Erectile Dysfunction

Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Diagnosis is via physical exam and history. Management is guided by clearly discussing patient expectations after explaining the benefits and risks. Treatment includes conservative management with lifestyle modifications, oral medications, and injectables. Invasive surgical penile implants may be considered when conservative measures fail. Ultimately, both the patient and partner must be in tune with the treatment modalities to optimize their overall satisfaction.

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Overview

Definition

Erectile dysfunction (ED) is the recurrent failure to achieve or maintain consistent rigid penile erection for satisfactory sexual intercourse.

Clinical importance:

  • Very common, but complex disorder with significant quality of life implications 
  • May be the initial symptom for underlying cardiovascular disease

Epidemiology

Globally, at least 150 million men suffer from ED:

  • In the United States, 52% of men between 40 and 70 years of age are affected.
  • By 40 years of age, about 40% of men experience ED, whereas, about 70% of men report ED by 70 years of age.

Prevalence of ED is closely related to increased age and presence of other systemic comorbidities.

Etiology

Erectile dysfunction is a multifactorial disease process with many contributing factors. There are many factors that can be prevented or adjusted to improve the ability to obtain or maintain erections:

  • Organic:
    • Peripheral arterial disease (PAD)
    • Aortoiliac occlusive disease 
    • Atherosclerosis and coronary artery disease (CAD) 
    • Sleep apnea
    • Diabetes mellitus (DM)
    • Liver disease 
    • Hyperlipidemia (HLD)
    • Hypogonadism
    • Alcohol use disorder
    • Stroke
    • Spinal cord injuries
    • Traumatic brain injury
    • Sickle cell anemia 
    • CKD
    • Genital trauma
    • Peyronie’s disease 
    • Post prostatectomy 
  • Psychogenic: 
    • Major depressive disorder
    • Generalized anxiety disorder
    • Performance anxiety 
    • Acute stress disorder
  • Medications:
    • Beta blockers
    • Antidepressants
    • Antipsychotics
    • Spironolactone
    • Ketoconazole 
    • Cimetidine

Pathophysiology

Anatomy

The penis is made of cylindrical structures (paired corpus cavernosa and corpus spongiosum):

  • Corpus cavernosa: 
    • Contained in a collagenous sheath called tunica albuginea 
    • Made of sinusoids supported by a fibrous skeleton
  • Corpus spongiosum:
    • Ventrally located, becoming the glans distally
    • Contains the urethra, surrounded by sinusoids

Vascular supply to penis is supplied by the internal iliac artery:

  • Internal pudendal artery becomes the common penile artery, which has 3 branches: 
    • Cavernosal artery: gives off helicine arteries that supply the corpora cavernosa 
    • Dorsal artery: provides engorgement of glans 
    • Bulbourethral artery: supplies the corpora spongiosum
  • Venous drainage of corporal bodies via emissary veins: 
    • Emissary veins connect to the deep dorsal vein of the penis. 
    • Rapid drainage of venous blood results in detumescence.

Male reproductive system:

Structures of the male reproductive system include the testes, epididymis, penis, and the ducts and glands that produce and carry semen. Sperm exit the scrotum through the ductus deferens, which is bundled in the spermatic cord. Seminal vesicles and prostate gland add fluids to the sperm to create semen.

Image: “Male reproductive system” by OpenStax College. License: CC BY 4.0

Normal erection

  • Sexual stimuli initiate a downstream cascade of complex neuronal and molecular pathways.
  • Neuroanatomic pathway: 
    • Reflex mediated by the CNS:
      • Parasympathetic nerve roots S2–S4 
      • Cholinergic neuronal fibers stimulate the cavernosal endothelial cells to produce NO.
    • NO is the predominant neurotransmitter of erection synthesized by NO synthase. 
      • NO stimulates guanylate cyclase (GC) in the penis.
      • GC cleaves guanosine triphosphate (GTP) into cGMP.
      • ↑ cGMP promotes protein kinase G-dependent smooth-muscle relaxation by decreasing intracellular calcium → penile erection 
    • Phosphodiesterase type 5 degrades cGMP and promotes detumescence (flaccid penis). 
  • Erection is a balance between arterial blood inflow and venous drainage.
    • Penile corpora cavernosal bodies are cylindrical structures that fill with blood during an erection.
      • Relaxation of sinusoidal smooth muscles allows for rapid blood filling and expansion. 
      • Venous occlusion restricts blood outflow via compression of venules beneath the rigid tunica albuginea, thereby maintaining penile rigidity. 
    • Sinusoids of the corpus spongiosum get engorged, pressurize the urethral lumen, and facilitate forceful ejaculation.

