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BPH

Histopathological diagnosis.

Not all male LUTS due to BPH – age related bladder dysfunction, systemic conditions, medications, nocturia and sleep disorders all play a role.

 

Epidemiology

  • Prevalence (number of cases at a certain time) is better used than incidence (number of diseased people per year) for benign diseases with long durations like BPH.
  • 40 % prevalence on autopsy at age 50.
  • 80 % prevalence on autopsy at age 80.
  • Over half of men in 70s will have moderate LUTS.
  • Appears to be similar between ethnicities and countries.

 

Risk factors:

  • Age
  • Genetics / family history
  • Metabolic syndrome ?inflammatory
    • Adipose tissue is where aromatisation of testosterone to oestrogen occurs
  • Presence of androgens important for prostate growth

 

Pathology

  • Increased number of epithelial and stromal cells in the periurethral prostate – hyperplasia (not hypertrophy).
  • Epithelial and stromal proliferation in the absence or reduction of programmed cell death.
  • BPH is primarily a stromal process with significant increase in smooth muscle.
  • First phase is increase in number of nodules of glandular proliferation.
  • Second stage is increase in size of these nodules.
  • The presence of the prostatic capsule plays a role in the transmission of pressure from BPH to urethra and voiding – hence BNI works, and variability of LUTS with prostate volume.

 

Aetiology

  1. Hormonal – androgens/DHT/testosterone
  2. Genetic susceptibility
  3. Stromal growth factors and stromal-epithelial interaction
  4. Inflammatory pathways

 

Hormonal

It is clear that testosterone and more importantly DHT is required for BPH development:

  • Men castrated prior to puberty do not get BPH
  • Men with congenital 5-AR deficiency do not get BPH
  • Prostatic levels of DHT remains high in older men, despite lower serum testosterone
  • Some reversal of BPH with ADT

Testosterone is converted to the more potent DHT by 5-alpha reductase.

Specifically type 2 5AR in the prostate, at the nuclear membrane.

The testosterone or DHT binds to androgen receptors and induces transcription and protein synthesis (including growth factor production). Withdrawal of androgens causes an increase in programmed cell death.

Oestrogen has been shown to induce BPH in dogs but its role in men is unclear – although ageing men do have higher oestrogen to testosterone ratios (and obese men have more fat for aromatisation of testosterone to oestrogen).

 

Genetic

  • Specific genes are not known but there is clearly increased risk in men with family history of BPH.
  • Men undergoing BPH surgery prior to 60s with high resection weights were 4 x more likely to have first degree relatives having had BPH surgery.
  • 50 % men undergoing TURP before age 60 could be attributable to inheritable disease, while only about 9 % needing surgery after 60 is thought to be inherited.

 

Stromal growth factors and stromal-epithelial interaction

  • Lab evidence shows stromal and epithelial cells have sophisticated paracrine communication
  • Growth factors such as FGF, VEGF, IGF (insulin like growth factor) and EGF are dysregulated and result in abnormal cell proliferation, and this is augmented by androgens and DHT.
  • TGF-β which usually inhibits epithelial proliferation seems to not have an effect in BPH – therefore increased proliferation and reduced normal cell death.
  • Stromal BPH nodules can resemble developmental mesenchyme – McNeal hypothesised BPH caused by ‘reawakening of embryonic processes’.

 

Inflammatory pathways

  • Inflammatory histological changes are often seen in BPH, and these may induce growth factors.
  • Emerging evidence about the links between inflammation in metabolic syndrome and BPH.

 

 

Pathophysiology

Pathological changes – increased epithelial and smooth muscle hyperplasia, plus transmission of pressures due to prostate capsule.

Static constriction refers to mechanical obstruction due to the size of the gland and the physical outlet obstruction.

Dynamic constriction is due to the increased smooth muscle tone of the prostate and bladder neck.

The end result is:

  • Detrusor hypertrophy to generate higher bladder contractility to overcome outlet obstruction
  • Increased collagen in bladder
  • Over time, bladder instability or reduced compliance
  • Decompensation with reduced contractility

 

Natural History

Rule of thumb:

  • 50 % of men develop histological BPH by age 60
  • 50 % of those with histological BPH will have BPE
  • 50 % of those with BPE have symptoms requiring treatment

A 50 year old man has a 25 – 30 % lifetime chance of requiring surgical intervention of LUTS associated with BPH.

Olmsted County study findings:

  • Risk for BPE, deterioration of flow rate and LUTS all age dependent
  • Prostate volume > 50 cc 3.5 x more likely to have LUTS
  • Average deterioration in IPSS of 0.18/year, decrease in flow rate by 2 % / year, and mean prostate growth 2 % / year

 

Risk factors for progression (AUR/surgery):

  • Age (> 70)
  • Symptom severity
  • Reduced flow rate (< 8 mL/sec)
  • Prostate size
  • PSA (> 1.4)

Regarding PSA and BPH:

  • PLESS study split patients into tertiles (PSA <1.3; 1.4 – 3.2; >3.3)
    • PSA 1.4 and above predicted progression of LUTS and worse flow rates, and bother
  • PSA of 1.5 and higher showed 3 x risk of TURP in Olmsted County study
  • PSA has also shown to be a predictor of progression to AUR in placebo arms of trials
  • PSA has a good predictive value for prostate volume
  • PSA is better predictor of prostate growth than for volume
  • Remember on patients treated with 5ARI that PSA levels drop 40 – 50 % after 12 months

 

Management of BPH

Conservative -> medical -> surgical.

If minimal bother, conservative treatment is appropriate.

 

Watchful waiting

  • Many men will have stable symptoms with no progression over years
  • RCT TURP vs WW – 36 % crossed over to surgery at 5 years (no medical rx)
  • 1 – 2 % risk of developing AUR or obstructive uropathy
  • Should be followed annually

 

Education and reassurance

  • Reassurance not cancer, discuss natural history and treatments available

 

Fluid management

  • Fluid restriction PRN for convenience, or before bed for nocturia

 

Caffeine and alcohol

  • Avoid or reduce

 

Review of medications

  • Lasix in the morning or not before long journeys, alternatives to diuretic antihypertensives

 

Behavioural strategies

  • Double voiding, urethral milking, bladder re-training, avoid constipation