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Introduction

There is increasing evidence that erectile dysfunction (ED) may be an early manifestation of coronary artery and peripheral vascular disease, preceding its onset by 8 - 10 years.  ED should not only be regarded as a quality-of-life issue but also as a potential risk factor for cardiovascular disease.  

One should, therefore, use the opportunity, when a man presents with ED, to offer screening for cardiovascular risk factors, with a view to risk prevention.

Dong JY, Zhang YH, Qin LQ. Erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. J Am Coll Cardiol 2011; 8(13): 1378-85


Physiological changes during normal erection

Sexual stimulation activates the hypothalamus, causing the autonomic nervous system to release nitric oxide (NO) from the cavernous nerves.  It is nitric oxide that triggers arteriolar dilatation:  

  • arteriolar dilatation in the corpus cavernosum is triggered, increasing systolic blood flow into the penis
  • blood becomes trapped in venous sinusoids which causes compression of the sub-tunical venous plexuses
  • the tunica albuginea becomes stretched, causing occlusion of the emissary vessels, resulting in an erection
  • contraction of the ischiocavernosus muscle causes further compression of the corpora cavernosa, resulting in full rigidity (see picture below)

Nitric oxide (NO) release from the cavernous nerves activates guanylate cyclase within the smooth muscle cells of the penis. This catalyses the conversion of GTP to cyclic-GMP (cGMP) which, in turn, activates specific protein kinases that decrease intra-cellular calcium levels, and lead to smooth muscle relaxation, vasodilatation and tumescence.

Phosphodiesterase type 5 (PDE-5) catalyses the conversion of the active cyclic-GMP to the inactive 5'-GMP, allowing the intra-cellular calcium level to return to normal, and resulting in vasoconstriction and loss of tumescence (see below).

 


Epidemiology & prevalence

ED is more common than most people think. Data from the USA suggests that, at the age of 40 years, almost 40% of men have some degree of ED. The overall prevalence of ED in non-institutionalised men aged 40 to 79 years was found to be 52%.

Severity of ED Age 40yr Age 70yr
Mild erectile dysfunction - score 12 to 21 on the Sexual Health Inventory for Men (see below) 17% 17%
Moderate erectile dysfunction - score 8 to 11 on SHIM 17% 34%
Severe (complete) erectile dysfunction - score 1 to 7 on SHIM  5% 15%

Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151(1): 54-61


Causes & classification of erectile dysfunction

Classification Specific disease / condition
ORGANIC
Vasculogenic Cardiovascular disease
Hypertension
Diabetes mellitus
Hyperlipidaemia
Smoking
Major surgery (radical prostatectomy) or radiotherapy
Neurogenic Central causes
degenerative disorders (e.g. multiple sclerosis, Parkinson's, multiple system atrophy)
spinal cord trauma or disease
stroke
CNS tumours


Peripheral causes
type 1 & 2 diabetes mellitus
chronic renal failure
polyneuropathy
surgery (pelvis or retroperitoneum e.g. radical prostatectomy, colorectal excision)

 

Anatomical (structural) Hypospadias / epispadias
Micropenis
Congenital curvature of the penis
Peyronie's disease
Hormonal Hypogonadism
Hyperprolactinaemia
Hyperthyroidism / hypothyroidism
Hypercortisolaemia (e.g. Cushing's) / hypocortisolaemia
Drug-induced Antihypertensives (especially diuretics)
Antidepressants (especially SSRIs & tricyclics)
Antipsychotics (including neuroleptics)
Anti-androgens, LHRH analogues / antagonists
Recreational drugs (alcohol, cocaine, marijuana, methadone, heroin)
PSYCHOGENIC
Generalised Lack of arousability
Disorders of sexual intimacy
Situational Partner-specific ED
Performance anxiety
Psychological stress

