Erectile Dysfunction

• It is a cardiovascular warning sign. Endothelial dysfunction in the smaller penile arteries frequently precedes coronary events by several years, so new erectile dysfunction warrants cardiovascular risk assessment rather than a prescription alone.
• Preserved nocturnal and early-morning erections point to a psychogenic cause; their loss suggests an organic one.
• Common contributors include diabetes, atherosclerosis, hypertension, smoking, hypogonadism, hyperprolactinaemia, pelvic surgery or radiation, neurological disease, and drugs — particularly thiazides, beta blockers, SSRIs, antipsychotics and antiandrogens.
• Phosphodiesterase-5 inhibitors are first line. The critical safety point is that they are contraindicated with nitrates, because combined nitric oxide potentiation causes profound hypotension.

Vasculogenic (most common overall)

• Atherosclerotic arterial insufficiency: reduced inflow through the cavernosal branches of the internal pudendal artery; shares every risk factor with coronary disease.
• Veno-occlusive dysfunction: failure of the subtunical venules to be compressed against the tunica albuginea, so the erection is achieved but not sustained. Seen with Peyronie disease, aging tunica, and cavernosal fibrosis.

Neurogenic

• Autonomic neuropathy (diabetes, chronic alcohol use) impairs the nitrergic pelvic splanchnic outflow from S2–S4.
• Cord and central lesions: multiple sclerosis, spinal cord injury, Parkinson disease, stroke.
• Iatrogenic cavernous nerve injury: radical prostatectomy, radical cystectomy, abdominoperineal resection, pelvic radiation.

Endocrine

• Hypogonadism: low testosterone chiefly reduces libido and lowers nitric oxide synthase expression.
• Hyperprolactinemia: suppresses GnRH pulsatility → secondary hypogonadism; the stem may add galactorrhea or bitemporal hemianopsia.
• Thyroid disease and poorly controlled diabetes.

Drug-induced (examiners' favorite)

• Antihypertensives: thiazides and beta blockers; ACE inhibitors, ARBs and calcium channel blockers are comparatively neutral.
• Psychotropics: SSRIs, antipsychotics (via hyperprolactinemia).
• Antiandrogens: spironolactone, cimetidine, ketoconazole, GnRH agonists, 5-alpha-reductase inhibitors.
• Chronic alcohol, opioids, tobacco, cocaine.

The normal erectile cascade

• Sexual stimulation activates parasympathetic pelvic splanchnic nerves (S2–S4) and non-adrenergic non-cholinergic (NANC) cavernosal nerves, which release nitric oxide; shear stress then recruits endothelial NOS for amplification and maintenance.
• NO diffuses into cavernosal smooth muscle and activates soluble guanylate cyclase → cGMP → protein kinase G → reduced intracellular calcium → smooth muscle relaxation.
• Relaxation of the helicine arteries increases inflow while relaxation of trabecular smooth muscle expands the sinusoids, which compress the subtunical venules against the rigid tunica albuginea — the veno-occlusive mechanism that converts inflow into rigidity.
• PDE5 hydrolyzes cGMP and terminates the signal; sympathetic tone (norepinephrine, endothelin-1) restores detumescence. Emission is sympathetic (T11–L2), consistent with "point and shoot."

How each insult breaks the chain

• Endothelial dysfunction (diabetes, smoking, dyslipidemia, hypertension): oxidative stress and advanced glycation end products quench NO and uncouple eNOS. Because the cavernosal arteries are small caliber, the same plaque burden becomes symptomatic here before it does in the coronaries — the basis for ED as a cardiovascular sentinel.
• Structural arterial stenosis limits inflow, so the patient cannot achieve rigidity at all.
• Cavernosal fibrosis / smooth muscle loss (aging, chronic ischemia, Peyronie plaque) prevents sinusoidal expansion, so venous outflow is never occluded — the erection is obtained and then rapidly lost.
• Neurogenic injury removes the NANC nitrergic trigger; residual eNOS cannot initiate the cascade, which is why post-prostatectomy patients respond poorly to PDE5 inhibitors (these drugs amplify existing NO rather than generate it).
• Hypogonadism downregulates NOS expression and blunts central libido.
• Psychogenic ED is excess central sympathetic outflow overriding parasympathetic tone; the reflexogenic and nocturnal (REM-associated) pathways remain intact, preserving morning erections.

