Sexual Dysfunction¶

Chapter 409 | Harrison's 22e · Part 12 – Endocrinology & Metabolism · Chapter 409

Key Clinical Points¶

Erectile dysfunction (ED) serves as a "sentinel symptom" for underlying cardiovascular and peripheral vascular disease.
Male sexual dysfunction affects up to 31% of middle-aged/elderly men; female dysfunction is more prevalent (~43%).
Erection is a neurovascular event requiring an intact cardiovascular system and specific nitric oxide (NO) signaling.
Nitric oxide (NO) promotes relaxation via the cGMP pathway, while endothelin-1 (ET-1) and Rho kinase mediate vascular contraction.
Prostaglandins (PGE, PGF 1α) increase cyclic AMP (cAMP) levels to facilitate relaxation.
Premature ejaculation is often related to anxiety or learned behavior; treated with behavioral therapy or SSRIs.
Retrograde Ejaculation (RE) results from failure of the internal urethral sphincter to close (e.g., diabetes, bladder neck surgery).
Anejaculation is commonly caused by alpha-blockers (tamsulosin, silodosin).
PDE-5 inhibitors (Sildenafil, Tadalafil, Vardenafil, Avanafil) are primary pharmacological treatments for ED.
Treatment follows a stepwise escalation: Oral PDE-5i → Intraurethral/Injection → Vacuum device or Surgery.
Successful PDE-5i use requires specific timing (30m to 2.5h prior), avoidance of high-fat meals (for sildenafil), and adequate physical/psychic stimulation.

DEFINITION & CLASSIFICATION¶

• Erection: A neurovascular event; requires an intact cardiovascular system. • Libido: Sexual desire influenced by visual, olfactory, tactile, auditory, imaginative, and hormonal stimuli (e.g., testosterone). • Ejaculation: Stimulated by the sympathetic nervous system; involves contraction of the epididymis, vas deferens, seminal vesicles, and prostate. • Detumescence: Mediated by norepinephrine (sympathetic), endothelin, and Rho kinase to restore the flaccid state. • Erectile Dysfunction (ED): Failure to achieve or maintain an erection; not a normal part of aging but a "sentinel symptom" for cardiovascular/peripheral vascular disease. • Premature Ejaculation: Often related to anxiety or learned behavior; amenable to behavioral therapy or SSRIs. • Retrograde Ejaculation (RE): Failure of the internal urethral sphincter to close; occurs in diabetes or after bladder neck surgery. • Anejaculation: Failure of the emission process; commonly caused by alpha-blockers (e.g., tamsulosin, silodosin).

EPIDEMIOLOGY¶

• Male Prevalence: Affects up to 31% of middle-aged and elderly men. • Female Prevalence: Higher prevalence than males (43%). • Age Trends: In the MMAS study, incidence of moderate/severe ED more than doubled between ages 40 and 70. • Risk Factors: Higher incidence in men with diabetes, obesity, LUTS/BPH, heart disease, low HDL, and systemic inflammation. • Clinical Significance: ED serves as a "sentinel symptom" for occult cardiovascular and peripheral vascular disease.

ETIOLOGY & PATHOPHYISIOLOGY¶

• Nitric Oxide (NO) Pathway: → Produced from L-arginine by nitric oxide synthase (NOS). → Released from NANC autonomic nerve supply. → Acts postjunctionally to increase cyclic 3′,5′-guanosine monophosphate (cGMP). → cGMP induces relaxation of smooth muscle cells. • Prostaglandin Pathway: → PGE and PGF 1α are synthesized in cavernosal tissue. → Increase cyclic AMP (cAMP) levels to promote relaxation. • Detumescence Factors: → Endothelin-1 (ET-1) and Rho kinase mediate vascular contraction. → Norepinephrine from sympathetic nerves mediates detumescence. • Mechanical Mechanism: → Increased blood flow into lacunar network → compression of trabecular smooth muscle against the fibroleastic tunica albuginea → passive closure of emissary veins → accumulation of blood in the corpora.

DIAGNOSTIC APPROACH¶

Initial Evaluation: • History (medical, sexual, psychosocial). • Physical examination. • Serum tests (specifically checking Testosterone and Prolactin levels). • Medication review. • Lifestyle management assessment.
Assessment of Response: • Determine if initial evaluation/lifestyle changes resolve the issue → If yes, treatment ends. • If problem persists → Proceed to education and goal-directed therapy planning.

