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Benign prostatic enlargement (BPE) and Nocturia
By Prof. Philip van Kerrebroeck
Benign prostatic enlargement (BPE) is a well-recognised feature of male ageing and is commonly associated with lower urinary tract symptoms (LUTS).
The enlargement of the prostate is a consequence of hypertrophy caused by on-going exposure to androgens, converted within the prostate by 5-α reductase, and giving rise to nodular overgrowth of the epithelium and fibromuscular tissue in the transition zone. The prostate grows outward, but can also potentially intrude into the urethral lumen, resulting in partial bladder outlet obstruction (BOO). Formally speaking, BOO is a urodynamic diagnosis, determined by the relationship between maximum flow rate (Qmax) and the associated detrusor pressure . Alongside anatomical compression, there is an additional muscular element mediated by alpha-1 adrenergic receptors, causing an active constriction in some patients .
BPE leading to BOO clearly results in obstructive type symptoms, now formally known as voiding symptoms, comprising poor flow, hesitancy, prolonged stream, and terminal dribbling. Voiding symptoms are often associated with post micturition symptoms (post-micturition dribbling and sensation of incomplete emptying). In addition, storage symptoms (OAB) are common in males in these age groups. However opinions are divided on whether the prostatic enlargement has a causal relationship with the storage symptoms .
Nocturia and nocturnal polyuria are often associated among men with BPE [4, 5]. A similar association of nocturia with BPE, bladder and prostate cancer has been described among 2934 men between 55-75 years of age. In that study BPE had a stronger association with nocturia in the presence of diabetes mellitus and hypertension .
Nocturia can be associated with BPE, but it is pertinent to ascertain whether other causes of nocturia, in particular polyuria, are present by using a frequency volume chart (FVC). Flow rate testing is helpful. If BOO is present, the pattern of flow should show a slight reduction in initial flow, a reduced Qmax and a prolonged, slowly declining stream, ending with terminal and post-micturition dribble. Post-void residual scanning may reveal the presence of incomplete bladder emptying. Significant post-void residuals are a potential contributor to nocturnal voiding symptoms .
One of the most pertinent aspects of the relationship between nocturia and BPE is whether successful treatment of BPE leads to a resolution of nocturia. Since BPE treatment is aimed particularly at relieving BOO, surgical studies demonstrating nocturia response in patients where urodynamic parameters have been moved from obstructed to unobstructed are most relevant. Nocturia does appear to improve after transurethral resection of the prostate (TURP) , but less than other OAB symptoms . For medical management of BOO, some studies report improvement in nocturia severity and bother, but the findings are often clinically marginal and poorly sustained. When nocturnal polyuria is present, there is usually no clinical response to alpha adrenergic blocker therapy .
If history, bladder diary and other diagnostic tests indicate that nocturia is primarily or in part related to urological problems, such as benign prostatic obstruction (BPO) due to benign prostatic enlargement (BPE) or overactive bladder syndrome (OAB), one may expect that disease-specific treatments with effects on the bladder or prostate can reduce or abolish nocturia episodes. Hence, α1- adrenoceptor antagonists (α1-blockers) could be indicated for male patients with nocturia when BPO is suspected. Similarly treatment with muscarinic receptor antagonists (antimuscarinics) can be indicated when symptoms of OAB are predominant. However, urological problems were found to be the only cause of nocturia in just 16% of patients, as demonstrated in a cohort of 324 trial participants . This percentage may underestimate the problem because nocturia as an own entity was rarely included, at least in a meaningful way, in clinical research outcome analyses for treatments for lower urinary tract symptoms (LUTS). When it was included, the benefits are modest at best. In a study using the antimuscarinic drug tolterodine (4 mg once daily), only those patients who had severe OAB at baseline, had a significant reduction of nocturia compared to placebo . A study with the antimuscarinic drugs solifenacin (5 or 10 mg once daily) or propiverine for men and women with OAB found improvements for most OAB symptoms, but for nocturia the greatest reduction was only 0.16 voids per night . With solifenacin 10 mg nocturia reduction was larger compared to placebo treated patients (p<0.025). In a sub-analysis of patients pooled from four phase III trials, the reductions in nocturia episodes were evaluated after treatment with solifenacin (5 or 10 mg) or placebo .Significantly more patients treated with solifenacin versus placebo experienced a mean nocturnal frequency of ≤1 episode/night. However, only OAB patients without nocturnal polyuria were included in this trial. In controlled studies of BPE patients who were treated with drugs targeting the prostate (α1- blockers or 5α reductase inhibitors) nocturia improvement was minimal. Several controlled trials of drugs aiming at relieving BPO have found no clinically meaningful difference between the active treatment group and placebo in terms of reduction in nocturia. A study with the α1-blocker tamsulosin OCAS demonstrated a mean decrease in the number of nocturnal voids of 1.1 with the active drug versus 0.7 for placebo. This result was not statistically significant (p=0.099) . A study with the α1-blocker alfuzosin also found a numerical improvement of –1.1 voids per night versus –0.8 with placebo (p=0.04) .
