Pathophysiology of Erectile Dysfunction

Background

• Definition of erectile dysfunction (ED): inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance

Epidemiology

Massachusetts Male Aging Study

• Survey of males aged 40-70 from Massachusetts
• Results:
  • Approximately 40% of men in their 40’s experienced ED of varying degrees of severity
  • Prevalence of ED increases about 10% per decade.
  • Prevalence of severe ED increased with age
    • Prevalence of severe ED tripled from 5% in men in their 40’s to 15% in men in their 70’s

Classification (Organic vs. Psychogenic vs. Mixed)

• See Tables 26-1 and 26-4

Organic

• ED VAN
  • Endocrinologic
  • Drug-induced
  • Vasculogenic
  • Anatomic
  • Neurogenic

Endocrinologic

• Conditions associated with ED:
  1. Hypogonadism
  2. Hyper/hypothyroidism
  3. Diabetes (altered modulation of androgen function)
  4. Hyperprolactinemia
     • Can be secondary to a pituitary adenoma or medications
     • Inhibits GnRH release
     • Results in both reproductive and sexual dysfunction.
       • Symptoms may include loss of libido, ED, galactorrhea, gynecomastia, and infertility.
• Effects of Testosterone
  1. Increases sexual interest
  2. Increases frequency of sexual acts
  3. Increases frequency of nocturnal erection but has little or no effect on psychogenic erections
     • Threshold level of testosterone for normal nocturnal erections is ≈200 ng/dL

Drug-induced

• See Tables 26-11 and 26-12
• Self-reported and questionnaire data concerning ED as a medication side effect should be interpreted with caution

Antihypertensive Agents

• Almost all antihypertensive drugs have ED listed as a potential side effect, though recent well-designed controlled clinical trials have clarified their association with ED
• Associated with ED
  1. α2-agonists (e.g. clonidine)
  2. Diuretics
     • Spironolactone is a nonselective mineralocorticoid receptor antagonist with moderate affinity for progesterone and androgen receptors. The latter property increases the likelihood of endocrine side effects, including loss of libido, gynecomastia, and impotence
• Not associated with ED
  1. ACE-inhibitors
  2. ARBs
  3. α1-blockers
     • May cause retrograde ejaculation
  4. Calcium channel blockers
  • ARBs and α-blockers may exert a positive effect of erectile function§
• Variably associated with ED
  • β-blockers:
    • Non-selective β antagonists (e.g. propranolol) are associated with ED
    • β1-selective antagonists (e.g. acebutolol) are not associated with ED
• Methyldopa, a centrally acting drug, is associated with ED

Psychotropics (antipsychotics, antidepressants, anxiolytics)

• Commonly produce sexual symptoms
• SSRIs
  • Up to 50% of patients experience increased sexual dysfunction, mainly anorgasmia.
    • Adverse effects can be modified by co-treatment with other drugs such as a PDE5 inhibitor or mianserin (atypical antidepressant).
  • Differ in their ability to cause ED
    • Paroxetine associated with higher rates of ED compared to citalopram
• GABAergic drugs - inhibit erection
• Tricyclics - orgasmic dysfunction and inhibit ejaculation
• Monoamine oxidase inhibitors - orgasmic dysfunction
• Benzodiazepines - higher rate of sexual dysfunction
• Bupropion
  • A norepinephrine-dopamine reuptake inhibitor
  • An alternative antidepressant that is not associated with ED
    • Addition of bupropion or a PDE5 inhibitor to an antidepressant seems to be an effective method to correct antidepressant-associated ED

Antiandrogens

• Cause partial or near-complete blockade of androgen’s action by inhibiting production of or antagonizing the androgen receptor
• The effects of androgen deficiency on sexual activity are variable, ranging from complete loss to normal function
• LHRH antagonists or agonists
  • Use results in a profound loss of sexual desire, which is usually accompanied by ED
• 5α-reductase inhibitors (finasteride and dutasteride)
  • Antiandrogens with the least effect on circulating testosterone
    • In randomized placebo-controlled studies of patients given finasteride (5 mg daily) for prostatic symptoms, approximately 5% complained of decreased desire and ED compared with 1% in the placebo group; at the lower dose used to treat male-pattern alopecia (1 mg daily), no sexual dysfunction was seen.  However, persistent sexual dysfunction, characterized by low libido, ED, decreased arousal, and difficulty with orgasm, has been reported for months to years after discontinuation of finasteride for hair loss

