Benign Prostatic Hyperplasia

Etiology

The etiology of BPH is influenced by a wide variety of risk factors in addition to direct hormonal effects of testosterone on prostate tissue.

Although they do not cause BPH directly, testicular androgens are required in the development of BPH with dihydrotestosterone (DHT) interacting directly with prostatic epithelium and stroma.[5][8] Testosterone produced in the testes is converted to dihydrotestosterone (DHT) by 5-alpha-reductase 2 in prostate stromal cells and accounts for 90% of total prostatic androgens.[7] DHT has direct effects on stromal cells in the prostate, paracrine effects in adjacent prostatic cells, and endocrine effects in the bloodstream, which influences both cellular proliferation and apoptosis (cell death).[9]

BPH arises as a result of the loss of homeostasis between cellular proliferation and cell death, resulting in an imbalance favoring cellular proliferation. This results in increased numbers of epithelial and stromal cells in the periurethral area of the prostate and can be seen histopathologically[5].

Risk Factors

Non-modifiable and modifiable risk factors also contribute to the development of BPH. These have been shown to include metabolic syndrome, obesity, hypertension, and genetic factors.[7]

• Metabolic syndrome refers to conditions that include hypertension, glucose intolerance/insulin resistance, and dyslipidemia. Meta-analysis has demonstrated those with metabolic syndrome and obesity have significantly higher prostate volumes.[10] Further studies looking at men with elevated levels of glycosylated hemoglobin (Hba1c) have demonstrated an increased risk of LUTS.[11] Limitations of these studies are that there were no subsequent significant differences in IPSS, and the effect of diabetes on LUTS has been shown to be multifactorial in nature.[10][12] Further studies are therefore required to establish causation in these individuals.
• Obesity has been shown to be associated with increased risk of BPH in observational studies.[13][14] The exact cause is unclear but is likely multifactorial in nature as obesity makes up one aspect of the metabolic syndrome. Proposed mechanisms include increased levels of systemic inflammation and increased levels of estrogens.[15][16]
• Genetic predisposition to BPH has been demonstrated in cohort studies, first-degree relatives in one study demonstrated a four-fold increase in the risk of BPH compared to control.[17] These findings have demonstrated consistency in twin studies looking at the disease severity of BPH, with higher rates of LUTS seen in monozygotic twins.[18][19]

Epidemiology

Differences in case definitions make interpretation of population-based studies regarding BPH difficult. Whereas BPH can refer to histology, benign prostate enlargement, and physician-diagnosis of BPH, LUTS refers to the urinary symptoms shared by disorders affecting the prostate and bladder.

Age is a significant predictor of both development of BPH and subsequent LUTS, with 50% of men over the age of 50 shown to have evidence of BPH and the association with the development of LUTS shown to increase with age in a linear fashion.[20][21] This is supported by studies that have demonstrated increases in prostate volume with age (2% to 2.5% increase in size per year).[22] In the US, studies have shown BPH prevalence to be as high as 70% in those between 60 and 69 years of age and more than 80% in those over 70 years.[23] The prevalence of male LUTS alone demonstrated a significant increase with age from 8% (30 to 39yrs) to 35% (60 to 69yrs) in the Boston area community health survey, other US population-based studies have shown 56% of men between 50-79yrs reported symptoms.[24][25]

At a population-level, the prevalence of BPH increased dramatically between 1998 and 2007 in the US, nearly doubling in the number of cases.[26] These increases are suggested to be attributable to an aging population, with those over 80 years of age projected to be around 19.5 million in 2030 (from 9.3 million in 2003).[27] As populations age, the number of cases can, therefore, be expected to rise.

International studies have suggested that Western populations have significantly higher prostate volumes compared to those from southeast Asia.[28] Further studies looking at the correlation of prostate volume with LUTS, however, found that lower prostate volumes did not necessarily correlate with symptoms, with higher mean IPSS (international prostate symptom scores) observed in a cohort of Indian men compared to western populations.[29]

Pathophysiology

Both the development of lower urinary tract symptoms and bladder outlet obstruction in men with BPH can be attributable to static and dynamic components.[30] Static obstruction is a direct consequence of prostate enlargement resulting in periurethral compression and bladder outlet obstruction. Here, periurethral compression requires increasing voiding pressures to overcome resistance to flow; in addition, prostate enlargement distorts the bladder outlet causing obstruction to flow.[31]

