Standard Assessment of Patients with LUTS Due to BPH

The importance of medical history in identifying potential causes of LUTS has been well recognized by all the available international guidelines [13]. History and physical examination aim at diagnosing concomitant conditions of the bladder, the central nervous system, or other organs that may be responsible for LUTS beyond benign and malignant disorders of the prostate. Clinicians should always investigate comorbidities, current medications, lifestyle habits, emotional and psychological factors which may explain symptoms. LUTS related to BPH, including storage (urgency, urge incontinence, frequency, nicturia), voiding (hesitancy, weak stream, intermittency) and post micturition symptoms (incomplete voiding sensation) should be also assessed.

Frequency Volume charts require patients to record the time, volume and type of every drink they take, and the time and amount of urine at each voiding episode. From these data, several variables are derived, e.g. the 24-h voiding frequency, nocturnal frequency and mean voided volume.

The International Continence Society has agreed definitions for these variables to ensure that practice is consistent and research is comparable [2]. The duration of FVCs is still a matter of debate, the latest evidence shows a range of durations between 1 and 7 days [14]. The available guidelines suggest using at least a 3-days diary to balance consistency and compliance.

Several validated questionnaires can be used to assess male LUTS (i.e. International Prostate Symptom Score: IPSS; International Consultation on Incontinence Questionnaire ICIQ-MLUTS; Danish Prostate Symptom Score DAN-PSS; AUA symptom score) and they may help clinicians in identifying/quantifying the predominant type of LUTS as well as in monitoring disease progression [15, 16]. More specifically, American Urological Association symptom index was found to be internally consistent (Cronbach’s α = 0.86) and the score generated had excellent test–retest reliability (r = 0.92). Scores were highly correlated with participants’ global ratings of the magnitude of their urinary problems (r = 0.65–0.72) and discriminated well between BPH and control individuals (receiver operating characteristic area 0.85). Finally, the index was sensitive to change with preoperative (surgical) scores decreasing from a mean of 17.6 to 7.1 by 4 weeks after prostatectomy (P < 0.001) [17]. All the available guidelines recommend using questionnaires in the evaluation of patients with BPH. A general physical examination with specific attention to the presence of absence of a distended bladder, excoriation of the genitals secondary to urinary incontinence, evidence of urethral discharge and a focused neurologic examination is also highly recommended. Physical examination is essential to investigate possible alternative diagnosis of LUTS as: urethral discharge, meatal stenosis, phimosis and penile cancer. Digital rectal examination (DRE) should always be performed in patients with LUTS in order to exclude cancer. In patients with BPH, DRE may be helpful in assessing prostate volume. According to the available evidence, there is a distinct underestimation of prostate size by digital rectal examination (DRE) when compared with ultrasound [18]. Data from the Krimpen study, suggest DRE is enough accurate to differentiate prostate volume higher or lower than 50 g (AUC = 0.92) [19].

Urinalysis is considered an inexpensive test which do not require sophisticated technologies and is generally recommended by almost all BPH guidelines [12]. In the past years the use of PSA as a screening tool has been an important matter of debate. According to the latest EAU guidelines, based on data from the Prostate Cancer Intervention Versus Observation Trial (PIVOT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial men who have less than a 15-year life expectancy are unlikely to benefit from PSA screening [20]. More specifically, guidelines suggest to offer an individualized risk-adapted strategy for early detection to a well-informed man with a good performance status and a life-expectancy of at least 10 to 15 years. In patients with BPH, PSA levels are well correlated with prostate volume [21]. Serum creatinine evaluation is recommended by several BPH guidelines. However, there is no evidence on its utility in the first-line evaluation of men with LUTS related to BPH. Renal insufficiency appears to be no more common in men with BPH than in men of the same age group in the general population. In several large clinical BPH trials, renal failure has been reported in less than 1% of the population evaluated [1].

Uroflometry is a recommended diagnostic test in the initial workup of patients with LUTS; it is a simple, non-invasive test that can identify patients with abnormal voiding pattern and monitor changes in voiding dynamics over time in watchful waiting programs and follow-up of medical therapy, physical treatment or surgical therapies. The prognostic ability of maximum free flow rate (PFR) in bladder outlet obstruction diagnosis is known to be in the range of 90, 67 and 30% for PFR values of less than 10 ml/s, 10–14 ml/s and greater than 15 ml/s respectively. Uroflow studies presented some limitations which include: variability over repeated test related to patient’s learning effect, circadian effect, uro-flowmeter artefacts and intra-observer, inter-observer variation from manual correction of uroflow traces [22].