Anticonvulsants

• Carbamazepine - orgasmic dysfunction
• Valproate - loss of sexual desire

Miscellaneous drugs

• Generally based on anecdotal case reports or post-marketing drug alerts rather than controlled trials.
• Digoxin
• Statins: underlying disease process appears to be the cause of ED in men treated rather than the drug itself
• Sexual dysfunction is a common event after the introduction of antiretroviral therapy. Because these patients may have diseases involving several organ systems and may be taking multiple drugs, the precise mechanism is difficult to determine.
• Alcohol in small amounts improves erection and sexual drive due to its vasodilatory effect and suppression of anxiety; however, large amounts can cause central sedation, decreased libido, and transient ED

Vascular

• Arteriogenic
  • Most common underlying mechanism of organic ED
  • Risk factors:
    1. Age
    2. Diabetes mellitus
    3. Dyslipidemia
    4. Hypertension
    5. Obesity
    6. Metabolic syndrome
    7. Sedentary lifestyle
    8. Smoking
    9. Blunt perineal or pelvic trauma
    10. Pelvic irradiation
  • Atherosclerotic or traumatic arterial occlusive disease can decrease perfusion pressure and arterial flow to the sinusoidal spaces, increasing time to maximal erection and decreasing the rigidity of the erect penis
    • In most patients with arteriogenic ED secondary to atherosclerosis, the impaired penile perfusion is a component of the generalized atherosclerotic process.
  • Lesions in the pudendal arteries are much more common in ED men than in the general population of similar age.
  • Cardiovascular disease is associated with ED. Because the size of the penile artery is smaller compared with coronary arteries, the same level of endothelial dysfunction causes a more significant reduction of blood flow in erectile tissues compared with that in coronary circulation
    • The degree of ED strongly correlates with severity of cardiovascular disease; recent studies suggest that ED may be considered a sentinel marker in men with occult cardiovascular disease
    • Remains controversial whether a diagnosis of ED alone should initiate a more thorough cardiovascular evaluation§
  • In hypertension, the increased blood pressure itself does not impair erectile function; rather, the associated arterial biochemical and structural changes are thought to be the causes; a narrowed lumen or increased wall/lumen ratio in the arteries contributes to increased peripheral vascular resistance in hypertension.
  • Cigarette smoking may induce vasoconstriction and penile venous leakage because of its contractile effect on the cavernous smooth muscle; second-hand smoke exposure is associated with a small, statistically insignificant increase in risk of ED
  • High body weight, BMI, and total body fat percentage are independently associated with greater prevalence of moderate to severe and complete ED.
  • Long-distance cycling is also a risk factor for vasculogenic and neurogenic-ED. ED does not commonly occur in men who engage in recreational bicycle riding
• Cavernous (venogenic)
  • Veno-occlusive dysfunction (failure of adequate venous occlusion)
    • Has been proposed as one of the most common causes of vasculogenic impotence
    • May result from various pathophysiologic processes, including:
      • Degenerative tunical changes
      • Fibroelastic structural alterations
      • Insufficient trabecular smooth muscle relaxation
      • Venous shunts
  • Degenerative changes (e.g., Peyronie disease, old age, and diabetes) or traumatic injury to the tunica albuginea (e.g., penile fracture) can impair the compression of the subtunical and emissary veins.

Anatomic

• Risk of iatrogenic impotence from pelvic surgery is high due to the close relationship between the cavernous nerves and the pelvic organs: radical prostatectomy (43-100%) abdominal perineal resection (15-100%)
• In pelvic fracture, ED can be a result of cavernous nerve injury or vascular insufficiency or both.

