Benign Prostatic Hyperplasia: Clinical Guidelines

List of Abbreviations

UT – upper urinary tract

WHO — World Health Organization

BPO – benign prostatic obstruction

BPH – benign prostatic hyperplasia

EBRT – external beam radiation therapy

UTI – urinary tract infection

CFU – colony-forming unit

CT — computed tomography

PUJ – pelviureteric junction

Urolithiasis – urolithiasis

ICD-10 – International Classification of Diseases 10th Revision

BL – bladder

MRI — magnetic resonance imaging

AUR – acute urinary retention

ARF – acute renal failure

DRE – digital rectal examination

PSA – prostate-specific antigen

РКИ – randomized controlled trial

PCa – prostate cancer

LUTS – lower urinary tract symptoms

BiTURP – bipolar transurethral resection of the prostate

MTURP – monopolar transurethral resection of the prostate

TUIP – transurethral incision of the prostate

OP – open prostatectomy

BiTUEP – bipolar transurethral enucleation of the prostate

HoLEP – holmium laser enucleation of the prostate

ThuLEP – thulium laser enucleation of the prostate

ThuFLEP – thulium fiber laser enucleation of the prostate

ThuVEP – thulium laser vapoenucleation of the prostate

ThuFVEP – thulium fiber laser vapoenucleation of the prostate

DiLEP – diode laser enucleation of the prostate

LAPE – laparoscopic prostatectomy

RAPE – robot-assisted prostatectomy

BiTUVP – bipolar transurethral vaporization of the prostate

PAE – prostatic artery embolization (endovascular vessel embolization)

PDE-5 – phosphodiesterase type 5

ED – erectile dysfunction

OAB – overactive bladder

IPSS – International Prostate Symptom Score

UDS – urodynamic study

Terms and Definitions

Benign prostatic hyperplasia (BPH) is a benign enlargement of the prostate gland.

Benign prostatic obstruction (BPO) is a form of bladder outlet obstruction diagnosed when the obstruction is caused by a benign enlargement of the prostate.

Bladder outlet obstruction (BOO) is a general term describing obstruction during urination, characterized by elevated detrusor pressure and reduced urinary flow rate. BOO is diagnosed by simultaneous measurement of urinary flow rate and detrusor pressure.

Acute urinary retention (AUR) is a condition in which the patient is unable to pass urine and presents with a painful, palpable, or percussable bladder.

Chronic urinary retention (CUR) is a condition in which the volume of post-void residual urine in the bladder exceeds the voided volume.

Detrusor overactivity (DO) is a urodynamic phenomenon characterized by involuntary detrusor contractions during the filling phase, which may be spontaneous or provoked.

Overactive bladder (OAB) is a condition characterized by urinary frequency of more than 8 times per day and/or the presence of sudden, compelling (urgent) desires to urinate. OAB is diagnosed only in the absence of signs of infection and inflammation of the lower urinary tract or other structural pathology at this level.

Prostate-specific antigen (PSA) is an oncofetal protein marker indicating the potential presence of a malignant prostate tumor.

Transurethral resection of the prostate (TURP) is an endoscopic procedure involving the removal of prostate tissue using an instrument passed through the urethra.

International Prostate Symptom Score (IPSS) is a questionnaire to assess the nature and severity of urinary symptoms.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Benign prostatic hyperplasia (BPH) is a multifactorial disease resulting from the proliferation of the periurethral glandular zone of the prostate, leading to lower urinary tract obstruction and impaired urination quality [1,2,4,6].

Until recently, the term "prostate adenoma" was widely used; however, today the vast majority of specialists recognize the term "benign prostatic hyperplasia", which most fully reflects the pathogenetic nature of the disease and its histological picture. Recently, terminology for various conditions in BPH has changed as a result of large-scale studies confirming the non-specificity of symptoms and clinical manifestations observed in this disease [1,2,4].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology of the disease remains poorly understood. Proven risk factors for BPH development include age and hormonal status. Men castrated before puberty do not develop BPH [4,5].

BPH is a multifactorial disease. Its pathogenesis involves hormonal (androgen/estrogen signaling pathway) and genetic factors, stromal-epithelial interactions and growth factors, prostatic congestion, tissue hypoxia, oxidative stress, chronic prostatic inflammation, etc. [7]. The combined action of these factors shifts the tissue balance in the prostate toward proliferation. Morphologically, this manifests as neo-proliferation of stromal and glandular tissue with the formation of new glandular structures, representing a local process characterized by nodule formation [7].

Studies have shown that BPH growth begins in the periurethral and transition zones of the prostate, where primary hyperplastic nodules form. This may be due to the fact that the peripheral zone of the prostate develops and is regulated under the control of androgens, whereas the central zone is more sensitive to estrogens. Glandular epithelial proliferation is secondary and induced by preceding stromal changes.

All cellular elements of the normal prostate can participate in the development of nodular hyperplasia. Depending on the predominant tissue composition, benign hyperplasia is classified into glandular, stromal, and mixed. Nodules of different histological types frequently coexist within the same prostate [7].

It is important to note that enlargement of the prostate alone is often insufficient to cause clinically significant urinary tract obstruction. For asymptomatic BPH to progress to clinically manifest disease, additional factors are required: inflammation, circulatory disorders (up to infarction), and congestion.

One of the central tenets of BPH pathogenesis concerns the role of 5α-reductase (5α-

R) and dihydrotestosterone (DHT). This concept was developed based on the observation of pseudohermaphroditism cases caused by congenital absence of the 5α-R enzyme. Against the background of normal serum testosterone levels in these men, a significant decrease in DHT levels was noted, accompanied by underdevelopment or near absence of the prostate. In BPH, elevated 5α-R activity and a DHT-related hormonal imbalance are observed: the intra-tissue concentration of the latter is 5 times higher than in normal prostate tissue, with its content in the transition zone being 2 to 3 times higher than in other areas of the organ [7].

However, androgens alone do not cause excessive prostate growth. The onset of BPH occurs under the action of androgens only in the presence of estrogens. Their biological role in the male body consists of a stimulating effect on interstitial gonadal cells, smooth muscle, connective tissue, and epithelium, which is significant for the development of BPH. Other hormonal factors play an important role in regulating the prostate: receptors for progesterone, glucocorticoids, growth hormone, and insulin have been identified in it.

In a normal prostate gland, cell proliferation and death (apoptosis) are in dynamic equilibrium, maintained by a balance of stimulating and inhibiting factors. The significance of the stroma and stromal-epithelial interactions for the induction of prostatic growth in BPH is emphasized. The mutual influence of the stroma and epithelium on each other, which existed during the embryonic development of the prostate, continues to exert an effect both on the regulation of normal gland growth and on the occurrence of pathological processes within it. Development, differentiation, proliferation, and cell survival in the prostate are regulated by delicate interactions of stimulatory and inhibitory growth factors. Numerous such factors (peptides and proteins) have been isolated from the prostate, and specific receptors have been identified for most of them. Growth factors are synthesized within cells and can act on receptors within the same cell in an autocrine, on receptors of neighboring cells in a paracrine, or on receptors of distant cells in an endocrine manner. Cellular growth is stimulated by: epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), and basic fibroblast growth factor (bFGF). Their effect is counterbalanced by the inhibitory influence of transforming growth factor beta (TGF-β). This state is maintained by the necessary level of androgenic steroids. In situations where the hormonal regulation of the organ breaks down, overexpression of growth-stimulating factors is observed against the background of decreased expression or reduced ability of prostatic cells to respond to inhibitory factors. A failure in the normal growth regulation system leads to an excessive enlargement of the prostate, i.e., to the development and progression of BPH [7].

The onset and development of obstruction in BPH are determined by two components: static—resulting from mechanical compression of the urethra by hyperplastic prostate tissue, and dynamic—caused by hyperactivity of $\alpha_1$-adrenoceptors ($\alpha_1$-AR) of the urinary bladder, its neck, the prostatic urethra, and the prostate. It is precisely these two mechanisms that underlie BOO in patients with BPH.

Progression of BPH can cause dramatic changes in all parts of the urinary tract. In the urethra, these changes manifest as compression, deformation, and elongation of its prostatic part. The bladder neck is elevated and deformed, and its lumen becomes slit-like. The urinary bladder also undergoes profound changes. Its response to increasing BOO goes through three stages: irritation, compensation, and decompensation. The bladder responds to the onset of obstruction by increasing detrusor contractions, which temporarily preserves the functional balance and ensures complete evacuation of urine. The progression of obstruction leads to compensatory hypertrophy of the bladder wall, during which it acquires a trabecular appearance due to the thickening and bulging of muscle bundles. Residual urine appears. Subsequently, dissociation of the hypertrophied muscle elements occurs, leading to the formation of so-called false diverticula, the walls of which gradually thin out due to increased intravesical pressure. Such diverticula are often multiple and sometimes reach significant sizes. As a result of prolonged obstruction, chronic urinary retention develops (up to paradoxical ischuria), and irreversible morphological changes in the bladder wall occur, which cannot be eliminated even after surgical treatment [3].

Pronounced BOO leads to increased intravesical pressure, impaired urine outflow from the upper urinary tract, vesicoureteral and renal refluxes, pyelonephritis, and—as a consequence of obstructive uropathy—chronic kidney disease (CKD). Timely elimination of the obstruction and restoration of normal urine flow promote the normalization of renal function in the majority of BPH patients.

Urinary tract infection significantly complicates the course of the disease. Pyelonephritis and renal failure account for up to 40% of deaths in patients with BPH. Infection enters the kidney via an ascending route from the urinary bladder, chronic inflammation of which is observed in approximately one-third of BPH patients [7].

Of great importance in the formation of the clinical picture of BPH is concomitant chronic inflammation in the prostate, the frequency of which is 70%. Prerequisites for this include: venous stasis, ischemia, compression of the excretory ducts of the acini by hyperplastic tissue, and congestion. Concomitant chronic prostatitis may clinically manifest as dysuria, which requires differential diagnosis with urination disorders caused by BPH proper. In addition, its presence leads to an increase in the number of early and late postoperative complications, which necessitates targeted detection and treatment of chronic prostatitis during the preoperative preparation stage.

Another complication of BPH is macrohematuria. Its source is dilated, varicose veins of the bladder neck. Bladder stones in BPH form secondarily as a result of impaired bladder emptying. They can be single or multiple and usually have a regular rounded shape.

A frequent complication of BPH is acute urinary retention (AUR), which can occur at any stage of the disease. In some cases, it is the culmination of an obstructive process combined with decompensation of detrusor contractility; in others, AUR develops suddenly against the background of mildly expressed lower urinary tract symptoms, and sometimes it becomes the first clinical manifestation of BPH. Precipitating factors for AUR include: dietary indiscretions, alcohol intake or consumption of spicy foods, hypothermia, constipation, delayed bladder emptying, stressful states, intake of certain medications (anticholinergics, antidepressants, diuretics, calcium channel blockers, etc.), and prostate infarction. In the initial stage of AUR, intravesical pressure increases due to enhanced detrusor contractile activity. Subsequent decompensation makes the resolution of AUR unlikely [7].

