Benign Prostatic Hyperplasia (BPH)

BACKGROUND

Benign prostatic hyperplasia (BPH) is a condition intimately related to ageing . Although it is not lifethreatening, its clinical manifestation as lower urinary tract symptoms (LUTS) reduces the patient's quality of life. Troublesome LUTS can occur in up to 30% of men older than 65 years . Prevalence Although many epidemiological clinical studies have been conducted worldwide over the last 20 years, theprevalence of clinical BPH remains difficult to determine. A standardized clinical definition of BPH is lacking, which makes it intrinsically difficult to perform adequate epidemiological studies. Among the published epidemiological studies, some include probability samples from an entire country, while others represent agestratified random samples or enroll participants from general practice, hospital populations or responders to selective screening programmes. There is also a lack of homogeneity among these studies in the way in which BPH is assessed, with different questionnaires and methods of administration. Barry et al. have provided the histological prevalence of BPH, based on a review of five studies relating age to histological findings in human male prostate glands .
Histological BPH was not found in men under the age of 30 years but its incidence rose with age, reaching a peak in the ninth decade. At that age, BPH was found in 88% of histological samples. A palpable enlargement of the prostate has been found in up to 20% of males in their 60s and in 43% in their 80s; however, prostate enlargement is not always related to clinical symptoms . Clinical BPH is a highly prevalent disease. By the age of 60 years, nearly 60% of the cohort of the Baltimore Longitudinal Study of Aging had some degree of clinical BPH.
In the USA, results of the Olmstead County survey, in a sample of unselected Caucasian men aged 40-79 years, showed that moderate-to-severe symptoms can occur among 13% of men aged 40-49 years and among 28% of those older than 70 years. In Canada, 23% of the cohort studied presented with moderate-to-severe symptoms. The findings for prevalence of LUTS in Europe are similar to those in the USA. In Scotland and in the area of Maastricht, the Netherlands, the prevalence of symptoms increased from 14% of men in their 40s to 43% in their 60s. Depending on the sample, the prevalence of moderate-to-severe symptoms varies from 14% in France to 30% in the Netherlands. The proportion of men with moderate-to-severe symptoms doubles with each decade of life.
Preliminary results of one of the most recent European epidemiological studies on the prevalence of LUTS show that approximately 30% of German males aged 50-80 years present with moderateto-severe symptoms according to the International Prostate Symptom Score (I-PSS > 7). A multicentre study performed in different countries in Asia showed that the age-specific percentages of men with moderate-to-severe symptoms were higher than those in America. The prevalence increases from 18% for men in their 40s to 56% for those in their 70s. Curiously, the average weight of Japanese glands seemed to be smaller than those of their American counterparts. Despite methodological differences, some conclusions can be drawn from the studies mentioned above:
· Mild urinary symptoms are very common among men aged 50 years and older
· Mild symptoms are associated with little bother, while moderate and severe symptoms are associated with increasingly higher levels of inconvenience and interference with living activities
· The same symptoms can cause different troublesome and daily living interference
· The correlation between symptoms, prostate size and urinary flow rate is relatively low It must be stressed that there is still a need for an epidemiological definition of BPH and its true incidence has yet to be determined.

Risk factors for developing the disease

The aetiology of BPH is multifactorial. Currently, there is no strong evidence that smoking, vasectomy, obesity or high alcohol intake are risk factors in the development of clinical BPH. Results of the different epidemiological studies are controversial, probably because of differences in sampling and methods of analysis. In most cases only insufficient marginal differences can be established. Chronic conditions, such as hypertension or diabetes, have been related to clinical BPH, but given the frequent occurrence of these conditions in ageing men a large proportion of patients can be expected to suffer from such an association. Recently, it has been stated that diabetes and clinical BPH are associated more frequently than would be expected based on chance alone. Although more severe BPH symptoms seem to be found in diabetic males even after age adjustment, the fact that both conditions increase with age and can cause partially similar voiding symptoms, produces a considerable bias. The only true factors related to the development of the disease are age and hormonal status. The crucial role of the testis has been recognized for more than a century and current research has extended into the field of molecular biology. Both of these risk factors are currently beyond prevention.

Is BPH a progressive disorder?

