Prostate disease

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48 Prostate disease

M. Martinez, M. Satheesh

Key points

Benign prostatic hyperplasia

• Benign prostatic hyperplasia (BPH) is a common condition which increases in prevalence with age.
• A combination of increased adrenergic tone in the prostatic stroma and bladder neck as well as the anatomical effects of an enlarging prostate lead to lower urinary tract symptoms (LUTSs) and bladder outflow obstruction (BOO).
• Surgical treatments such as transurethral resection of the prostate (TURP) are effective, but less invasive procedures such as laser therapy, and less commonly thermotherapy, are used.
• α-Adrenoceptor blocking drugs are effective in reducing symptoms.
• 5α-Reductase inhibitors reduce prostate size, improve symptoms, increase urinary flow rates and reduce the risk of developing complications such as acute urinary retention (AUR) or the need for prostate surgery.

Prostate cancer

• Prostate cancer (PC) typically progresses slowly but is influenced by factors such as tumour grade, stage of the disease, co-morbidities and life expectancy.
• Aetiology is multi-factorial and includes age, race, family history and dietary habit.
• Early detection is difficult because there are no symptoms specific to PC.
• A combination of digital rectal examination (DRE), serum prostate-specific antigen (PSA) and transrectal ultrasonography (TRUS) is used to confirm diagnosis.
• Curative treatments include radical prostatectomy or radiotherapy.
• Treatment depends on the grade and stage of tumour, life expectancy and patient choice.

Prostatitis

• Prostatitis is classified as acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome and asymptomatic inflammatory prostatitis.
• There is no absolute diagnostic tool for prostatitis. Diagnosis is based on physical examination and clinical history.
• The pathophysiology of prostatitis is poorly understood and the aetiology is unclear in the majority of patients.
• Prostatitis cases associated with infection or inflammation are treated with antibiotics.
• α-Adrenoceptor antagonists are used for the treatment of chronic prostatitis/chronic pelvic pain syndrome.

Benign prostatic hyperplasia

Epidemiology

Benign prostatic hyperplasia (BPH) is the most common benign tumour in men and is responsible for urinary symptoms in the majority of males over the age of 50 years. Autopsy studies have revealed the histological presence of BPH in 50% of males aged 51–60 years, increasing to 90% in those over 85. By the age of 80 years, virtually all men exhibit one or more of the symptoms associated with BPH.

BPH is seen in all races although the overall size of the prostate varies from race to race.

Pathophysiology

The prostate is a part glandular, part fibromuscular structure about the size of a walnut that surrounds the first part of the male urethra at the base of the bladder (Fig. 48.1). In simple terms, the prostate can be divided into a lobular inner zone encapsulated by an external layer. The inner zone is where benign hypertrophic changes are generally found, whereas most malignant changes originate in the peripheral zone.

image

Fig. 48.1 Male urinary system demonstrating the location of the prostate.

Prostatic hypertrophy is directly related to the ageing process and to hormone activity. Within the prostate, testosterone is converted by 5α-reductase to dihydrotestosterone (DHT). DHT is five times more potent than testosterone and is responsible for stimulating growth factors that influence cell division leading to prostatic hyperplasia and enlargement.

Histologically, depending on the predominance of the type of prostatic tissue present, prostatic hypertrophy can be stromal, fibromuscular, muscular, fibroadenomatous or fibromyoadenomatous.

As the prostate enlarges, it can compress the urethra (Fig. 48.2) and this, together with increased adrenergic tone, can lead to bladder outflow obstruction (BOO) and lower urinary tract symptoms (LUTSs). Therefore, the term BPH includes benign prostatic enlargement (BPE), the clinical features associated with urinary obstruction and LUTSs.

image

Fig. 48.2 Diagrammatic representation of the impact of prostate hyperplasia on the urethra demonstrating overgrowth of cells in the inner zone of the prostate.

Symptoms

Men with BPH can develop bothersome LUTSs that can impact negatively on their quality of life. It is important to emphasise that not all men who experience LUTSs have BPH. LUTSs can have different aetiologies including bladder cancer or stones, urinary tract infection (UTI) or urethral stricture. Furthermore, a histological diagnosis of BPH does not mean the patient will suffer from LUTSs.