Dynamic components include the tension of prostate smooth muscle (hence the use of 5-alpha reductase inhibitors to reduce prostate volume and alpha-blockers to relax smooth muscle).[32] This is explained by decreases in elasticity and collagen in the prostatic urethra in men with BPH, which may further exacerbate bladder outlet obstruction due to loss of compliance and increased resistance to flow and may explain why prostate size alone is not always a predictor of disease.[33]

Histopathology

Histological examination demonstrates that BPH is a hyperplastic process with an increase in cell number on histology (hyperplasia); these occur both in the periurethral and transition zones. Histological studies have demonstrated both glandular and stromal proliferation. Specifically, periurethral zones demonstrate stromal nodules, whereas glandular nodular proliferation is seen within the transition zone.[34]

History and Physical

History

In the elective setting, a focused medical history should include all aspects of symptomatology, and this includes onset, timing, exacerbating, and relieving factors.

Lower urinary tract symptoms can be divided into storage (frequency, nocturia, urgency) and voiding symptoms (stream, straining, hesitancy, prolonged micturition) and can help establish other causes of urinary symptoms such as urinary tract infections/overactive bladder, in addition to determining the site affected (bladder vs. prostate). Men with BPH are likely to report predominant symptoms of nocturia, poor stream, hesitancy, or prolonged micturition.

Red flags help point to more sinister causes of urinary symptoms such as bladder/prostate cancer, neurology such as cauda equina, or chronic high-pressure retention (which can lead to silent renal failure). The presence of these can be established by asking about visible haematuria/bone pain/weight loss, neurology, and nocturnal enuresis/incontinence, respectively.

Complete medication history should be taken, including any medications they have tried and use of anticoagulants or antiplatelets, which may increase the risk of intra-operative bleeding or need to be held before surgery.

The overall fitness of the patient should also be established to determine suitability for any future interventions (fitness for anesthesia, independence, exercise tolerance, ability to complete activities of daily living), and the symptom burden on quality of life should also be established.

Physical Examination

In the elective setting, the examination should include abdominal examination (looking for a palpable bladder/loin pain) and examination of external genitalia (meatal stenosis or phimosis). The examination should then conclude with a digital rectal examination making a note in particular of the size, shape (how many lobes), and consistency (smooth/hard/nodular) of the prostate (BPH is characterized by a smooth enlarged prostate).

Further bedside evaluation includes

• Urine dipstick (rule out other causes such as infection)
• Post-void residual volume (whether the bladder is emptied properly)
• IPSS (international prostate symptom score)
• Frequency-volume chart

Questionnaires

Both the American urological association symptom index and IPSS can be used to assess the impact of LUTS on quality of life.[35] They are useful when quantifying the disease burden on the patient and can be used to stratify patients into disease categories for treatment.[7] The IPSS stratifies patients into three groups on the basis of symptoms. They are mild (0-7), moderate (8-19), and severe (20-35). Those with more severe symptoms are less likely to benefit from conservative or medical measures.

Evaluation

Standard investigation of BPH may include bedside urine dipstick, post-void residual, IPSS, and urine flow studies to establish if there is evidence of obstructive voiding. Further tests may be indicated depending on the patient/history.

Blood Tests

Blood tests, including renal function tests, are useful to establish baseline renal function and can help support the diagnosis of renal failure/acute kidney injury in someone with chronic high-pressure retention or acute retention, for example.

Urinalysis

Urine specimen testing can help detect infection, non-visible haematuria, or metabolic disorders (glycosuria). Leucocytes and nitrites are common findings with infection; the presence of proteinuria may point towards nephrological conditions. The American urological association recommend urinalysis using a dipstick test, further tests may be requested based on abnormal dipstick findings (culture, etc.).

Prostate-Specific Antigen (PSA)

Prostate-specific antigen testing has been shown to predict prostate volume.[36] Prostate-specific antigen (PSA) testing should be used with caution, however, and should not be done routinely in the investigation of BPH. Levels may be raised in a large range of conditions (large prostate, infection, catheterization, prostate cancer) and can cause undue anxiety or further unnecessary investigations for the patient. It is the author's preference to conduct PSA testing in specific circumstances, i.e., where cancer is suspected (malignant feeling prostate, metastatic disease suspected) or a previous baseline established.

Ultrasound

Ultrasound scans are used to look for evidence of hydronephrosis and are indicated in patients with high residual volumes or renal impairment. Other indications include suspicion of urinary tract stones or the investigation of haematuria.

