mens health

Benign prostate hyperplasia

Patients with enlarged prostate

Majority of men above 50 years old and the frequency of the disease is increased with age

BPH is dependent on the androgen 5-alpha dihydrotestosterone (5α-DHT)

Testosterone secreted by the testicles and the adrenal glands, is quickly metabolized into DHT by the enzyme 5α-reductase at the prostate gland

Can become malignant -> good to treat early

Characterized by a non-malignant growth of some components of the prostate (e.g. transitional zone)

Progressive condition: Lower urinary tract signs and symptoms (LUTS), Negative impact on Quality of Life (QoL)

BPH - physiology of prostate

Composed of:

Epithelial (glandular) tissue → androgens stimulate its growth

Stromal (smooth muscle) tissue → innervated by α1 adrenergic receptors

Testosterone is converted to dihydrotestosterone (DHT) by enzyme called Type II 5α-reductase, in the prostate

DHT is needed for normal growth/enlargement of prostate

BPH - physiology

Physiology: tone of the human prostate smooth muscle is maintained primarily by noradrenaline released from adrenergic nerves and stimulating post-junctional α1-adrenoceptors.

Prostate and lower urinary tract tissues exhibit a high proportion of α1A receptors.

This provides the rationale for the use of α1- adrenoceptor antagonists for lower urinary tract symptoms associated with BPH

Activation of adrenoceptors leads to a contraction of the internal sphincter of the bladder, stops urine flow

Outcome of blockage: relaxes smooth muscle of bladder and urethra to improve urine flow

BPH - pathophysiology

Etiology is not well known => Likely age & hormonal factors

Static component (slowly over time) -> Hormonal Factors (Testosterone → DHT) -> enlargement of prostate tissue

Dynamic component -> increased smooth muscle tissue & agonism of a1 receptors -> narrowing of urethra outlet

Both lead to Urethral Obstruction / Signs & Symptoms

Long term - bladder response to obstruction

In the early phases, the bladder muscle can force urine through the narrowed urethra by contracting more forcefully

Over time, the bladder muscle gradually becomes thicker (hypertrophy) to overcome the obstruction

Once the detrusor muscle has achieved the highest state of hypertrophy, the muscle decompensates

Detrusor muscle becomes irritable and/or overly sensitive (detrusor overactivity or instability), contracting abnormally in response to small amounts of urine in the bladder, resulting in a need to urinate frequently

BPH - signs and symptoms

Many patients remain asymptomatic -> s/s start to occur in 1/3 men older than 65 yo. Symptoms only when detrusor decompensates

Lower urinary tract symptoms (LUTS): Weak stream, frequency, nocturia, intermittent stream, incomplete emptying, straining, and urgency

LUTS is not specific to BPH, many other causes: Urinary tract infections (UTIs), prostate or bladder cancer, diabetes mellitus

Obstructive/ Voiding Symptoms -> Early in disease course: Hesitancy, Weak stream, Sensation of incomplete emptying, Dribbling, Straining, Intermittent flow

Irritative/ Storage Symptoms -> Occurs after several years of untreated BPH: Dysuria, Frequency, Nocturia, Urgency, Urinary Incontinence (UI)

BPH - assessment

Digital Rectal Exam (DRE)

Ultrasonography

Maximum Urinary Flow Fate (Qmax)

Postvoid Residual (PVR): < 100 ml normal, > 200 ml inadequate emptying

Prostate specific antigen (PSA)

Might be elevated in BPH and positively correlated with prostate volume

Can help predict progression of BPH (> than 1.5 ng/mL)

Higher risk for prostate cancer

Controversial – not clear cut

BPH - MOH guidelines

BPH - medication history

Anticholinergics -> decrease bladder muscle contractibility

Antihistamines, tricyclic antidepressants (TCAs), etc

α1 adrenergic agonist -> contraction of prostate smooth muscles

Decongestants

Opioid Analgesics -> increase urinary retention

Diuretics -> increase urinary frequency

Testosterone -> can stimulate prostate growth

BPH - management

BPH - non-pharm management

Limit fluid intake in evening

Minimize caffeine and alcohol intake

Educate pt to take time to empty bladder completely and often

Avoid medications that can exacerbate symptoms

BPH - Current treatment guidelines

The goal of treatment is to relieve LUTS* and slow the clinical progression of BPH while improving patient QOL.