Core symptoms

• Inability to achieve rigidity — suggests arterial inflow disease or absent neural NO signaling.
• Inability to maintain rigidity after penetration — the signature of veno-occlusive dysfunction or cavernosal fibrosis.
• Gradual, progressive, non-situational onset with loss of nocturnal and early-morning erections — organic disease.
• Abrupt onset, situational, partner-specific, with preserved morning and masturbatory erections — psychogenic; often follows a stressor or new relationship.
• Temporal link to a new drug (thiazide, beta blocker, SSRI, finasteride) — drug-induced.

Findings that localize the cause

• Low libido plus fatigue, decreased shaving frequency, small soft testes, gynecomastia, loss of body hair — hypogonadism.
• Galactorrhea, headache, bitemporal hemianopsia — prolactinoma.
• Diminished femoral/pedal pulses, femoral bruit, buttock or thigh claudication — aortoiliac disease (Leriche syndrome: claudication, absent femoral pulses, erectile dysfunction).
• Palpable dorsal penile plaque with curvature and painful erection — Peyronie disease.
• Absent bulbocavernosus reflex, saddle anesthesia, reduced anal sphincter tone — sacral cord or cauda equina pathology.
• Stocking-distribution sensory loss, absent ankle reflexes, orthostatic hypotension — diabetic autonomic and peripheral neuropathy.
• Depressed mood, anhedonia — either the cause or the consequence.

Step 1 — history and validated instrument

• **International Index of Erectile Function (IIEF), or its 5-item short form the *SHIM***: scores severity and provides a reproducible measure of treatment response. Symptoms should be present for at least 3 months.
• Distinguish libido, erection, ejaculation and orgasm — the stem often hides hypogonadism in a complaint of "low desire."

Step 2 — laboratory screen for reversible and comorbid disease

• Early-morning total testosterone (repeat an abnormal value; the Endocrine Society recommends confirming low testosterone on two morning fasting specimens). If low, add LH/FSH and prolactin to separate primary from secondary hypogonadism and to catch prolactinoma.
• Fasting glucose or HbA1c, lipid panel, blood pressure — new erectile dysfunction is an indication for global cardiovascular risk assessment (ACC/AHA pooled cohort equations), and the Princeton Consensus framework is used to decide whether a man is fit to resume sexual activity or needs stress testing first.
• TSH, CBC, renal and hepatic function as clinically indicated.

Step 3 — specialized testing (only for young men, trauma, refractory cases, or medicolegal need)

• Nocturnal penile tumescence and rigidity testing (RigiScan): normal REM-associated erections indicate a psychogenic cause; absent tumescence indicates organic disease.
• Intracavernosal vasoactive injection with penile duplex Doppler ultrasound — the practical reference standard for vasculogenic disease. Low peak systolic velocity indicates arterial insufficiency; persistently elevated end-diastolic velocity with a low resistive index indicates venous leak.
• Dynamic infusion cavernosometry/cavernosography and pudendal arteriography are reserved for candidates for vascular reconstruction, typically young men after pelvic trauma.

Before prescribing

• Cardiac risk stratification: sexual activity carries a modest exertional load; the Princeton Consensus framework defers therapy in unstable or high-risk cardiac patients until they are stabilized or stress-tested.
• Lifestyle and risk-factor modification (AUA): smoking cessation, weight loss, aerobic exercise, glycemic and lipid control, alcohol reduction — these improve endothelial NO bioavailability and are recommended for all patients.
• Substitute offending drugs: change a thiazide or beta blocker to an ACE inhibitor/ARB or calcium channel blocker; switch an SSRI to bupropion where appropriate.
• Treat endocrinopathy: dopamine agonist (cabergoline) for prolactinoma; the Endocrine Society supports testosterone replacement only in men with confirmed, symptomatic hypogonadism, not for eugonadal men.

First line (AUA)

• PDE5 inhibitors: sildenafil (short-acting, take on an empty stomach ~1 hour before activity) or tadalafil (long half-life, allows daily dosing and "weekend" flexibility); also vardenafil, avanafil. They block cGMP breakdown and therefore require intact neural/endothelial NO — counsel that sexual stimulation is still needed and that up to several attempts at maximal dose may be required before declaring failure.