Measurement of post-void residual has been recommended as part of the initial evaluation although there is a weak evidence for it. The relation between elevated PVR and UTI is in fact evident in the pediatric and neurogenic populations but scanty in the BPH patient. PVR values below 50–100 mL are considered to be normal and value >300 mL is used to identify patients at risk of unfavorable outcome. Data from Oelke study on diagnostic accuracy of noninvasive tests to evaluate bladder outlet obstruction in men suggest using a PVR threshold of 50 mL, the diagnostic accuracy of PVR measurement has a PPV of 63% and a negative predictive value (NPV) of 52% for the prediction of BOO [22]. In the evaluation of patients with LUTS due to BPH ultrasound may play an important role in the differential diagnosis particularly in the evaluation of patients with haematuria, large PVR and history of urolithiasis. Prostate ultrasound gives us information on total prostate volume, transitional zone volume and prostate shape and is indicated when prostate size can influence medical or surgical treatment [12]. US may be performed either transrectally or supra-pubically considering that a very strong correlation exists between supra-pubically and transrectally performed measurements for both the total prostate gland (r = 0.948, p < 0.001) and the TZP volume (r = 0.953, p < 0.001) [23].

Optional or Investigational Tests

Pressure flow studies are considered an optional test by several international guidelines. The gold standard for the diagnosis of BOO is represented by invasive urodynamics, however discomfort and complications may limit its use. Pressure-flow study has the unique capacity to diagnose BPO, detrusor overactivity and detrusor underactivity. According to EAU guidelines, in patients younger than 50 or older than 80, patients who have had previous un-successful invasive treatments, who cannot void more than 150 cc, who have Qmax>10 ml/s or in men who have post void urine volume (PVR) > 300 cc should undergo PFs.

Endoscopy is an optional test in all guidelines in patients with BPH, considering that it cannot diagnose BOO. The test could be useful in the evaluation of patients with LUTS but is appropriate in men with a history of microscopic or gross haematuria, urethral stricture, bladder cancer, or prior lower urinary tract surgery. It should not be performed whenever watchful waiting or medical therapy has been proposed as the treatment of choice and it remains optional in patients scheduled for surgery.

Some other non-invasive tests have been proposed however none of them can substitute invasive urodynamics. The penile-cuff test (PCT) and the external condom test have been introduced as a non-invasive alternative to PFS to determine the isovolumetric bladder pressure and also flow rate. This method, in which flow is interrupted to estimate isovolumetric bladder pressure, shows promising data, with good test repeatability and interobserver agreement. Bladder, detrusor wall thickness and bladder weight can be measured simply with suprapubic ultrasound. Overall some evidence suggests good accuracy of this measurements in diagnosing BOO due to BPH however the lack of standardization, and lack of evidence to indicate which measurement (BWT/DWT) is preferable render the test still investigational. Ultrasound measurement of IPP assesses the distance between the tip of the prostate median lobe and bladder neck in the midsagittal plane, using a supra-pubically positioned US scanner, with a bladder volume of 150–250 mL; grade I protrusion is 0–4.9 mm, grade II is 5–10 mm and grade III is >10 mm. Although the available evidence suggests a good performance in diagnosing BOO, the lack of standardization, and of data on inter-intra observer variability and learning curve still render the test investigational. According to the latest systematic review performed by the EAU non neurogenic LUTS guidelines panel and although all these tests have shown promising results for the noninvasive assessment of BOO, invasive urodynamics remain the gold standard [24].

Watchful Waiting

The simple diagnosis of LUTS due to BPH does necessarily trigger treatment. Most national and international guidelines suggest that patients with mild symptoms and no bother can be safely managed in a watchful waiting program. A good number of patients will never progress to pharmacological or surgical treatment [12]. Watchful waiting is a viable option for many men with non-bothersome LUTS as few will progress to AUR and complications (e.g. renal insufficiency or stones) [12], whilst others can remain stable for years. Some studies report as much as 85% of the patients may remain stable at 1 year. The available guidelines recommend watchful waiting in men with mild/moderate symptoms, minimally bothered by their symptoms.