Flow Studies

Urine flow studies are used to determine the volume of urine passed over time. This can help establish whether there is objective evidence for obstruction to flow. Urodynamic studies are used to see how the bladder empties and fills. They can help further assess patients where the diagnosis is not certain or where a neurogenic/overactive bladder is suspected (i.e., neurological conditions that may affect the bladder, flow studies equivocal, diagnosis not clear).

Cystoscopy

Flexible cystoscopy should be used to investigate red flag symptoms such as visible haematuria/suspected bladder cancer and can also be used to look for urethral strictures, which may also result in poor flow/decreased urinary flow studies.

Treatment / Management

Men with BPH may present acutely with urinary retention or may be seen in the clinic or primary care setting. Management of male urinary retention is covered in a separate topic.

In those with LUTS, treatment options range from watchful waiting to medical and surgical intervention and depend on the degree of "bother" or disease burden to the patient (as assessed by IPSS).

Observation

Watchful waiting is a process to manage patients by giving lifestyle advice. Examples include weight loss, reducing caffeine intake or reducing fluid intake in the evening, and avoiding constipation to try and reduce risk factors and improve LUTS. Patients should be involved in the discussion and informed of the risks of disease progression. Clinical progression has shown to be around 31% in one observational study, with 5% developing acute urinary retention.[37] These measures may be trialed in those with mild symptoms (IPSS<7).[7]

Medical Therapy

Both static and dynamic components contribute to the pathophysiology of BPH. Medical therapy aims to address both of these components.

Alpha-blockers:

Alpha 1-adrenoreceptors are present on prostate stromal smooth muscle and bladder neck. Alpha 1-adrenoreceptor blockage results in stromal smooth muscle relaxation addressing the dynamic component of BPH and thus improving flow. Examples include selective Alpha-blockers such as Tamsulosin (400mcg once daily) and Alfuzosin (10mg once daily).

5 alpha-reductase inhibitors:

Alpha-reductase inhibitors such as finasteride (5mg once daily) and dutasteride block conversion of testosterone to DHT.[38]. This addresses the static component of BPH by causing shrinkage of the prostate and takes several weeks to show noticeable improvement, with six months needed for maximal effectiveness.[7] As a result of treatment serum, PSA can be reduced by 50%, with prostate volume decreasing by up to 25%. This has been shown to alter the disease process and subsequent disease progression.[39](A1)

Antimuscarinics:

Bladder detrusor instability can develop in patients with worsening bladder outlet obstruction. This can result in increased urgency (overactive bladder) and frequency. Muscarinic receptor antagonists can help with these symptoms by blocking muscarinic receptors on detrusor muscle. This reduces smooth muscle tone and can improve symptoms in those with overactivity. Examples include solifenacin, tolterodine, and oxybutynin. Those who fail antimuscarinic treatment may be considered for mirabegron use (a Beta-3 adrenoreceptor agonist), which causes detrusor relaxation.

In practice, the combination of an alpha-blocker and alpha-reductase inhibitor is often used to achieve improvements in voiding symptoms. This is backed by studies confirming the effectiveness of combination therapy over monotherapy.[40][41](A1)

Surgery

Guidelines for the indications for surgery in BPH as outlined by the European Association of Urology (EAU) are as follows:[42]

• Refractory urinary retention
• Recurrent urinary infections
• Haematuria refractory to medical treatment (other causes excluded)
• Renal insufficiency
• Bladder stones
• Increased post-void residual
• High-pressure chronic retention (absolute indication)

Surgical management of BPH has broadened significantly over the years, with the development of further minimally invasive techniques. Recommended procedures include transurethral incision of the prostate, transurethral resection fo the prostate, in addition to newer techniques such as laser vaporization and holmium laser enucleation, which have largely replaced open prostatectomy. Surgical management options are outlined below.

TURP/TUIP

Transurethral resection surgery focuses on debulking the prostate to produce an adequate channel for urine to flow. This is achieved using diathermy to produce a high-frequency current that allows the cutting of tissue. By resecting all obstructing prostatic tissue, an adequate channel can be created to allow urine to flow. Bipolar diathermy has largely replaced monopolar diathermy techniques for TURP, with increased benefits such as resection in saline and reduced risk of "TUR syndrome."

HOLEP

Previously, open prostatectomy allowed adenoma to be removed or enucleated off its capsule. This can now be achieved with laser enucleation, referred to as HoLEP (Holmium laser enucleation of the prostate). Meta-analysis has shown improved Qmax (flow rate), reduction in post-void residual, and IPSS compared to TURP.

