  • Local specialist services could publish a checklist for GPs to use when assessing a patient with ED:
    • checklists can be built into ’autoconsultation templates’ on GP computer systems to ensure the necessary examinations and blood tests are carried out
  • Clinical commissioning groups and local providers could design local ED care pathways to help identify men with ED who require specialist intervention or treatment, and to support GPs appropriately in managing those men who do not
  • Clinical commissioning groups should assess the indications for PDE5 inhibitors in local formularies and issue guidance on their use for both ED and LUTS, and their relative acquisition costs
  • The price of generic sildenafil is now low. If this lower price is reflected in the prices pharmacies charge, men who do not qualify under current NHS rules for treatments for ED may be encouraged to purchase drugs from GPs on private prescription, instead of attending specialist clinics to receive them under the ’severe distress’ clause.
  • ED=erectile dysfunction; PDE5= phosphodiesterase type 5; LUTS=lower urinary tract symptoms
  1. Nehra A, Jackson G, Miner M et al. The Princeton III consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc 2012; 87 (8): 766–778.
  2. Hackett G, Kell P, Ralph D. British Society for Sexual Medicine guidelines on the management of erectile dysfunction. J Sex Med 2008; 5 (8): 1841–1865.
  3. British Society for Sexual Medicine. British Society for Sexual Medicine guidelines on the management of erectile dysfunction (2013 edition). Available at: www.bssm.org.uk/downloads/BSSM_ED_Management_Guidelines_2013.pdf
  4. British Medical Association, NHS Employers. Quality and outcomes framework guidance for GMS contract 2013/14. London: BMA, NHS Employers, 2013. Available at: gpqofguidance20132014-4.pdf
  5. Home P, Mant J, Diaz J, Turner C; on behalf of the guideline development group. Management of type 2 diabetes: summary of updated NICE guidance. BMJ 2008; 336 (7656): 1306–1308.
  6. Pye S, Huhtaniemi I, Finn J et al; and the EMAS study group. Late onset hypogonadism and mortality in elderly men. J Clin Endocrin Metab. doi:10.1210/jc.2013–2052. [Epub ahead of print.]
  7. Jackson G, Boon N, Eardley I et al. Erectile dysfunction and coronary artery disease prediction: evidence-based guidance and consensus. Int J Clin Pract 2010; 64 (7): 848–857.
  8. Inman B, Sauver J, Jacobson D. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc 2009; 84 (2): 108–113.
  9. Dong J, Zhang Y, Qin L. Erectile dysfunction and risk of cardiovascular disease meta-analysis of prospective cohort studies. J Am Coll Cardiol 2011; 58 (13): 1378–1385.
  10. Kirby M, Chapple C, Jackson G et al. Erectile dysfunction and lower urinary tract symptoms: a consensus on the importance of co-diagnosis. Int J Clin Pract 2013; 67 (7): 606–618.
  11. Bohm M, Baumhakel M, Teo K et al. Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials. Circulation 2010; 121 (12): 1439–1446.
  12. Gazzaruso C, Solerte S, Pujia A. Erectile dysfunction as a predictor of cardiovascular events and death in diabetic patients with angiographically proven asymptomatic coronary artery disease: a potential protective role for statins and 5-phosphodiesterase inhibitors. J Am Coll Cardiol 2008; 51 (21): 2040–2044.
  13. Rosen R, Altwein J, Boyle P et al. Lower urinary symptoms and male sexual function: the multinational survey of the ageing male (MSAM-7) Eur Urol 2003; 44 (6): 637–649.
  14. Monthly Index of Medical Specialities website. Viagra. Available at: www.mims.co.uk/Drugs/endocrine/erectile-dysfunction-premature-ejaculation/viagra/ (accessed 27 February 2014).
  15. PharmaTimes website. Generic firms poised as Viagra goes off-patent in Europe. www.pharmatimes.com/article/13-06-24/Generic_firms_poised_as_Viagra_goes_off-patent_in_Europe.aspx (accessed 19 February 2014).
  16. Department of Health. Treatment for impotence: patients with severe distress. HSC 1999/177. London: DH, 1999. Available at: webarchive.nationalarchives.gov.uk/+/www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_4012101.pdf
  17. Hackett G. Schedule 11—impact on treating erectile dysfunction. Br J Diabetes Vasc Dis 2002; 2: 315–318.
  18. NICE website. ESNM18 Lower urinary tract symptoms secondary to benign prostatic hyperplasia: tadalafil.www.nice.org.uk/mpc/evidencesummariesnewmedicines/ESNM18.jsp (accessed 14 February 2014).
  19. Monthly Index of Medical Specialities website. Cialis. Available at: www.mims.co.uk/Drugs/genito-urinary-system/bph-urinary-retention/cialis/ (accessed 27 February 2014).
  20. Uckert S, Oelke M. Phosphodiesterase (PDE) inhibitors in the treatment of lower urinary tract dysfunction. Br J Clin Pharmacol 2011;
    72 (2): 197–204.
  21. Seftel A, Rosen R, Kuritzky L. Physician perceptions of sexual dysfunction related to benign prostatic hyperplasia (BPH) symptoms and sexual side effects related to BPH medications. Int J Impot Res 2007; 19 (4): 386–392.
  22. Bhasin S, Cunningham G, Hayes F. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95 (6): 2536–2559.
  23. Buvat J, Montorsi F, Maggi M. Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). J Sex Med 2011; 8 (1): 284–293.
  24. Hackett G, Cole N, Bhartia M et al; BLAST Study Group. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med 2013. doi: 10.1111/jsm.12404. [Epub ahead of print.]
  25. Traish, Haider A, Doros G. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study.Int J Clin Pract 2014; 68 (3): 314–329G