Clinical assessment

Modality      Points requiring specific attention
History
  • true nature & severity of the problem
  • speed of onset & psychological context
  • loss of libido (associated with testosterone deficiency
  • relationship status
  • non-coital erections (especially at night)
  • previous treatments (and their success/failure)
  • drug consumption
  • past medical & surgical history (e.g. pelvic surgery, pelvic radiotherapy)
Examination
  • blood pressure & pulse
  • secondary sexual characteristics
  • penis and testes
  • rectal examination (especially if > 40 yr)
  • general neurological/vascular assessment
Investigations
  • fasting blood glucose
  • fasting lipid profile
  • serum testosterone (between 08.00 and 10.00hr because of diurnal variation)
  • International Index of Erectile Function (IIEF)

PLEASE NOTE
This is an ideal opportunity to identify primary cardiovascular risk factors and institute preventive measures


Symptom scores in erectile dysfunction

The International Index of Erectile Function (IIEF) is a 15-item questionnaire with five domains covering erections, orgasm, libido, intercourse satisfaction & overall satisfaction. Although it was designed primarily for use in clinical trials, it is a useful tool to assess baseline function and to measure the response to treatment.

The Sexual Health Inventory for Men (SHIM), also known as the IIEF-5, is widely used in clinical trials to assess response to treatment and is useful for categorising the severity of erectile dysfunction. The questions are similar to those in the IIEF but the responses are classified in a different way.

Download the International Index of Erectile Function (IIEF)

Download the Sexual Health Inventory for Men (SHIM)

Rosen R, Riley A, Wagner G, et al. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology, 1997, 49: 822-830


Conservative treatment

Simple lifestyle advice is important:

  • avoid recreational drugs
  • stop implicated therapeutic drugs (if possible)
  • lose weight
  • increase exercise levels
  • stop smoking
  • reduce alcohol consumption
  • psychosexual counselling (for psychogenic problems)

Hypogonadism & testosterone replacement

The hypothalamic-pituitary-testis axis controls the production of testosterone (as well as spermatogenesis) in the testes through a complex series of negative-feedback systems:

Testosterone is very important for erectile function and all patients should have their testosterone levels measured. Men with serum testosterone levels less than 8 nmol/L should be investigated endocrinologically to exclude pituitary/hypothalamic abnormalities (e.g. prolactinoma).

Testosterone replacement therapy (TRT) may be indicated if there is no underlying endocrinological abnormality; TRT is sometimes sufficient to allow the return of normal erections without any further medical treatment. The role of pituitary investigations and TRT is more controversial when testosterone levels are between 8 and 12 nmol/L.

TRT (given either by intra-muscular injection or trans-dermal patches) is highly effective but should only be started when significant endocrine abnormalities have been excluded. Before starting treatment, all patients receiving TRT should have the following investigations:

  • digital rectal examination (DRE)
  • serum PSA
  • liver function tests (LFTs)
  • lipid profile

TRT is contra-indicated in men with untreated prostate cancer or unstable cardiac disease.


First-line medical treatment

With the advent of phosphodiesterase type-5 (PDE-5) inhibitors  such as sildenafil (Viagra™), the treatment of ED has been revolutionised.

PDE-5 inhibitors are now first-line treatment for the majority of patients with ED, regardless of the underlying cause. The drugs work by inhibiting the degradation of active cyclic-GMP (cGMP) to inactive 5'-GMP, thus allowing cGMP to accumulate and cause muscle relaxation within the penis, resulting in vasodilatation and erection (see "The cellular physiology of erection" above).

Caution & contraindications

PDE-5 inhibitors are contra-indicated in patients taking nitrate medications (they may cause profound hypotension), should be used with caution in men with unstable cardiac disease (the exertion associated with sexual activity may be hazardous) and can worsen postural hypotension in men taking alpha-blockers.