Benefits include a lower transfusion rate with no increase in complications compared to TURP. However, limitations include specialized equipment required making it less readily available.[43](A1)

Urolift

Tissue-sparing approaches, such as Urolift, have also been developed. This can help minimize the risk of bleeding in co-morbid patients and the associated risks of more invasive surgery (such as anesthesia risk, prolonged surgery time, etc.). By compressing prostate lobes, the channel can be widened in the prostatic urethra, improving LUTS. Studies have shown benefits, including the possibility of day-case surgery, preserved sexual function, and improved symptom scores (IPSS), and flow rates (QMax).[44]

Differential Diagnosis

Differential diagnoses for lower urinary tract infections are broad and include the following:

Red flag conditions:

• Bladder/prostate cancer
• Cauda equina (can present with acute retention)
• High-pressure chronic retention (presentation insidious or with acute renal failure)

Other conditions:

• Urinary tract infections/sexually transmitted infections
• Prostatitis
• Neurogenic bladder (can be secondary to Parkinson's, Multiple sclerosis, etc.)
• Urinary tract stones (bladder stones)
• Urethral stricture

Prognosis

Deterioration in LUTS/increasingly problematic voiding symptoms is the most common indicator of disease progression. In addition to this, patients may present with complications, including acute retention, infections, or haematuria.

Observational studies have demonstrated that when left without treatment, clinical progression of BPH increased over a 48 month period, with 31% of the cohort requiring presentation at 48 months and 5% developing acute retention in the 48 month period.[37]

The risk of acute urinary retention also increased with age, in the Olmsted County study, the incidence of retention in men increased over ten-fold, from 3/1000 (40-49yrs) to 34.7/1000 (70-79yrs).[45] Left untreated, BPH, therefore, has a significant risk of progression and presentation. Indeed, up to 42% of men who presented with retention in 1 study, went on to have surgery.[46] Men with significantly enlarged prostates (>30ml) have also been shown to be at an increased risk of disease progression.[47]

Complications

Common Complications

• Urinary retention
• Chronic retention
• Urinary tract infection (due to incomplete emptying)
• Haematuria
• Bladder calculi

Other complications may arise as a result of catheterization for management of LUTS in BPH and include:

• Failed trial without catheter
• Long-term catheter complications (blocked catheters, retention, haematuria, urinary tract infection)

Urinary Retention

International studies have demonstrated that BPH accounts for over two-thirds of cases of acute urinary retention.[48] Further to this, 15% of those who experience acute urinary retention experience another episode in the future, with 75% requiring surgery compared to those with precipitating causes (only 26%).[49]

Men with BPH can also develop chronic retention. This is usually chronic high-pressure retention due to high voiding detrusor pressures in the bladder as a result of outflow obstruction.[48] Due to the inability to empty the bladder completely, the pressure within the bladder can increase, resulting in hydronephrosis and subsequent deterioration in renal function leading to renal failure. Management of these subsets of patients is, therefore, urgent catheterization and urgent surgery to relieve the obstruction (TURP) or long-term catheter (those with high-pressure retention should not undergo TWOC).

Urinary Tract Infections

This occurs due to incomplete bladder emptying resulting in incomplete bladder emptying and stagnant urine. Recurrent infections may indicate a need for treatment or long-term antibiotics to prevent associated co-morbidity (admissions with urosepsis).

Haematuria

This is a common complication in BPH and a common cause for referral for further investigation. Due to the increased vascularity of larger prostate vessels may be disrupted, causing bleeding.[48] Finasteride has been shown to decrease the density of vessels and can help manage problematic BPH related haematuria.[50]

High-pressure Chronic Retention

Chronic retention is commonly referred to as either high or low-pressure retention. High-pressure chronic retention commonly occurs in bladder outflow obstruction as a result of high detrusor pressures required to overcome the obstruction (BPH). Persistence of this high-pressure causes reflux and subsequent hydronephrosis.[48] Over time this can result in an insidious deterioration in renal function, which may be missed. High-pressure retention is characterized by nocturnal enuresis - due to decreased resting pressure of the bladder neck overnight.

Management consists of catheterization to relieve the bladder pressure and definitive management to prevent retention and further renal dysfunction. Management options include TURP or long-term catheter/intermittent self-catheter. Following catheterization, the patient may undergo post-obstructive diuresis. This is characterized by increased urine output in the following 24 to 72 hours and may require IV fluid supplementation if exceeding >200 ml per hour. There is no evidence to suggest any benefit in gradual vs. rapid decompression, and so patients should be left on free drainage following catheterization for HPCR.[51]