The 2010 updated treatment guideline from the AUA recommends that if the patient presents with LUTS, with or without uncomplicated prostate enlargement, and the symptoms are not affecting his QOL, then no further evaluation or treatment is recommended

LUTs: Obstructive symptoms (include urine hesitancy, straining, weak flow, prolonged voiding, partial or complete urinary retention, and urinary incontinence), and Irritative symptoms (include urinary frequency, urgency, nocturia, dysuria, and decreased void volume)

PSA = prognostic factor, but its not a 100% confirmation

Current oral pharmacotherapy options for managing BPH

(1) alpha-adrenergic antagonists (α-blockers),

(2) 5α-reductase inhibitors (5ARIs),

(3) muscarinic receptor antagonists (MRAs), and

(4) phosphodiesterase 5 (PDE5) inhibitors

BPH - selective Alpha Adrenergic Antagonist (tamsulosin)

BPH - tamsulosin safety consideration

A: well absorbed orally (0.4mg once a day)

D: highly bound to plasma proteins (>90%) small V d (0.2L/kg)

M: metabolized by CYPs (eg. CYP3A4, CYP2D6). T1/2 ~10 - 15h

E: ~10% excreted unchanged in urine

Adverse effect: abnormal ejaculation, back pain

Contraindication: Concurrent use of another α1-adrenoceptor antagonist (eg. Prazosin – non-selective α1 blocker)

BPH - NS Alpha Adrenergic Antagonist

BPH - Alpha Adrenergic Antagonist AE

General side effects: muscle weakness, fatigue, ejaculatory disturbance, headache, etc

Bedtime administration to decrease orthostatic effects

Non selective: Dizziness (most common), first dose syncope and orthostatic hypotension

Uroselective:

Low to none peripheral vascular dilatation → less hypotension or syncope

Ejaculatory Disturbance (delayed or retrograde ejaculation) Silodosin > Tamsulosin > Alfuzosin

Still related with less sexual dysfunction than 5ARI

BPH - Alpha Adrenergic Antagonist - Intraoperative Floppy Iris Syndrome (IFIS)

Condition that complicates cataract surgery

MOA linked to blockage of α1 receptors in iris dilator muscle

Most commonly associated with tamsulosin

Men with planned cataract surgery should avoid the initiation until the surgery has been completed (or hold at least 14 days before surgery)

BPH - Alpha Adrenergic Antagonist selection

Non selective agents-

Could be beneficial in those hypertensive patients that need additional blood pressure (BP) lowering effect

In BEERs List as drugs to avoid in Should not be used as monotherapy for a patient that has HTN and BPH concurrently

Selective agents may be used in patients that don’t need added BP lowering effect

BPH - 5 alpha reductase inhibitors (5ARIs)

MOA: Competitive inhibitors of 5α-reductase (Type II). Inhibit conversion of testosterone to dihydrotestosterone (DHT), which drives prostate growth and male-pattern hair loss

↓ DHT levels, ↓ prostate size, ↑ hair growth. Improve urine flow and reduce acute urinary retention

Lower need for prostate surgery (e.g., transurethral resection, prostatectomy)

Do not bind to androgen receptors

For moderate to severe lower urinary tract symptoms (LUTS) with large prostates (>40g)

Suitable for patients wanting to avoid surgery or unable to tolerate α1-antagonist side effects

Slow onset: effects take 6–12 months

Decreases serum prostate-specific antigen (PSA) levels; consider if PSA >1.5 ng/mL

BPH - 5ARIs safety consideration

A: well absorbed orally (5mg once a day) F ~ 0.65. No dosage readjustment needed for patients with renal insufficiency, liver failure and elderly patients

D: high plasma protein bound (~90%)

M: metabolized by liver (eg. CYP3A4) T 1/2 ~6h

E: 50% unchanged drug excreted in feces; metabolites excreted in urine & feces

Contraindications: Women and children, pregnancy

BPH - 5ARIs AE

Ejaculatory disorders (reduced semen during ejaculation or delayed ejaculation) -> higher risk than alpha antagonist

Decreased Libido (3 - 8%)

Erectile Dysfunction (ED) (3-16%)

Gynecomastia and breast tenderness (1.0%)

Lesser risk of hypotension

BPH - 5ARIs considerations

Pregnant/ child bearing age females should NOT handle these agents

Obtain PSA before initiating therapy -> not easily interpretable after initiation

BPH - Phosphodiesterase 5 Inhibitor (PDE5I)

