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A. Normal Physiology of Erection

  1. Erection (tumescence) is due to engorgement of corpora cavernosa with blood
  2. Complex interplay of central (cerebral, spinal), local factors, and hormonal status
  3. Local factors are smooth muscle (SmM) and endothelium
  4. Interplay of vasodilator and vasoconstrictor mechanisms
  5. Usual flaccid state of penis results from contraction of arterial and corporal SmM
    1. This contraction is mediated by three mechanisms:
    2. Alpha2-adrenergic neurons, intrinsic myogenic activity, and vasoconstrictors
    3. Vasoconstrictors include prostaglandin F2alpha and endothelins
    4. Contracted arterial and corporal SmM lead to limited penile blood supply
  6. Erection occurs when the SmM relax
    1. Resistance of penile arterioles and cavernosal sinusoids decreases
    2. This allows >3 fold increase in blood flow into corpus cavernosa
    3. Decrease in adrenergic tone occurs
    4. Parasympathetic neurons are main central conduits for initiation of vasodilation
    5. These neurons are noncholinergic, nonadrenergic
  7. Mechanisms of Vasodilation
    1. Vasodilation due mainly to nitric oxide (NO), also to prostaglandins E1 and E2 (PGE)
    2. Nitric oxide is produced from arginine by NO synthetase in neurons and endothelium
    3. NO stimulates guanylyl cyclase to produce cyclic-GMP
    4. Cyclic GMP inhibits calcium influx into cavernosal SmM
    5. Reduction of calcium influx causes relaxation of cavernosal SmM
    6. PGE1 inhibits calcium uptake by a different mechanism
    7. Vasoactive intestinal polypeptide (VIP) also plays a role in vasodilation
    8. Cyclic GMP degraded by a penile-specific phosphodiesterase, mainly isozyme V (PDE V)
  8. Engorgement of sinusoids leads to compression in subtunical venous plexus
    1. This leads to reduction in venous outflow
    2. Both increased inflow and reduced outflow maintain an erection
  9. Detumescence is due to a reversal of these events mediated mainly by norepinephrine

B. Causes of Erectile Dysfunction

  1. Erectile dysfunction defined as consistent inability to attain or maintain a mpenile erection of sufficient quality to permit satisfactory sexual intercourse [1]
  2. Affects 25-30 million men in USA (age related increases)
    1. Overall, 35% of men aged 40-70 report moderate or complete impotence
    2. Affects 25% of men 65 years or older
    3. Affects 55% of men 75 years or older
    4. Affects 65% of men 80 years or older
  3. Classification of Causes
    1. Many causes are related to impairment of SmM physiology
    2. Organic, non-organic (psychogenic), and mixed causes
    3. Organic: neurogenic, hormonal, arterial (vascular), cavernosal, drug induced
  4. Risk Factors (Table 1, Ref [1])
    1. Metabolic syndrome / Insulin Resistance / Diabetes Mellitus (DM)
    2. Benign Prostatic Hyperplasia (BPH)
    3. Cardiovascular (CV) and other Vascular Diseases
    4. Tobacco smoking
    5. Central neurologic conditions: Parkinson's, stroke, tumors, Alzheimer's, encephalitis, Shy-Drager Syndrome
    6. Spinal Cord Injury
    7. Depression / Anxiety / Stress Disorders
    8. Endocrine Conditions
  5. Vascular Diseases
    1. Circulatory insufficiency, usually pudendal or common penile artery atherosclerosis
    2. Often with other peripheral (PAD), coronary artery (CAD), and/or cerebral vascular disease
    3. Stroke is a common cause of erectile dysfunction
    4. More common in DM patients (overall likely >15% of cases)
    5. Smoking, hypertension, hyperlipidemia all contribute
    6. DM contributes to both atherosclerosis and autonomic neuropathy [9]
    7. Erectile dysfunction is associated with 1.25-1.45X risk of 5-year CV events [23]
  6. Neurogenic
    1. Diabetes mellitus (~9% of cases) [9]
    2. Neurodegenerative: Parkinson's Disease, Alzheimer's Disease
    3. Radical prostatectomy (including nerve sparing) - recovery in 60-80% by 2 years [4]
    4. Bladder cancer surgery
    5. Castration (surgical or medical) - treatment for prostate cancer
    6. Other pelvic surgery or pelvic trauma
    7. Quadraplegia
    8. Lower spinal cord lesions
    9. Multiple sclerosis
  7. Endocrine Disorders [9]
    1. Androgen Deficiency (as above for castration)
    2. Hypothyroidism ~5%
    3. Hyperthyroidism ~1%
    4. Hyperprolactinemia ~4%
    5. Secondary hypogonadism ~9%
  8. Drug-Induced
    1. ß-adrenergic drugs - probably by potentiating alpha1-adrenergic constriction in penis
    2. Spironolactone - reduces libido, causes gynecomastia
    3. Antidepressants - primarily serotonin transporter antagonists (SSRI, SNRIs)
    4. Dopamine agonists
    5. Alpha-2-adrenergic agonists
    6. Cimetidine (higher doses)
    7. Estrogens
    8. LHRH analogs
  9. Psychogenic
    1. Directly causes ~15% of cases; important contributing factor in many other cases
    2. Performance anxiety
    3. Strained relationship
    4. Lack of sexual arousability
    5. Overt psychiatric idsease: depression, schizophrenia
  10. Peyronie's Disease [14]
    1. Connective tissue disorder
    2. Plaque formation in tunica albuginea of corpora cavernosa
    3. Men typically 40-60 years old
    4. Incidence ~1%
    5. Plaque usually unifocal in penile dorsum causing dorsal deviation of penus
    6. Spontaneous resolution in ~50% of patients in early stage disease
    7. Diagnosis by MRI recommended
    8. Extracorporeal shock wave therapy and iontophoresis used
  11. Hyperlipidemia / Metabolic Syndrome