Structural compartments of the penis during the flaccid (top) and erected (bottom) states:
As seen in bottom images (erect: lateral view and erect: transverse view), rapid filling of the sinusoids and subsequent compression of veins and venules maintain penile rigidity.

Image: “The Structural Compartments of the Penis” by School of Information and Communications, Gwangju Institute of Science and Technology, Gwangju, 500-712, Korea. License: CC BY 4.0

Pathogenesis

  • Neurogenic:
    • Intact nervous system is a key component for initiation of erection
    • Any neurological compromise can inhibit the ability to achieve an erection:
      • Peripheral nerve damage (e.g., penile surgery) 
      • Central nerve damage (e.g., spinal cord injury, multiple sclerosis) 
      • Impaired contractility of cavernosal smooth muscle (seen in defects in neurotransmitters, including NO and cGMP)
  • Psychogenic:
    • Decreased sexual desire or stimulation will cause difficulty in achieving an erection. 
    • Generalized or performance-related anxiety, depression, and stress can cause ED.
  • Vascular:
    • Vascular compromise with arterial insufficiency or venous leak can impair blood flow to the erectogenic tissue.
    • Hypertension, diabetes, HLD, smoking, and cardiovascular disease can affect local (and systemic) vasculature.
  • Hormonal:
    • Low testosterone levels can affect erectile mechanism, but the exact level corresponding to ED is not known.
    • Others: thyroid and adrenal disorders

Biochemical mechanism of erection:

Nitric oxide is released from the cavernous nerves upon sexual stimulation, which leads to the activation of guanylate cyclase within the smooth muscle cells of the penis. Guanylate cyclase facilitates the conversion of guanosine triphosphate to cGMP. Specific protein kinases then are acted on by cGMP, causing a decrease in intracellular calcium levels. General effects are smooth-muscle relaxation, vasodilatation, and tumescence. The active cyclic GMP is converted to inactive 5′-GMP by phosphodiesterase type 5 (PDE-5), allowing intracellular calcium levels to normalize, thereby leading to vasoconstriction and loss of tumescence. Phosphodiesterase type 5 inhibitors are used in the management of erectile dysfunction, resulting in tumescence.

Image by Lecturio.

Clinical Presentation and Diagnosis

Initial encounter

  • Men of any age complaining of a recurrent inability to sustain an erection rigid enough for sexual activity 
  • ED is a very sensitive topic and patients may not present with this condition as their main complaint.
  • Patients may initially present with vague complaints about their sex life or depression.

Diagnosis

Majority of cases are diagnosed based on history and physical examination.

Comprehensive medical and sexual history:

  • Marital or relationship issues 
  • Performance anxiety 
  • Validated International Index of Erectile Function (IIEF) is a 15-question scale, assessing the following 5 domains of male sexual activity:
    • Sexual desire 
    • Erectile function 
    • Intercourse satisfaction 
    • Orgasmic function 
    • Overall sexual satisfaction 
  • Depression 
  • Assess for lifestyle factors:
    • Smoking 
    • Alcohol use 
    • Illicit drug use 
  • Relevant medical and surgical history 
    • Any prior genitourinary surgeries 
    • CAD
    • DM
    • PAD
    • HLD
  • ED history: 
    • Is the penis hard enough for penetrative sexual activity?
    • Do you wake up in the morning with an erection? 
    • Any history of premature ejaculation?
    • Pain with sexual activity?

