L19 - Reproductive Pharmacology: BPH and Erectile Dysfunction

Benign Prostatic Hyperplasia (BPH)

• Affects a significant portion of the male population, with prevalence increasing with age:

  • Approximately 50% of men aged 60+.

  • Approximately 90% of men aged 85+.

• Characterized as a non-malignant, hyperplastic, and progressive change in the prostate's stromal and epithelial cells.

• Results in:

  • Enlargement of the prostate gland.

  • Compression of the urethra.

  • Potential increase in smooth muscle tone.

• Leads to:

  • Obstruction of the bladder neck.

  • Urinary retention.

  • Increased risk of bacterial infections.

  • Hydronephrosis (swelling of the kidney due to urine buildup).

  • Possible renal failure.

Prevalence, Risk Factors, and Symptoms of BPH

• Prevalence:

  • Globally, 94 million cases reported in 2019.

  • Peak incidence in men aged 65-69.

  • Highest age-specific prevalence in men aged 75-79.

• Risk Factors:

  • Age 40 years or older.

  • Family history of BPH.

  • Obesity.

  • Cardiovascular disease.

  • Type 2 diabetes.

  • Lack of physical exercise.

  • Erectile dysfunction.

• Symptoms:

  • Difficulty initiating urination.

  • Weak or interrupted urine stream.

  • Dribbling at the end of urination.

  • Frequent urination.

  • Nocturia (frequent nighttime urination).

Causes and Mechanisms of BPH

• The exact cause is unknown, but the prostate continues to grow throughout life.

• BPH arises from an imbalance between cellular proliferation and apoptosis within the prostate gland.

• Testosterone conversion:

  • Testosterone is converted to dihydrotestosterone (DHT) by the 5-alpha reductase type 2 enzyme in prostate stromal cells.

  • DHT accounts for 90% of prostate androgens.

  • DHT promotes tissue growth and cellular proliferation by binding to androgen receptors, modulating gene expression.

  • However, no direct correlation exists between testosterone or DHT levels and symptomatic BPH.

• Elevated smooth muscle tone contributes to urethral obstruction due to increased alpha-1 adrenergic receptor activity.

• BPH exacerbation: Anabolic agents can exacerbate BPH due to their androgenic effects.

Cellular Processes in BPH

• Normal Prostate: Balanced cell proliferation and cell death, resulting in normal prostate size.

• Androgens (DHT): Act as agonists for cell proliferation by activating androgen receptors and inhibitors of cell death by suppressing pro-apoptotic signals.

• BPH: Imbalance where cell proliferation increases, and cell death decreases, leading to gland enlargement. This is due to altered signaling pathways affecting cell growth and survival.

• DHT's Role: DHT drives cell proliferation, making 5-alpha reductase a therapeutic target to reduce DHT levels and slow prostate growth.

5-Alpha Reductase Inhibitors

• Mechanism: Target the 5-alpha reductase enzyme responsible for converting testosterone to DHT, thus reducing DHT-mediated cell proliferation.

• DHT Importance: DHT has a greater affinity for androgen receptors and modulates genes responsible for cell proliferation, leading to prostate enlargement.

• Isoforms:

  • Type 1: Predominantly in sebaceous glands, skin, scalp, and liver.

  • Type 2: Primarily in the prostate, seminal vesicles, hair follicles, and liver; responsible for two-thirds of circulating DHT.

• Drugs:

  • Duasteride: Targets both isoenzymes, causing near-complete DHT suppression, leading to a more significant reduction in prostate size.

  • Finasteride: Targets only type 2 isoenzyme, reducing serum DHT levels by about 70%, primarily affecting prostate tissue.

  • Duasteride sees a 20% higher reduction in DHT levels compared to Finasteride, leading to potentially greater symptom relief.

• Mechanism of Action:

  • Inhibit the conversion of testosterone to DHT within prostate cells.

  • Reduce DHT available to bind to androgen receptors, thus reducing receptor activation.

  • Reduce gene expression associated with cell proliferation and prostate growth.

• Duasteride's long half-life: Takes 3-6 months to reach steady state, requiring consistent use for maximal effect.

• Adverse Reactions:

  • Decreased libido and potency due to reduced androgen levels.

  • Decreased sperm count, affecting fertility.

  • Allergic reactions, including rash and swelling.

Alpha Blockers

• Rationale: BPH is associated with increased smooth muscle tone in the bladder outlet and prostate, mediated by alpha-1 adrenergic receptors, contributing to urinary obstruction.

• Mechanism: Alpha blockers relax prostatic smooth muscle tone, reducing urinary resistance and improving urine flow.

• Example: Prazosin.

  • Selective alpha-1 adrenoreceptor blocker.