BPH - combi therapy

MTOPS & CombAT study – both support that combination therapy provided benefits beyond monotherapy

MTOPS - finasteride + doxazosin

CombAT - dutasteride + tamsulosin

Provide empiric evidence that long-term use of this combination is safe with only mild adverse effects

Individuals with moderate symptoms (e.g., IPSS 8–19, IPSS QOL 5-6) and prostate size > 25 g are most likely to benefit from an initial treatment that encompasses two drugs

BPH combi - a1 antagonist + 5ARI

Most common combination: α-blockers typically provide benefit within weeks, whereas 5-ARIs require months for optimal effect

Reserved for symptomatic patients with an enlarged prostate

SMART-1 trial: after 6 months of combination therapy, discontinuation of the α-blocker can be considered in moderate BPH

BPH combi - 5ARI + PDE5 inhibitor

Beneficial to mitigate the sexual adverse effects that may arise from 5-ARIs / Concomitant erectile dysfunction

However, individuals with BPH & ED often have cardiac comorbidities

If unstable angina, should not be initiated on a PDE5 inhibitor as contraindicated with concomitant use of nitrates

BPH combi - a1 antagonist + PDE5 inhibitor

Rarely used initial combination therapy: can cause severe life threatening hypotension

If used, recommend to choose uro-selective α1 instead

Must optimize/stabilize α1 antagonist dose first before adding PDE5i

Use lowest effective PDE5 inhibitor dose possible

Would not address enlargement of the prostate

BPH - anti-muscarinics

Add on for those patients who present irritative voiding symptoms, which mimic overactive bladder (OAB)

MOA: Block muscarinic receptors in detrusor muscle→ decreasing involuntary contraction of the bladder

Agents: oxybutynin, tolterodine, solifenacin, trospium, darifenacin, fesoterodine

PVR must be less than 250 ml (or 150 ml for more conservative guidelines)

Historically, anticholinergics were considered contraindicated in BPH because of concern for urinary retention

A meta-analysis of seven controlled trials showed minimal risk

BPH - treatment pathway

BPH - conclusion

Lifestyle changes are recommended at any stage for a person with LUTS secondary to BPH

Watchful waiting should be consider for patient with mild symptoms, who are not bothered by LUTS

Pharmacotherapy is considered as an alternative for moderate to severe symptoms, which are bothersome

Surgery is indicated when complications of BPH are present

erectile dysfunction

Inability to achieve or maintain an erection of sufficient duration and firmness to complete satisfactory intercourse

Can get an erection sometimes, but not every time sex is desired or Can get an erection, but it does not last long enough for fulfilling or satisfactory sex or Are unable to get an erection at any time

Low in men < 40y/o, increases as age increases. Estimated that around 50% of men 40 y/o and older experience ED

Highly correlated with CV disease, DM, HTN, hyperlipidemia, obesity, smoking, alcoholism, BPH, depression

Usually if symptoms for > 6 months is ED

ED - physiology of erection

ED - physiology of detumescence

Deactivating of Parasympathetic System

cGMP is deactivated by an enzyme called phosphodiesterase type 5 (PDE-5) => stops the vasodilation

PDE-5 is the predominant enzyme found in penis

Activated Sympathetic System

Induces smooth muscle contraction via α2 adrenergic receptors of arterioles resulting in a reduction of blood flow

Serotonin has been postulated to have inhibitory effects on sexual arousal

ED - etiology

Organic ED: Vascular, nervous, or hormonal systems compromised, Medication Induced

Psychogenic ED: Due to thoughts or feelings (psychological reasons) rather than physical pathology

Mixed ED: Combination of both: Organic and Psychogenic ED

Others:

Social habits: smoking, excessive ethanol intake, and illicit drug use

Obesity

organic ED - causes

Vascular: Arteriosclerosis, Peripheral vascular disease(PVD), HTN, Diabetes

Hormonal

Hypogonadism - not enough testosterone

Hyper-prolactinemia - too much prolactin -> inhibits testosterone

Nervous

Central: Spinal cord trauma or disorders, Stroke, CNS Tumors

Peripheral: Diabetes, Neuropathy, Urethral surgery

organic ED - medication induced

psychogenic ED - causes

Malaise

Loss of attraction

Stress

Performance anxiety

Mental Disorders

Sedation

ED - signs and symptoms / complications

Loss of interest in sexual activities

Depression

Performance anxiety

Embarrassment

Angry

Low self-esteem

Disharmony in a relationship

ED - evaluation

Signs/symptoms

Sexual Health Inventory for Men (SHIM)