As it is almost impossible to obtain agreement on what it is that defines a man with LUTS/BPH, it seems logical to say that progression cannot be defined in terms of a transition from non-cases to cases. Instead, progression must be measured by documenting deterioration in any number of physiological variables that we associate with the LUTS/BPH syndrome. Traditionally these have included the following:

• decrease in maximum flow rate
• increase in residual volume
• increase in prostate size
• deterioration (increase) in symptom score.

In addition, definable events, such as the occurrence of acute urinary retention or prostate surgery, have been used. Less commonly, changes in urodynamic variables and deterioration in disease-specific quality of life have been advocated. Considerable interest currently rests with PSA. It appears to be as good a predictor of progression as any of the variables mentioned above.

Indicators of progression

Risk factors for progression were found to be age , PSA and prostate volume (combined 2-year placebo analysis). Other baseline risk factors can be identified, such as symptom severity and decreased urinary flow rate, but current data are not as convincing as those for age, PSA level and prostate volume. Several other complications, such as renal impairment and bladder dysfunction, have been associated with progression of BPH. Although these are important, they are very rare and therefore could not be evaluated accurately in community-based and clinical studies.

ASSESSMENT

Symptom scores Probably the best way to assess symptom severity is with a validated symptom score A number of instruments exist that can measure symptom severity, bother and quality of life. Most instruments in current use conform to acceptable standards of validity, reliability and responsiveness; in other words they measure what they purport to measure, are stable over time and are able to reflect clinically important changes

1) International Prostate Symptom Score (I-PSS) By adding the scores (with equal weighting) to its constituent questions, a summary or index score is generated which has been shown to be an accurate reflection of a man's overall symptoms over the preceding month

2) Quality-of-life assessment It is a self-completed questionnaire used to measure general health status and quality of life.


Prostate-specific antigen (PSA) measurement
• Various factors (cancer, BPH, infection, trauma, age) may influence serum PSA levels
• the level of PSA correlates with the volume of the prostate gland
• the PSA level might predict the natural history of BPH


Digital rectal examination (DRE)

Digital rectal examination (DRE) is an important examination in men with LUTS for two reasons. Firstly, it can help to determine the co-existence of prostatic carcinoma. Secondly, it enhances the capacity to estimate prostate volume, and in this way may assist in choosing the right treatment, as prostate size has been shown to be a determining factor for certain treatment options.

Imaging of the urinary tract

Imaging of the entire (including the upper) urinary tract, particularly prior to prostate surgery, has been an integral part of the diagnostic assessment of elderly men with LUTS due to BPH during past decades. In parallel with endoscopy, the role of routine imaging of the upper and lower urinary tract in all patients with LUTS has been increasingly questioned in recent years. Ideally, an imaging modality for patients with LUTS should provide both imaging of the urinary tract and demonstrate the morphological effects of prostate pathology upon the rest of the lower and/or upper urinary tract.
The prostate can be imaged using:
•TAUS (trans abdominal ultrasound)
•TRUS (trans rectal ultrasound)
•Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) (including transrectal MRI).

Uroflowmetry

Uroflowmetry is recommended as a diagnostic assessment in the work-up of patients with LUTS and is an obligatory test prior to surgical intervention. It is a simple, non-invasive test that can reveal abnormal voiding. Flow rate machinery provides information on voided volume, maximum flow rate (Qmax), average flow (Qave) and time to Qmax, and this information should be interpreted by the physician to exclude artifacts. Serial flows (two or more) with a voided volume exceeding 150 mL are recommended to get a representative flow rate.

MANAGEMENT

Watchful waiting-behavioural treatment

Many men with LUTS do not complain of high levels of bother and are therefore suitable for non-medical and non-surgical management a policy of care known as watchful waiting (WW). It is customary for this type of management to include the following components: education, reassurance, periodic monitoring, and lifestyle advice. In many patients, it is regarded as the first tier in the therapeutic cascade and most men will have been offered WW at some point. Watchful waiting is a viable option for many men as few, if left untreated, will progress to acute urinary retention and complications such as renal insufficiency and stones . Similarly, some men's symptoms may improve spontaneously, while others' symptoms remain stable for many years.