Second line (PDE5 failure or contraindication)

• Intracavernosal alprostadil (PGE1), alone or as trimix with papaverine and phentolamine — works downstream of NO via cAMP, so it succeeds in neurogenic and post-prostatectomy disease.
• Intraurethral alprostadil suppository (MUSE) — less effective, causes penile/urethral pain.
• Vacuum erection device with constriction ring — non-pharmacologic, useful when drugs are contraindicated.

Of the disease

• Occult cardiovascular disease: penile endothelial dysfunction typically antedates coronary events by years — the finding that should trigger risk assessment, not just a prescription. Missing this is the classic examination trap.
• Depression, anxiety, relationship breakdown, and non-adherence to the cardiovascular drugs blamed for the symptom.
• Infertility when erectile dysfunction accompanies hypogonadism or neurologic ejaculatory failure.

Of PDE5 inhibitors

• Headache, flushing, dyspepsia, nasal congestion — systemic vasodilation and smooth muscle relaxation (nasal mucosal engorgement, lower esophageal sphincter relaxation).
• Cyanopsia / blue-tinged vision — cross-inhibition of retinal PDE6; most characteristic of sildenafil.
• Back pain and myalgia — attributed to PDE11 inhibition with tadalafil.
• Life-threatening hypotension with nitrates or riociguat — an emergency; treat with fluids, Trendelenburg and vasopressors, not more nitrate.
• Non-arteritic anterior ischemic optic neuropathy: sudden painless monocular vision loss with an afferent pupillary defect and a crowded "disc at risk" — emergency ophthalmology referral and permanent drug discontinuation.
• Sudden sensorineural hearing loss — abrupt unilateral hearing loss; stop the drug and refer urgently.

Of injection and device therapy

• Priapism (also with intracavernosal alprostadil/trimix, trazodone, and in sickle cell disease): a painful rigid erection beyond 4 hours is a urologic emergency — ischemic (low-flow) priapism causes cavernosal necrosis and permanent impotence. Per AUA/SMSNA, management is corporal aspiration with irrigation and intracavernosal phenylephrine, escalating to a surgical shunt.
• Cavernosal fibrosis and Peyronie-like plaque from repeated injections; urethral bleeding and pain with intraurethral alprostadil; penile bruising or numbness from vacuum constriction rings.
• Prosthesis infection, mechanical failure or erosion — fever, purulent drainage or device extrusion mandates explantation.

• "Point and Shoot": Parasympathetic (S2–S4, nitric oxide) produces erection; Sympathetic (T11–L2) produces emission; pudendal somatic fibers produce ejaculation. A lesion tells you which one is lost.
• Preserved nocturnal/morning erections = psychogenic; their loss = organic. The confirmatory study is nocturnal penile tumescence (RigiScan) testing.
• The single best next step in a new middle-aged patient is cardiovascular risk assessment, not an immediate prescription. Erectile dysfunction is an early marker of endothelial dysfunction and often precedes coronary events.
• PDE5 inhibitor + nitrate = catastrophic hypotension — an absolute contraindication, as is riociguat. This is the most frequently tested drug interaction in the topic. If a man on sildenafil presents with chest pain, do not give nitroglycerin.
• **Blue-tinged vision (cyanopsia) with sildenafil = PDE6 cross-inhibition in retinal photoreceptors; back pain/myalgia with tadalafil = PDE11. Sudden painless monocular vision loss = NAION**, an emergency.
• PDE5 inhibitors only amplify existing nitric oxide, so they fail when the cavernous nerves are destroyed (post–radical prostatectomy). The correct escalation is intracavernosal alprostadil, which raises cAMP downstream of NO.
• Erection lasting >4 hours is ischemic priapism — a urologic emergency treated with aspiration/irrigation and intracavernosal phenylephrine; think trazodone, intracavernosal injections, or sickle cell disease.
• Common distractor: giving testosterone to a man with normal morning testosterone. The Endocrine Society restricts replacement to confirmed, symptomatic hypogonadism; testosterone does not fix vasculogenic disease and causes erythrocytosis and infertility.
• **Absent femoral pulses + buttock claudication + erectile dysfunction = *Leriche syndrome*** (aortoiliac occlusive disease).