1.3 Epidemiology of the Disease or Condition

Despite a large number of conducted studies, the true prevalence of BPH is difficult to determine due to the inaccuracy of the clinical definition of the disease. BPH is a condition inextricably linked with aging; it is frequently encountered in elderly men and may manifest at the age of 40 and older [8]. Due to the lack of uniform criteria for BPH used in epidemiological studies, data on the prevalence of the disease vary. In recent years, the term LUTS has gained increasing popularity, uniting various urinary disorders arising from a whole range of causes, including BPH. The prevalence of LUTS in men averages 62.5%. The majority of elderly men exhibit at least one LUTS. Storage symptoms are encountered, on average, in 51.3% of men, voiding symptoms in 25.7%, and post-micturition symptoms in 16.9% [13]. It should be borne in mind that LUTS are non-specific for BPH and are not always caused by prostate diseases. Various types of bladder dysfunction and other structural or functional changes of the urinary tract and surrounding tissues can manifest as LUTS [14]. Inflammation can also be accompanied by LUTS [15]. Furthermore, many non-urological conditions are capable of contributing to the development of LUTS, especially nocturia. The correlation between symptom severity according to the IPSS scale, uroflowmetry parameters, and residual urine volume is weak [16]. It is also important to bear in mind that the relationship between symptoms, prostate size, and urinary flow rate is extremely low [16].

Pathomorphological studies provide the most accurate picture. Autopsy studies show that BPH is extremely rare in men younger than 40 years, reaching 88% after 80 years of age [8]. Palpable enlargement of the prostate is detected in 20% of men aged 60–70 years and in 43% aged 80–90 years [7, 8]. According to population-based study results, moderate and severe lower urinary tract symptoms (LUTS) were observed in 13% of men aged 40–49 years and in 28% of those over 70 [8]. Other studies demonstrate similar results. The presence of LUTS and prostate enlargement determined by ultrasound was identified in 14% of men aged 40–49 years and in 43% aged 60–69 years [9]. During preventive examinations of men over 50 years of age, BPH is detected in 10–15%, and via ultrasound scanning in 30–40% within the same age group [10].

It is believed that BPH is observed slightly more frequently in Black men than in White men. A lower prevalence rate of BPH among residents of Eastern countries, primarily Japan and China, is associated with genetic factors as well as dietary characteristics containing a high amount of phytosterols [7, 9].

1.4 Features of Coding the Disease or Condition

N40 Hyperplasia of prostate.

1.5 Classification of the disease or condition

Currently, there is no universally accepted clinical classification of BPH. In practice, the three-stage Guyon classification [7] is sometimes used, which divides the clinical course of BPH into stages of compensation, subcompensation, and decompression:

• in stage I of the disease, patients experience urination disorders with complete bladder emptying;

• in stage II, bladder function is significantly impaired and residual urine appears;

• in stage III, complete decompensation of bladder function and paradoxical ischuria occur, along with complications affecting the kidneys and upper urinary tracts.

The drawback of this classification is its reliance on the volume of residual urine. A series of subsequent studies has shown that the presence of residual urine is not always associated with BPH, making the relevance of this classification low [11].

In clinical practice, four parameters are used to characterize BPH (severity of LUTS according to the IPSS questionnaire, prostate volume, amount of residual urine, and presence/absence of complications), without staging the disease.

1.6 Clinical presentation of the disease or condition

BPH is a slowly progressive disease whose clinical presentation is characterized by a "fluctuating" course and may be accompanied by periods of symptomatic deterioration, stabilization, or improvement. Individual features of the clinical presentation depend on changes in the size and configuration of hyperplastic nodules, the nature of bladder dysfunction, the degree of BOO, the development of secondary congestion, infection, and the development of complications [7].

Lower urinary tract symptoms (LUTS) were previously referred to as BPH symptoms (prostatic adenoma) or "prostatism." It has been proven that their occurrence is associated not only and not so much with prostate disease as with changes in bladder function. These symptoms occur with approximately equal frequency in elderly men and women. LUTS are subdivided into storage and voiding symptoms [2,4].

Storage symptoms were previously called irritative symptoms. They occur during the urine storage phase. These include: frequent urination in small portions, nocturia, urinary urgency, feeling of incomplete bladder emptying, and urinary incontinence. Such symptoms are common in elderly men and women. In addition to BPH, they may accompany a number of other pathological processes: chronic prostatitis and prostate cancer, inflammatory diseases and neoplasms of the bladder, and urinary tract infections. However, most overactive bladder (OAB) symptoms manifest as OAB, which may develop secondarily against the background of bladder outlet obstruction (BOO), but in some cases may be caused by other factors: bladder "aging," neurological status, and comorbidities [2,4]. The prevalence of OAB in men over 40 averages 15.6% and increases with age. This condition occurs with approximately equal frequency in elderly men and women [13, 19]. Nocturia is recorded in an average of 48.6% of men, and urgency in 10.8% [19]. Nocturia two or more times per night, causing distress, is observed in 30% of men aged 50-54 and 60% of men aged 70-78 [20]. It has been shown that significant dysuria manifested by small-volume urination during the day and night reliably correlates with symptom severity on the IPSS scale and quality of life score [21].

Voiding symptoms are associated with the act of urination. Previously, they were designated as obstructive. These include difficult and/or intermittent urination, weak urinary stream, straining to void, dribbling, and paradoxical ischuria. It has been established that such symptoms can be caused not only by BOO, but also by decreased contractility of the detrusor muscle [2,4].

The presence of morphological signs of BPH, as well as its enlargement determined by palpation or ultrasound, does not always correlate with the degree of clinical manifestations of the disease and BOO. Only 50% of men with morphological signs of BPH have a palpable prostate enlargement, and subsequently only half of them exhibit clinical manifestations of the disease requiring treatment. Moreover, prostate size may not correspond to the degree of urinary impairment and the severity of clinical symptoms [7].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis of BPH is based on complaints, medical history, physical examination data, and laboratory and instrumental methods. The use of diagnostic methods is necessary for diagnosis, monitoring, prognosis of disease progression, treatment planning, and prediction of treatment efficacy. Clinical examination of patients allows for the following tasks:

• perform differential diagnosis of the disease and confirm the diagnosis of BPH;

• determine the patient's clinical profile (including the severity of LUTS, voiding disorders, presence of complications, and assessment of disease progression risk);

• determine the optimal treatment tactics.

Criteria for establishing a BPH diagnosis

Main criteria for establishing a diagnosis of BPH [4,5,7]:

• pathomorphological - histological confirmation of the presence of BPH;

• clinical - benign enlargement of the prostate volume to more than 25 cm3.

Additional clinical criteria:

• presence of LUTS (varying severity);

• presence of BOO (varying severity);

• age over 40 years.

Comments: The average prostate weight in autopsies of men under 40 years of age was 20 + 6 grams [6]. Therefore, taking into account the tissue density of the prostate (~ 1 g/ml1), its volume not exceeding 20-25 cm³ is considered normal [12].

1 In the described study, prostate volume was measured in milliliters (ml)

2.1 Complaints and Anamnesis

The clinical presentation of BPH distinguishes symptoms associated with pathophysiological changes in the lower urinary tract, symptoms caused by secondary changes in the kidneys and upper urinary tracts, and the presence of complications. Patients most frequently complain of urinary disorders. Bladder dysfunction and urethral narrowing are the main factors determining the clinical manifestations of the disease. It may present as BOO, overactivity, or hypotonia [2,4,7].

When analyzing patient complaints, depending on the phase of urination, groups of storage, voiding, and post-micturition symptoms can be distinguished. Typical voiding symptoms: decreased urinary stream strength, difficult urination, hesitancy in initiating urination; need to strain the abdominal wall during urination, prolonged urination time, intermittent urination, dribbling, and paradoxical ischuria. Typical storage symptoms: frequent urination in small portions, urinary urgency, imperative urinary incontinence, nocturia.

Post-micturition symptoms: terminal or post-void dribbling, feeling of incomplete bladder emptying.

Comments: The International Prostate Symptom Score (IPSS) consists of eight questions, including seven symptom questions and one quality of life (QoL) question. Symptom severity is graded by the degree of impairment as: none (0 points), mild (1–7 points), moderate (8–19 points), and severe (20–35 points). The IPSS scale allows for a quantitative assessment of LUTS, determination of their predominant type, and evaluation of the patient's quality of life. The scale has high sensitivity (79%) and specificity (83%) [17]. At the same time, the IPSS scale does not allow for identifying patients with BOO [27]. Limitations of the IPSS scale are also related to the lack of assessment of bother for each symptom, as well as urinary incontinence and post-micturition symptoms [4,5].

• Patients with increased daytime and/or nighttime urination frequency are recommended to complete a "Frequency-Volume Chart" (Appendix A3) [21].

LoR CLoE 4Level of Recommendation C (Level of Evidence – 4)

Comments: the patient completes a bladder diary for at least 3 days, including information on the time of each micturition, volume of urine voided, volume and characteristics of fluid intake, presence of urinary urgency, episodes of urinary incontinence, and the need to interrupt sleep to empty the bladder [21,22]. Parameters that can be assessed using the bladder diary include micturition frequency, total diuresis volume, volume of each voided portion, and the ratio of daytime to nighttime diuresis. The 24-hour diuresis volume can vary significantly. The influence of circumstances and individual variations cause differences in bladder diary parameters. The bladder diary is particularly important in nocturia and allows for the differentiation of the patient's condition. It is simple to complete, cost-free, and complements the clinical picture by objectifying the patient's complaints, for example, distinguishing nocturia from nocturnal polyuria [23].

The IPSS score and bladder diaries allow for the assessment of lower urinary tract function and reduce subjectivity during patient interviews [18].

• When taking a medical history in patients with LUTS, it is recommended to identify comorbid conditions, including systemic and neurological disorders; information must be obtained regarding medications taken by the patient, previous surgeries, lifestyle-related factors, bad habits, and emotional and mental status [2,4,5,7].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: the purpose of taking a medical history is to identify potential causes of LUTS and clinically significant comorbidities, including systemic and neurological ones. In addition, it is necessary to obtain information on medications taken by the patient, previous surgical interventions, lifestyle-related factors, bad habits, and emotional and mental state. It is important to note any past episodes of acute urinary retention and hematuria. It is necessary to ascertain what treatment has been or is currently being administered for LUTS/BPH. The nature of comorbid conditions is clarified. Special attention is paid to conditions capable of causing urination disorders (multiple sclerosis, parkinsonism, cerebrovascular disorders, stroke, spinal cord diseases, diseases and injuries of the spine, diabetes mellitus, alcoholism, etc.). In addition, the patient's general health status and readiness for potential surgical interventions are assessed [7].

2.2 Physical Examination

Comments: During the physical examination of a patient with LUTS/BPH, the suprapubic region should be inspected and palpated to rule out bladder distension, along with the external genitalia; a rough assessment of motor function and skin sensation in the lower limbs should be performed to detect signs of concomitant neurogenic disorders [7]. Urethral discharge, phimosis, meatal stenosis, and penile cancer must be ruled out [2,4,5,7].

Comments: Digital rectal examination (DRE) makes it possible to determine the size, consistency, and configuration of the prostate gland, note its tenderness (in the presence of concomitant chronic prostatitis), changes in the seminal vesicles, and detect signs of prostate cancer (PCa). In one study, the authors concluded that DRE makes it possible to differentiate patients with a prostate volume > or < 50 cm³ [24]. During DRE, it is necessary to assess the tone of the rectal sphincter and the bulbocavernosus reflex, which may indicate the presence of neurogenic pelvic floor dysfunction [2,4,7]. DRE is classified as a mandatory examination method for men with BPH and LUTS [2,4].

DRE aids in the diagnosis of prostate cancer (PCa), and methods for quality control of the examination have been described [25]. Most cases of PCa are located in the peripheral zone of the prostate and can be detected by DRE when the tumor volume is ≥ 0.2 ml. In 18% of cases, PCa is detected only during DRE, regardless of the PSA level [43]. However, it has been shown that in men with suspected cancer during DRE, the diagnosis was confirmed in only one out of three cases [25].