Patient selection

All men with LUTS should be formally assessed prior to starting any form of management in order to identify those with complications that may benefit from intervention therapy. Men with mild to moderate uncomplicated LUTS (causing no serious health threat), who are not too bothered by their symptoms, are suitable for a trial of WW Approximately 85% of men will be stable on WW at 1 year, deteriorating progressively to 65% at 5 years. The reason why some men deteriorate with WW and others do not is not well understood.

Education, reassurance, and periodic monitoring

There now exists level of evidence that self-management as part of WW reduces both symptoms and progression- Nobody is quite sure which key components of self-management are effective, but most experts believe the key components are:

• education about the patient's condition
• reassurance that cancer is not a cause of the urinary symptoms
• framework of periodic monitoring.

The precise role of lifestyle advice in conferring benefit seen in the studies reported to date remains uncertain. Minor changes in lifestyle and behaviour can have a beneficial effect on symptoms and may prevent deterioration requiring medical or surgical treatment. Lifestyle advice can be obtained through informal and formal routes. If it is offered to men, it should probably comprise the following:

• Reduction of fluid intake at specific times aimed at reducing urinary frequency when most inconvenient, e.g. at night or going out in public. The recommended total daily fluid intake of 1500 mL should not be reduced.
• Avoidance or moderation of caffeine and alcohol which may have a diuretic and irritant effect, thereby increasing fluid output and enhancing frequency, urgency and nocturia.
• Use of relaxed and double-voiding techniques.
• Urethral stripping to prevent post-micturition dribble.
• Distraction techniques, such as penile squeeze, breathing exercises, perineal pressure and mental 'tricks' to take the mind off the bladder and toilet, to help control irritative symptoms.
• Bladder re-training, by which men are encouraged to 'hold on' when they have sensory urgency to increase their bladder capacity (to around 400 mL) and the time between voids.
• Reviewing a man's medication and optimising the time of administration or substituting drugs for others that have fewer urinary effects.
• Providing necessary assistance when there is impairment of dexterity, mobility or mental state
• Treatment of constipation.

MEDICAL TREATMENT

Adrenoceptor antagonists ( alfa-blockers)

Mechanism of action
Historically, it was assumed that alfa-blockers act by inhibiting the effect of endogenously released noradrenaline on prostate smooth muscle cells, thereby reducing prostate tone and bladder outlet obstruction. Contraction of the human prostate is mediated predominantly, if not exclusively, by 1A-adrenoceptors. However, it has been shown that alfa-blockers have little effect on urodynamically determined bladder outlet resistance and treatment-associated improvement of LUTS is correlated only poorly with obstruction. Hence, there has been a lot of discussion about the role of alfa-1-adrenoceptors located outside the prostate (e.g. in the urinary bladder and/or spinal cord) and other alfa-adrenoceptor subtypes (alfa-1B- or alfa-1D-adrenoceptors) as mediators of beneficial effects of alfa-blockers. Alfa-1-adrenoceptors in blood vessels, other non-prostatic smooth muscle cells, and central nervous system are considered to be mediators of side-effects during alfa-blocker treatment, and all three receptor subtypes seem to be involved. This concept has favoured the use of alfa-1A-selective adrenoceptor antagonists. However, it remains to be determined whether alfa-1A-selectivity is the only and main factor determining good tolerability.

Available drugs
Following the early use of phenoxybenzamine and prazosin in BPH-LUTS treatment, four alfa-blockers are currently mainly used:
• alfuzosin HCL (alfuzosin)
• doxazosin mesylate (doxazosin)
• tamsulosin HCL (tamsulosin)
• terazosin HCL (terazosin)

Efficacy
Indirect comparisons between alfa-blockers, and limited direct comparisons, demonstrate that all alfa-blockers have a similar efficacy in appropriate doses. Controlled studies have shown that -blockers typically reduce the International Prostate Symptom Score (IPSS), after a run-in period, by approximately 35-40% and increase the maximum urinary flow rate (Qmax) by approximately 20-25%. Although these improvements take a few weeks to develop fully, statistically significant efficacy over placebo was demonstrated within hours to days. Alfa-blocker efficacy does not depend on prostate size and is similar across age groups and they do not reduce prostate size.