C. Diagnostic Questions

  1. Morning Erection
    1. Normal for men to awake with an erection
    2. Presence of normal erection suggests psychogenic cause of erectile dysfunction
  2. Presence of Atherosclerotic Disease
    1. Cardiovascular Disease
    2. Cerebrovascular Disease
    3. Peripheral Vascular Disease
  3. Assess the following risk factors for erectile dysfunction [3]
    1. Diabetes
    2. Hypertension
    3. Renal Failure
    4. Pelvic or perineal injury or surgery
    5. Spinal cord injury
    6. Central nervous system disease including multiple sclerosis
    7. Drug Abuse
    8. Alcoholism
    9. Cigarette smoking
    10. Medications with vascular activity (as above)
    11. Endocrinopathy (as above)
    12. Hypercholesterolemia (also low HDL)
    13. Psychiatric Disease - mainly depression and anxiety, also anger
  4. Laboratory Studies
    1. Blood pressure
    2. Cholesterol panel
    3. Gonadal Function assessment: luteinizing hormone (LH), free testosterone (TST)
    4. Thyroid Stimulating Hormone (TSH)

D. Treatment

  1. Focus on underlying causes and drugs which can contribute
    1. Determination of serum testosterone levels will uncover hypogonadism
    2. Oral phosphodiesterase type 5 (PDE5) inhibitors agents are first line with normal TST
    3. Failure of oral agents suggests parenteral therapy or vacuum constriction device
    4. Failure of these modalities: penile vascular surgery or penile implant
  2. PDE5 Inhibitor Overview [17]
    1. Effective in 50-80% of patients with erectile dysfunction of various etiologies
    2. Sildenafil and vardenafil have onset ~25 minutes with 4 hour duration
    3. Tadalafil has 36 hour duration, onset ~45 minutes
    4. Any of these agents are reasonable as initial therapy
    5. Take 1-2 hours prior to sexual activity; not more than once per 24 hours
    6. Best results when used with psychic (fantasy) and physical (penile) stimulation
    7. Increase dose if not effective
    8. Main side effects: headache, flushing and dyspepsia, mild hypotension
    9. Should not be used with nitrates; may cause severe hypotension due to NO increases
    10. Caution in patients with CAD, though little effect on cardiac blood flow found [8]
    11. Transient abnormal vision can occur, probably due to effects on retinal PDE6
    12. Hearing dysfunction can also occur
  3. Sildenafil (Viagra®) [5,6]
    1. Oral therapy which inhibits PDE5 (specifically found in the penis; see above)
    2. Potentiates NO-dependent physiological responses causing erection after sexual arousal
    3. Also inhibits PDE type 6 (retina) but not type 3 (heart)
    4. Initial dose 50mg, target dose typically 100mg po qd prn
    5. Onset of action ~25 minutes; 4 hour duration
    6. Response rate is >70%; nearly 100% at 100mg po given 1 hour prior to erection
    7. For impotence related to radical prostatectomy, response was 43% versus 15% placebo
    8. Effective for impotence due to heart failure, diabetes, spinal cord injuries, prostate surgery, psychogenic disease
    9. Overall response in diabetic patients 56% versus 10% placebo [7]
    10. Effective in improving erectile and other sexual dysfunction due to SSRIs, SNRIs [15]
    11. Has been used chronically as a vasodilator for pulmonary hypertension [18,19]
    12. Safe and effective in men with moderately severe congestive heart failure (CHF) [20]
    13. Also improves hypoxia at low altitudes and in mountain sickness conditions [21]
    14. Some questions about vision disturbances and loss in very small numbers of patients [22]
  4. Vardenafil (Levitra®) [16]
    1. Oral PDE5 inhibitor similar to sildenafil
    2. Efficacy and side effects similar to sildenafil
    3. Starting dose 10mg taken ~1 hour prior to sexual activity
    4. Onset of action ~25 minutes; 4 hour duration
    5. Increase dose to maxmium 20mg or reduce to 5mg
    6. Initial dose lower in men >65 years or with hepatic dysfunction
  5. Tadalafil (Cialis®) [17]
