Drug treatment of benign prostatic hypertrophy

Benign symptomatic prostatic hypertrophy will affect up to 25% of men. Transurethral resection of the prostate is an effective therapy, but has adverse effects and may not be required in less severe cases. Medical therapies such as alpha blockers and 5alpha reductase inhibitors may be indicated in uncomplicated cases or in patients who are unfit, unwilling or waiting to undergo surgery. Alpha1 adrenergic blocking drugs such as prazosin and terazosin are more effective than placebo at relieving obstructive urinary symptoms. Finasteride (a 5alpha reductase inhibitor) acts by blocking the conversion of testosterone to active intracellular dihydrotestosterone and will often decrease the size of the prostate. Although it has minimal adverse effects, finasteride only slightly improves urinary flow rates. It may take 6 months for the maximum benefit to occur and finasteride must be continued indefinitely, otherwise the prostate will return to its previous size and symptoms will return.

Benign prostatic hypertrophy (BPH) will eventually occur in a microscopic form in all men if they live long enough. Only half develop the macroscopic form and only half of these develop symptoms which require treatment. The cause of symptomatic BPH is not completely understood, but there are at least 3 components which contribute to the symptoms of BPH:

• mechanical obstruction by the enlarged prostate
• dynamic obstruction caused by the tone of the prostatic smooth muscle
• the reaction of the bladder to the obstruction

Only one third of patients with symptomatic BPH present to their general practitioner. A minority of the patients who present will have serious complications due to urethral obstruction (see below).

The management of symptomatic BPH depends on the severity of the symptoms, an accurate diagnosis, the presence of complications and the general health of the patient.

Unfortunately, symptomatic BPH has a very variable course and a placebo will improve 40% of patients, so the results of uncontrolled studies must be interpreted cautiously.

Surgery is the gold standard of treatment, but it does not help every patient. Transurethral resection of the prostate (TURP) and bladder neck incision are costly and have adverse effects including bleeding, infection and sexual dysfunction such as retrograde ejaculation. There is a need to develop other treatments, especially for patients unfit for surgery or with less severe symptoms. Medical treatments include alpha1 adrenergic blocking drugs such as prazosin and 5alpha reductase inhibitors such as finasteride.

Also evolving, although still experimental, are minimally invasive procedures which have lower morbidity than conventional surgery. These include prostate stents, laser prostatectomy, radio frequency ablation of the prostate, high intensity focused ultrasound and cryotherapy.

An algorithm (Fig. 1) is suggested for the assessment and management of symptomatic BPH. In patients with less severe symptomatic BPH, observation has a definite role. Regular follow up reduces the chance of subsequent complications.

Selective alpha1 adrenergic blocking drugs can be used in patients who do not need urgent surgery. Other indications include patients unwilling to undergo surgery or awaiting surgery, and those in whom surgery is contraindicated. Drug treatment is inappropriate if the patient has any of the serious complications of urethral obstruction.

The alpha blockers work by decreasing the smooth muscle tone of the prostate and bladder neck. They are more effective at relieving obstructive symptoms than irritative symptoms. As alpha1 adrenergic blocking drugs are also antihypertensives, patients may develop hypotension. Caution is advised when prescribing for frail patients and those with a history of syncopal attacks or postural hypotension. Starting treatment at a low dose then increasing it slowly to achieve a balance between symptomatic response and adverse effects is recommended. Once patients are stabilised on treatment, they should be reviewed annually for an examination of the prostate and measurement of prostate specific antigen (PSA).¹The drugs have no effect on PSA concentrations.

Fig1.
Suggested management of benign prostatic hypertrophy

The alpha blockers are relatively inexpensive and exert their effects quickly. Only prazosin and terazosin are available in Australia, but doxazosin²and tamsulosin are being studied.

Prazosin

Prazosin is the most commonly used alpha blocker. Controlled studies show an effect superior to placebo on urinary symptoms as well as urinary flow rates.³ Therapy should commence with 0.5 mg at night, then increase gradually over 2 weeks to 2 mg twice a day. The most important adverse effect is postural hypotension, but stuffy nose, headache and retrograde ejaculation may also occur.

Results are rapid and can generally be evaluated by 4 weeks. When used for more than two years, prazosin becomes less effective and higher doses may be required. This may be due to tachyphylaxis or a progressive increase in prostatic size which is not influenced by prazosin's effects on muscle tone.