Side effects
The most frequent side-effects of alfa-blockers are asthenia, dizziness and (orthostatic) hypotension. Although a reduction in blood pressure may benefit hypertensive patients, at least some of the observed asthenia and dizziness can be attributed to a decrease in blood pressure

Practical considerations
Alfa-blockers represent the first-line drug treatment of male LUTS. All alfa-blockers are available in formulations, which are suitable for once-daily administration. To minimise adverse events, it is recommended that dose titration is used to initiate treatment with doxazosin and terazosin; however, this is not necessary with alfuzosin and tamsulosin. Because of their rapid onset of action, alfa-blockers can be considered for intermittent use in patients with fluctuating intensity of symptoms not needing long-term treatment.

5 alfa-reductase inhibitors

Mechanism of action Androgen effects on the prostate are mediated by dihydrotestosterone (DHT), which is converted primarily in the prostatic stroma cells from its precursor testosterone by the enzyme 5 alfa-reductase, a nuclear-bound steroid enzyme. Two isoforms of this enzyme exist:

· 5alfa-reductase type 1, with minor expression and activity in the prostate but predominant activity in extraprostatic tissues, such as skin and liver

· 5 alfa-reductase type 2, with predominant expression and activity in the prostate.

Finasteride inhibits only 5 alfa-reductase type 2, whereas dutasteride inhibits 5alfa-reductase types 1 and 2 with similar potency (dual 5 alfa-reductase inhibitor). However, the clinical role of dual inhibition remains unclear.

5 alfa-reductase inhibitors act by inducing apoptosis of prostate epithelial cells leading to prostate size reduction of about 15-25% and circulating PSA levels of about 50% after 6-12 months of treatment. Mean prostate volume reduction may be even more pronounced after long-term treatment.

Available drugs

Two 5 alfa-reductase inhibitors are available for clinical use: dutasteride and finasteride. The elimination half-time is longer for dutasteride (3-5 weeks). Both 5 alfa-reductase inhibitors are metabolised by the liver and excreted in the faeces. Continuous treatment reduces the serum DHT concentration by approximately 70% with finasteride and 95% with dutasteride. However, prostate DHT concentration is reduced to a similar level (85-90%) by both 5 alfa-reductase inhibitors.

Efficacy

Clinical effects relative to placebo are seen after minimum treatment duration of at least 6 to 12 months. After 2 to 4 years of treatment, 5 alfa-reductase inhibitors reduce LUTS (IPSS) by approximately 15-30%, decrease prostate volume by approximately 18-28% and increase Qmax of free uroflowmetry by approximately 1.5-2.0 mL/s in patients with LUTS due to prostate enlargement.

The precise mechanism of action of 5 alfa-reductase inhibitors in reducing disease progression remains to be determined, but it is most likely attributable to reduction of bladder outlet resistance.

Due to the slow onset of action, 5 á -reductase inhibitors are only suitable for long-term treatment (many years). Their effect on the serum PSA concentration needs to be considered for prostate cancer screening.

Tolerability and safety

The most relevant adverse effects of 5 alfa-reductase inhibitors are related to sexual function and include reduced libido, erectile dysfunction and, less frequently, ejaculation disorders, such as retrograde ejaculation, ejaculation failure, or decreased semen volume. The incidence of sexual dysfunction and other adverse events is low and even decreased with trial duration. Gynaecomastia (breast enlargement with breast or nipple tenderness) develops in approximately 1-2% of patients.

Muscarinic receptor antagonists

Mechanism of action

The predominant neurotransmitter of the urinary bladder is acetylcholine that is able to stimulate muscarinic receptors (m-cholinoreceptors) on the surface of detrusor smooth muscle cells. However, muscarinic receptors are not only densely expressed on smooth muscle cells but also on other cell types, such as epithelial cells of the salivary glands, urothelial cells of the urinary bladder, or nerve cells of the peripheral or central nervous system. Five muscarinic receptor subtypes (M1-M5) have been described in humans, of which the M2 and M3 subtypes are predominantly expressed in the detrusor. Although approximately 80% of these muscarinic receptors are M2 and 20% M3 subtypes, only M3 seems to be involved in bladder contractions in healthy humans. The role of M2 subtypes remains unclear. However, in men with neurogenic bladder dysfunction and in experimental animals with neurogenic bladders or bladder outlet obstruction M2 receptors seem to be involved in smooth muscle contractions as well. The detrusor is innervated by parasympathic nerves which have their origin in the lateral columns of sacral spinal cord on the level S2-S4 which itself is modulated by supraspinal micturition centres. The sacral micturition centre is connected with the urinary bladder by the pelvic nerves which release acetylcholine after depolarisation. Acetylcholine stimulates postsynaptic muscarinic receptors leading to G-protein mediated calcium release in the sarcoplasmatic reticulum and opening of calcium channels of the cell membrane and,

