Benign prostatic hyperplasia

  • rowland rees

Contributed by Mr Rowland Rees, consultant urological surgeon, Royal Hampshire County Hospital, Winchester, Hampshire.

Section 1: Epidemiology and aetiology
BPH is a prevalent condition resulting from an increase in epithelial and stromal cell numbers in the peri-urethral area of the prostate.

Progressive benign prostatic enlargement (BPE) results in gradual encroachment of the prostatic urethra, with consequent benign prostatic obstruction (BPO) lower urinary tract symptoms (LUTS), and reduced quality of life of the ageing male.

Epidemiology and history
Post-mortem studies have found that BPH does not occur below the age of 30, but significant hyperplasia is present in 50 per cent of 50 year olds and 70 per cent of 70 year olds,1 where the prostate may grow from its normal 20g to over 100g. An average gland with BPH weighs around 35g.

Community-based studies demonstrated that 43 per cent of men over 65 had symptomatic BPH, and that half of these men had a significant drop in their quality of life as a result.2 This equates to more than two million men in the UK.

‘Watchful waiting’ studies have shown that for men presenting with moderate-to-severe symptoms, a third will improve spontaneously, while a quarter eventually require surgical intervention.3

Longitudinal natural history studies have demonstrated that a rising prostate volume correlates with steadily worsening symptom scores, and the larger the prostate at baseline, the greater the risk of acute urinary retention or the requirement for surgical intervention.4

A higher PSA (as a marker of increased prostate volume, in the absence of prostate cancer) is also a predictor of progression.

Pathophysiology
At the heart of prostate growth and development is the complex interaction between stromal and epithelial cells, a process mediated by a host of growth factors.

It is thought that derangement of this stromal-epithelial interaction may lead to prostatic hyperplasia. The precise mechanism is as yet unclear, though there appears to be both increased cell proliferation and decreased apoptosis at varying stages of the disease.

Type II 5-alpha reductase in the nucleus of stromal cells converts testosterone to the more potent dihydrotestosterone (DHT), which generates growth factor release from the stromal cell.

However, as testosterone decreases with age but BPH increases, the relationship between testosterone and prostate pathology is complex and unclear. Given the frequent association between BPH, erectile dysfunction, hypertension and bladder overactivity, attention is also being given to the possibility of autonomic or vascular dysfunction as a common factor in these conditions.

Smooth muscle cells within the prostate stroma contract in response to alpha-1a adrenoreceptor stimulation, causing increased tone within the gland.

BPH is said to cause both dynamic (smooth muscle contraction) and static (volume-related) obstruction. This explains how some men can have urodynamic evidence of obstruction despite only having modest prostate enlargement.

When not diagnosed, chronic BPO can lead to bladder hypertrophy, overactivity, and consequent irritative LUTS such as urge incontinence. When there is high-pressure chronic retention, the more severe effects of hydronephrosis and renal failure may develop.

Prior to the modern surgical therapies, bladder calculi were commonplace and urinary fistulae were a recognised entity.

Section 2: Diagnosis
A full urological history is an important component of the assessment, the main aim of which is to distinguish BPO from other causes of LUTS (eg overactive bladder, hypotonic bladder, UTI and other obstructive causes).

As well as the standard storage and voiding symptoms, it is important to ask about haematuria, back/neurological symptoms, frequency/urgency and bladder pain and nocturnal incontinence. The most predictive symptom is reduced flow.

An International Prostate Symptom Score (IPSS) – a seven-point questionnaire that also quantifies ‘bother’ caused by LUTS – is also recommended.

Examination
The minimum requirement is a digital rectal examination (DRE) and a basic neurological examination. Abdominal examination will also help detect a chronic retention bladder, and the DRE will screen for any malignant features and estimate prostate volume/risk of progression.

Investigations
Urinalysis should be performed.

A baseline serum creatinine should be obtained to screen for renal impairment.

PSA in this context can help calculate the risk of progression, but clearly the patient must be aware of the implications of finding a raised PSA.

If a patient being investigated for LUTS has an elevated risk of prostate cancer, then consideration must be given to prostate biopsy, depending on life-expectancy and co-morbidity.

Risk of progression
Percentage risk of detecting prostate cancer using a combination of PSA
and DRE
PSA <4 PSA 4-10 PSA >10
Negative DRE 9% 20% 31%
Positive DRE 17% 45% 77%

Some guidelines recommend the use of uroflowmetry and post-void residual assessment, and these can be useful to determine who will require surgery, or in whom it is safe to offer watchful waiting, particularly when serial measurements are made.

Pressure-low studies (urodynamics) are an accurate assessment and predictor of who will respond well to surgery, but are not deemed necessary or cost-effective in all patients undergoing bladder outflow surgery. These are useful if there are significant irritative symptoms or an equivocal clinical picture, or determining the next step after failure of transurethral resection of the prostate (TURP).

Renal tract ultrasound may be used to examine for hydronephrosis if the serum creatinine is raised.

Section 3: Management
A clear impression of ‘bother’ caused as well as risk of progression are key to deciding the way forward.

Watchful waiting
A significant proportion of patients presenting with mild LUTS are merely worried that they represent a more serious condition such as prostate cancer or impending acute retention. Once these conditions have been excluded, the patient may respond well to reassurance, and feel that his symptoms do not warrant intervention. It may also be useful to quantify the risk to the patient (see box).