LUTSs can be divided into symptoms of failure of urine storage (irritative) and those caused by failure to empty the bladder (obstructive or voiding).

Irritative symptoms

• Frequency
• Nocturia
• Urgency and urge incontinence

Obstructive symptoms

• Poor urinary flow
• Hesitancy in initiation of micturition
• Post-micturition dribble
• Sensation of incomplete emptying
• Occasional acute retention of urine requiring emergency treatment

Examination and investigations

There is a range of investigations and diagnostic tests available for the evaluation of patients with suspected BPH. Some tests are standard during the assessment of all men with LUTSs. Other investigations are optional and are only performed depending on the patient’s presentation and the clinician’s judgement.

History

A focussed medical history of all men with LUTSs should be taken to elucidate the aetiology of their symptoms. As part of the process, LUTSs should be evaluated using a validated scoring tool such as the international prostate symptom score (IPSS). This can be used to monitor the severity and progression of the disease and assess the impact of therapy on LUTSs.

Physical examination

All patients who present with suspected BPH should undergo a digital rectal examination (DRE) which involves the examiner palpating the prostate with a finger through the rectum wall. A DRE is performed to exclude the presence of prostate cancer (PC) and can also be used to estimate the shape and size of the prostate, although transrectal ultrasonography (TRUS) provides a more accurate measurement of prostate volume.

Urodynamic studies

Simple non-invasive urodynamic studies provide a surrogate measure of BOO. These include maximum flow rate and post-void residual (PVR). Large PVRs of 300 mL, for example, are indicative of bladder dysfunction and predict a poor response to therapy. Definitive proof of BOO requires invasive pressure flow studies.

Imaging

In the past, upper tract imaging involving an ultrasound scan and intravenous urography were used routinely to evaluate LUTSs associated with BPH. These tests are not normally undertaken except in patients with abnormal renal function and LUTSs who should have an ultrasound scan of their kidneys. The following represent the imaging options used for the assessment of men with BPH.

Flexible cystoscopy

Flexible cystoscopy provides an endoscopic image of the bladder for the assessment of prostatic obstruction and informs possible management options. For example, if the prostate has grown and there is intravesical extension, each time the patient tries to void the internal urethral meatus is obstructed. This type of tissue requires surgical removal, whereas simple lateral lobe enlargement may well respond to non-surgical measures.

Prostatic ultrasound scan

Prostatic ultrasound or TRUS uses high-frequency scanners to produce images of the prostate. This imaging is used to obtain an accurate evaluation of the prostate volume and to detect malignant change. TRUS is also used to guide the placement of the needle when obtaining prostatic biopsies.

Other investigations

Other investigations may be carried out to facilitate the diagnostic assessment of patients with LUTSs due to BPH, and these include urinalysis, urine cultures if infection is suspected, and serum creatinine to assess renal function and establish possible upper urinary tract damage. The measurement of serum prostate-specific antigen (PSA) can be considered after counselling the patient, particularly if DRE reveals a nodular or hard prostate.

Treatment

Most men over the age of 50 years exhibit some of the symptoms of BPH. The range of treatment options for the management of BPH includes watchful waiting, medical therapies and surgical interventions. The key issue, therefore, is deciding who should be treated and when.

The British Association of Urological Surgeons has published guidelines for the management of BPH in primary care (Speakman et al., 2004), focussing on when urological referral is required and when non-invasive treatment can be initiated (Fig. 48.3).

image

Fig. 48.3 Algorithm for the treatment of lower urinary tract symptoms (LUTSs) in males in primary care (from Speakman et al., 2004) (DRE, digital rectal examination; MSU, mid-stream urine sample; PSA, prostate-specific antigen).

Watchful waiting

Men with mild or moderate and not significantly bothersome LUTSs should be offered a trial of watchful waiting. This management strategy does not include any medical or surgical treatment but involves regular active monitoring. In some cases, symptoms remain unchanged for years and no further interventions are necessary since disease progression is minimal. Patients that adopt this modality should be offered education and lifestyle advice (Box 48.1) to manage their urological symptoms together with a review of their medication, particularly diuretics or other medicines known to affect the urinary system.