2.3 Laboratory Diagnostics

Comments: A PSA level of 4 ng/ml is still conventionally considered the upper limit of normal, although many experts advocate for lowering it. The probability of having non-palpable PCa, including cases with a Gleason score > 7, is: 23.9% and 4.6% for a PSA of 2.1–3.0 ng/ml, and 26.9% and 6.7% for a PSA of 3.1–4.0 ng/ml, respectively [26].

The PSA level also depends on the patient's age and prostate volume. Additionally, calculated parameters such as PSA density, PSA velocity, PSA doubling time, and the free-to-total PSA ratio are used. Determination of the latter ratio should not be used when PSA > 10 ng/ml [27]. A digital rectal examination is performed on any urological patient during a prostate assessment, regardless of the PSA level. The presence of suspicious changes on digital examination in patients with a PSA level ≤ 2 ng/ml has a positive predictive value of 5–30% [28]. PSA is a better predictor of PCa compared to DRE or transrectal ultrasound [27]. PSA is an organ-specific, but not tumor-specific marker; therefore, it can be elevated in BPH, prostatitis, and other non-malignant conditions [29]. If PSA is elevated and/or palpable signs of PCa are present, further evaluation must be carried out in accordance with guidelines dedicated to PCa. A pooled analysis of placebo-controlled trials in BPH demonstrated that PSA levels correlate with prostate volume [30]. The value of PSA as a reliable predictor of clinical progression of BPH, the risk of acute urinary retention (AUR), and the need for surgical treatment has been demonstrated [31,32].

Comments: A complete urinalysis (with sediment microscopy (microscopic examination of urine sediment) or using test strips) makes it possible to detect urinary tract infection, proteinuria, hematuria, or glucosuria, which require further investigation taking into account guidelines on urinary tract cancers and urological infections [2,4]. Most guidelines recommend including urinalysis in the initial diagnostic workup for LUTS [2,4,5,33].

Comments: Blood creatinine level is determined to clarify the total functional state of the kidneys and to rule out renal failure. In one study, renal failure was detected in 11% of patients with LUTS / BPH [33]. A large epidemiological study observed a correlation between BOO signs and symptoms and chronic kidney disease [35]. Another study demonstrated that maximum urinary flow rate (Qmax) correlates with the glomerular filtration rate in middle-aged men with moderate to severe LUTS [36]. Hydronephrosis, renal failure, or urinary retention are more common in patients with BOO signs and symptoms [34]. Although BOO may partially contribute to these complications, there is no convincing evidence that obstruction is the primary cause. The most likely reasons for elevated creatinine levels in these patients may be diabetes mellitus and arterial hypertension. Thus, in patients with LUTS, a decrease in Qmax and a history of arterial hypertension and/or diabetes mellitus were associated with chronic kidney disease [37]. Published results of a study indicate that voiding phase symptoms of non-neurogenic etiology are not a risk factor for elevated creatinine levels, and symptom score and quality of life indices do not correlate with blood creatinine levels [38]. Nevertheless, patients with renal failure have an increased risk of postoperative complications, which justifies the inclusion of blood creatinine determination in the evaluation program for patients with LUTS / BPH [39].

2.4 Instrumental Diagnostics

Instrumental diagnostic methods include imaging, functional, and endoscopic diagnostics.

Comments: The study evaluates the size (volume), configuration, echographic tissue characteristics of the prostate, intraprostatic lesions (nodular structures, cysts, stones), and inclusions. Attention is paid to the presence of the median lobe and intravesical prostatic protrusion. Some specialists separately calculate the prostate volume and the volume of hyperplastic nodules. Ultrasound allows suspecting the presence of prostate cancer and chronic prostatitis. Changes in the bladder wall, its trabeculation, and the presence of diverticula or pseudodiverticulosis are recorded. The method makes it possible to detect bladder stones and concomitant bladder neoplasms [7]. There is no correlation between the IPSS score and prostate volume [16]. Assessment of prostate size is important for choosing a surgical treatment method, such as open prostatectomy, enucleation, transurethral resection, or minimally invasive methods. Prostate size is also important before prescribing 5-ARIs. Prostate size allows predicting symptom progression and complication risk [40].

Comments: TRUS makes it possible to assess in detail the condition and growth direction of the prostate, make accurate measurements of its size and volume (including by zones), separately calculate the volume of hyperplastic nodules, and detect ultrasound signs of prostate cancer, chronic prostatitis, and prostate sclerosis. TRUS is superior to transabdominal ultrasound in measuring prostate volume. The results of the study can be used when planning conservative or surgical treatment tactics. Detecting an enlarged median lobe of the prostate is of fundamental importance, since the rapid progression of BOO in these patients makes the use of conservative treatments unpromising [2,4,7].

Comments: Post-void residual (PVR) volume can be determined using transabdominal ultrasound or catheterization. The presence of residual urine is not always associated with BOO, as elevated PVR can be a consequence of either obstruction or poor detrusor contractility (detrusor underactivity) [42,43]. At a volume of 50 ml, the positive and negative predictive values of PVR in determining BOO are 63% and 52%, respectively [44]. A large PVR is not considered a contraindication to watchful waiting or medical therapy, although it may reflect bladder dysfunction and predict a poor response to treatment. In a number of studies, a large baseline PVR correlated with an increased risk of worsening symptoms [31]. Assessing changes in PVR helps identify patients at risk for acute urinary retention [31]. This is especially important when treating patients receiving antimuscarinics. Conversely, baseline PVR has a low predictive value in determining the risk of invasive treatment in patients receiving α1-blockers [45]. However, due to the high variability of repeated test results, a PVR threshold for deciding on a particular type of treatment has not yet been established [4,5].

Comments: The study allows visualizing the kidneys and upper urinary tracts, determining kidney size, the state of their parenchyma, the presence of pathological changes in the kidneys (stones, tumors, etc.), and detecting dilatation of the pelvicalyceal system. International guidelines prescribe performing a kidney ultrasound according to indications: in case of a large post-void residual volume, hematuria, or urolithiasis [2, 4, 5]. This is because in men with LUTS, the risk of upper urinary tract malignancies or other changes does not exceed the rates in the general population [4, 5]. A number of arguments are made in favor of performing ultrasound instead of excretory urography. Ultrasound provides a better description of kidney formations, the ability to examine the liver and retroperitoneal space, and simultaneous assessment of the urinary bladder, PVR, and prostate, along with a lower cost, complication rate, and the absence of radiation exposure [40]. Given the current state of the domestic healthcare system and the large number of insufficiently examined elderly patients [46], it was decided to include ultrasound of the kidneys and upper urinary tracts in the primary examination program for patients with LUTS / BPH.

Comments: Uroflowmetry is a widely used, basic, non-invasive, and inexpensive urodynamic method that allows an objective assessment of urination characteristics. The method is based on the graphic recording of changes in volumetric urine flow rate. Most commonly, UFM data are evaluated using the maximum urine flow rate (Qmax), average flow rate (Qave), voided volume (Vcomp), and the type of uroflowmetric curve (normal, obstructive, non-obstructive, equivocal). UFM parameters depend on the voiding volume, patient age, and the conditions under which the study is performed, and may vary. To obtain more reliable data, it is recommended to perform UFM at least twice, under conditions of functional bladder filling (150–350 ml), when a natural urge to urinate occurs [47, 48]. Qmax values exceeding 15 ml/s are considered normal for patients with BPH. A decrease in Qmax to 10–15 ml/s is regarded as a moderate impairment, and below 10 ml/s as significant. At the same time, UFM results alone do not allow for a reliable conclusion regarding the presence or absence of BOO. This is especially true for the group of patients with a Qmax of 10–15 ml/s, where the number of patients with and without BOO was approximately equal. A low Qmax may be the result of BOO, detrusor underactivity, or inadequate bladder filling [49]. The diagnostic accuracy of UFM in detecting BOO varies significantly and largely depends on the chosen threshold values. At a Qmax threshold of 10 ml/s, the specificity of the method for BOO is 70%, the positive predictive value is 70%, and the sensitivity is 47%. The specificity at a Qmax threshold of 15 ml/s is 38%, the positive predictive value is 67%, and the sensitivity is 82% [50]. Even if Qmax is greater than 15 ml/s, BOO cannot be completely ruled out, given the potential physiological compensatory processes. Therefore, the value of UFM as a diagnostic method is limited, as it does not identify the cause of the decreased Qmax. UFM should be performed before prescribing medical or surgical treatment and subsequently used to evaluate its efficacy [2, 4, 5]. It is advisable to determine the post-void residual urine volume by ultrasound following uroflowmetry [2, 4, 5].

Comments: In men with LUTS/BPH, the most widely used methods are filling cystometry and pressure-flow studies. The main objectives of VRS include studying the functional mechanisms of LUTS and identifying potential risk factors for unfavorable treatment outcomes (to make an informed decision). When examining patients with LUTS, the following main types of lower urinary tract urodynamic disorders may be detected: mechanical BOO (caused by BPH growth); dynamic functional obstruction (caused by spasm of the smooth muscle elements of the bladder neck, prostate, and prostatic urethra); decreased detrusor contractility; detrusor overactivity; neurogenic detrusor overactivity [2, 4, 7]. The pressure-flow study is the only method that allows separating men with a low maximum urine flow rate due to detrusor dysfunction from patients with true BOO [2, 4, 6].

Indications for urodynamic studies (UDS): patient age under 50 years; voided volume on uroflowmetry less than 150 ml; post-void residual urine volume of 300 ml or more; Qmax $\ge$ 15 ml/s in patients presenting with LUTS; suspected neurogenic bladder dysfunction and/obin presence of neuropathy; persistence of LUTS following surgical treatment of BPH; failure of conservative therapy [2,4]. Performing UDS is advisable when planning surgical treatment in men with a history of clinical or suspected subclinical pathology of the central and peripheral nervous system (diabetic polyneuropathy, cerebral or spinal circulatory disorders, Parkinson's disease, multiple sclerosis, lumbosacral disc herniation/pathology, etc.). UDS makes it possible to differentiate the causes of voiding dysfunction: bladder outlet obstruction (BOO), impaired detrusor contractility, and complex neurogenic voiding disorders such as detrusor overactivity, impaired bladder sensation, detrusor underactivity, detrusor-sphincter dyssynergia, etc. The pressure-flow study makes it possible to diagnose BOO, which is characterized by increased detrusor pressure and decreased urine flow rate during voiding. BOO in benign prostatic obstruction must be differentiated from detrusor underactivity, which manifests as decreased detrusor pressure during voiding combined with a reduced urine flow rate [8]. A correlation between BOO and detrusor overactivity has been described [51]. In men with LUTS associated with benign prostatic enlargement, detrusor overactivity is observed in 61% of cases. This parameter correlates independently with the degree of BOO and age [51]. The prevalence of detrusor underactivity in men with LUTS is approximately 11–40% [52]. It is believed that detrusor contractility does not significantly decrease during long-standing BOO, and surgical relief of BOO does not improve contractility [53]. There are no published randomized controlled trials in the literature describing men with LUTS and suspected BOO comparing standard diagnostic methods (uroflowmetry and PVR measurement) with pressure-flow studies [4,5]. Performing UDS prior to surgery influences treatment tactics, helping to reduce the number of surgical interventions, but does not decrease the number of men with persistent LUTS after surgery [54]. Urodynamic methods are of particular importance when examining patients with a history of clinical or subclinical CNS pathology combined with prostate enlargement. Detailed urodynamic studies in this category of patients can help determine the contribution of existing neurogenic disorders to BPH symptoms [2,4]. Nevertheless, universally accepted indications for UDS in patients with LUTS/BPH have not been established to date. Due to the invasive nature of urodynamic studies, they are generally not performed during the initial evaluation, but rather when a change in treatment strategy is required due to insufficient efficacy. Various approaches to prescribing pressure-flow studies in men aged > 80 and < 50 years are proposed, reflecting a lack of convincing clinical trial data and expert consensus. Furthermore, a consensus has not been reached regarding pre-operative UDS in men with predominantly storage/voiding symptoms and Qmax > 10 ml/s. At the same time, experts acknowledge that when Qmax < 10 ml/s, the presence of BOO is highly probable, and a pressure-flow study is not mandatory [4,5]. Patients with comorbid neurological diseases, including those with a history of pelvic surgery, should be evaluated according to neurourology guidelines [55].