    1. Oral PDE5 inhibitor with long half-life
    2. Less affinity than vardenafil and sildenafil for PDE6
    3. Higher affinity than vardenafil and sildenafil for PDE11 (skeletal muscle, testes, heart, kidney, prostate, liver, pituitary; unknown function)
    4. Initial dose 10mg for normal renal function; 5mg with chronic renal insufficiency
    5. Dose can be increased to 20mg in persons with normal renal and hepatic function
    6. Onset of action ~45 minutes
    7. Duration of action 24-36 hours, considerably longer than sildenafil
    8. Approved both on as needed 5mg/10mg dose, or as once daily dosing 2.5-5mg po qd [25]
  6. Testosterone (TST) Supplementation [1,2]
    1. Hypogonadism usually presents with reduced libido and ED
    2. TST replacement only for documented reduced serum TST levels (hypogonadism)
    3. Injectable, topical gel and patch TST formulations available
    4. Digital rectal exam (DRE) and serum prostate specific antigen (PSA) should be performed prior to initiation of TST therapy
    5. Abnormal DRE or PSA should prompt a prostate biopsy
    6. Evaluate at months 1 and 3 and at least annually for TST levels, erectile function
    7. Adverse effects: gynecomastia, sleep apnea, BPH symptom increased, reduced fertility
    8. Laboratory: reduced HDL levels, erythrocytosis, liver enzyme elevations
    9. Discontinue if no response within 3 months
  7. Prostaglandin E1 (alprostadil, Caverject®) [10]
    1. Injection of 1.25-5µg or more into corpus cavernosum or transurethrally [11]
    2. Smooth muscle relaxant and vasodilator
    3. Increases arterial inflow and decreases venous outflow
    4. Unilateral injection acts bilaterally through cross-circulation
    5. Pain after injection, prolonged erection, priapism (0.4%), penile fibrosis (long term) [10]
    6. 94% success with 5% prolonged erections and 1% priapism
    7. Improved efficacy when added to papavarine (60µg) alone
    8. Generally recommended that first dose administered be supervised by health professional
  8. Prostaglandin E1 (alprostadil, MUSE®) [11,12]
    1. Pellet microsuppository form for intraurethral administration
    2. 3-6mm long pellet, 1.4mm diameter
    3. Studied in men with impotence due to prostatectomy or other surgery
    4. Impotence due to diabetes, sickle cells disease, CNS based paralysis, others excluded
    5. With transurethral alprostadil self-injection, >60% of patients had intercourse [11]
    6. Side Effects: 3% hypotension, dizziness 2%, penile pain in 32%
    7. Should be avoided in men who have intercourse with pregnant women
  9. Phentolamine (Regitine®) [1]
    1. Alpha1 adrenergic antagonist
    2. Often combined with papavarine (60µg), a nonspecific PDE inhibitor
    3. Trimix is a combination of PGE1, phentolamine, and papaverine with ~90% efficacy
    4. Success of combination therapy is >65%
    5. May also be used with vasoactive intestinal polypeptide (VIP) intracavernous injection
    6. Side effects are hypotension and reflex tachycardia
  10. Yohimbine [3,13]
    1. Centrally acting alpha2-adrenergic antagonist
    2. Also has serotonin 5-HT2B antagonist activity
    3. Efficacy above placebo for all types of erectile dysfunction
    4. Most effective for non-organic causes
  11. Psychotherapy, usually with partner, should also be considered
  12. Vacuum constrictive device
  13. Surgery
    1. Usually vascular surgery - success rates in 50% range
    2. Implantation of penile prosthesis (mechanical implants)
  14. Penile Prosthesis
    1. High satisfaction rates
    2. Natural appearance and normal sensation
    3. Saline filled cylinders placed within the corpus cavernosa
    4. Pump mechanism within the scrotum is used to transfer fluid in the company
    5. Ease of use and reliability
    6. Surgical implantation is a single day protocol
  15. DHEA + testosterone has shown no benefit on body composition, physical performance, insulin sensitivity, or quality of life in elderly men [24]