Physical examination:

  • Obtain resting vital signs.
  • Measure waist circumference and BMI. 
  • Observe the chest for gynecomastia.
  • Palpate peripheral pulse. 
  • General genitourinary exam: 
    • Scrotal exam with assessment of testicle size, consistency, and location 
    • Penile exam to assess for lesions, plaques, or any anomalies

Laboratory tests:

  • Early morning total testosterone levels to establish baseline 
  • Hemoglobin and hematocrit to rule out anemia 
  • Hemoglobin A1C to determine glucose status 
  • Comprehensive metabolic panel
  • Lipid profile

Ancillary diagnostic tests:

  • Simple “stamp” test: 
    • Wrap a ring of stamps around the penis and assess if the stamp breaks in the morning. 
    • Positive erection = broken stamp 
  • Office intracavernous injection (ICI) with prostaglandin (PG) E1 (erectogenic agent) into the corpora cavernosa of the penis: 
    • PGE1 produces vasodilation.
    • Assesses for erectile response and the ability to maintain an erection 
  • Penile duplex Doppler ultrasound: 
    • Used to identify possible veno-occlusive dysfunction or arterial insufficiency 
    • Performed after ICI to stimulate an erection
  • Invasive vascular testing, such as pudendal angiography, is rarely used and only indicated for severe vascular disruption arising from pelvic trauma.

Management

Treatment approach

  • Holistic approach to address the underlying cause:
    • Medical condition-related ED
    • Anatomical or surgical correction of factors leading to ED 
    • Psychogenic factors
  • Proceed from least to maximally invasive options as needed.
  • There are 2 individuals to keep in mind: patient and partner

Medical treatment

  • Lifestyle modifications:
    • Reduce cardiac risk factors.
    • Adjust anti-hypertensive drug doses as indicated. 
    • Optimize diabetes care. 
    • Decrease alcohol use. 
    • Smoking cessation 
    • Weight loss 
    • Diet low in saturated fats 
    • Increase physical exercise. 
  • Vacuum erection device: 
    • Mechanical pump used to generate negative pressure around the penis and sustain erection 
    • Causes dilation of the cavernous spaces of the penis 
    • Erection maintained with a constrictive ring/band placed at the base of the penis 
    • Contraindications: 
      • Men on long-term anticoagulants are at increased risk of bleeding or bruising. 
      • Unexplained priapism
    • Adverse reactions: 
      • Hematoma if over-pressurized 
      • Ecchymosis if constrictive band left on for too long 
  • Phosphodiesterase-5 (PDE-5) inhibitors: 
    • Sildenafil, vardenafil, tadalafil
    • Oral medications that promote increased levels of cGMP in the penile vasculature
    • To be taken before planned sexual activity and must involve sexual stimulation 
    • Contraindicated in patients taking nitrates, as it may cause an unsafe drop in BP
    • Adverse reactions: 
      • Headache 
      • Flushing 
      • Heartburn 
      • Nasal congestion 
      • Visual changes 
      • Rarely may cause priapism (erection lasting > 4 hours) 
  • Intra-urethral suppository: 
    • PGE1 (alprostadil) suppository:
      • Also known as Medicated Urethral System for Erection (MUSE)
      • Administered via urethral meatus 
      • Dissolves into the corpus spongiosum and increases cAMP levels in smooth muscles 
      • Leads to corporal smooth-muscle relaxation and erection 
    • Contraindications: 
      • Patients with urethral stricture disease, hypospadias, urethritis 
      • Sickle cell disease or hematological disorders 
      • Not to be used with a pregnant partner, as it may induce labor
    • Adverse reactions: 
      • Penile pain 
      • Urethral burning or irritation 
      • Priapism possible, but rare
  • ICI therapy: 
    • Direct PGE1, papaverine, phentolamine combination administered as a penile injection into the corpora cavernosa: 
      • PGE1 increases cAMP levels in the penis. 
      • Papaverine is a non-specific PDE inhibitor that increases cAMP and cGMP levels.
      • Phentolamine is an alpha-1 adrenergic blocker that reduces sympathetic tone in the penis. 
    • Contraindications: 
      • Patients unable to tolerate penile injections 
      • Hematological disorders, increased risk of bleeding 
      • Patients taking monoamine oxidase inhibitors may experience hypertensive crisis. 
    • Adverse reactions: 
      • Penile pain 
      • Bruising 
      • Hematoma 
      • Priapism
    • Patients should not increase the dose without approval, and must proceed to emergency for reversal therapy if the erection persists > 4 hours (priapism)