Comments: Urethrocystoscopy is not a routine examination method for patients with LUTS and suspected BPH. It is considered indicated in the presence of a history of micro- or macrohematuria, urethral stricture, bladder cancer, long-standing bladder infection, or when ultrasound reveals changes in the bladder wall, to rule out neoplasms [2, 4]. The necessity for endoscopic examination is determined on a case-by-case basis depending on the clinical situation. In some cases, pronounced changes in the detrusor resulting from hypertrophy, trabeculation, diverticulosis, or stone formation do not allow bladder tumors to be ruled out, which is an indication for an endoscopic examination. A correlation has been established between the cystoscopic picture (degree of bladder trabeculation and urethral obstruction) and urodynamic parameters, detrusor overactivity, and low bladder compliance. However, it should be noted that approximately 15% of patients with normal cystoscopy findings were diagnosed with BOO, and 8% of patients had no obstruction even in the presence of pronounced trabeculation [56].

Comments: Voiding cystourethrography is not performed during routine evaluation of men with LUTS. Nevertheless, in selected patients, voiding cystourethrography makes it possible to diagnose vesicoureteral reflux, bladder diverticula, or pathological urethral changes. Retrograde urethrography is indicated when urethral stricture is suspected [2, 4].

Comments: Plain and excretory urography are not considered mandatory examinations in patients with BPH and are performed selectively in the presence of urinary tract infections, urolithiasis, a history of urinary tract surgeries, suspected urinary tract tumors, or hematuria [2, 4].

Comments: These examinations are prescribed only in diagnostically complex cases to rule out prostate cancer, urinary tract tumors, and other conditions [2, 4].

2.5 Other Procedures

In the majority of elderly and senile men presenting with frequent and difficult urination, weak urinary stream, and urgency, when prostate enlargement is detected during palpation and ultrasound, the diagnosis of BPH is unquestionable. However, in 16–20% of patients, such symptoms are not associated with prostatic hyperplasia. Differential diagnosis of BPH should be carried out with obstructive and non-obstructive processes of other etiologies that present with similar clinical symptoms. For storage symptoms, these are: urinary infection, prostatitis, detrusor overactivity, bladder cancer, foreign body (stone) in the bladder, and lower ureteral stone. For voiding symptoms, these are: urethral stricture, bladder neck and prostate sclerosis, impaired detrusor contractility, and prostate cancer [2, 4].

A thorough study of the patient's history and complaints, as well as the methodologically correct application of recommended research methods, makes it possible to perform a differential diagnosis and avoid diagnostic errors.

It has been established that in men with LUTS, the risk of urogenital malignancies does not exceed that of the general population [4]. Nevertheless, the proposed examination program for patients with LUTS allows for the diagnosis of potential concomitant oncological diseases. Thus, physical examination can diagnose prostate cancer, neoplasms of the male genital organs, and the rectum. Ultrasound examination of the urogenital system may reveal renal cancer, bladder cancer, and prostate cancer. An elevated PSA level will contribute to the detection of prostate cancer, while the presence of microhematuria may indicate cancer of the bladder, upper urinary tract, and kidneys.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

3.1.1 Non-pharmacological treatment

3.1.1.1 Watchful waiting

• Watchful waiting (WW) is recommended for patients with uncomplicated mild-to-moderate LUTS who are not bothered by their symptoms [58].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Many men with LUTS are not bothered enough by their symptoms to require medical or surgical treatment. All patients with LUTS must be evaluated prior to initiating any treatment to assess LUTS severity and to differentiate the vast majority of patients with so-called uncomplicated LUTS, which are not life-threatening, from the rarer patients with complicated LUTS. WW is considered a reasonable option for many men with mild symptoms, since only a fraction of untreated patients will develop AUR and complications such as renal failure or stones, while other men have stable symptoms during a year of follow-up [57].

3.1.1.2 Behavioral therapy

Behavioral therapy includes providing the patient with necessary information about their condition and lifestyle modifications that can lead to an improvement in the clinical picture of the disease.

Comments: Behavioral therapy is administered to patients with moderate symptoms as a primary treatment method or as an adjunct to pharmacotherapy. Lifestyle modification is necessary before starting therapy or concurrently with primary therapy. Follow-up examinations by a urologist every 6–12 months. The watchful waiting approach in BPH consists of patient education, active surveillance, and lifestyle modification recommendations (behavioral therapy) [58].

• The following measures are recommended for the patient during behavioral therapy:

– fluid restriction during specific periods to reduce urination frequency at the least convenient times (at night or before visiting public places);

– avoiding or correcting the intake of caffeine or alcohol, which may have diuretic and irritant effects, thereby increasing diuresis and urination frequency, and exacerbating urgency and nocturia;

– using relaxed and double voiding techniques;

– massage of the bulbar urethra to prevent post-micturition dribbling;

– interruption techniques, such as penile glans squeezing, breathing exercises, perineal compression, and psychological tricks to distract from the bladder and toilet, for better control of storage symptoms;

– bladder training, which helps suppress the urge when sensory urgency occurs, to increase bladder capacity and intervals between voids;

– review of medications and optimization of administration times or switching to alternative drugs with fewer urinary tract side effects; these recommendations are particularly applicable to diuretics [58, 59].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

3.1.2 Pharmacotherapy

3.1.2.1 Alpha-blockers

α1-blockers block the action of endogenously released norepinephrine on α1A-adrenoceptors of prostate smooth muscle cells, thereby decreasing the tone of the prostate smooth muscle stroma and reducing BOO severity.

Comments: international data indicate a 30–40% reduction in IPSS score and an increase in maximum urinary flow rate of approximately 20–25% with the use of α1-blockers. These drugs can reduce the severity of both storage and voiding symptoms. The efficacy of α1-blockers does not depend on prostate size or patient age, but with long-term follow-up their efficacy is higher in patients with a smaller gland volume [60].

Given the progressive nature of this disease, pharmacotherapy for LUTS should be administered long-term (sometimes for the patient's lifetime). Depending on whether voiding or storage symptoms predominate, pharmacotherapy may differ significantly [61].

α1-blockers have no adverse effect on libido, slightly improve erectile function, but sometimes lead to ejaculation disorders [220].

This group of drugs is represented by 5 medications, whose efficacy when prescribed in the doses below is identical. The drugs differ in their safety profile—the probability of developing side effects, the most frequent of which is blood pressure decrease. Their efficacy when prescribed in adequate doses (maximum dosages for titratable drugs) is identical. In long-term studies, they have not demonstrated the ability to prevent BPH progression, do not reduce the likelihood of acute urinary retention, do not affect prostate volume, and do not prevent the gradual increase in prostate size [59-61].

• Tamsulosin** at a dose of 0.4 mg/day. Tamsulosin**-based medications have a favorable safety profile and ease of administration (do not require dose titration, taken once daily).

• Alfuzosin** is prescribed at a dose of 10 mg/day and also has a high level of safety.

• Silodosin is used at a dose of 8 mg once daily. The drug has a higher selectivity for prostate α1A-adrenoceptors compared to vascular smooth muscle α1B-adrenoceptors and selectivity for α1A-subtype receptors compared to α1B and α1D subtypes [62]. When prescribing the drug, one should consider the fact that more than 20% of patients experience ejaculation disorders during silodosin treatment. The effect is transient, disappears shortly after drug discontinuation, and is very rarely the reason for treatment refusal in patients with LUTS secondary to BPH.

• Terazosin is an α-blocker that may cause a slight decrease in blood pressure. The drug dose is increased gradually from 1 to 10 mg/day and is taken preferably at bedtime.

• Doxazosin** also belongs to drugs requiring dose titration. The drug is prescribed starting at 1 mg/day, gradually increasing the dose to 8 mg/day. Blood pressure levels should also be monitored when prescribing it.

Testosterone 5-alpha-reductase inhibitors Drugs of this group block the enzyme that promotes the conversion of testosterone in the prostate into its active hormonal form—dihydrotestosterone, thereby exerting a peripheral antiandrogenic effect on prostate tissue. The 5-AR enzyme exists in two isoforms: 5-AR type 1, expressed in small amounts and poorly active in the prostate, but providing the major part of enzyme activity in other tissues, such as skin and liver; 5-AR type 2, expressed and acting mainly in the prostate.

Comments: if well tolerated, these drugs must be taken long-term or for life, since their therapeutic effect begins to manifest no earlier than 6–12 months after treatment initiation [65]. Short courses of testosterone 5-alpha-reductase inhibitors are not justified. Testosterone 5-alpha-reductase inhibitors are the only group of drugs that reduce prostate volume. After 2–4 years of 5-AR inhibitor therapy in patients with LUTS caused by prostate enlargement, symptom severity (by IPSS) decreases by approximately 15–30%, prostate volume by approximately 18–28%, and maximum urinary flow rate increases by approximately 1.5–2.0 ml/s. [67,86,87]

With continuous long-term use, 5α-reductase inhibitors reduce the risk of surgical intervention and acute urinary retention [66,67].

• Finasteride** (inhibits type 1 testosterone 5-alpha-reductase) is prescribed at a dose of 5 mg/day

• Dutasteride (inhibits type 1 and type 2 testosterone 5-alpha-reductase) is prescribed at a dose of 0.5 mg/day

The most frequent adverse effect of drugs in this group is impaired sexual function. Recent studies have demonstrated that the severity of this effect decreases after one year of continuous drug administration [68,69]. It is important to remember that testosterone 5-alpha-reductase inhibitors reduce serum PSA concentration by half, which is of great importance for the diagnosis of prostate cancer. During therapy with drugs of this pharmacological group, laboratory PSA values should be doubled to obtain the true value [70].

3.1.2.3 Muscarinic receptor antagonists (included in the ATC group G04BD — Urologicals, drugs used in frequent urination and urinary incontinence)

Comment: The detrusor is innervated by parasympathetic nerves, the main neurotransmitter of which is acetylcholine, which has the ability to stimulate muscarinic receptors (M-cholinergic receptors) on the surface of smooth muscle cells. However, muscarinic receptors are densely expressed not only on smooth muscle cells, but also on other cell types, such as the transitional cell epithelium of the urinary bladder. Five subtypes of muscarinic receptors (M1–M5) have been described in humans, of which the M2 and M3 subtypes are predominantly present in the detrusor. Although the majority of receptors belong to the M2 subtype, the M3 subtype plays a functionally more important role in detrusor contraction in healthy individuals. Drugs with antimuscarinic activity allow influencing the contractile activity of the bladder and reducing the severity of spontaneous detrusor contractions observed in OAB [71]. Their administration is accompanied by positive dynamics regarding nocturia, daytime urinary frequency, and urgency severity. A certain decrease in the IPSS score is also noted. Their main mechanism of action is blocking conduction along the fibers of the parasympathetic nervous system. The following muscarinic receptor antagonists (G04BD Urologicals, drugs used in frequent urination and urinary incontinence) are approved for the treatment of OAB/storage symptoms: fesoterodine; oxybutynin; solifenacin**; tolterodine and trospium chloride. The use of drugs from this pharmacotherapeutic group requires ultrasound monitoring of the post-void residual urine volume [73].

