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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 [1]. Alongside anatomical compression, there is an additional muscular element mediated by alpha-1 adrenergic receptors, causing an active constriction in some patients [2]. 

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 [3]. 

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 [6]. 

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 [7].

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) [8], but less than other OAB symptoms [9]. 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 [10]. 

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 [11]. 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 [12]. 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)[13]. 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 [14].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) [15]. 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) [16].

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% [17]. 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% [18]. 

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) [19]. 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 [20]. Data is also available on the combination of a muscarinic receptor antagonists and α1-blockers in men with BPE and OAB [21]. 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[22]. 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 [23]. 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 [24].

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 [25]. 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 [26]. 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 [27]. TURP, however, seems to confer a greater improvement in BPE-related symptoms than either transurethral microwave therapy or oral α1- blocker therapy[26]. A mean reduction of 1.3 nocturia episodes has been noted after TURP [26]. 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[29]. Post-TURP improvement in symptoms, including nocturia, has also been attributed to a reduction in detrusor overactivity after relief of BPO [30]. Additionally, post-void residual urine reduction leads to increased nocturnal bladder filling time and, consequently, to a reduction of nocturia frequency [31]. It has been reported that the positive effects of TURP on nocturia are not correlated with the amount of resected tissue [28]. Transurethral microwave therapy in obstructed patients can reduce nocturia episodes by 32% after 6-12 months [26]. 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.

Literature:

1. Schafer W, Abrams P, Liao L, Mattiasson A, Pesce F, Spangberg A, et al. Good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies. Neurourol Urodyn2002;21(3):261-74.

2. Price D. Potential mechanisms of action of superselective alpha(1)-adrenoceptor antagonists.Eur Urol 2001;40 Suppl 4:5-11.

3. Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol 2006;49(4):      651-8.

4. Blanker MH, Bohnen AM, Groeneveld FP, Bernsen RM, Prins A, Ruud Bosch JL. Normal voiding patterns and determinants of increased diurnal and nocturnal voiding frequency in elderly men. J Urol 2000;164(4): 1201-5.

5. Abrams PA, Mattiasson A, Van Kerrebroeck P, Robertson G. Is nocturnal polyuria a key factor in nocturia?. Neurourol Urodyn 2004; 23: 466.

6. Gourova LW, van de Beek C, Spigt MG, Nieman FH, van Kerrebroeck PE. Predictive factors for nocturia in elderly men: a cross-sectional study in 21 general practices. BJU Int 2006;97(3):528-32.

7. George NJ, O’Reilly PH, Barnard RJ, Blacklock NJ. High pressure chronic retention. Br Med J(Clin Res Ed) 1983;286(6380):1780-3.

8. Margel D, Lifshitz D, Brown N, Lask D, Livne PM, Tal R. Predictors of nocturia quality of life before and shortly after prostatectomy. Urology 2007;70(3):493-7.

9. Seki N, Yuki K, Takei M, Yamaguchi A, Naito S. Analysis of the prognostic factors for overactive bladder symptoms following surgical treatment in patients with benign prostatic obstruction. Neurourol Urodyn 2009; 28(3):197-201.

10. Koseoglu H, Aslan G, Ozdemir I, Esen A. Nocturnal polyuria in patients with lower urinary tract symptoms and response to alpha-blocker therapy. Urology 2006; 7(6):1188-92.

11. Klingler HC, Heidler H, Madersbacher H, Primus G. Nocturia: an Austrian study on the multifactorial etiology of this symptom. Neurourol Urodyn 2009; 28: 427-31.

12. Nitti VW, Dmochowski R, Appell RA, Wang JT, Bavendam T, Guan Z. Efficacy and tolerability of tolterodine extended-release in continent patients with overactive bladder and nocturia. BJU Int. 2006; 97: 1262-6.

13. Yamaguchi O, Marui E, Kakizaki H, Itoh N, Yokota T, Okada H, Ishizuka O, Ozono S, Gotoh M, Sugiyama T, Seki N, Yoshida M, Japanese Solifenacin Study Group.

Randomized, double-blind, placebo- and propiverine controlled trial of the once-daily antimuscarinic agent solifenacin in Japanese patients with overactive bladder. BJU Int. 2007; 100; 579-87.