Alpha Blockers

α1-blockers are the first-line treatment in the management of BPH because of their speed of action, safety, tolerability and efficacy. α1-blockers aim to inhibit the effect of noradrenaline on smooth muscle cells in the prostate, resulting in a reduce prostate tone and BOO. Alfuzosin, doxazosin, and terazosin are usually considered nonselective drugs, inhibiting all the different α1-receptor subtypes conversely, tamsulosin and, above all, silodosin has higher selectivity for α-1A- receptors. Multiple, placebo-controlled, randomized, double- blind study of adequate size and duration confirmed the positive effect of α1AR antagonists on LUTS. Although head-to-head comparative studies are rare, they are currently regarded as equally clinically effective drugs in improving patient symptoms (IPSS improvement of about 35–40%), patient quality of life, and maximum flow rate (Q max; Q max improvements of 20–25%) [25]. Adverse events most frequently involve orthostatic hypotension, dizziness, and asthenia suggesting that AR receptors expressed in blood vessels and CNS are of importance. Major differences do exist in the adverse events (AEs) of the different drugs. Postural hypotension is more prevalent with nonselective α -blockers (prevalence rates close to 10%). Conversely, ejaculatory dysfunction is more frequent with tamsulosin and silodosin (prevalence more than 10%) [25]. Alpha 1 blockers are considered first line treatment because of rapid onset of action, good efficacy and low rate of AEs. Ophthalmologist should be informed before cataract surgery. Elderly patients should be aware of the risk of orthostatic hypotension as well as sexually active patients about the risk of EjD.

5α-Reductase Inhibitors

5-ARIs decrease the conversion of testosterone to dihydrotestosterone, which is the more powerful metabolite. Finasteride inhibits subtype 2 of 5α-reductase, mainly present within the prostate, whereas dutasteride blocks both subtypes 1 and 2 of 5α-reductase. 5α-reductase inhibitors act by inducing apoptosis of prostate epithelial cells leading to prostate size reduction of about 18–28% and a decrease in circulating PSA levels of about 50% after 6–12 months of treatment [26, 27]. Several RCTs showed that 5ARI was significantly more efficacious than placebo both in treating LUTS and reducing prostate volume if prostate volume was larger than 30 cc and therapy was continued for at least 6–12 months. After 2–4 years of treatment, 5-ARIs improve IPSS by approximately 15–30%, decrease prostate volume by 18–28%, and increase Qmax by 1.5–2.0 mL/s in patients with LUTS due to prostate enlargement. Both finasteride and dutasteride are usually well tolerated. However, AEs are not uncommon, especially regarding sexual function. Loss of libido, ED, and ejaculatory dysfunction are present in about 5, 6, and 3%, respectively, in patients taking finasteride according to a recent Cochrane meta-analysis [19]. Similarly, Dutasteride is associated with risks of loss of libido, ED, and ejaculatory dysfunction in 4, 7, and 2%, respectively. Treatment with 5-ARIs should be considered in men with moderate-to-severe LUTS and an enlarged prostate (>40 mL) and/or elevated PSA concentration (>1.4–1.6 ng/mL). Due to the slow onset of action, they are suitable only for long-term treatment (years). Their effect on the serum PSA concentration needs to be considered in relation to PCa screening.

Combination Treatment with Alpha Blockers and 5ARI

Due to the opportunity to prevent disease progression with long-term use of 5-ARIs as well as to obtain short-term improvement with α-blockers, combination therapies with the two categories of drugs have been widely tested. CombAT (Combination of Avodart and Tamsulosin) study and MTOPS (Medical Therapy of Prostatic Symptoms) trials have confirmed efficacy and safety of combination treatment [26]. Long term data showed that combination treatment is superior to monotherapy for symptoms and Qmax, and superior to α-blocker alone in reducing the risk of AUR or need for surgery, and BPH progression defined by an IPSS increase of at least four points, UTI, incontinence, or an increase in creatinine >50%. Moreover, data from CONDUCT study compared efficacy and safety of a fixed-dose combination (FDC) of dutasteride and Tamsulosin to a WW approach with the potential initiation of tamsulosin (step-up approach) in a two-year RCT. The change in IPSS at 24 months was significantly greater for FDC than WW-All (−5.4 vs. −3.6 points, P < 0.001). With FDC, the risk of BPH progression was reduced by 43.1% (P < 0.001); 29% and 18% of men in the WW-All and FDC groups had clinical progression, respectively, comprising symptomatic progression in most patients [28]. Side effects were more common in the combination arm [26]. According to the available guidelines combination therapy should be offered to symptomatic patients, at increased risk of progression and with prostate volume >40 cc when long term treatment is planned.