  • Inhibits phospholipase C, reducing intracellular signaling.

  • Decreases intracellular calcium levels in smooth muscle cells.

  • Causes smooth muscle relaxation in the bladder neck and prostate.

  • Reduces urinary flow resistance and improves bladder emptying.

  • Reduces lower urinary tract symptoms.

• Adverse Reactions:

  • Dizziness due to reduced blood pressure.

  • Headache.

  • Fast heartbeat (reflex tachycardia).

  • Weakness.

Erectile Dysfunction (ED)

• Definition: Inability to attain or maintain an erection for satisfactory sexual intercourse or inability to ejaculate due to physiological or psychological factors.

• Prevalence: Affects approximately 25% of men over 55, increasing with age and comorbidities.

• Possible Causes:

  • Diabetes due to nerve damage and vascular insufficiency.

  • Arterial disease, reducing blood flow to the penis.

  • Hypertension, affecting vascular function.

  • Renal failure, leading to hormonal imbalances and nerve damage.

  • Infections (e.g., syphilis), causing neurological damage.

  • Radical prostatectomy, damaging nerves involved in erection.

  • Endocrine deficiency, affecting hormone levels crucial for sexual function.

  • Lifestyle factors (smoking, excessive alcohol), impairing vascular health.

  • No known cause (idiopathic).

Physiological Mechanism of Erection

• Initiation: Dilation of arterioles in the penis, increasing blood flow into the erectile tissues.

• Process: Erectile tissue fills with blood, veins are compressed, blocking outflow, leading to engorgement and erection.

• Parasympathetic Nervous System: Triggers erection by releasing nitric oxide (NO), a key vasodilator.

• NO Production:

  • Action potentials in parasympathetic nerves cause calcium influx into endothelial and nerve cells.

  • Calcium activates neuronal nitric oxide synthase (nNOS).

  • nNOS converts L-arginine to NO.

  • NO diffuses to vascular smooth muscle.

• Role of Nitric Oxide:

  • NO activates soluble guanylyl cyclase in smooth muscle cells.

  • Guanylyl cyclase converts GTP to cyclic GMP (cGMP), a secondary messenger.

  • cGMP opens ion channels and reduces intracellular calcium levels in penile smooth muscle cells.

  • Results in arterial smooth muscle relaxation, increased arterial inflow, and engorgement, causing an erection.

• Phosphodiesterase-5 (PDE5): Breaks down cGMP, thus terminating the erection by reducing smooth muscle relaxation.

Phosphodiesterase-5 (PDE5) Inhibitors

• Mechanism: Inhibit PDE5, preventing the breakdown of cGMP, thus prolonging smooth muscle relaxation and erection.

• Example:

  • Sildenafil (Viagra): Used for erectile dysfunction and pulmonary arterial hypertension by enhancing cGMP levels.

• Action:

  • Prolonged availability of cGMP activates cGMP-dependent protein kinase (PKG).

  • PKG causes dephosphorylation of myosin light chain, leading to smooth muscle relaxation.

  • Closes vascular smooth muscle calcium channels, reducing intracellular calcium levels.

  • Results in vasodilation, increased blood flow, and sustained erection.

• Adverse Effects:

  • Headache due to vasodilation.

  • Flushing.

  • Dyspepsia due to smooth muscle relaxation in the lower esophageal sphincter.

• Contraindications: Use with nitro vasodilators due to potentiation of hypotensive effects, leading to severe hypotension.

Recap of the Erection Mechanism

• Initiation: Sexual excitement triggers nitric oxide release from parasympathetic nerves.

• Nitric Oxide Synthase: Uses L-arginine to generate nitric oxide, activating guanylyl cyclase.

• Guanylyl Cyclase: Activated by nitric oxide, converts GTP to cyclic GMP in smooth muscle cells.

• Cyclic GMP: Activates PKG, leading to smooth muscle relaxation through ion channel closure and reduced intracellular calcium.

• Vasodilation: Arterial dilation and increased blood flow into erectile tissues.

• PDE5: Induces feedback inhibition on cyclic GMP, causing vasoconstriction and flaccidity, thus ending the erection.

Summary

• BPH: Enlargement of the prostate gland, leading to lower urinary tract symptoms.

  • Treatment: 5-alpha reductase inhibitors to reduce prostate growth by blocking DHT production and alpha blockers to reduce smooth muscle tone in the bladder neck and prostate.

• Erectile Dysfunction: Inability to achieve or maintain an erection.

  • Treatment: Phosphodiesterase type 5 inhibitors to increase cGMP levels in penile smooth muscle cells, promoting vasodilation and erection.

• Reference: Chapter 35 of Rang and Dale's Pharmacology, 10th edition for further learning.