finally, smooth muscle contraction. Inhibition of muscarinic receptors by muscarinic receptor antagonists inhibit/decrease muscarinic receptor stimulation and, hence, reduce smooth muscle cell contractions of the bladder. Antimuscarinic effects might also be induced or modulated by the urothelium of the bladder and/or by the central nervous system .

Available drugs

The following muscarinic receptor antagonists are licensed for treating overactive bladder/storage symptoms in men and women :

· darifencacin hydrobromide (darifenacin)

· fesoterodine fumarate (fesoterodine)

· oxybutynin HCL (oxybutynin)

· propiverine HCL (propiverine)

· solifenacin succinate (solifenacin)

· tolterodine tartrate (tolterodine)

· trospium chloride.

This drug class is still officially contraindicated in men with BPH/bladder outlet obstruction due to the possibility of incomplete bladder emptying or development of urinary retention.

Efficacy

Although studies in elderly men with LUTS and overactive bladder symptoms were exclusively carried out with tolterodine or fesoterodine it is likely that similar efficacy and adverse events will also appear with other antimuscarinic agents. Long-term studies on the efficacy of muscarinic receptor antagonists in men with LUTS are still missing; therefore, these drugs should be prescribed with caution, and regular re-evaluation of IPSS and post-void residual urine is advised.

Phytotherapy

Mechanism of action

Phytotherapy comprises the medical use of various extracts of different plants. It remains controversial which components of the extracts are responsible for symptom relief in male LUTS. The most important compounds are believed to be phytosterols, fatty acids, and lectins. In vitro studies have shown that plant extracts:

· have anti-inflammatory, antiandrogenic, or oestrogenic effects

· decrease sexual hormone binding globulin (SHBG)

· inhibit aromatase, lipoxygenase, growth-factor stimulated proliferation of prostatic cells, alfa-adrenoceptors, 5 alfa-reductase, muscarinic cholinoceptors, dihydropyridine receptors, or vanilloid receptors

· improve detrusor function

· neutralize free radicals

However, most in vitro effects have not been confirmed in vivo and the precise mechanisms of action of plant extracts remain unclear.

Available drugs

Herbal drug preparations are made of roots, seeds, pollen, bark, or fruits of a single plant (monopreparations); others combine the extracts of two or more plants to one pill (combination preparations). A large number of different plants are used for the preparation of extracts. The most widely used plants are:

· Cucurbita pepo (pumpkin seeds)

· Hypoxis rooperi (South African star grass)

· Pygeum africanum (bark of the African plum tree)

· Secale cereale (rye pollen)

· Serenoa repens (syn. Sabal serrulata; berries of the American dwarf palm, saw palmetto)

· Urtica dioica (roots of the stinging nettle).

Different producers use different extraction techniques, distribute active ingredients with different qualitative and quantitative properties, or combine two or more herbal compounds in one pill. The extracts of the same plant produced by different companies do not necessarily have the same biological or clinical effects so that the effects of one brand cannot be extrapolated to others . To complicate matters, even two different batches of the same producer might contain different concentrations of active ingredients and cause different biological effects.Thus, the pharmacokinetic properties can differ significantly between different plant extracts

Tolerability and safety

Side-effects during phytotherapy are generally mild and comparable to placebo with regard to severity and frequency. Serious adverse events were not related to study medication. Gastrointestinal complaints were the most commonly reported side-effects. In formulations with Hypoxis rooperi ; erectile dysfunction appeared in 0.5% of patients. Trial withdrawals were almost equal in both placebo and phytotherapy groups.

Practical considerations

Phytotherapeutic agents are a heterogeneous group of plant extracts used to improve BPH-LUTS.