In the Veterans Affairs Cooperative Study, a placebo-controlled 12 months trial to investigate the effects of the α1-blocker terazosin, the 5α-reductase inhibitor finasteride, or the combination of both drugs on LUTS/BPH, a 50% or greater reduction of nocturia was achieved with terazosin in 39%, finasteride in 25%, the drug combination in 32% and with placebo in 22% . Hence, finasteride monotherapy failed to show a beneficial effect on nocturia and the effects of terazosin were only marginal when compared to placebo. In contrast to findings in controlled trials, an open-label study based on real-life clinical practice demonstrated that tamsulosin monotherapy can reduce the number of nocturnal voids by about 50% .
There has been limited research concerning the use of combined pharmacological therapy for the treatment of nocturia, although its multifactorial nature suggests that combination therapies are likely to be effective. Combination therapy has been investigated, for example using α1-blockers and 5α-reductase inhibitors in patients with LUTS/BPH during a period of more than 4 years (MTOPS trial) . Doxazosin and finasteride combination therapy significantly reduced nocturia when compared to placebo but the net benefit of the active drug(s) was only –0.54 for doxazosin and –0.58 for the combination of doxazosin and finasteride at 1 and 4 years follow-up . Data is also available on the combination of a muscarinic receptor antagonists and α1-blockers in men with BPE and OAB . This combination therapy achieved a reduction of nocturia of only 0.2 voids more than it was achieved with placebo (–0.59 vs. –0.39; p<0.05), a statistically significant but clinically non-significant reduction. One pilot-study looked on the efficacy of a diuretic agent (hydrochlorothiazide) as second-line therapy after failed α1-blocker therapy in men with nocturia. The conclusion is that hydrochlorothiazide in combination with terazosin can be effective in reducing nocturnal frequency in some men after failed terazosin therapy. However, this result needs to be confirmed by other trials. Studies investigating the value of combination therapy with desmopressin together with drugs addressing BPO or BPE (α1-blockers, 5α-reductase inhibitors) or OAB (muscarinic receptor antagonists) are sparse. One study investigated the utility of adding desmopressin in 79 patients with storage symptoms in whom nocturia had not responded to first-line therapy with α1-blockers, finasteride, antimuscarinics, or calcium antagonists . All patients had >3 voids per night at baseline, and subjects were categorised into three groups: I) males with BPE (n=46), II) males without BPE (n=21), III) females (n=12). Overall, nocturia was reduced to <3 voids in 83.5% of patients, mean number of episodes was <2 in all groups following desmopressin therapy, time to the first nocturia episode was significantly extended (p<0.01) and quality-of-life improved (p<0.05, Groups I and II). While this study was not controlled, the improvements with antidiuretic therapy compared with the effects of first-line treatment suggest that desmopressin in combination with other therapies can be useful in patients with unresolved nocturia. A other study demonstrated that desmopressin at 100 μg significantly decreased the number of nocturia episodes in men compared to placebo. All men were already being treated with α1-blockers and one third of them had previously received antimuscarinics .
Surgical interventions aiming at reducing bladder outflow resistance due to benign BPE, including minimally invasive procedures, transurethral resection of the prostate (TURP) or open prostatectomy, are frequently offered to men for the treatment of nocturia as a symptom related to BPE. However, nocturia is the least specific symptom of BPE and also the symptom that is least responsive to therapies directed at alleviating prostatic obstruction . The absence of double-blind, placebo controlled trials to evaluate the effects of prostate surgery on nocturia has limited the ability to assess its efficacy . It is difficult to evaluate the value of TURP or other prostatic operations in nocturia due to the poor correlation between objective and subjective measures in patients with BPO . TURP, however, seems to confer a greater improvement in BPE-related symptoms than either transurethral microwave therapy or oral α1- blocker therapy. A mean reduction of 1.3 nocturia episodes has been noted after TURP . Another study found a 19.2% reduction in nocturia after TURP, with an average of a 1 IPSS point reduction for nocturia but this was the lowest degree of improvement among the 7 individual IPSS questions. Post-TURP improvement in symptoms, including nocturia, has also been attributed to a reduction in detrusor overactivity after relief of BPO . Additionally, post-void residual urine reduction leads to increased nocturnal bladder filling time and, consequently, to a reduction of nocturia frequency . It has been reported that the positive effects of TURP on nocturia are not correlated with the amount of resected tissue . Transurethral microwave therapy in obstructed patients can reduce nocturia episodes by 32% after 6-12 months . Despite the lack of strong evidence, TURP or other operations with removal of prostatic tissue seem to be reasonable treatment options in men with proven BPO and nocturia since both conditions typically improve in the majority of properly selected patients.
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