Prof. Giacomo Novara — Urology, University of Padova
Andrology — Pathophysiology, assessment and treatment
The two most widely used definitions are complementary and each slightly imperfect:
DSM-IV: persistent or recurrent inability to attain or maintain a penile erection adequate for satisfactory sexual performance.
NIH: inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse.
The vast majority of patients have partial erectile dysfunction (insufficient rather than absent erection). Complete erectile dysfunction is less common and is observed mainly in patients with advanced diabetes or after radical pelvic surgery.
Prevalence increases with age, obesity, diabetes, and physical inactivity — all of which are rising in Western populations. In Europe, moderate or severe ED affects approximately 10% of men between 40 and 70 years of age.
Erection is a neurovascular event. Sexual stimulation generates a parasympathetic signal that releases nitric oxide (NO) from non-adrenergic non-cholinergic fibres within the corpora cavernosa. NO activates guanylate cyclase → production of cGMP → reduction of intracellular calcium → smooth muscle relaxation → dilatation of the sinusoids and helicine arteries.
Arterial blood rapidly fills the corpora cavernosa. Their expansion compresses the subtunical venules against the tunica albuginea → obstruction of venous outflow. The result is pooling of oxygenated arterial blood → penile rigidity.
Phosphodiesterase type 5 (PDE5) inactivates cGMP by converting it to linear GMP, leading to detumescence. PDE5 inhibitors enhance the effect of cGMP and prolong erection, but only in the presence of sexual stimulation and functional NO production (i.e., intact cavernous nerves).
Atherosclerosis of the penile vasculature secondary to the metabolic syndrome: hypertension, diabetes, smoking, obesity, dyslipidaemia, physical inactivity. ED often precedes overt ischaemic heart disease.
Radical prostatectomy (most common), sigmoid rectal resection, other pelvic surgery. Direct or indirect injury to the cavernous nerves running lateral to the prostate.
Multiple sclerosis, Parkinson's disease, cerebrovascular stroke, spinal cord injury. The parasympathetic signal for NO production does not reach the corpora cavernosa.
Hypogonadism (low testosterone), prolactin-secreting pituitary adenoma, thyroid or adrenal disorders. These lead to reduced libido and secondarily to ED.
Almost all antihypertensive agents (except ACE inhibitors and ARBs) can cause ED. Hypertension itself is a risk factor, but its treatment may also impair erectile function.
Peyronie's disease (induratio penis plastica): fibrotic plaques of the tunica albuginea → penile curvature + venous leak. Unrepaired penile fracture: post-traumatic fibrosis.
Vasculogenic erectile dysfunction is the warning sign of silent ischaemic heart disease. The penile arteries are smaller than the coronaries: atherosclerosis obstructs them first, causing ED years before myocardial infarction.
The EAU Guidelines recommend applying the ASCVD score (American College of Cardiology/American Heart Association) in patients with vasculogenic ED, even in the absence of cardiovascular symptoms. Depending on the estimated 10-year risk, intervention targets include:
Correct hyperglycaemia and dyslipidaemia.
Appropriate targets, preferring ACE inhibitors or ARBs.
Smoking cessation — independent cardiovascular risk factor.
Improvement in endothelial function and insulin sensitivity.
In obese patients, weight reduction significantly improves erectile function.
When the ASCVD score is elevated, even in the absence of symptoms.
5 questions covering the past 6 months. Classifies ED as: mild (17–21), mild-to-moderate (12–16), moderate (8–11), severe (<7). An essential tool for quantifying the problem and monitoring treatment response.
Testosterone (total and free), prolactin (if reduced libido), TSH. Identifies treatable endocrine causes.
Fasting glucose, full lipid panel, resting ECG. ASCVD score to estimate 10-year cardiovascular event risk.
Body hair distribution (signs of hypogonadism), weight/BMI, genitalia (phimosis, Peyronie's plaques, testicular volume), blood pressure.
Assesses cavernous arterial flow at baseline and after intracavernous injection of prostaglandin. Allows distinction between arterial and venous vasculogenic ED. Not routinely indicated.
Before prescribing PDE5 inhibitors, it is necessary to assess whether the patient has sufficient coronary reserve for sexual activity:
Asymptomatic with <3 risk factors, well-controlled stable angina, NYHA class I–II, controlled hypertension.
≥3 risk factors, moderate angina, MI >6 weeks ago, moderate left ventricular dysfunction. Echocardiography → if residual function is adequate → PDE5 permitted.