Terazosin

Terazosin has recently been marketed in Australia. It is also the only alpha blocker approved by the U.S.A. Food and Drug Administration for the specific indication of BPH. Terazosin has a longer half life than prazosin and can be given once a day. Due to its once daily dosing, compliance and tolerance may be better than the shorter acting alpha blockers. Longer acting alpha blockers taken at night may be associated with better compliance and fewer adverse effects. However, at optimal dose levels, their effectiveness is similar.

Approximately 70% of patients taking 10 mg of terazosin daily can expect to have a greater than 30% improvement in total symptom score and 52% of patients will have a greater than 30% improvement in flow rate. Clinically significant adverse effects occur in up to 10% of patients. Adverse effects include asthenia, peripheral oedema and postural symptoms.⁴To reduce some of the adverse effects, treatment should be introduced slowly and be taken at night. Preliminary data suggest that efficacy may be sustained for up to 4 years.

5alpha reductase inhibitors such as finasteride and other 4aza steroids block the conversion of testosterone to dihydrotestosterone. This decreases prostatic and serum dihydrotestosterone. Dihydrotestosterone is the androgen primarily responsible for prostatic growth, so inhibition selectively reduces prostatic growth with minimal effects on other androgens.

The indications for finasteride are similar to those for alpha blockade and include symptomatic patients who do not require immediate surgery. Other considerations are the patients' preferences and fitness for surgery.

Treatment can reduce the volume of the prostate by at least 20% in over 40% of patients. Although the accompanying improvements in symptoms and urinary flow rates are statistically significant, the clinical benefits are modest compared with placebo. After one year of treatment, men treated with finasteride will increase their flow rate by 1.6 mL/second⁵ (see Table 1). The changes in flow rate, symptoms and prostate size, if established by 6-12 months, are maintained for at least 3 years. Longer term outcome has not yet been fully evaluated.

Finasteride has a very low risk of adverse effects and few interactions with other medications. In clinical trials, only 2% of patients ceased finasteride because of adverse effects which include a decrease in the volume of ejaculate, impotence and decreased libido.

The patient should be informed that symptomatic improvement may take between 6 and 12 months and it is impossible to predict who will respond. If improvement occurs, the medication must be continued forever, otherwise the prostate will regrow to its original size.

The dosage is 5mg/day with no dose modification for age or chronic renal failure. The patient is reviewed after 6 months to assess the response. If treatment is then continued, I would recommend a repeat digital rectal examination and a measurement of PSA after one year to check for prostate cancer.

As finasteride reduces prostate volume, the concentration of PSA falls by 50% from pretreatment levels. This fall must be taken into consideration at the routine annual check. Failure of PSA to decrease during treatment may signal unrecognised prostate cancer or noncompliance. However, a decrease in PSA does not exclude prostate cancer.⁵An increase of more than 0.75 nanogram/mL is an indication for referral and possible biopsy. Patients with suspected prostate cancer or the complications of obstruction are not suitable for finasteride complications of obstruction are not suitable for finasteride treatment.

These drugs are notused for obstruction due to BPH, but rather for bladder instability (frequency, urgency) which may mimic or coexist with BPH.

Anticholinergics such as propantheline bromide, penthienate bromide and oxybutynin or tricyclic antidepressants with anticholinergic effects such as imipramine, nortriptyline and amitriptyline are occasionally used where there are severe irritative symptoms but few obstructive symptoms. These drugs should only be considered after a urodynamic assessment which confirms bladder instability and excludes significant obstruction. The patients must be warned that the drugs can precipitate retention.

The commonly used medications are propantheline bromide or amitriptyline, but penthienate bromide and oxybutynin can be tried if these fail. The dose is titrated against response to find the smallest dose which will provide adequate symptomatic relief. The adverse effects include dry mouth, drowsiness and constipation and these medications should not be used in patients with glaucoma.

Medical therapy will have an increasing role in symptomatic BPH, but our current lack of understanding of the disease limits our ability to predict which patients are going to respond to which treatment. As our understanding improves, we may be able to select the most effective treatment for each individual patient.

At present, alpha blockers and finasteride are the only medications with acceptable adverse effects which benefit the patient slightly more than placebo. There are no published data comparing their relative efficacy, but a placebo controlled study comparing finasteride, terazosin and their combination is in progress. However, although such drugs offer an alternative to surgery, they are much less effective.