Antimuscarinics (AM)

Antimuscarinics are mainly indicated in those patients with predominant storage LUTS. Antimuscarinics act predominantly on M2 and M3 receptors which are located in the detrusor muscle. Antimuscarinic effects might also be induced or modulated through other cell types, such as the bladder urothelium or by the central nervous system. Several randomized clinical trials have assessed the efficacy of antimuscarinics in patients with storage LUTS when compared to placebo. In 2008 a large systematic review and metanalysis by Chapple et al. summarized data from 73 randomized clinical trials. Active treatments were more effective than placebo in terms of reduction in incontinence episodes, mean change in the number of micturitions per day, mean change in the number of urgency episodes per day and the mean change in the volume voided per micturition. In terms of tolerability most of the active treatments presented high rates of withdrawals (RR range: 1.33-2.44) when compared to placebo. In terms of side effects dry mouth was the most frequently reported adverse event, reported by 29.6% and 7.9% of active treatment and placebo-arm patients, respectively. The next most common adverse event was pruritus (15.4% on treatment vs. 5.2% on placebo) [29]. Not all antimuscarinics have been tested in elderly men, and long-term studies on the efficacy of muscarinic receptor antagonists in men of any age with LUTS are not yet available. In addition, only patients with low PVR volumes at baseline were included in the studies. These drugs should therefore be prescribed with caution, and regular re-evaluation of IPSS and PVR urine is advised.

Combination Between Alpha Blockers and AM

In patients with both storage and voiding symptoms combining alpha blockers and antimuscarinics is indicated according to the latest EAU guidelines [12]. Kim et al. evaluated efficacy and safety of initial combination treatment of an alpha blocker with an anticholinergic in benign prostatic hyperplasia patients in a metanalysis including 16 studies with a total sample size of 3548 subjects. The pooled overall SMD change of storage IPSS improvement from baseline was −0.28 (95% CI: −0.40–0.17). The pooled overall SMD changes of QoL, Qmax, and PVR were − 0.29 (95% CI: −0.50–0.07), 0.00 (95% CI: −0.08–0.08), and 0.56 (95% CI: 0.23–0.89), respectively. There was no significant difference in the number of acute urinary retention (AUR) events or PVR. Study discontinuation occurred more frequently in patients with add-on combination therapy than in patients with placebo add-on (4.7–7% and 1.5–4%, respectively) [30].

Phosphodiesterase 5 Inhibitors

Phosphodiesterase 5 inhibitors (PDE5Is) increase intracellular cyclic guanosine monophosphate, thus reducing smooth muscle tone of the detrusor, prostate and urethra. Moreover, reflex pathways and neurotransmission of the urethra, prostate, or bladder may be altered. Only recently PDE5i have been introduced in the guidelines for the treatment of storage LUTS with/or without concomitant ED. According to the latest metanalysis on 13 randomized clinical trials including a total of 3973 treated patients, tadalafil 5 mg improves total IPSS (SMD = − 2.02, 95% CI = − 2.52 to −1.53, P < 0.00001), BPH index (SMD = −0.58, 95% CI = −0.84 to −0.33, P < 0.00001) and erectile function when compared to placebo. Improvement may be seen within a week of initiation of treatment. A Meta-regression of available clinical trials showed that baseline IPSS, dosage of PDE 5I, and country affect clinical improvement compared with placebo. No effect on urinary flow has been recorded in clinical trials. Adverse events mainly include: flushing, gastroesophageal reflux, headache, dyspepsia, back pain and nasal congestion [31, 32]. The latest EAU guidelines recommend the use phosphodiesterase type 5 inhibitors in men with moderate-to-severe LUTS with or without erectile dysfunction. It is important to consider the limited information on long term effects reduction of prostate size and disease progression. Only small, clinical, pilot studies were conducted to assess α1-blocker/PDE5-I for the treatment of LUTS/BPH. These data were pooled in a meta-analysis by Gacci and colleagues. The metanalysis evaluated a total of 278 patients with PDE5-I/α1-blocker combination therapy and demonstrated increases of IPSS (1.8 points), International Index of Erectile Function (3.6 points), and Qmax (1.5 ml/s) when compared to α1-blockers alone. AEs with combination therapy occurred in 6.8% of patients and in 5.1% of patients receiving α1-blockers. Overall, there were no serious AEs, and combination treatment was well tolerated [31]. The present combination may be use-full particularly in sexually active patients with both storage and voiding LUTS, however no specific recommendations are yet available on the guidelines.