E. Priapism

  1. Prolonged, usually painful, penile erection not initiated by sexual stimulation
  2. Penile erection is due to arterial engourgement of blood into the corpus cavernosae with controlled venous constricion, causing high pressure blood buildup in penis
  3. Types
    1. Ischemic (Low Flow) - decreased penile venous outflow
    2. Arterial (High Flow) - increased arterial inflow to cavernosal sinusoids
  4. Abuse of sildenafil can lead to severe priapism

References

  1. McVary KT. 2007. NEJM. 357(24):2472 abstract
  2. Morgentaler A. 2004. JAMA. 291(24):2994 (Case Discussion) abstract
  3. Lue TF. 2000. NEJM. 342(24):1802
  4. Burnett AL. 2005. JAMA. 293(21):2648 abstract
  5. Goldstein I, Lue TF, Padma-Nathan H, et al. 1998. NEJM. 338(20):1397 abstract
  6. Sildenafil. 1998. Med Let. 40(1026):51 abstract
  7. Rendell MS, Raifer J, Wicker PA, Smith MD. 1999. JAMA. 281(5):421 abstract
  8. Herrmann HC, Chang G, Klugherz BD, Mahoney PD. 2000. NEJM. 342(22):1622 abstract
  9. Bhasin S, Enzlin P, Coviello A, Basson R. 2007. Lancet. 369(9561):597 abstract
  10. Alprostadil. 1995. Med Let. 37(958):83 abstract
  11. Padama-Nathan H, Hellstrom WJG, Kaiser FE, et al. 1997. NEJM. 336(1):1 abstract
  12. Alprostadil. 1997. Med Let. 39(997):32 abstract
  13. Yohimbine. 1994. Med Let. 36:115 abstract
  14. Hauck EW and Weidner W. 2001. Lancet. 357(9273):2049 abstract
  15. Nurnberg HG, Hensley PL, Gelenberg AJ, et al. 2002. JAMA. 289(1):56
  16. Vardenafil. 2003. Med Let. 45(1166):77 abstract
  17. Tadalafil. 2003. Med Let. 45(1172):101 abstract
  18. Sildenafil in Pulmonary Hypertension. 2004. Med Let. 46(1177):18 abstract
  19. Ghofrani HA, Wiedemann R, Rose F, et al. 2002. Lancet. 360(9337):895 abstract
  20. Webster LJ, Michelakis ED, Davis T, Archer SL. 2004. Arch Intern Med. 164:514 abstract
  21. Ghofrani HA, Reichenberger F, Kohstall MG, et al. 2004. Ann Intern Med. 141(3):167
  22. Viagra and Loss of Vision. 2005. Med Let. 47(1211):49 abstract
  23. Thompson IM, Tangen CM, Goodman PJ, et al. 2005. JAMA. 2294(23):2996
  24. Nair KS, Rizza RA, O'Brien P, et al. 2006. NEJM. 355(16):1647 abstract
  25. Tadalafil Once Daily. 2008. Med Let. 50(1283):27 abstract