Phytotherapy remains problematic to use because of different concentrations of the active ingredient(s) in different brands of the same phytotherapeutic agent. Hence, meta-analyses of extracts of the same plant do not seem to be justified and results of these analyses have to be interpreted with caution.

New emerging drugs

Phosphodiesterase (PDE) 5 Inhibitors (with or without alfa -blockers)

Mechanism of action

Nitric oxide (NO) represents an important non-adrenergic, non-cholinergic neurotransmitter in the human body and is involved in signal transmission in the human urinary tract. NO is synthesised from the amino acid L-arginine by NO synthases (NOS), which are classified based on their original tissues of detection as neuronal (nNOS), endothelial (eNOS), and immune cells (inducible NOS, iNOS). After being synthesised, NO diffuses into cells and stimulates the synthesis of cyclic guanosine monophosphate (cGMP) mediated by the enzyme guanylyl-cyclase. cGMP can activate protein kinases, ion channels, and cGMP-binding phosphodiesterases (PDEs) leading to smooth muscle cell relaxation via depletion of intracellular Ca2+ and desensitisation of contractile proteins. The effects of cGMP are terminated by PDE isoenzymes catalysing the hydrolysis of cGMP to an inactive form. PDE inhibitors increase the concentration and prolong the activity of intracellular cGMP, hereby reducing smooth muscle tone of the detrusor, prostate, and urethra. Until now, 11 different PDEs have been identified of which the PDEs 4 and 5 are the predominant ones in the transition zone of the human prostate, bladder, and urethra. NO might also be involved in the micturition cycle by inhibiting reflex pathways in the spinal cord and neurotransmission in the urethra, prostate, or bladder .

Available drugs

Three selective oral PDE5 inhibitors (sildenafil , tadalafil, and vardenafil) have been licensed in Europe for the treatment of erectile dysfunction or pulmonary arterial hypertension (sildenafil and tadalafil), but these drugs have not yet been officially registered for the treatment of male LUTS.

The available PDE5 inhibitors differ primarily in their pharmacokinetic profile. All PDE5 inhibitors are rapidly resorbed from the gastrointestinal tract, have a high protein binding in plasma, and are metabolised primarily by the liver and eliminated predominantly by the faeces. However, their half-lives differ markedly. PDE5 inhibitors are taken on-demand by patients with erectile dysfunction but tadalafil is also registered for daily use in lower dose (5 mg) than for on-demand use

Practical considerations

To date, PDE5 inhibitors have been officially licensed only for the treatment of erectile dysfunction and pulmonary arterial hypertension. Treatment beyond this indication (e.g. male LUTS) is still experimental and should not be used routinely in the clinical setting. Long-term experience in patients with LUTS is still lacking. The value of PDE5 inhibitors in the context of other available potent drugs remains to be determined. Insufficient information is available about combinations between PDE5 inhibitors and other LUTS medications.

SURGICAL TREATMENT

Transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP) and open prostatectomy are the conventional surgical options.

Indications for surgery

The most frequent indication for surgical management is bothersome LUTS refractory to medical management. The following complications of BPH are considered strong indications for surgery:

• refractory urinary retention

• recurrent urinary retention

• recurrent haematuria refractory to medical treatment with 5-alpha reductase inhibitors

• renal insufficiency

• bladder stones.

• Increased post-void residual volume

However, there is a great intra-individual variability and an upper limit requiring intervention has not been requiring intervention has not been defined.

Conclusions

Surgery should be considered for those men:

· who are moderately/severely bothered by LUTS, yet who do not improve after non-surgical

(including medical) treatment.

· with bothersome LUTS, who not want medical treatment but who request active intervention.

· with a strong indication for surgery.

In addition:

· Surgical prostatectomy (open, TURP, TUIP) results in significant subjective and objective improvements superior to medical or minimally invasive treatment. All three surgical procedures have been evaluated in randomised controlled trials.

· TUIP is the surgical therapy of choice for men with prostates < 30 mL and no middle lobes

Lasers

The use of lasers to treat BPH has been contemplated since 1986 but was anecdotal until the early 1990s, when Shanberg et al. reported the use of the Nd:YAG laser to perform prostatectomy in 10 patients with BPH, resulting in marked improvement in their voiding symptoms. With the development of the right-angle fibre and the refinement of both equipment and technique, the results of many studies have been published.