Treatment-related adverse events include dry mouth (up to 16% of cases), constipation (up to 4%), dysuria (up to 2%), nasopharyngitis (up to 3%), and dizziness (up to 5%). Drug therapy with muscarinic receptor antagonists (G04BD Urologicals, drugs used in frequent urination and urinary incontinence) may be accompanied by worsening of cognitive dysfunction. This is especially typical for patients over 65 years of age who experience increased permeability of the blood-brain barrier. These drugs should be used with caution in patients receiving other agents with anticholinergic activity [221]. Muscarinic receptor antagonists (G04BD Urologicals, drugs used in frequent urination and urinary incontinence) can be prescribed as first-line therapy in patients with pronounced storage phase urinary disorders in the absence of or with minimal voiding phase disorders. Another official indication for their prescription is persistent LUTS after one month of continuous therapy with alpha-blockers at an active therapeutic dosage. Muscarinic receptor antagonists (G04BD Urologicals, drugs used in frequent urination and urinary incontinence) have been the drugs of "choice" in the treatment of overactive bladder for over 20 years [71].

• Muscarinic receptor antagonists (G04BD Urologicals, drugs used in frequent urination and urinary incontinence) are recommended to be used with caution in patients with bladder outlet obstruction [72].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: The prescription of muscarinic receptor antagonists (G04BD Urologicals, drugs used in frequent urination and urinary incontinence) in patients with severe bladder outlet obstruction and a large amount of post-void residual urine is not indicated due to the risk of acute urinary retention [71]. In other patients, the probability of developing acute urinary retention during therapy with these drugs does not exceed 1 case per 10,000 prescriptions [73].

3.1.2.4 Beta-3 adrenergic receptor agonists (included in the ATC group G04BD — Urologicals, drugs used in frequent urination and urinary incontinence)

Beta-3 adrenergic receptors are the predominant type of beta receptors expressed in detrusor smooth muscle cells, and their stimulation causes detrusor relaxation. Mirabegron at a dose of 50 mg became the first beta-3 adrenergic receptor agonist available for clinical practice, approved for the treatment of OAB in adults. It should be understood that OAB coexists with LUTS/BPH in more than half of cases, is often a consequence of BOO, and is the cause of most "storage phase" urinary disorders. The efficacy of mirabegron was studied in three 12-week RCTs conducted in Europe, Australia, and North America [74,75]. The results demonstrated the efficacy of mirabegron regarding OAB symptoms, including urinary frequency, urge urinary incontinence, urgency, and patient perception of treatment benefit. An Asian study with a higher proportion of men (approximately 1/3) described the superiority of mirabegron over placebo in reducing urinary frequency [76].

Based on the evaluation of urodynamic parameters in men with coexisting BOO and OAB, it has been proven that mirabegron has no adverse effect on urodynamic parameters compared to placebo regarding $Q_{max}$, detrusor pressure at $Q_{max}$, and bladder contractility index [77,78].

According to a pooled analysis of three 12-week trials and one 1-year trial, in patients older than 65 years, mirabegron has a more favorable safety profile compared to muscarinic receptor antagonists [222]. In a retrospective analysis of treatment duration and persistence involving 21,996 patients (30% men), the median time to discontinuation was higher in the mirabegron group (169 days) compared to tolterodine (56 days) and other muscarinic receptor antagonists (30–78 days) (p <0.0001). The authors found no differences in treatment persistence between men and women [224].

Phase IV study PILLAR demonstrated the safety and efficacy of mirabegron 50 mg in 888 patients aged over 65 years (approximately 30% men) [223]. Mirabegron is contraindicated in patients with severe uncontrolled hypertension (systolic blood pressure >180 mm Hg, or diastolic >110 mm Hg, or both).

Comments: Mirabegron is contraindicated in patients with severe uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic >110 mm Hg or both). Before initiating therapy, it is necessary to measure blood pressure and monitor it at regular intervals. The proportion of patients with dry mouth and constipation in the mirabegron group is significantly lower than the rates in RCTs of other OAB drugs or in the active control group [77].

3.1.2.5 Phosphodiesterase type 5 inhibitors (PDE5 inhibitors) (included in the ATC group G04CB — Testosterone 5-alpha-reductase inhibitors)

Comments: Phosphodiesterase type 5 inhibitors (PDE5is) have been successfully used in recent years not only for the treatment of erectile dysfunction, but also in patients with lower urinary tract symptoms (LUTS). By increasing intracellular cyclic guanosine monophosphate concentrations, drugs of this pharmacological group reduce the smooth muscle tone of the detrusor, prostate, and urethra [79]. Another proven mechanism of their action on the pelvic organs is improved blood flow in this area [80]. They also help reduce the activity of chronic inflammatory processes in the prostate and bladder [81]. The only drug from this group officially approved for the treatment of LUTS in patients with BPH is tadalafil, prescribed daily at a dosage of 5 mg/day. It causes a 22–37% reduction in the IPSS score by alleviating both symptom groups—voiding and storage phases. At the same time, no significant change in the maximum urinary flow rate was registered in most conducted studies [82, 83]. A Cochrane review including 16 RCTs compared the effects of PDE5is, placebo, and other standard drugs (α1-blockers and 5-ARI) in men with LUTS. According to this meta-analysis, PDE5is show a slight reduction in the IPSS score compared to placebo (mean difference 1.89, 95% CI 2.27–1.50; n = 4293) [224].

Tadalafil can be prescribed as monotherapy or in combination with α-blockers. A safe combination is its simultaneous administration with tamsulosin or silodosin. Combination therapy improves the

IPSS score (-1.8), IIEF score (+3.6), and Qmax (+1.5 mL/s) compared to α1-blocker monotherapy [225]. Information on the effect of PDE5is on prostate volume and disease progression risk is lacking [82].

A standard contraindication to prescribing PDE5is due to a high risk of hypotension is their combination with nitrates. In addition, they are contraindicated in patients with myocardial infarction within the last 3 months, unstable angina, or angina occurring during sexual activity (New York Heart Association class II heart failure or higher within the last 6 months), patients with uncontrolled arrhythmias, arterial hypotension (<90/50 mm Hg) or poorly controlled blood pressure, and stroke (within the last 6 months) [226].

3.1.2.5 Phosphodiesterase type 5 (PDE5) inhibitors (included in the ATC group G04CB -...

Herbal medicinal products are made from roots, seeds, pollen, and bark, and can be derived from extracts of a single plant (monocomponent preparations) or two or more plants (combination preparations). The most important constituents of herbal preparations are phytosterols, β-sitosterol, fatty acids, and lectins [84]. In vitro studies have shown that they possess anti-inflammatory, anti-androgen, antiproliferative, and estrogenic activities; affect α-adrenoceptors and muscarinic acetylcholine receptors; reduce sex hormone-binding globulin levels; and inhibit aromatase, lipoxygenase, fibroblast growth factors (FGF), along with many other mechanisms of action. Most of these properties have not been confirmed in vivo, and the exact mechanism of action of herbal preparations remains incompletely understood [85].

Efficacy: extracts of the same plant produced by different companies do not always have identical biological or clinical properties, so the efficacy of the same drug manufactured by different producers may vary. Furthermore, even two different batches of a drug made by the same manufacturer may contain varying concentrations of active ingredients [227]. According to the interpretation by the Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency (EMA), only the hexane extract of Serenoa repens has been granted the status of "well-established medicinal use". Other Serenoa repens-derived preparations that have also shown clinical efficacy in limited clinical studies have been assigned the HMPC "traditional use" status, which means there are sufficient data on safety and probable efficacy based on long-standing use and experience. The results of systematic reviews indicate a good safety and tolerability profile. Gastrointestinal adverse events are the most common among patients (mean frequency 3.8%). Serenoa repens extract has a minimal impact on sexual function. [84]

Comments: A large meta-analysis of 30 RCTs (n = 5222) with a follow-up duration of 4 to 60 weeks showed no efficacy of Serenoa repens compared with placebo in reducing LUTS severity [228]. Another systematic review analyzed 12 RCTs on the efficacy and safety of hexanic extract of Serenoa repens [229]. According to this meta-analysis, the hexanic extract of Serenoa repens is superior to placebo in reducing nocturia episodes and improving Qmax in patients with enlarged prostate volume. The reduction in LUTS severity is comparable to tamsulosin** and a short course of finasteride**. In an updated systematic review, compared with placebo, the phytotherapy group experienced a reduction in nocturia episodes by 0.64 (95% CI 0.98–0.31), and the mean increase in Qmax was 2.75 mL/s (95% CI 0.57–4.93). Serenoa repens extract causes a comparable improvement in the IPSS score compared to α1-blockers (weighted mean difference 0.57, 95% CI 0.27–1.42) and an increase in Qmax compared to tamsulosin** (weighted mean difference 0.02, 95% CI 0.71–0.66) [230].

The works of Russian authors present a three-year experience with the use of ethanolic extract of Serenoa repens in 50 patients with early manifestations and risk factors for BPH progression and in the same number of control subjects. A decrease in IPSS symptoms and an improvement in the quality of life of patients in the main group compared to the control were demonstrated. Prostate volume in the group of patients taking ethanolic extract of Serenoa repens significantly decreased, while PSA levels remained unchanged [243]. A 15-year observational study provided data showing no progression of BPH during the use of ethanolic extract of Serenoa repens, with no reported side effects [244].

3.1.2.6 Herbal medicinal products

Comments: Desmopressin** is a synthetic analogue of the antidiuretic hormone that significantly increases tubular reabsorption in the kidneys and reduces urine output. The drug is an effective method for managing nocturia if nocturnal polyuria is the underlying cause. Desmopressin** has no effect on all other LUTS. Desmopressin** enhances water reabsorption and urine osmolarity, decreases water excretion, and reduces total urine volume. It should be used with caution, monitoring serum sodium levels at 3 days, 1 week, and 1 month after initiating treatment, and every 3–6 months thereafter during continuous therapy. It is advisable to prescribe this drug after consultation with and under the supervision of a general practitioner [86].

3.1.2.7 Vasopressin analogues

3.1.3.1 Combined use of testosterone 5-alpha-reductase inhibitors and alpha-blockers.

Comments: This is the optimal medical therapy for patients at high risk of disease progression: patients with moderate to severe BPH symptoms. Before starting treatment, the long-term nature of such therapy (more than 12 months) must be discussed with the patient. In patients with moderately severe LUTS, the possibility of subsequent withdrawal of the alpha-blocker (no earlier than 6 months later) may be considered [89].