There are four main PDE-5 inhibitors available:

  • Avanafil (Stendra™)
  • Sildenafil (Viagra™)
  • Tadalafil (Cialis™)
  • [Vardenafil (Levitra™) - is no longer actively marketed by the manufacturers]

All are "on-demand" drugs, although tadalafil and avanafil, because of their long half-lives, can be taken as a once-daily, regular dose to aid spontaneous erections. Generic sildenafil (pictured) is now available from general practitioners, without any prescribing restrictions, and is usually the first-choice PDE-5 inhibitor.

Biological Parameter Individual PDE-5 Inhibitors (with equipotent dosages)
Avanafil
(100mg)
Sildenafil
(100mg)
Tadalafil
(20mg)
Vardenafil
(20mg)
Delay before max effect 30 - 45 min 14 - 60 min 15 - 45 min 25 min
Half-life 10.5 hr 4 hr 17.5 hr 4 hr
Duration of action Up to 6 hr Up to 4 hr Up to 36 hr Up to 5 hr

Side-effects

Overall, 16% of patients suffer side-effects from PDE-5 inhibitors.  The commonest side effects are facial flushing, nasal congestion & dizziness; less common are headaches, muscle aches (including back pain), and indigestion. After taking sildenafil, a few men can experience a blue tinge to their vision (due to a cross-reaction with PDE-6 in retinal photoreceptors).

Most side-effects are not troublesome. They tend to last only an hour or so and, if the drugs are effective in producing erection, it is uncommon for men to stop taking them simply because of side-effects.


First-line treatment failure

30 - 35% of men fail to respond to initial treatment with PDE-5 inhibitors. Most treatment failures are due to inadequate counselling and unrealistic expectations. Common problems include:

  • inadequate or absent sexual stimulation
  • inadequate dosage
  • inadequate delay between taking the medication and attempting intercourse (ideally 15 - 30 minutes)
  • use of black-market products (which may be less effective or even contain no active ingredient)

Changing to a different PDE-5 inhibitor, ensuring a minimum treatment duration of six weeks, increasing dosage incrementally and providing detailed counselling may make first-line treatment more likely to be effective. 

Severe penile vascular disease, unrecognised hypogonadism, uncorrected co-morbid disease, vascular risk factors and psycho-social problems are also associated with initial PDE-5 inhibitor failure.


Second-line medical treatment

Treatment type Details

Vacuum erection assistance devices (VEDs)

 

VEDs provide passive engorgement of the corpora cavernosa by sucking blood into the penis.

A constriction ring is used around the base of the penis to maintain the engorgement.

Treatment is effective, but the constriction ring impairs ejaculation is some men and can only be left in place for 30 minutes.

Intra-cavernous injection of prostaglandin (PGE1)

Self-administered intra-penile injections of alprostadil (prostaglandin-E1) can result in a near-normal erection, with efficacy dependent on the dose injected.

Treatment is effective in the majority of patients but requires a significant degree of manual dexterity.

There is a small (2%) risk of priapism. Bruising and haematoma may occur, as may injection-induced fibrosis of the corpora cavernosa.

Medicated urethral system for erection (MUSE)

The medicated urethral system for erection (MUSE) uses a pellet of alprostadil (prostaglandin-E1) inserted into the tip of the urethra. Insertion can be uncomfortable and success rates are low (35%); as a result, MUSE is no longer widely used.


Third-line surgical treatment

Insertion of penile prostheses may be considered in patients who do not respond to first- and second-line treatments, or in men who are seeking a permanent solution. Penile prostheses come in two basic forms:

INFLATABLE
Can be inflated or deflated "on-demand"
MALLEABLE
Permanently semi-rigid but "bendy"

Implantation of prostheses should be regarded very much as a "last resort". The erectile tissue within the penis is destroyed during implantation of the prostheses, so the procedure should be regarded as irreversible.

The main risks of the procedure are infection and mechanical failure.


ED treatment summary

Download general information about erectile dysfunction.

Hatzimouratidis K et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010; 57(5): 804-14