Surgical treatment

  • Must 1st undergo comprehensive diagnosis and medical management 
  • Indicated for failed non-surgical management 
  • Obtain cardiac and medical clearance for safe sexual activity: 
    • Ability to undergo general anesthesia and surgery 
    • Establishment of baseline performance status
  • Penile implants (2 broad categories) 
    • Non-inflatable: 
      • Malleable or semi-rigid 
      • 2 flexible rods inserted into each corporal body 
      • Not associated with a pump device 
      • Can be manipulated (straight or bent position)
      • There is no flaccid state upon implantation. 
    • 3-piece inflatable implant:
      • Allows for flaccid and erect states 
      • Fluid from the intraabdominal reservoir connects to tubing to the pump in the scrotum. 
      • Pump in the scrotum is activated by the patient to inflate the penile cylinders inserted into the corpora cavernosa. 
  • Complications: 
    • Associated with infections, as these implants are foreign bodies (usually requires the removal of device and treatment with antibiotics) 
    • Device malfunction 
    • Urethral injury during insertion of the implant 
    • Device crossover, where penile cylinder may encroach on the contralateral side 
    • Penile or scrotal pain due to device placement

Clinical Relevance

  • Peyronie’s disease: a condition caused by a fibrous-tissue disorder of the tunica albuginea that results in penile deformity, pain, and ED. Diagnosis is based on history and physical examination. Ultrasound can help define the fibrotic tissue. Medical treatments include intralesional collagenase Clostridium histolyticum (breaks up fibrous substances), verapamil, or interferon alpha-2b injection. Surgical therapy (e.g., plication, grafting, or penile prosthesis) is an option for patients refractory to medical therapy.
  • Hypogonadism: a condition characterized by the decreased production of sex steroids in the gonads. In men, hypogonadism can result from primary or secondary testicular failure due to pituitary or hypothalamic disorders. Symptoms of hypogonadism include ED, decreased libido, and regression, or absence of secondary sexual characteristics.
  • DM: a heterogeneous group of metabolic diseases characterized by chronic hyperglycemia. Diabetes mellitus leads to various complications including ED. Poor glycemic control, long duration of diabetes, and the presence of microvascular and cardiovascular diseases correlate with the severity of ED. 
  • Prostate-cancer treatment: Prostate cancer is a slow-growing malignancy affecting the prostate gland. Treatment options include radiotherapy and radical prostatectomy, both of which are commonly complicated in individuals with ED. Effects of treatments can temporarily or permanently damage the nervous and vascular structures integral for erection. Nerve-sparing surgery is performed when indicated for better erectile function postoperatively. Medications for ED are also generally effective in patients scheduled for the treatment of prostate cancer.

References

  1. Kim, E. (2020). Erectile Dysfunction. Medscape. Retrieved February 28, 2021, from https://emedicine.medscape.com/article/444220-overview
  2. Simhan, J. (2021). Erectile Dysfunction. AUA Core Curriculum. Retrieved February 28, 2021, from https://www.auanet.org/education/auauniversity/for-medical-students/medical-students-curriculum/medical-student-curriculum/ed
  3. Lakin, M., Wood, H. (2018) Erectile Dysfunction. Cleveland Clinic Center for Continuing Education. Retrieved March 4, 2021, from https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/erectile-dysfunction/
  4. Sooriyamoorthy, T., Leslie, S. (2021) Erectile Dysfunction. StatPearls. Retrieved March 4, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK562253/

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