Recent studies have proven the complex pathogenesis of voiding disorders in patients with BPH. The causes of urinary disturbances are bladder outlet obstruction and impaired detrusor function. Information was cited above regarding the ability of testosterone 5-alpha-reductase inhibitors to reduce the risk of BPH progression. The mechanism of action of alpha-adrenoceptor blockers is based on the relaxation of the smooth muscle of the bladder neck and urethra through the blockade of alpha1-adrenoceptors and the elimination of the dynamic component of bladder outlet obstruction. The combined prescription of drugs from two different pharmacological groups allows for targeting the complex mechanisms of LUTS pathogenesis and producing a significant improvement in the quality of life of BPH patients [67,87]. The most significant results in this field have been achieved through the MTOPS and CombAT studies [67,86,87]. In the former, the risk of BPH progression with combination therapy of finasteride and doxazosin was 64% lower than in the placebo group, and the likelihood of surgical intervention was 67% lower. The results of 4-year combination therapy with dual testosterone 5-alpha-reductase inhibitors—dutasteride and the superselective alpha-adrenoceptor blocker tamsulosin** (CombAT study)—showed that the overall risk of BPH progression decreased by 41%, the likelihood of acute urinary retention by 68%, and the need for surgical intervention by 71%. It should be noted that CombAT is a unique study that included patients at high risk for BPH progression. MTOPS and CombAT proved the definitive superiority of long-term combination therapy over monotherapy with a testosterone 5-alpha-reductase inhibitor or an alpha-adrenoceptor blocker across all studied parameters—LUTS dynamics, quality of life score, and the risk of disease progression. Moreover, the efficacy of combination therapy was proven for all patients included in the study, regardless of baseline data (initial symptom severity, baseline prostate volume, prior therapy, patient age, baseline PSA value, and other factors) [67,86,87] and prevents disease progression. However, combination therapy is accompanied not only by higher efficacy but also by a greater risk of adverse events; therefore, it is indicated primarily for men with moderate or severe LUTS and a risk of disease progression (high prostate volume, elevated PSA level, advanced age, high PVR, low Qmax, etc.).

3.1.3.2 Combined use of alpha-blockers and muscarinic receptor antagonists (included in ATC group G04BD - Drugs for urinary frequency and incontinence)

A number of RCTs and prospective studies have evaluated the efficacy of combining alpha-blockers and muscarinic receptor antagonists (G04BD: Drugs for urinary frequency and incontinence) both as initial therapy in men with OAB and suspected BOO, and as sequential therapy in men with persistent storage symptoms despite α-blocker treatment. Combination therapy is more effective in reducing the severity of urgency, urinary frequency, nocturia, IPSS score, and quality of life compared to alpha-blocker monotherapy or placebo [90]. The results of two systematic reviews on the efficacy and safety of anticholinergics indicate the effectiveness of such combination therapy [91,92]. In most publications over the last 5 years, tamsulosin**, silodosin, or doxazosin** has been used as the alpha-blocker, while tolterodine and solifenacin** have been used as the muscarinic receptor antagonists (G04BD Drugs for urinary frequency and incontinence) [91].

Administration of a fixed-dose combination containing solifenacin** (6 mg) and tamsulosin** (0.4 mg) demonstrated a reduction in bother from OAB symptoms in >80% of patients with LUTS who had persistent symptoms on monotherapy, with high treatment adherence (77% from week 40 to 52) and a low risk of AUR [231]. According to an RCT comparing combined behavioral strategies and pharmacotherapy for OAB symptoms in men, behavioral therapy enhances the efficacy of drug therapy, despite the lack of a reverse dependency [232]

Comments: In patients with pronounced bladder outlet obstruction, this treatment should be prescribed with caution and under the control of post-void residual urine volume measurement [93].

To understand the pathogenesis of LUTS, the theory explaining the role of the urinary bladder muscle (detrusor) in the formation of voiding symptoms is of certain interest. It has been proven that spontaneous detrusor contractions lead to frequent and sometimes imperative urges to urinate. This constellation of storage phase symptoms is encompassed by the term "overactive bladder". The high probability of OAB in patients with BPH accounts for the efficacy of the combined use of an alpha-blocker and agents with antimuscarinic activity. The first class of drugs effectively relieves the symptoms of bladder outlet obstruction, while the second can significantly reduce the severity of storage symptoms.

3.1.3.3 Combined use of alpha-blockers and beta-3 adrenergic receptor agonists (included in ATC group G04BD Drugs for urinary frequency and incontinence)

Combination therapy with α-blockers and beta-3 adrenergic receptor agonists (G04BD Drugs for urinary frequency and incontinence) demonstrated an improvement in the OAB symptom score, a reduction in the severity of urgency and daytime urinary frequency, as well as storage symptoms and the IPSS quality of life index compared to monotherapy [233]. The phase IV PLUS study compared the efficacy of mirabegron versus placebo in patients receiving a standard dose of tamsulosin** (0.4 mg). After a 4-week monotherapy period, 715 patients were randomized to placebo or mirabegron 25 mg with a dose increase to 50 mg after 1 month. The treatment group showed a decrease in the mean number of micturitions (adjusted mean difference 0.39 per 24 hours). Similar results were obtained for mean voided volume and the number of urgency episodes. However, the total IPSS score and OAB symptom score did not differ between the groups [234]. The most frequent adverse events included hypertension, headache, and nasopharyngitis [234].

Comments: the addition of mirabegron in men with persistent OAB symptoms receiving alpha-blockers has been evaluated only in short-term observational studies. Given the small effect size in reducing urinary frequency compared to placebo, short-term efficacy remains controversial, and studies with longer follow-up durations are needed. The concept of adding pharmacotherapy with OAB drugs in patients with persistent symptoms despite alpha-blocker therapy has proven valid regarding the addition of muscarinic receptor antagonists (included in ATC group G04BD - Drugs for urinary frequency and incontinence). According to RCT data, solifenacin** and mirabegron have equivalent efficacy as a component of combination therapy, but mirabegron has a more favorable safety profile [235].

3.2 Surgical Treatment

The essence of any surgical intervention for BPH is the relief of mechanical obstruction at the level of the prostatic urethra. In recent years, in addition to historically established open prostatectomy and monopolar transurethral resection of the prostate, minimally invasive surgeries utilizing bipolar and laser technologies have been gaining increasing popularity. Despite the active introduction of BPH pharmacotherapy into clinical practice, the proportion of patients undergoing surgical treatment (specifically transurethral resection of the prostate) increased from 22.9% in 1988 to 42.9% in 2008 [94]. On average, 30% of men undergo some form of surgery for this disease during their lifetime [95], and the risk of acute urinary retention increases 5-fold by age 70 [96].

Indications for surgical treatment of BPH [2,4,97]:

• recurrent urinary retention;

• pronounced bladder outlet obstruction;

• bladder stones;

• intermittent gross hematuria;

• hydronephrosis caused by BPH, with or without CKD;

• large post-void residual urine volume (chronic urinary retention);

• failure of prior medical therapy.

A relative indication for surgery is the presence of a median lobe, the presence of which, as is well known, significantly reduces the likelihood of successful medical therapy.

Prostatic enlargement, even if very pronounced, not accompanied by severe symptoms, is not an indication for surgical intervention, but at the same time it is one of the risk factors for disease progression.

The arsenal of a modern urologist includes many different surgical techniques for treating LUTS due to BPH, which are divided into 5 main types:

1. Prostate resection (TURP, B-TURP, ThuFVARP, TUIP);

2. Prostate enucleation (open - OPE, bipolar - B-TUEP, laser - HoLEP, ThuLEP, ThuFLEP, ThuVEP, ThuFVEP, DiLEP, endovideosurgical - LAE, robot-assisted - RAAE);

3. Vaporization (bipolar - B-TUVP, laser);

4. Alternative methods – Endovascular prostatic artery embolization (PAE);

5. Non-ablative methods – Prostatic stents (stent placement in the urinary tract)

Taking into account long-term observational data available in the literature, TURP and open prostatectomy should serve as the standard for evaluating the efficacy of minimally invasive surgical treatments for BPH [97].

A meta-analysis of 23 modern clinical trials comparing functional outcomes and complications following mono- and bipolar TURP, bipolar TUEP, bipolar TUVP, and laser enucleation for BPH with a maximum follow-up duration of 5 years showed statistically comparable efficacy and safety of these techniques, and the choice of surgical method for each patient should be individualized and depend on their clinical status [98].

It should be noted that in particularly severe cases of decompensated LUTS with prominent chronic urinary retention, severe CKD, and other conditions, a "two-stage treatment" approach may be performed. In this case, the first stage is supravesical urinary diversion (cystostomy), which subsequently allows the patient to receive specific therapy to restore bladder contractility and eliminate the clinical manifestations of CKD. Later, a "delayed surgery" is performed to remove the adenomatous nodes using one of the methods listed above. The prostate disease screening system presented at the beginning of this chapter has significantly reduced the number of patients requiring "two-stage treatment".

Comments: in some clinics with extensive experience in M- and BiTURP, the upper limit of prostate volume may be increased to 120 cm³. The method is effective in 80% of patients. The result of this surgery is an increase in the maximum urinary flow rate by 163%, a decrease in the IPSS score by 70%, and the QoL score by 69%. The volume of residual urine decreases by 77% [98].

Transurethral resection of the prostate has been considered the "gold standard" of surgical treatment for BPH with sizes up to 80 cm³ for many years.

Depending on the volume of removed prostate tissue, the following types of TURP should be distinguished:

• "pseudo-TUR" (only a small part of the hyperplastic tissue is removed — 10–20% of the volume, no more than 10–15 g) mainly from the bladder neck area, or part of the middle lobe of BPH (creation of a "urinary path");

• "partial TUR" (30–80% is removed). Depending on the volume of resection, "partial TUR" is subdivided into "palliative TUR" and "subtotal TUR";

• "total TUR" (transurethral adenomectomy): almost 90–100% of the volume of hyperplastic tissue is removed, which corresponds to an open surgery.

The radicality of TURP determines the risk of needing re-intervention. On average, this risk is 1–2% per year. Using the example of more than 20,000 patients, it was demonstrated that reoperation (repeat TURP, urethrotomy, or bladder neck resection) was required in 5.8, 12.3, and 14.7% of patients at 1, 5, and 8 years of follow-up [99].

Complications of TURP:

Mortality after TURP is currently only 0.1%. Meanwhile, the proportion of complications still remains significant at 11.1% and increases with prostate volume [98,100].

Intra- and early postoperative complications include:

Ø TUR syndrome can develop in 0.8–1.4%. Its incidence increases with prostate volume [100];

Ø Bleeding requiring blood transfusion reaches 2.9% [98,100];

Ø Bladder clot tamponade can develop in 4.9% [98,100];

Ø Infectious complications reach 22%;

Ø AUR is observed in an average of 4.5%;

Long-term complications [98,100]

Ø retrograde ejaculation after TURP occurs in an average of 65.4% of patients;

Ø bladder neck sclerosis is observed in 4.7%;

Ø urethral stricture can occur in 3.8%;

Ø erectile dysfunction develops in 6.5%;

Ø urinary incontinence occurs in 2%.

Indications for BTURP coincide with those for standard MTURP. The surgical technique is identical to monopolar transurethral resection of the prostate. The difference between "standard" and "bipolar" M-TURP is that the bipolar procedure is performed in saline (Sodium chloride** 0.9% ATX Code: B05BB01 Electrolytes), and energy does not pass through the patient's body, spreading between two poles on the loop (true bipolar resection) or between the loop and the resectoscope sheath (pseudo-bipolar resection). Bipolar resection has a more pronounced coagulative effect and a higher safety profile in patients with increased bleeding tendencies and/or using pacemakers. Individual publications comparing short- and long-term surgical outcomes have not revealed a statistically significant difference between bipolar and monopolar variants of MTURP [101-113]. BTURP complications have a more favorable profile than MTURP due to the absence of TUR syndrome, lower blood loss, and lower incidence of clot tamponade [104-106].

• TUIP is recommended for patients with moderate and severe LUTS and a prostate volume <30 cm³ without a middle lobe [112-113].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: A prerequisite for performing this surgery is the absence of a "middle lobe" and a prostate volume <30 cm³, taking into account the larger number of conducted clinical trials with an established prostate volume threshold of up to 30 cm³, although in three studies the prostate volume was up to 60 cm³. The efficacy of TUIP is comparable to TURP, but it has a lower complication rate (no TUR syndrome, low risk of bleeding); however, it should be remembered that according to a meta-analysis of 6 clinical trials, reoperation is performed more than twice as often after TUIP (18.4%) than after prostate TUR (7.2%) [112-113].