Neurogenic

• Any disease or dysfunction affecting the brain, spinal cord, and cavernous or pudendal nerves (Parkinson disease, stroke, encephalitis, temporal lobe epilepsy, tumors, dementias, Alzheimer disease, multiple system atrophy, trauma, spina bifida, disk herniation, syringomyelia, tumor, transverse myelitis, multiple sclerosis) can induce dysfunction
• In men with a spinal cord injury, the nature, location (see Normal Erectile Physiology Chapter Notes), and extent of the injury largely determine erectile function. In addition to ED, these men may have impaired ejaculation and orgasm.
• Studies on sexual function in males with spina bifida have demonstrated that paternity is associated with an L5 or sacral neurologic level. This neurologic level was present in 80% of patients who fathered children.
• In diabetics, impairment of neurogenic and endothelium-dependent relaxation results in inadequate NO release.
• Because autonomic penile innervation cannot be tested directly, clinicians should be cautious in diagnosing neurogenic ED.
• Sensory evaluation should be an integral part of the evaluation for ED in all patients with or without an apparent neurologic disorder

Psychogenic

• Can be generalized or situational
• May be related to a history of psychosocial stress, performance anxiety and mental illness
• Proposed mechanisms (2):
  • Direct inhibition of the spinal erection center by the brain as an exaggeration of the normal suprasacral inhibition
  • Excessive sympathetic outflow or elevated peripheral catecholamine levels, which may increase penile smooth muscle tone to prevent its necessary relaxation

Aging, Systemic Disease, and Other Causes

• Aging is the most important contributing factor to ED. The aging process can affect the central regulatory mechanism, hormonal and neural function, and penile structure.
• Changes in older males:
  • Greater latency to erection
  • Less turgidity
  • Loss of forceful ejaculation and decreased volume
  • Longer refractory period
• Diabetes mellitus and metabolic syndrome may affect multiple organ systems and cause premature aging of central and peripheral structures and molecules that regulate erectile process.
• The diseases that cause chronic renal failure may also cause ED, and the condition may persist despite successful renal transplantation.

Associated conditions

1. Premature ejaculation
2. Anorgasmia
3. Low libido
4. Peyronie's
5. Lower urinary tract symptoms/benign prostatic hyperplasia
6. Chronic prostatitis/chronic pelvic pain syndrome

Primary ED

• Lifelong inability to initiate and/or maintain erections beginning with the first sexual encounter
• May be due to
  • Psychogenic cause (most common)
  • Inexperience
  • Congenital arterial insufficiency
  • Abnormal venous channels

Micropenis

• The erectile tissue in micropenis often functions normally; sexual dysfunction usually relates to lack of penile length or the degree of chordee, rather than to ED

Questions

1. Describe the classification and sub-classification of the etiology of ED? List 15 causes of ED
2. What are symptoms of hyperprolactinemia?
3. Which antidepressant is not associated with ED?
4. Which antihypertensive drugs are not associated with increased risk of ED?

Answers

1. Describe the classification and sub-classification of the etiology of ED? List 15 causes of ED
   • Organic ED VAN
   1. 1. Endocrine
      2. Drug-induced
      3. Vascular
      4. Anatomic
      5. Neurologic
   • Psychologic
   • Mixed
   • Diabetes, obesity, hyperprolactinism, pelvic surgery, trauma, Peyronie’s disease, drug-induced, priapism, congenital venous leak, smoking, primary hypogonadism, secondary hypogonadism, hypo/hyperthyroidism, hypertension, dyslipidemia, pelvic radiation, depression, sedentary lifestyle
2. What are symptoms of hyperprolactinemia?
   1. ED
   2. Loss of libido
   3. Infertility
   4. Galactorrhea
   5. Gynecomastia
3. Which antidepressant is not associated with ED?
   • Bupropion
4. Which antihypertensive drugs are not associated with increased risk of ED?
   • ACE-inhibitors, ARBs, calcium channel blockers, alpha-1 blockers (but may cause retrograde ejaculation), or beta-1 selective blockers

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 1, chap 26