MEDICAL MANAGEMENT OF BPH

Medical management of BPH: alpha blockers
The rationale for  α  blocker therapy in BPH
As described earlier, BPO is caused partly by  α 1 adrenoceptor mediated prostatic smooth muscle contraction, and this is the rationale for  α  adrenoceptor blocker treatment for symptomatic BPO.
There are two broad subtypes of  α  adrenoceptor (AR)  α 1 and  α 2. Molecular cloning studies have identified three  α 1 AR subtypes  α 1a (predominant in human stroma and therefore mediates prostate smooth muscle contraction),  α 1b (predominant in human prostate epithelium), and  α 1L (believed to be a conformational state of the  α 1a AR). The AR subtypes mediating efficacy and side effects of  α  adrenoceptor blocking drugs are unknown.

Alpha blocker classification
Alpha blockers are categorized by their selectivity for the AR, and by their elimination half life.
- Non selective: phenoxybenzamine effective symptom control, but high side effect profile
- α 1: prazosin, alfuzosin, indoramin
- Long acting  α 1: terazosin, doxazosin, alfuzosin SR
- Subtype selective: tamsulosin relatively selective for (1a AR subtype compared to the  α 1b subtype.
No study has directly compared one alpha blocker with another in terms of efficacy or side effects.

Indications for treatment
Bothersome lower urinary tract symptoms where watchful waiting has failed or the patient wishes to have treatment.

Efficacy
Percentage of patients who respond to alpha blockers
If  response  is defined as >25% improvement in symptoms relative to placebo, most studies describe response rates of 30   40%.16 The mean probability for improvement in symptom score after TURP is in the order of 80% (i.e. 8 out of 10 men will notice an improvement in their symptoms after TURP). Improvements in symptom score in men who  respond  to alpha blockers
The average improvement in symptom score after TURP is about 85%.17 While some of this may represent a placebo response, this improvement is considerably better than that seen with the alpha blockers which result in a 10   30% improvement in symptom score relative to placebo.18 This equates to a 4   5 points  improvement in symptom score over placebo.

Side effects
A substantial proportion of men stop taking their medication either because of side effects (15   30% report some constellation of side effects) or because of a perceived lack of effectiveness. Side effects: asthenia (weakness, in 5%), dizziness (6%), headache (2%) and postural hypotension (1%), and retrograde ejaculation (8%).

Medical management of BPH: 5 α  reductase inhibitors
5 α  reductase inhibitors inhibit the conversion of testosterone to dihydrotestosterone, the more potent androgen in the prostate. This causes shrinkage of the prostatic epithelium and therefore a reduction in prostate volume, thereby reducing the  static  component of benign prostatic enlargement. This takes some months to occur, so urinary symptoms will not improve initially. Finasteride is a competitive inhibitor of the enzyme 5 α  reductase (type II isoenzyme) which converts testosterone to DHT. Finasteride therefore lowers serum and intraprostatic DHT levels. Epristeride is a dual inhibitor of 5 α  reductase. Whether it has any clinically significant advantages over finasteride remains to be established.

Efficacy
A number of large studies have shown symptom improvement over placebo in the order of 2   3 points on the IPSS and improvements in flow rate in the order of 1   2ml/s (SCARP19 (Scandinavian BPH Study Group), PROSPECT20 (Proscar safety plus efficacy Canadian two year study), PROWESS Study Group,21 and more recently, PLESS22 (Proscar long term efficacy and safety study)). The PLESS data also shows a small reduction in the risk of urinary retention.

Side effects
Generally speaking, fairly mild. Principally centre around sexual problems (e.g. loss of libido, 5%; impotence, 5%; reduced volume of ejaculate in a few percent).

5 α  reductase inhibitors and the risk of urinary retention
The PLESS data22 have been widely publicized as showing a substantial reduction in the risk of urinary retention. In this 4 year follow up study, 42 of 1471 men on finasteride went into urinary retention (3%), while 99 of 1404 on placebo experienced an episode of retention (7%). This represents an impressive 43% relative reduction in risk in those taking finasteride. However, the absolute risk reduction over a 4 year period is a less impressive 4%. So, finasteride does reduce the risk of retention, but it is reducing the risk of an event which is actually quite rare as suggested by the fact that 93% of men on placebo in this study did not experience retention over a 4 year period. Put another way, to prevent 1 episode of retention, 25 men would have to continue treatment with finasteride for 4 years.