Comments: The largest meta-analysis included 9 RCTs and 7 non-randomized studies. The results indicate no clinically significant differences in efficacy (IPSS score, quality of life, and Qmax) between ThuFVARP and mono- or bipolar TURP at 12 months of follow-up [120-124].

• Open adenomectomy (transvesical, retropubic, perineal) is recommended for patients with moderate and severe LUTS caused by BOO, and a prostate volume >80 cm³, when BTUEP, HoLEP, ThuLEP, ThuFLEP, ThuVEP, ThuFVEP, LAE, or PAAE cannot be performed [129-141].

GCR BLOC 1Grade of Recommendation B (Level of Evidence 1)

Comments: Despite its high efficacy, this surgical option is the most invasive and is associated with a higher risk of complications compared to endoscopic methods [132-140]. The long-term efficacy of this surgery is unquestionable, as demonstrated by numerous RCTs [129, 130].

The effect of the surgery is lasting; relapses are recorded very rarely and are mostly "false" (caused by the growth of residual adenomatous tissue not removed during the initial surgery.

Mortality after open prostatectomy is <1%, blood transfusion rate is 7–14%, the probability of urinary incontinence is up to 10%, bladder neck sclerosis and urethral strictures are recorded in 6% of patients [129, 130].

One of the main conditions for providing high-quality surgical care to patients with BPH is minimizing invasiveness and complications while maintaining high efficacy. An alternative to open adenomectomy for a prostate volume >80 cm³ is transurethral enucleation of the prostate, which became possible with the introduction of modern laser technologies and bipolar instruments into clinical practice. These surgeries have efficacy comparable to open adenomectomy and a lower risk of complications [132-140].

• Transurethral enucleation of the prostate (BTUEP, HoLEP, ThuLEP, ThuFLEP, ThuVEP, ThuFVEP) is recommended for patients with moderate and severe LUTS caused by BOO and is preferred in patients with a prostate volume >80 cm³; however, it can also be used for smaller volumes, as well as in patients taking anticoagulants (ATC code: B01AA Vitamin K antagonists) and antiplatelet agents (ATC code: B01AC Platelet aggregation inhibitors excluding heparin) [168,169,182,183,190].

GCR BLOC 3Grade of Recommendation B (Level of Evidence 3)

Comments: The surgical technique for these procedures has specific nuances and requires special training, as the surgeon's experience is the most critical factor for high efficacy and a lower complication rate [170-173]. It should be noted that most publications on this topic cover the HoLEP technique. However, over the past 10 years, numerous RCTs and systematic reviews have been published comparing various techniques of transurethral enucleation of prostate hyperplasia, demonstrating comparable results in terms of efficacy and safety [141-169, 174-190]. ThuFLEP may be considered as an alternative to HoLEP. Thus, several studies have shown that ThuFLEP has efficacy and safety comparable to HoLEP [245-247]. Furthermore, like HoLEP, ThuFLEP is characterized by high efficacy and a low complication rate in long-term follow-up [248].

Comments: several RCTs with a follow-up of up to 12 months compared DiLEP (greenlight laser) with ThuVEP, ThuLEP, and HoLEP in patients with a prostate volume of <80 cm³ and demonstrated comparable efficacy in terms of IPSS score, quality of life, and Qmax [192-196]. This method can be considered an alternative and requires further study.

• LAEE and RAEE are recommended for patients with moderate to severe LUTS secondary to BPO with a prostate volume of >80 cm³ as an alternative to transurethral enucleation of prostate hyperplasia and PAE [199,200,201,202].

GGR BLOC 2Grade of Recommendation B (Level of Evidence – 2)

Comments: endovideosurgical adenomectomy can be performed laparoscopically, extraperitoneoscopically, and robotically. Being an alternative to open adenomectomy, it shows comparable functional results with less blood loss, shorter hospital stay, and shorter catheterization time. In some cases, when bladder outlet obstruction caused by BPH is accompanied by large bladder stones and diverticula, endovideosurgical adenomectomy is a safe and effective alternative to open adenomectomy [197-204].

• ThuVEP is recommended for patients with moderate to severe LUTS secondary to BPO, with a prostate volume of 30 to 80 cm³, and is preferred in patients taking anticoagulants (ATC code: B01AA Vitamin K antagonists) and antiplatelet agents (ATC code: B01AC Platelet aggregation inhibitors excluding heparin) [102, 196, 205-209].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: Modern laser and bipolar technologies allow for not only effective endoscopic adenomectomy, but also prostate vaporization/resection comparable to TURP in short- and medium-term treatment outcomes. These methods include vaporization using holmium, thulium, greenlight, and diode lasers, as well as bipolar systems. These methods are considered alternatives to TURP. It should be noted that in recent years, fewer publications regarding these methods have appeared in the literature due to the growing experience with more radical operations—prostate enucleation techniques. [137, 205-209].

Over the past 10 years, only plasma systems with a "mushroom" or "button" type electrode have been studied. The results of RCTs have been combined into three meta-analyses and two systematic reviews with narrative synthesis [102, 205-209]. In most RCTs, the follow-up duration was 12 months. The longest follow-up period (36 months) was in a small RCT (n = 40), and in another RCT (n = 340) it was 18 months. Early combined results indicate no differences in short-term efficacy (up to 12 months, IPSS score, quality of life, Qmax) between plasmakinetical vaporization and TURP.

• Prostatic arterial embolization (PAE) is recommended for patients with absolute contraindications to surgery for LUTS secondary to BPO [215-218].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: the principle of the method is based on reducing arterial blood supply to the prostate gland, which leads to a fairly rapid decrease in its volume and relief of lower urinary tract symptoms. Selective embolization of the prostatic arteries with microparticles ranging from 45–700 µm in diameter is performed in an angiographic suite. There is a systematic review and meta-analysis on this technique [215, 216]. Since April 2018, PAE has been included in the list of methods recommended for the treatment of BPH in the UK, according to NICE (National Institute for Health and Care Excellence) [217]. In August 2016, the FDA (Food and Drug Administration) approved PAE for use in the USA [218].

• Prostatic stents are recommended for patients with contraindications to surgery for BPO. They can be an alternative to bladder drainage with an indwelling urethral catheter or self-catheterization [219].

GRC CLeE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Prostatic stents can be permanent or temporary and, when endoscopically placed into the prostatic urethra, they widen its lumen. A meta-analysis of their outcomes indicates that in 16% of patients, the efficacy of stents can be considered unsatisfactory within the first 12 months after placement. The main reasons are spontaneous stent migration (37%) and recurrence of bladder outlet obstruction (14%). Within the first 5 years after placement, stents prove ineffective in approximately 1/3 of patients [219].

3.2.1 Postoperative management of patients

Comments: postoperative measures are aimed at normalizing bladder, rectal, and sexual function and include both pharmacotherapy and physiotherapeutic and spa-based treatment methods. The scope of rehabilitation measures depends on the severity of postoperative disorders and is determined on a case-by-case basis by the attending physician.

The need for postoperative monitoring is due to the fact that the wound surface after most prostate surgeries comes into contact with urine, so the healing process of the postoperative wound can take up to 2.5–3 months. During this time, urination quality may progressively improve. Throughout this period, monitoring the activity of a potential inflammatory process in the prostate area should be based on blood tests, as urinalysis may have low informative value.

Despite well-defined patient selection criteria for surgical treatment of BPH, some patients remain dissatisfied with the surgical outcomes. According to various authors, this group of patients reaches up to 25%, with persistent irritative voiding symptoms remaining the main problem for those who have undergone surgery. The pathogenesis of these disorders is diverse, but the primary causes are generally considered to be detrusor-sphincter dyssynergia against the background of chronic urinary tract infection, concomitant chronic prostatitis, and overactive bladder, as well as involutional changes in the lower urinary tract in old age, etc. The cause of postoperative voiding disorders should be differentiated, and pathogenetically justified therapy should be administered. Isolated antibacterial and anti-inflammatory therapy in this category of patients does not always provide a good result and almost always requires supplementation. In cases of persistent, severe postoperative voiding disorders refractory to ongoing medical therapy, cystoscopy is indicated to clarify the structural state of the lower urinary tract, along with a urodynamic study to detect detrusor overactivity and adjust therapy.

Comments: Pharmacoprophylaxis should be the primary method for preventing phlebothrombosis and associated pulmonary embolism in moderate- and high-risk patients. Direct and indirect anticoagulants have proven efficacy. In clinical practice, low-molecular-weight heparins are currently preferred; their efficacy and safety have been confirmed by numerous studies [238-240]. The first injection of an unfractionated or low-molecular-weight drug from the ATC heparin group is administered 3–12 hours before surgery and then repeated at equal intervals after the surgical intervention. If there is a high probability of technical complications during the procedure or a risk of bleeding, prophylaxis may be initiated 6–12 hours after its completion, but no later than this timeframe, since thrombus formation typically begins already on the operating table or immediately after the end of the procedure. Sodium heparin** is administered 3 times daily at 5000 IU every 8 hours, while low-molecular-weight heparins are administered subcutaneously once daily. Approximate dosages for moderate/high risk are: enoxaparin sodium** 20/40 mg, nadroparin calcium 0.3/0.6 ml. As a rule, the duration of pharmacoprophylaxis is 7–10 days [238-240].

Comments: Thromboembolic complications in patients with urological pathologies, and particularly with BPH, are an extremely pressing issue. This is due, on the one hand, to the abundance of pelvic venous plexuses and the duration and scale of surgeries, and on the other hand, frequently to advanced age and concomitant therapeutic and cardiological comorbidities [238]. Out of 8,000 autopsies over a five-year period in two major Moscow city hospitals, pulmonary embolism served as the cause of death in every 10th patient overall, every 6th surgical patient, and every 4th postoperative patient [236]. It has been proven that while the relative risk of deep pelvic vein thrombosis after transurethral resection of the prostate is relatively low, the probability of pulmonary embolism is considered "moderate" [237]. Based on the combination of predisposing factors, urological patients undergoing surgical treatment belong to the groups of moderate or medium risk for thromboembolic complications and therefore require comprehensive preventive measures: early mobilization should be implemented, and compression stockings should be used intraoperatively and in the postoperative period [237].

3.3 Other Treatment

Among the medicinal products used for the treatment of patients with prostatic hyperplasia, there are also two groups of medicinal products in the Russian Federation developed by Russian scientists that do not fall into the above pharmacological classification groups.

One such drug is created on the basis of technologically processed (ultra-high dilutions) affinity-purified antibodies to nitric oxide synthase (NOS) and prostate-specific antigen (PSA). Antibodies to PSA modify the functional activity of endogenous PSA altered in benign prostatic hyperplasia, which is accompanied by an enhancement of the regulatory influence of this antigen on functional and metabolic processes in the prostate tissue, exerting a preventive and therapeutic effect. Antibodies to endothelial NO synthase help increase blood flow velocity in the vessels of the penis and prostate gland; they exert a protective effect on the endothelium (help reduce vascular reactivity, diminish vascular spasm, and improve peripheral microcirculation). A recently published multicenter, placebo-controlled, double-blind, randomized study lasting 12 months demonstrated statistically significant efficacy compared to placebo in improving lower urinary tract symptoms and reducing prostate volume [241].