Mild to no ED: 17 to 21 points

Moderate to Severe: <11 points

Workup to identify underlying causes of ED

Medical history / Medications

Social history

Surgical history

Lab results -> blood glucose, lipid profile, testosterone, among others

ED - CVD evaluation

Cardiovascular (CV) evaluation should be conducted, in all patients with ED:

ED might be an early symptom of unidentified comorbid CVD

Sexual activity -> sympathetic activation may increase BP and heart rate (HR) → increasing the risk of myocardial infarction (MI)

Low risk of CV: okay

If unknown/ not low risk: Exercise stress testing to evaluate exercise capacity

If unstable or severe symptomatic CVD: defer until condition stabilized

Cardiac rehabilitation and regular exercise useful to reduce the risk of CV complications with sexual activity

ED - non-pharm management

First step is to recognize and, if possible, reverse or treat the underlying cause(s)

Non-pharmacological:

Addressing modifiable risk factors: Stop smoking, Control weight, Control glucose / BP / lipids, Exercise, Decrease alcohol

Psychotherapy

Devices: Vacuum erection devices (VEDs)

Surgery eg penile implant

ED - pharm management

Phosphodiesterase Type 5 Inhibitors (PDE-5 Inhibitors)

Testosterone replacement

Alprostadil (Prostaglandin E1 analog)

Yohimbine (Derivative of African yohimbine tree, α-2 Antagonist. Efficacy controversial; not recommended according to HSA)

ED - PDE-5 inhibitors

MOA: Inhibit PDE 5 enzyme which induces catabolism of cGMP → enhancing cGMP activity →inducing smooth muscle relaxation→ erection

Considered as first line agents

Cause and enhance erection only after sexual stimulation

Failure rates is approximately 30 to 40% -> similar among the agents

ED - PDE-5 inhibitors dose

A lower initial dose for:

Patients ≥ 65y/o

Those taking alpha blockers

Patients with renal failure

Taking CYP3A4 Inhibitors (e.g. erythromycin, cimetidine, ketoconazole, itraconazole, clarithromycin, grapefruit or grapefruit juice, ritonavir, saquinavir, among others), as they may increase the serum concentrations of PDE5 Inhibitors

ED - PDE-5 inhibitors AE

ED - PDE-5 inhibitors DDI

Contraindication: Nitrates + PDE5 Inhibitors = potentially fatal hypotension

Nitrates should be avoided for 12 hrs after avanafil, 24 hrs after sildenafil or vardenafil, and 48hrs after tadalafil

Risk of hypotension increases with use of multiple antihypertensives

PDE5 Inhibitors + Alcohol = hypotension

CYP3A4 Inhibitors + PDE5 Inhibitors (3A4 substrates) = ↑ Concentration of PDE5 Inhibitors

ED - PDE-5 inhibitors monitoring

Efficacy:

If failure reported; Administration with food? Timing and frequency of dosing. Lack of adequate sexual stimulation. Titration to maximum dose

If all modifiable factors are addressed, may be treated with a different PDE5 inhibitor or proceed with other more invasive therapy

Safety: BP, Side effects, Drug interactions

Changes in cardiac health status

ED - testosterone replacement

Restore serum testosterone levels to normal range (300–1100 ng/dL; 10.4– 38.2 nmol/L)

Indicated for symptomatic hypogonadism as confirmed by (1) decreased libido and (2) low serum testosterone concentrations

SE: irritability, aggressive behaviour, undesirable hair growth, increased BP, hepatotoxicity, dyslipidemia, polycythemia, prostatic hyperplasia (CI for prostate CA)

Dosage forms: IM injection, buccal, patches, topical gel, body spray, nasal spray & PO

Monitor serum testosterone within 1–3 months and at 6- to 12-month intervals -> discontinue if no improvement after 3 months

ED - Alprostadil

ED - conclusion

ED is defined as failure to achieve and/or maintain a penile erection appropriate for sexual intercourse

Evaluation of a patient with ED requires identifying organic and/or psychological causes & CVD workup

PDE5 Inhibitors are consider as first line agents for ED

Have similar efficacy profile, but have different onset and duration of action, and side effect profile

Pain and priapism may occur with alprostadil, and should be avoided in those at risk of priapism

Testosterone indicated as first line agent for those patients with ED and symptomatic hypogonadism