Plant Extracts

Phytotherapy is a popular prescribed treatment for LUTS/BPH that falls within the framework of complementary medicine in most countries although some products are registered as drugs particularly in Europe. Plant extracts suffer differences in the pharmaceutical preparation as the extraction procedures may differ among different commercial products, so the activity (efficacy, bioavailability, and pharmacodynamics) of individual components is not comparable; furthermore, some preparations contain mixture of different extracts. The origin of phytotherapeutic agents include: American dwarf palm, Saw palmetto, African plum tree, South African star grass, Pine Spruce, Stinging nettle, Rye, Pumpkin and Cactus flower extracts. Active components comprise: phytosterols (alpha-sitosterol), phytoestrogens fatty acids (lauric and myristicacid), lectins, flavonoids, plant oils, and polysaccharides. Serenoa repens, extracted from the American dwarf palm is one of the most frequently used products commercialized worldwide. The drug is considered to have antiandrogen, antiproliferative, and anti-inflammatory activities. Two meta analyses of Permixon studies performed by P. Boyle suggested a significant improvement of IPSS (−4.7), nocturia (1.0 over placebo), and maximum flow rate (2.3 mL/s over placebo). A Cochrane meta-analysis suggesting that men treated with Pygeum africanum were twice as likely to report symptom improvement whilst men treated with Secale cereale were twice as likely to benefit from therapy compared to placebo and that Serenoa repens was not superior to placebo, finasteride, or Tamsulosin for IPSS but confirmed that several different extract technique can influenced the observed results. Side-effects during phytotherapy are generally mild and comparable to placebo. Serious adverse events were not related to the study medication [33]. Due to the large heterogeneity in composition and formulation, guidelines do not give specific recommendation on the use of plant extract for the treatment of patients with BPH.

Beta-3 Agonist

Beta-3 adrenoceptors are the predominant beta receptors expressed in the smooth muscle cells of the detrusor and their stimulation is thought to induce detrusor relaxation. Mirabegron 50 mg is the first clinically available beta-3 agonist with approval for use in adults with OAB. A metanalysis identified five RCTs which compared solifenacin with mirabegron. Mirabegron achieved the same effect as solifenacin in treating OAB. The mean number of incontinence episodes per 24 h (p = 0.20), mean number of micturitions per 24 h (p = 0.11), mean number of urgency episodes per 24 h (p = 0.23), and mean volume voided per micturition (P = 0.05) suggested that mirabegron and solifenacin had no significant differences in terms of OAB treatment. With regard to drug-related AEs and dry mouth, mirabegron showed better tolerance than solifenacin. Post-voiding residual volume showed a distinct difference in the two groups. Hypertension and tachycardia did not show a significant difference between the two groups, but the pulse rate did [34]. The most common treatment-related adverse events in the mirabegron groups were hypertension, urinary tract infections, headache and nasopharyngitis. The current EAU guidelines recommend to use beta-3 agonists in men with moderate-to-severe LUTS who mainly have bladder storage symptoms. It is important to consider the lack of data on long term efficacy and safety. Overall four randomized clinical trials have evaluated the use of combination/add-on therapy in the management of patients with OAB symptoms [35–38]. These trials have evaluated different combination doses of Solifenacin (2.5 mg, 5 mg and 10 mg) and Mirabegron doses (25 mg and 50 mg). In terms of improvement in symptoms and incontinence episodes all combinations were superior Solifenacin monotherapy. In terms of tolerability combination treatment was well tolerated across all trials. AEs were slightly more frequent in the combination arms when compared to the monotherapy arms. The abovementioned trials have been published between 2015 and 2018 therefore no recommendations are yet available on the guidelines.