MANAGEMENT & TREATMENT¶

Education and Goal-Directed Therapy Planning: • Include patient/partner education. • Consider "Special testing" or "Sex therapy" if indicated during this phase.
Oral PDE-5 Inhibitors (First line pharmacological): • Sildenafil: → Dose: 25–100 mg (Starting dose: 50 mg). → Onset: T 30–120 min; Duration: 4 h. → Note: High-fat meal decreases absorption; Alcohol may affect efficacy. • Tadalafil: → Dose: 10 or 20 mg (Daily dose: 2.5 or 5 mg). → Onset: T 30–60 min; Duration: 12–36 h. → Note: Not affected by food or alcohol. • Vardenafil: → Dose: 5–10 mg. → Onset: T 30–120 min; Duration: 4–5 h. → Note: High-fat meal decreases absorption; ETOH may affect efficacy. • Avanafil: → Dose: 50, 100, and 200 mg. → Onset: T 30 min; Duration: 2 h.
Escalation if Oral PDE-5i Fails: • Intraurethral or injection therapy.
Final Options for Non-responders to Injections/Pills: • Vacuum device. • Implantation or vascular surgery.

COMPLICATIONS & PROGNOSIS¶

• Drug Interactions: → PDE-5 inhibitors are contraindicated in patients with Nitrates, Hypotension, Cardiovascular risk factors, or Retinitis pigmentosa. → Caution: Change dose with some antiretrovirals; ensure stable dose of alpha blockers.

SPECIAL POPULATIONS¶

• Female Sexual Dysfunction Risk Factors: → Neurologic (stroke, spinal cord injury, parkinsonism). → Trauma/Surgery (genital surgery, radiation). → Endocrinopathies (diabetes, hyperprolactinemia). → Organ Failure (Liver and/or renal failure). → Cardiovascular (especially hypertension). → Psychological (sexual abuse, life stressors). → Medications: → Antihistamines, Antidepressants, Alcohol, Hypnotics, Sedatives. → Antiestrogens or GnRH antagonists. → Antihypertensives (diuretics, calcium channel blockers). → Alkylating agents; Anticholinergic drugs.

KEY PEARLS & HIGH-YIELD POINTS¶

• Sentinel Symptom: ED is a critical indicator of cardiovascular and peripheral vascular disease. • Mechanism of Action (PDE-5i): These drugs inhibit the breakdown of cGMP, maintaining smooth muscle relaxation. • Troubleshooting PDE-5i Failure: → Ensure trial on ≥ 6 different days at max dose. → Confirm no high-fat meal before sildenafil. → Ensure physical/psychic stimulation is present to induce endogenous NO. → Verify timing: Avanafil (30 min), Sildenafil/Vardenafil (1 h), Tadalafil (2.5 h) prior to activity. → Rule out unrecognized hypogonadism. • Drug-Induced Anejaculation: Often caused by alpha-blockers like tamsulosin or silodosin.

TABLES & FIGURES¶

• Table 409-1 (Drugs Associated with ED): Includes Diuretics (Thiazides, Spironolactone), Antihypertensives (CCBs, Methyldopa, Clonidine, Reserpine, Beta blockers, Guanethidine), Cardiac/antihyperlipidemics (Digoxin, Gemfibrozil, Clofibrate), Psychotropics (SSRIs, TCAs, Lithium, MAOIs, Butyrophenones, Phenothiazines), Anticholinergics (Ranitidine, Cimetidine), Hormones (Progesterone, Estrogens, Corticosteroids, GnRH agonists, 5α-Reductase inhibitors, Cyproterone acetate, Cyclophosphamide, Methotrexate, Roferon-A), and others (Disopyramide, Anticonvulsants, Ethanol, Cocaine, Marijuana). • Table 409-2 (PDE-5 Inhibitors): Details Sildenafil (30–120m onset, 4h duration), Tadalafil (30–60m onset, 12–36h duration), Vardenafil (30–120m onset, 4–5h duration), and Avanafil (30m onset, 2h duration). • Table 403-3 (Troubleshooting PDE-5i): Lists 5 key checks: 1. Trial on ≥ 6 days at max dose; 2. No high-fat meal (sildenafil); 3. Include physical/psychic stimulation; 4. Correct timing (Avanafil 30m, Sildenafil/Vardenafil 1h, Tadalafil 2.5h); 5. Check for hypogonadism. • Table 409-4 (Female Risk Factors): Lists Neurologic disease, Trauma, Endocrinopathies, Organ failure, Cardiovascular disease, Psychological factors, and specific medications like Antihistamines, Antidepressants, and Antihypertensives.