14. Brubaker L, Fitzgerald MP. Nocturnal polyuria and nocturia relief in patients treated with solifenacin for overactive bladder symptoms. Int Urogynaecol J Pelvic Floor Dysfunct 2007; 18: 737-41.

15. Djavan B, Milania S, Daviesb J, Bolodeoglu J. The impact of tamsulosin oral controlled absorption system (OCAS) on nocturia and the quality of sleep: preliminary results of a pilot study. Eur Urol Suppl 2005; 4: 61-8.

16. Roehrborn CG, Van Kerrebroeck P, Nordling J. Safety and efficacy of alfuzosin 10 mg once-daily in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a pooled analysis of three double-blind, placebo-controlled studies. BJU Int. 2003; 92: 257-61.

17. Johnson TM 2nd, Jones K, Williford WO, Kutner MH,IssaMM,Lepor H. Changes in nocturia from medical treatment of benign prostatic hyperplasia: secondary analysis of the Department of Veterans Affairs Cooperative Study Trial. J Urol 2003; 170: 145-8.

18. Michel MC, Mehlburger L, Bressel HU, Schumacher H, Schäfers RF, Goepel M. Tamsulosin treatment of 19,365 patients with lower urinary tract symptoms: does co-morbidity alter tolerability?. J Urol 1998; 160: 784-91.

19. McConnell JD, Roehrborn CG, Bautista OM, et al. Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349: 2387-98.

20. Johnson TM 2nd, Burrows PK, Kusek JW, Nyberg LM, Tenover JL, Lepor H, Roehrborn CG; Medical Therapy of Prostatic Symptoms Research Group. The effect of doxazosin, finasteride and combination therapy on Management of Nocturia and Treatment Algorithms nocturia in men with benign prostatic hyperplasia. J Urol 2007; 178: 2045-50.

21. Rovner ES, Kreder K. Sussman DO, Kaplan SA, Carlsson M, Bavendam T, Guan Z. Effect of tolterodine extended release with or without tamsulosin on measures of urgency and patient reported outcomes in men with lower urinary tract symptoms. J Urol 2008; 180: 1034-41.

22. Cho MC, Ku JH, Paick JS. Alpha-blocker plus diuretic combination therapy as second-line treatment for nocturia in men with LUTS: a pilot study. Urology 2009; 73: 549-53.

23. Nam S, Moon D, Kim J. Efficacy of desmopressin in treatment of adult nocturia. Korean J Urol2004; 45: 49- 55.

24. Wang CJ, Lin YN, Huang SW, Chang CH. Low dose oral desmopressin for nocturnal polyuria in patients with benign prostatic hyperplasia: a double-blind, placebo controlled, randomized study.J Urol 2011; 185: 219-23.

25. Homma Y, Yamaguchi T, Kondo Y, Horie S, Takahashi S, Kitamura T. Significance of nocturia in the International Prostate Symptom Score for benign prostatic hyperplasia. J Urol 2002; 167: 172-6.

26. Van Dijk MM, Wijkstra H, Debruyne FM, De la Rosette JJ, Michel MC. The role of nocturia in the quality of life of men with lower urinary tract symptoms. BJU Int. 2010; 105: 1141-6.

27. Seki N, Yunoki T, Tomoda T, Takei M, Yamaguchi A, Naito S. Association among the symptoms, quality of life and urodynamic parameters in patients with improved

lower urinary tract symptoms following a transurethral resection of the prostate. Neurourol Urodyn 2008; 27: 222-5.

28. Antunes AA, Srougi M, Coelho RF, Leite KR, Freire G de C. Transurethral resection of the prostate for the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia: how much should be resected? Int Braz J Urol 2009; 35: 683-9.

29. Yoshimura K, Ohara H, Ichioka K, Terada N, Matsui Y, Terai A, Arai Y. Nocturia and benign prostatic hyperplasia. Urology 2003; 61: 786-90.

30. Seki N, Yuki K, Takei M, Yamaguchi A, Naito S. Analysis of the prognostic factors for overactive bladder symptoms following surgical treatment in patients with benign prostatic obstruction. Neurourol Urodyn 2009; 28: 197-201.

31. Margel D, Lifshitz D, Brown N, Lask D, Livne PM, Tal R. Predictors of nocturia quality of life before and shortly after prostatectomy. Urology 2007; 70: 493-7.

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