Unstable angina, recent MI (<6 weeks), decompensated heart failure, NYHA class III–IV, uncontrolled arrhythmias.
These agents inhibit phosphodiesterase type 5, slowing the degradation of cGMP → enhancing NO-induced cavernous vasodilatation. They work only in the presence of sexual stimulation and functional cavernous nerves.
| T½ | ~4 hours |
| Tmax | ~1 hour |
| Doses | 25, 50, 100 mg |
| Food | Delays absorption |
Requires precise timing of intercourse. The efficacy window is narrow (~3 hours). Interaction with retinal PDE → visual disturbances.
| T½ | ~18 hours |
| Tmax | ~2 hours |
| Doses | 10, 20 mg (on demand) · 5 mg (daily) |
| Food | No effect on absorption |
Long half-life → more spontaneous and natural intercourse. The 5 mg/day once-daily regimen is ideal for patients with frequent intercourse (≥2/week). Typical side effect: back pain.
| T½ | ~4–5 hours |
| Tmax | ~1 hour |
| Doses | 5, 10, 20 mg |
Similar profile to sildenafil. Comparable efficacy in network meta-analyses.
| T½ | ~5 hours |
| Tmax | ~0.5 hours |
| Doses | 50, 100, 200 mg |
Faster onset than other PDE5 inhibitors. Less interaction with retinal PDE.
All PDE5 inhibitors have comparable efficacy in network meta-analyses. The choice is based on frequency of intercourse and patient preference:
Infrequent intercourse (<1/week): tadalafil 20 mg or sildenafil 50–100 mg on demand. Frequent intercourse (≥2/week): tadalafil 5 mg/day (plasma steady state → always available). Side effects are mild: headache, nasal congestion, flushing, back pain (tadalafil).
Mechanism not fully elucidated. Meta-analyses show efficacy only in mild ED. A significant placebo effect is likely in moderate-to-severe forms. Not a solution for patients who do not respond to PDE5 inhibitors.
The patient self-injects the drug laterally into the corpus cavernosum, avoiding the dorsal (neurovascular bundle) and ventral (urethra) aspects. Erection occurs independently of NO and sexual stimulation. Starting dose is 2.5 µg, titrated to effect. Injection sides should be alternated to prevent fibrosis. Main risk: prolonged painful erection → priapism. Indicated in patients who fail PDE5 inhibitors (advanced diabetes, non-nerve-sparing surgery).
Two cylinders in the corpora cavernosa, reservoir in the space of Retzius, pump in the hemiscrotum contralateral to the dominant hand. The patient activates and deactivates erection by squeezing the pump. A definitive solution for refractory ED. Risks: mechanical failure, infection, erosion.
Priapism is a prolonged erection (>4 hours), painful, unrelated to sexual stimulation. It requires urgent treatment: untreated low-flow priapism leads to corporal fibrosis and permanent ED.
Cause: perineal trauma with fistula formation. Less pain; corpus spongiosum not erect. Blood gas: high PO₂, low PCO₂. Doppler: high flow. Treatment: fistula embolisation (non-urgent).
Causes: prostaglandins, cocaine, sickle cell disease, haematological disorders. Severe pain. Blood gas: low PO₂, high PCO₂. Doppler: absent flow. Treatment: ice → corporal irrigation → intracavernous catecholamine injection → cavernosal-spongiosal shunt if refractory.
The cavernous nerves run along the lateral aspects of the prostate. Their preservation during radical prostatectomy (nerve-sparing surgery) is the primary determinant of erectile function recovery.
Spontaneous erections return early in the majority of patients. PDE5 inhibitors work well: NO is available.
No spontaneous erections. PDE5 inhibitors are ineffective (no NO → no cGMP to preserve). Intracavernous alprostadil injections are used instead.
Variable recovery over time. PDE5 inhibitors on demand as soon as the patient wishes to resume sexual activity.
For years we administered daily PDE5 inhibitors for months after prostatectomy to "rehabilitate the corpora cavernosa" and prevent fibrosis. The REACT trial demonstrated that this practice makes no difference at one year.
The REACT trial randomised patients after nerve-sparing radical prostatectomy to: no treatment (placebo), tadalafil 5 mg/day, or tadalafil 20 mg on demand for 9 months, followed by a washout period and assessment at 12 months.
Result: during the first 9 months, those receiving medication had better erections (the drug worked). However, at one year post-surgery, regardless of what had been done during the first 9 months, all patients responded equally to tadalafil.