5 α  reductase inhibitors for haematuria due to BPH
Shrinking large vascular prostates probably helps reduce the frequency of haematuria in men with BPH.

Medical management of BPH: combination therapy
A combination of an alpha blocker and a 5( reductase inhibitor. The studies:
- MTOPS study (Medical Therapy of Prostatic Symptoms): this combination prevented progression of BPH (progression being defined as a worsening of symptom score by 4 or more, or the development of complications such as UTI or acute urinary retention).
- Veterans Affairs Combination Therapy Study: 1200 men randomized to placebo, finasteride, terazosin, or a combination of terazosin and finasteride. At 1 year follow up, relative to placebo, finasteride had reduced the symptom score by an average of 3 points, whereas terazosin alone or in combination with finasteride had reduced the symptom score by an average of 6 points.
- PREDICT study (Prospective European Doxazosin and Combination Therapy): randomized over 1000 men to placebo, finasteride, doxazosin, or a combination of finasteride and doxazosin. The difference in symptom score at baseline and at 1 year follow up were  5.7 and  6.6 for placebo and finasteride, and  8.3 and  8.5 for doxazosin and combination therapy.
- ALFIN study (Alfuzosin, Finasteride, and combination in the treatment of BPH): 1000 men were randomized to alfuzosin, finasteride, or a combination. At 6 months, the improvement in the IPSS was not significantly different in the alfuzosin versus the combination group.
Thus most studies, except for the MTOPS, suggest that combination therapy is NO more useful than an alpha blocker alone. Enthusiasm for dual therapy has been dampened somewhat by the Prostate Cancer Prevention Trial. Over 18,000 men were randomized to finasteride or placebo over a 7 year period. Those in the finasteride group had a lower prevalence of prostate cancer detected on prostate biopsy. However, higher grade tumours, which are biologically more aggressive than low grade cancers were more common in the finasteride group. The jury is out on whether finasteride causes higher grade cancers or not.

Medical management of BPH: alternative drug therapy
Anticholinergics
For a man with frequency, urgency, and urge incontinence symptoms suggestive of an overactive bladder consider prescribing an anticholinergic (e.g. oxybutynin, tolterodine, trospium chloride, or flavoxate). There is the concern that these drugs could precipitate urinary retention in men with BOO (because they block parasympathetic/cholinergic mediated contraction of the detrusor), but the risk of this occurring is probably very low, even in men with urodynamically proven BOO.

Phytotherapy
An alternative drug treatment for BPH symptoms, and one which is widely used in Europe and increasingly in North America, is phytotherapy. 50% of all medications consumed for BPH symptoms are phytotherapeutic ones.36 These agents are derived from plants and include the African plum (Pygeum africanum), purple cone flower (Echinacea purpurea), South African star grass (Hipoxis rooperi), and saw palmetto berry (Seronoa Repens, Permixon).

Saw palmetto contains an anti inflammatory, antiproliferative, oestrogenic drug with 5 α  reductase inhibitory activity, derived from the American dwarf palm. It has been compared with finasteride in a large double blind, randomized trial, and equivalent (40%) reductions in symptom score were found with both agents over a 6 month period. A meta analysis of 18 randomized controlled trials of almost 3000 men suggests that Seronoa repens produces similar improvements in symptoms and flow rates to those produced by finasteride.

South African star grass (Hipoxis rooperi, marketed as Harzol) contains beta sitosterol, which may induce apoptosis in prostate stromal cells, by causing elevated levels of TGF β1. In a double blind, RCT symptom improvement was 5 points over that with placebo.

For other agents (e.g. Urtica dioica stinging nettle; the African plum) the studies have not been placebo controlled and lack sufficient statistical power to prove conclusively that they work.