Box 48.1 Advice for the management of lower urinary tract symptoms

Limit fluid consumption before going out and before going to bed (to reduce urinary frequency and nocturia)
Reduce alcohol and caffeine intake
Schedule toilet visits
Manage constipation
Review medication (including diuretics and other medicines that can affect the urinary system)
Bladder training (encourage patient to go longer between voiding and increase the volume voided)
Use distraction techniques (practice breathing exercises and penile squeezing to control symptoms of irritation)

Therapeutic management

The principal treatment options are α-adrenoceptor blocking drugs, 5α-reductase inhibitors and combination therapy. Phytotherapy is also used in the management of BPH, although the benefits remain unproven.

α-Adrenoceptor blocking drugs

The prostate gland is very responsive to adrenergic stimulation. In fact, prostatic outlet obstruction in BPH is partly due to the hypertrophied bulk of the gland, but it also arises from an increase in adrenergic tone. In the prostate, α1-receptors predominate and mediate the contraction of the gland’s smooth muscle. At least three subtypes of this receptor exist (α1A, α1B and α1D). The α1A is thought to be the dominant receptor in the prostate, although its role clinically has still to be confirmed. This increase in sympathetic tone is potentially reversible by α-adrenoceptor antagonists.

In general, all the agents are considered to produce similar clinical improvements of LUTSs and urinary flow. Benefits can be seen usually within the first few days of therapy and can be maintained in the long-term. α-Adrenoceptor antagonists also have a comparable side-effect profile, which includes postural hypotension, dizziness, fatigue, headache, drowsiness, nasal congestion and ejaculatory dysfunction.

Patients with BPH frequently experience erectile and ejaculatory dysfunction. The treatment of BPH should also aim to improve sexual function. However, the effect of α1-adrenoceptor antagonists on male sexual function is variable and influenced by the choice of agent and patient characteristics (Van Dijk et al., 2006).

Prazosin

Prazosin was the first α1-blocker used to relieve the symptoms of BPH but it lacks relative selectivity for α1A receptors and has been associated with many adverse affects such as drowsiness, weakness, headache and postural hypotension (especially after the first dose).

Terazosin

Terazosin was the first in the category to appear in controlled trials aimed at evaluating the efficacy and safety profile of long acting α1-blockers in the management of BPH. Efficacy is dose dependant and dose titration is necessary, as terazosin can cause postural hypotension. Adverse effects, although generally mild, occur more frequently than with other α1-adrenoceptor antagonists, resulting in up to a fourfold increase in treatment discontinuation.

Indoramin

Indoramin is readily absorbed from the gastro-intestinal tract and undergoes extensive first-pass hepatic metabolism. Its hypotensive effect may be increased by diuretics and other anti-hypertensive agents. Alcohol has been reported to increase the bioavailability and sedative effects of indoramin.

Doxazosin

Doxazosin has a long half-life of about 22 h, which allows for once-daily dosing. When starting treatment, dose titration is recommended to limit postural hypotension. There would appear to be no significant difference in symptom score regardless of whether the standard or controlled-release preparation is used (Kirby et al., 2001).

Tamsulosin

Tamsulosin is a selective inhibitor of the α1A– and α1B-adrenoceptor. It has an elimination half-life of about 13 h and is available as a prolonged release formulation that allows once-daily dosing. There is no requirement to titrate the dose upward when initiating treatment. Although the side-effect profile of tamsulosin is similar to other α1-adrenoceptor antagonists, it is normally well tolerated (O’Leary, 2001). Intraoperative floppy iris syndrome (IFIS) has been reported during cataract surgery in men treated with tamsulosin, as it is highly selective to iris dilator muscle (Chaim et al., 2009). IFIS can lead to complications and poor outcomes during cataract surgery. As a result, it is essential that patients inform their cataract surgeon that they are taking tamsulosin during the pre-operative assessment. It has been recommended to avoid starting treatment and to discontinue treatment with tamsulosin 1–2 weeks before cataract surgery.