The second group consists of bioregulatory peptides, which are a biologically active extract of bovine prostate glands. The most complete analysis of domestic fundamental and clinical studies is presented in the meta-analysis by I.A. Korneev [242]. After analyzing the results of 9 studies conducted by Russian urologists, it was concluded that the obtained data confirm the efficacy of using a bovine prostate-based drug in treating patients with moderately severe LUTS and bladder outlet obstruction due to BPH, with the aim of reducing the degree of dysuria, improving quality of life, and normalizing urodynamic parameters. However, these studies pooled only 380 patients, and none of them were placebo-controlled. Further long-term, randomized, placebo-controlled studies are required [242].

Developments by Russian scientists and the creation of new groups of medicinal products for the treatment of patients with prostatic hyperplasia require further studies to confirm their efficacy and determine the categories of patients for whom this therapy is most appropriate.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not provided.

5. Prevention and Dispensary Observation

• To monitor symptom dynamics in BPH, it is recommended to use the International Prostate Symptom Score (IPSS) and the Quality of Life (QoL) due to urinary disorders scale [2,4].

GRC CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For early detection of prostate cancer, it is recommended to perform a digital rectal examination (DRE) and monitor serum PSA levels every 12 months in all men over 50 years of age (in the presence of a family history of prostate cancer) [2,4,5].

GRC CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: PSA testing in patients with a life expectancy of less than 10–15 years has moderate prognostic significance and does not significantly impact their life expectancy [2,4].

• To monitor for urinary tract infections (UTIs) and renal function, it is recommended to perform a urinalysis and determine serum creatinine concentration once a year [2,4].

GRC CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For the early detection of adverse effects of drug therapy, it is recommended to check the tolerability of prescribed medications at each patient visit [2,4].

GRC CLEL 5Grade of Recommendation C (Level of Evidence – 5)

6. Organization of Medical Care

Indications for planned hospitalization in a medical organization:

Presence of indications for surgical intervention

Indications for emergency hospitalization:

1. Acute urinary retention

2. Macrohematuria

Indications for hospital discharge

1. Restoration of urodynamics;

2. Absence of signs of systemic inflammation;

3. Absence of complication risk.

7. Additional Information

No.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Rasner, Pavel Ilyich — MD, Professor, Deputy Chief Physician for Urology, Head of the Urology Clinic at K+31, Board Member of the Russian Society of Urology.

2. Sivkov, Andrey Vladimirovich – PhD in Medical Sciences, Deputy Director of the Lopatkin Scientific Research Institute of Urology and Interventional Radiology – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health

3. Kharchilava, Revaz Revazovich - PhD in Medical Sciences, Director of the Praxi Medica Training Center for Practical Medicine at the I.M. Sechenov First Moscow State Medical University

Conflict of interest

All members of the Working Group have confirmed that they have no financial support or conflicts of interest to disclose.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines: specialists with higher medical education in the following specialties:

1. urology

2. internal medicine

3. general practice (family medicine)

4. surgery

5. anesthesiology and intensive care medicine

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Table 1. Level of reliability of evidence (LRE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of reliability of evidence (LRE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions).

Table 3. Scale for determining the level of clinical recommendations (LCR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. European Association of Urology Guidelines [4].

2. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 137n dated March 14, 2018 "On approval of the professional standard 'Urologist'" (with amendments and additions)

3. Clinical Guidelines of the Russian Society of Urology.

4. Clinical Guidelines of the Russian Society of Urooncology.

Voiding diary

Patient's Full Name                                                        

Date of birth:

Gender:                                

Date of completion:

Notes to the voiding diary:

* 1 – mild, 2 – moderate, 3 – severe urinary leakage, urine is practically not retained.

** 1 is the weakest grade and 10 is the strongest grade of urgent desire to urinate.

Explanatory notes: Parameters assessed by the bladder diary include urinary frequency, total diuresis volume, volume per void, as well as the ratio of daytime and nighttime diuresis. Total daily diuresis volume can vary significantly. The influence of circumstances and individual variations cause differences in bladder diary parameters. The bladder diary is particularly important for nocturia and helps differentiate the patient's condition. It is easy to complete, requires no financial cost, and complements the clinical picture by objectifying patient complaints, for example, distinguishing nocturia from nocturnal polyuria

Appendix B. Physician Action Algorithms

1. Algorithm for choosing a non-surgical treatment method in BPH patients with LUTS

Alpha-blocker – alpha-adrenoreceptor antagonist; 5-ARI – 5-alpha-reductase inhibitor

PDE5i – phosphodiesterase type 5 inhibitor (C01CE: Phosphodiesterase inhibitors)

Antimuscarinic drugs (G04BD Drugs for urinary frequency and incontinence)

Beta-3 agonists – beta-3 adrenoceptor agonists (G04BD Drugs for urinary frequency and incontinence)

2. Algorithm for choosing a surgical treatment method in BPH patients with LUTS

Benign prostatic hyperplasia

Appendix C. Patient Information

Many know that one of the common diseases in elderly men is prostate adenoma. However, not everyone knows that this term is now obsolete — specialists in recent years have been using the term benign prostatic hyperplasia (BPH).

BPH is so widespread that many researchers speak of the inevitability of this condition in men who have lived long enough for BPH to develop. By the age of 80, 80% of men suffer from this condition. Approximately half of them have clinical manifestations of the disease that require treatment.

Benign prostatic hyperplasia as a disease should only be diagnosed when prostatic enlargement is combined with lower urinary tract symptoms.

The causes of BPH are not fully understood. Nevertheless, numerous studies in this field have proven that all theories are based on the concept of hormonal changes in the body starting at age 45-55, known as the "male climacteric". Gradual enlargement of the prostate gland begins around age 35-40 and continues into old age. Consequently, this affects the urethra, which passes through the prostate gland. The enlargement of the gland leads to narrowing of the urethral lumen and impaired urine outflow from the bladder. An equally important cause is the weakening of the bladder muscle contractility, which is primarily due to deteriorated blood supply and depletion of compensatory capabilities caused by the constant need to "fight" increasing resistance in the prostatic urethra.

SYMPTOMS

Clinically, this disease manifests with various symptoms. In the final stages of BPH, the risk of acute urinary retention increases sharply – a condition where the bladder is overdistended, the patient experiences severe urges to urinate but cannot void or urinates "drip by drip".

Symptoms of voiding dysfunction in BPH:

1. Weak urinary stream

2. Intermittent stream

3. Straining to void

4. Sensation of incomplete bladder emptying after urination

5. Need to strain to begin urination

6. Urinary hesitation

7. Increased daytime and nighttime urinary frequency

8. Inability/significant difficulty to hold urine when experiencing an urge to urinate

Not all symptoms are necessarily present in every patient. Their severity is individual. It should be remembered that these symptoms are not strictly specific to BPH and can occur in prostate cancer, prostatitis, neurogenic voiding disorders, cystitis, bladder tumors, and many other conditions. One should not rush into making a diagnosis as soon as the first symptoms appear. A proper examination and diagnostic methodology are of great importance in the treatment of BPH.

At the initial stage of the disease, the bladder empties completely after urination, and there is no kidney damage. At the final stage, the patient develops "residual urine" (incomplete bladder emptying after urination), which can lead to the formation of stones and diverticula (herniial protrusions of the bladder wall) in the bladder. Due to impaired urine outflow from the bladder, the ureters and renal pelves gradually dilate, leading to chronic inflammation – pyelonephritis. In the absence of adequate treatment, chronic renal failure develops in the final stages of the disease, posing a threat to the patient's life.

EXAMINATION

The treatment strategy for a patient suffering from BPH should be determined after a preliminary examination. According to World Health Organization recommendations, the minimum list of necessary examinations includes:

1. completion of a special questionnaire – IPSS (International Prostate Symptom Score), consisting of 7 questions (see at the end of the article);

2. assessment of quality of life using a 6-point scale (QOL) (see at the end of the article);

3. digital rectal examination (DRE), during which tenderness, consistency, shape, and volume of the prostate gland are specified;

4. urinalysis;

5. determination of blood serum urea and creatinine;

6. ultrasound examination of the prostate gland with determination of the presence and amount of residual urine;

7. urine flow rate study (uroflowmetry);

8. bladder diary (recording the time of urination and the volume of urine excreted over 2-3 days)

9. determination of the level of prostate-specific antigen (PSA) in blood serum; An elevated PSA level may indicate the presence of such a formidable disease as prostate cancer;

10. if PSA levels are elevated or if prostate involvement is suspected during a digital rectal examination, a prostate biopsy is indicated.

11. if necessary, X-ray or radionuclide examination of the kidneys;

TREATMENT

Possible treatment options include surgical intervention, drug therapy, and active surveillance.

Based on current concepts, drug therapy should be prescribed to BPH patients with initial manifestations of voiding disorders without upper urinary tract involvement and complications, patients with relative and absolute contraindications to surgical treatment, and patients who have refused surgical treatment or are postponing it for various reasons. According to statistics, these patients account for 60-70% of the total number of patients seeking care for various voiding disorders caused by BPH.

Active surveillance is acceptable in patients with mild symptoms whose quality of life is not significantly impaired by the existing symptoms, and involves monitoring blood and urine tests, PSA, ultrasound, and uroflowmetry results every 6-12 months. Active surveillance, as well as medical treatment, necessarily includes elements of so-called behavioral therapy – fluid restriction in the evening, avoiding diuretic foods and beverages (fruits, coffee, tea, alcohol, dairy products) three hours before bedtime, correction of concomitant drug therapy, etc.

Surgical treatment is indicated for patients with severe symptoms, upper urinary tract involvement, who have contraindications to medical therapy or in whom the latter does not yield the desired effect. Absolute indications for surgery include recurrent hematuria, bladder stones, and acute or chronic urinary retention.

Depending on the patient's general condition, comorbid conditions, the degree of prostate enlargement (its volume), the presence of complications, and a number of other factors, the doctor may advise which surgery is most suitable for each specific case. Its efficacy, potential risk of complications and side effects, and possible alternatives should be discussed before deciding on surgery, if necessary.

It must be understood that prostate enlargement per se, no matter how large it may be, is not a sufficient indication for surgery. Surgical treatment is performed only when severe symptoms are combined with prostate enlargement.

Urologists have long moved away from standard treatment regimens for BPH and approach each patient individually. Only this approach makes it possible to achieve a sustained positive effect with a minimal risk of complications and side effects. It should be remembered that any chosen strategy, whether surgical treatment, active surveillance, or drug therapy, requires regular check-ups and examinations by a specialist for potential adjustment of the ongoing treatment.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. International Prostate Symptom Score (IPSS) and Quality of Life (QoL) Scale

International Prostate Symptom Score (IPSS) and Quality of Life (QoL) Scale [18]

Russian version of the scale (International Prostate Symptom Score):

Source: https://uro-info.ru/tests/mezhdunarodnaya-sistema-summarnoy-otsenki- zabolevaniypredstatelnoy-zhelezy-v-ballakh-ipss-/

Original: Barry, M. J., Fowler, F. J., O’leary, M. P., Bruskewitz, R. C., Holtgrewe, H. L., Mebust, W. K., & Cockett, A. T. K. (2017). The American Urological Association Symptom Index for Benign Prostatic Hyperplasia. The Journal of Urology, 197(2), S189–S197. doi:10.1016/j.juro.2016.10.071

Type: patient questionnaire

Purpose: the questionnaire is suitable for all patients, regardless of the nature of LUTSD, the presence or absence of spontaneous urination, and the method of urine diversion

Key and explanations: Symptom severity is graded by the degree of impairment as follows: none (0 points), mild (1–7 points), moderate (8–19 points), and severe (20–35 points). The IPSS scale allows for a quantitative assessment of LUTS, determining their predominant type, and evaluating the patient's quality of life. The scale has high sensitivity (79%) and specificity (83%).