Reference Tables¶

TABLE 409-1 Drugs Associated with Erectile Dysfunction CLASSIFICATION Diuretics Antihypertensives¶

Harrison's 22e, p.3157

CLASSIFICATION	DRUGS	POSSIBLE SUBSTITUTES
Diuretics	Thiazides
	Spironolactone
	Calcium channel blockers Methyldopa Clonidine Reserpine Beta blockers Guanethidine
Cardiac/ antihyperlipidemics	Digoxin
	Gemfibrozil
	Clofibrate
	Selective serotonin reuptake inhibitors Tricyclic antidepressants Lithium Monoamine oxidase inhibitors
Tranquilizers	Butyrophenones
	Phenothiazines
	Ranitidine Cimetidine
Hormones	Progesterone
	Estrogens
	Corticosteroids
	GnRH agonists
	5α-Reductase inhibitors
	Cyproterone acetate
	Cyclophosphamide Methotrexate Roferon-A
Anticholinergics	Disopyramide
	Anticonvulsants
	Ethanol Cocaine Marijuana

TABLE 409-2 PDE-5 Inhibitors a DRUG Sildenafil¶

Harrison's 22e, p.3159

DRUG	ONSET OF ACTION	T 1/2	DOSE	ADVERSE EFFECTS	CONTRAINDICATIONS
Sildenafil	T 30–120 min max Duration 4 h High-fat meal decreases absorption Alcohol use may affect efficacy	2–5 h	25–100 mg Starting dose 50 mg	Headache, flushing, dyspepsia, nasal congestion, altered vision	Nitrates Hypotension Cardiovascular risk factors Retinitis pigmentosa Change dose with some antiretrovirals Should be on stable dose of alpha blockers
	T 30–120 min max Duration 4–5 h High-fat meal decreases absorption ETOH may affect efficacy	4.5 h	5–10 mg	Headache, flushing, rhinitis, dyspepsia
Tadalafil	T 30–60 min max Duration 12–36 h Plasma concentration not affected by food or ETOH	17.5 h	10 or 20 mg; 2.5 or 5 mg for daily dose	Headache, dyspepsia, backpain, nasal congestion, myalgia	Same as sildenafil
	T 30 min max Duration 2 h Plasma concentration not affected by food	3–5 h	50, 100, and 200 mg dose	Headache, flushing, nasal congestion nasopharyngitis back pain

TABLE 409-3 Issues to Consider if Patients Report Failure of Phosphodiesterase Type 5 Inhibitor (PDE-5i) to Improve…¶

Harrison's 22e, p.3159

1. A trial of medication on at least 6 different days at the maximal dose should
  be performed before declaring patient nonresponsive to PDE-5i use.
  2. Confirm that the patient did not partake in a high-fat meal prior to taking
  medication; pertains to sildenafil.
  3. Failure to include physical and psychic stimulation at the time of foreplay to
  induce endogenous NO.
  4. Took medications at an appropriate time frame prior to step 3: half-hour prior
  for avanafil, 1 h for sildenafil/vardenafil, or 2.5 h for tadalafil.
  5. Unrecognized hypogonadism.

TABLE 409-4 Risk Factors for Female Sexual Dysfunction Neurologic disease: stroke, spinal cord injury, parkinsonism…¶

Harrison's 22e, p.3160

Neurologic disease: stroke, spinal cord injury, parkinsonism
Trauma, genital surgery, radiation
Endocrinopathies: diabetes, hyperprolactinemia
Liver and/or renal failure
Cardiovascular disease, especially hypertension
Psychological factors and interpersonal relationship disorders: sexual abuse, life
stressors
Medications
Antiandrogens: cimetidine, spironolactone
Antidepressants, alcohol, hypnotics, sedatives
Antiestrogens or GnRH antagonists
Antihistamines, sympathomimetic amines
Antihypertensives: diuretics, calcium channel blockers
Alkylating agents
Anticholinergics