Alfuzosin

Alfuzosin displays a higher selectivity for the prostate compared with tamsulosin or doxazosin. It has a half-life of 5 h, but it is available as a once-daily formulation. It has a rapid onset of action and good tolerability (MacDonald and Wilt, 2005). It reduces the overall clinical progression of BPH and it appears to have a sustained beneficial effect on quality of life (Roehrborn, 2006). Alfuzosin has the least effect on ejaculatory function. Alfuzosin should not be co-administered with potent inhibitors of cytochrome P450 3A4 such as itraconazole, ketoconazole and ritonavir, since this can lead to a several fold increase to exposure in alfuzosin.

5α-Reductase inhibitors

The primary androgen responsible for the development and progression of BPH is DHT. There are two isoenzymes of 5α-reductase: type 1 is found in most 5α-reductase producing tissues such as the liver, skin and hair; type 2 is predominant in genital tissue, including the prostate. 5α-Reductase inhibitors downregulate prostate growth by blocking the conversion of testosterone to the more potent DHT.

The two agents currently available in this group are finasteride and dutasteride. Both have been shown to reduce prostate volume, to improve symptom scores and flow rates, and reduce the incidence of complications such as acute urinary retention (AUR) and the need for surgical intervention to treat BPH (Roehrborn et al., 2000, 2002). Improvements in LUTSs are normally seen after the first 6 months of treatment and are sustained during continuous treatment (Lam et al., 2003).

Finasteride

Finasteride is a type 2, 5α-reductase inhibitor that can reduce prostate size by about 30%, improve symptom scores and increase urinary flow. Those most likely to benefit are men with a prostate larger than 40 mL. Side effects include decreased libido, impotence, reduced ejaculatory volume and, less commonly, gynaecomastia and breast tenderness. Serum concentrations of PSA may be reduced by 50% in the first year of treatment with finasteride, a fact which must be taken into account when attempting to interpret the PSA concentration in men with suspected PC.

Dutasteride

Dutasteride inhibits both type 1 and type 2 isoenzymes of 5α-reductase. Although the clinical significance of this is unclear, this double inhibition can reduce serum dihydotestosterone levels by about 90%. Dutasteride decreases prostate volume by up to 26% and reduces the risk of progression to serious complications of BPH. LUTSs also improve after 6 months of treatment. Dutasteride is well tolerated although side effects which include erectile and ejaculatory dysfunction and breast enlargement occur with similar frequency to finasteride.

Combination therapy

It is well established that α-adrenoceptor antagonists are best for managing acute symptoms but have no impact on reducing the risk of complications such as AUR or progression to prostate surgery. In contrast, 5α-reducatase inhibitors have little impact on short-term acute symptoms but reduce prostate size, improve urinary flow and obstructive symptoms in the long-term. Furthermore, α-adrenoceptor antagonists are effective regardless of prostate volume, whereas the 5α-reductase inhibitors are more suited for the management of LUTSs in men with large prostates. In terms of long-term benefits, continued treatment with 5α-reductase inhibitors decreases the risk of AUR and BPH-related surgery. Therefore, it appears logical to use a combination of an α-adrenoceptor antagonist and a 5α-reductase inhibitor to manage acute symptoms and reduce progression of BPH.

The benefits of using a combination of doxazosin and finasteride compared to monotherapy have been demonstrated in over 3000 men (McConnell et al., 2003). Similarly, the combAT trial (Roehrborn et al., 2010) involved nearly 5000 men with moderate to severe symptoms of BPH and prostate enlargement treated with a combination of dutasteride and tamsulosin. This study demonstrated a significant improvement in BPH symptoms over a 4-year period when compared to either agent used alone. The combination was also found to reduce AUR and progression to BPH-related surgery and, although superior to tamsulosin with respect to these complications, combination therapy was not better than dutasteride. Overall, the adverse events associated with combination therapy were few and treatment was well tolerated.

Combination therapy with an α-adrenoceptor antagonist and a 5α-reductase inhibitor has now been adopted widely into routine practice for the early management of LUTSs and to reduce progression of BPH.