Medical therapy
For men with sufficiently bothersome symptoms, or those who have failed watchful waiting, a trial of medical therapy may be appropriate. Medical treatment should not be offered to patients with complicated BPO – ie renal impairment/hydronephrosis and also recurrent urinary retention, infections or haematuria as a result of BPO.

What is not clear is whether treatment merely delays surgical treatment over a long period, and if so what effect this has on the detrusor muscle function.

Alpha-blockers
Alpha-blockers act by blocking the alpha-1 adrenoreceptors in the prostatic and bladder neck smooth muscle, and so act on the ‘dynamic’ component of BPO.

They have a relatively rapid onset, and delay but do not prevent BPH progression. On average, patients achieve a 30-40 per cent improvement in symptom scores (cf TURP 85 per cent), and they are usually effective within two to four weeks. Urinary flow rates increase by 1.5-3.5ml/second.

One study reported a 50 per cent discontinuation over four years due to a perceived lack of effectiveness.5 A further proportion also stop taking alpha-blockers because of side-effects.

Adverse events arise from the cardiovascular and cerebral effects of alpha-1 blockade, and include tiredness, dizziness, headache (10-15 per cent), retrograde ejaculation (8 per cent) postural hypotension (2 per cent), and are generally less frequent with the long-acting or slow-release preparations.

Alfuzosin and tamsulosin have better tolerability than doxazosin and terazosin. More recently, ophthalmological reports of intraoperative floppy iris syndrome have emerged in association with alpha-blockers, although the exact relationship is unclear. It would appear prudent to avoid the use of these drugs in patients awaiting cataract surgery.

5-alpha reductase inhibitors
Finasteride and dutasteride inhibit the conversion of testosterone to the more potent DHT, thereby shrinking the prostatic epithelium and reducing prostate volume by up to 20 per cent.

They affect the ‘static’ component of BPO and take three months or more to reduce symptoms. Symptom scores improve by around 30 per cent, and patients with larger prostates benefit most.6

Much attention was given to the reduction in risk of acute retention with these drugs, but although the relative risk reduction was high (43 per cent), it should be noted that the absolute risk reduction was 4 per cent (from 7 per cent (placebo) to 3 per cent (finasteride)) over a four-year period.

Side-effects are few. Up to 5 per cent of patients may experience either a reduced libido or ejaculatory volume, or erectile dysfunction, and a small number develop breast enlargement with or without tenderness.

It is worth mentioning that both 5-alpha reductase inhibitors have been shown to reduce the incidence of prostate cancer by 25 per cent when given over a seven-year period.7,8

Combination therapy
Studies have examined whether there is additional benefit to combination therapy with alpha-blockers and 5-alpha reductase inhibitors.

Three out of four large randomised studies failed to show a symptomatic advantage of adding a 5-alpha reductase therapy to alpha-blockade alone.9

Risk of Urinary Retention
Annual risk of urinary retention according to age and symptom severity4
Age Mild symptoms (IPSS<7) Moderate/severe symptoms (IPSS<7)
40-49 3/1,000 3/1,000
70-79 9/1,000 34/1,000

Section 4: Surgery
There have been a number of less invasive procedures introduced to try to match the success rates of TURP while offering lower morbidity, but none have so far proved more durable than what is often termed the ‘gold standard’ treatment for BPH.

A number of therapies based mainly on heat or ‘thermotherapy’ have been developed: radiofrequency ablation via transurethal needle ablation (TUNA), microwave therapy, high-intensity focused ultrasound (HIFU), electrovapourisation and prostatic stents. None have been shown to be an improvement on TURP.

Laser therapy
The possibility of treating BPH with laser energy has long been an attractive one, and in the last few years, both green light and holmium laser treatment have gained in popularity, with a large number of centres offering laser treatment. They have also been endorsed by NICE.

With green-light (or KTP) laser energy, the prostate tissue is vapourised by absorption of the green light by haemoglobin.

The procedure takes longer than a traditional TURP, but far less bleeding is encountered. Shorter catheterisation times and inpatient stays are seen with laser prostatectomy, and the procedure can be safely carried out as a day case. There is no risk of TURP syndrome, and it can be safely carried out in large (>100g) prostates and patients taking anticoagulants.

Initial data suggest that equivalent short-term efficacies are seen, but given that less tissue is removed on average, longer-term data are required to assess durability.

Side-effects include transient but occasionally severe irritative symptoms/dysuria, acute retention and haematuria.

Holmium lasers can be used to ablate (HoLAP) and enucleate (HoLEP) the prostate. The technique of enucleation is more technically demanding, and involves a longer learning curve than either of the ablative techniques. Due to the amount of tissue removed, some studies suggest equivalence to TURP in terms of symptomatic improvement and durability at the limited (seven year) follow up.

TURP
TURP remains the most common procedure for BPH, and has excellent outcomes, with up to 90 per cent symptom improvement. However, this has to be balanced against the risk of complications, namely bleeding, TURP syndrome and cardiovascular complications, as well as the longer term complications of retrograde ejaculation (70 per cent), erectile dysfunction (5 per cent), incontinence (<1 per cent), urethral stricture and the need for further surgery (15 per cent over eight years).

Open prostatectomy
Open prostatectomy is now a very infrequently performed operation, and reserved for those with very large prostates, those with coexistent pathology such as large bladder calculi, or where TURP has failed.

It is carried out via a lower midline incision, via the bladder (transvesical) or direct retro-pubic route.

There is significant blood transfusion rate, and it is therefore not suitable for the medically unfit.

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