Phytotherapy

A number of plant extracts are reputed to be effective in the management of symptoms of BPH. They include saw palmetto berry (Serenoa repens), African plum tree (Pygeum africanum), stinging nettle (Urtica dioica) and rye grass pollen. Their mechanism of action remains unclear but may exert an anti-inflammatory effect by inhibition of prostanoid formation and perhaps produce some degree of inhibition of 5α-reductase. Most of the data available to support the use of plant extracts derive from poorly designed studies. As evidence to assess efficacy and safety is lacking, phytotherapy remedies are not currently recommended by international guidelines for the management of BPH.

Surgical treatments

Surgical interventions are commonly performed in men with LUTSs caused by BPH that have failed to respond to medical treatment. Surgery is also indicated in patients who develop complications such as intractable or recurrent urinary retention, renal impairment, persistent haematuria, recurrent UTIs or bladder stones.

Transurethral resection of the prostate

Transurethral resection of the prostate (TURP) is a common and effective procedure which achieves a high level of improvement in symptoms and flow rate. It is the preferred surgical intervention in men with a prostate volume between 30 and 80 mL. Sections of prostate are removed using electrical wire loops attached to a tube-like telescope (resectoscope) inserted into the urethra. The tissue removed is collected for histological assessment. There is a small incidence of perioperative mortality associated with TURP along with complications such as bleeding, UTIs and epididymitis. Long-term complications include stress incontinence, urethral and bladder neck strictures and erectile dysfunction.

Open prostatectomy

Open prostatectomy involves the surgical removal of an enlarged prostate. Typically, an incision is made through the lower abdomen although sometimes the incision is between the rectum and the base of the penis. This procedure is now performed infrequently and restricted to very enlarged prostate glands (larger than 100 mL) and those with large bladder stones or bladder diverticula (Stoevelaar and McDonnell, 2001). Open prostatectomy requires a longer hospital stay than transurethral resection and is associated with a higher incidence of bleeding and other complications.

Minimally invasive techniques

Various treatment modalities have been tried as alternatives to TURP to reduce the risks associated with resection. Thermotherapy and laser technology are the most commonly used. Thermotherapy uses techniques such as electrovaporisation and transurethral microwave heat treatment (TUMT), which heats the prostate to cause vaporisation of the tissue. Various types of laser energy can also be used to destroy prostatic tissue mainly by coagulation or vaporisation.

Patient care

Patients generally seek medical help for BPH because of the impact of symptoms on their quality of life. Most men tolerate a high degree of symptoms and impact on daily activities before they seek help. Table 48.1 lists some common therapeutic problems in the management of BPH. Patients should receive information about the management options available, the investigations that they need to undergo and possible treatment outcomes and adverse effects. Patients receiving drug therapy should receive specific information about their treatment, including potential benefits, timeline of expected outcomes and possible side effects.

Table 48.1 Common therapeutic problems and proposed management strategies in benign prostatic hyperplasia

Problem Solution
Patient taking α-blocker still symptomatic after 2 weeks Patients should be advised that it may take 2–6 weeks before symptomatic treatment relief is seen
Patient taking an α-adrenoceptor blocker complains of cardiovascular adverse effects such as dizziness, syncope, palpitations, tachycardia or angina These side effects are more likely in elderly patients. They are most common after the first dose and reflect the hypotensive effects of the drugs. They can be reduced by titrating the dose or using more uroselective drugs such as tamsulosin
Sexual dysfunction Decreased libido or impotence can occur in patients taking finasteride and dutasteride. Abnormal ejaculation can be caused by α-blockers. Tamsulosin in particular can cause a dry climax (retrograde ejaculation). Patients should be forewarned when discussing treatment options
Patient taking finasteride notices breast enlargement Unilateral or bilateral gynaecomastia is a frequently reported side effect with finasteride and patients need to be counselled accordingly when discussing treatment options
Patient taking finasteride or dutasteride has a sexual partner who is pregnant Exposure to semen should be avoided as both drugs can cause abnormalities to genitalia in a male fetus. The patient should be advised to use a condom

There are two websites which produce particularly useful educational material on prostatic disease: the Men’s Health Forum (http://www.menshealthforum.org.uk/) and the Prostate Research Campaign (http://www.prostateuk.org/index.htm).

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