However, as far as durability is concerned, long-term follow-up results are only available from initial studies.

Four types of laser have been used to treat the prostate:

• Nd:YAG,

• Holmium:YAG

• KTP:YAG

• Diode.

Energy can be delivered through a bare fibre, right-angle fibre or interstitial fibre. The use of contact lasers using a bare fibre has been abandoned. In addition, energy levels can be varied to achieve coagulation or vaporization.

The difference between coagulation and vaporization is that coagulation causes little vaporization and depends on temperature changes to achieve permanent tissue damage. There is also secondary tissue slough, which is associated with tissue oedema. Vaporization depends upon temperature changes of over 100°C, which cause the tissue to be dehydrated. This effect decreases forward scatter into tissue and may cause less tissue oedema. Interstitial treatments depend on inserting the fibre into the prostatic tissue and the use of coagulation techniques .

Nd:Yag Laser

From 1991 onward, reports describing a TRUS-guided, side-firing Nd:YAG laser instrument (the TULIPTM device) for BPH therapy appeared in the urological literature. These, and other, reports documented the fact that prostatic tissue ablation could be achieved using the Nd:YAG laser. In subsequent years, the TULIPTM device was abandoned and other authors experimented with even greater prostatic tissue ablation using a much simpler side-firing Nd:YAG laser delivery system. This consisted of a gold-plated mirror affixed to the distal end of a standard, flexible, silica-glass, laser transmission fibre (UrolaseTM fibre)

Operative technique

Side-firing laser prostatectomy is performed using Nd:YAG laser light at 1064 nm and relatively high power settings (typically between 40 and 80 W), delivered via an optical fibre equipped with a distal reflecting mechanism. This fibre fits through standard cystoscopes and all laser applications are performed transurethrally under the direct visual control of the surgeon. The operation may be performed under general or regional anaesthesia, or under local peri-prostatic block as described by Leach et al.. The operating time is approximately 45 minutes or less. Optimal tissue ablation is achieved using long-duration (60-90 seconds) Nd:YAG laser applications to fixed spots along the prostatic urethra. These laser applications are repeated systematically and with considerable overlap until all visible obstructing prostatic tissue has been coagulated

Interstitial Laser Coagulation (ILC)

ILC as a therapy for BPH was first mentioned by Hofstetter in 1991. Since then, several variations and technical and procedural developments have been introduced and tested in clinical trials. The objective of ILC of BPH is to achieve marked volume reduction and to decrease urethral obstruction and symptoms. Coagulation necrosis is generated within the adenoma, sparing its urethral surface. As the applicator can be inserted as deeply and as often as necessary, it is possible to coagulate any amount of tissue at any desired location. Post-procedure, the intraprostatic lesions result in secondary atrophy and regression of the prostate lobes rather than sloughing of necrotic tissue.

Operative technique

Fibres employed for ILC must emit laser radiation at a relatively low power density. ILC can be carried out using the transurethral approach, with local, regional or systemic anaesthesia. The laser fibre is introduced from a cystoscope within the urethra. The total number of fibre placements is dictated by the total prostate volume and configuration. As a general guideline, one or two placements are used for each estimated 5-10 cm3 of prostate volume. In general, the sites for fibre placement are chosen according to where the bulk of hyperplastic tissue is found

Holmium laser resection of the prostate (HoLRP)

The Holmium laser (2140 nm) is a pulsed, solid-state laser that has been used in urology for a variety of endourological applications in soft tissues and for the disintegration of urinary calculi. Prostatectomy using this energy source is a relatively new technique with the first patient reports appearing in 1995. The Ho:YAG wavelength is strongly absorbed by water and the zone of coagulation necrosis in tissue is limited to 3-4 mm, sufficient to obtain adequate haemostasis. The peak power achieved results in intense tissue vaporization and in precise and efficient cutting ability in the prostatic tissue.

Operative technique

Instrumentation for this technique includes a 550- ? m end-firing quartz fibre and an 80-W Ho:YAG laser. A continuous flow resectoscope is required with a working element; normal saline is used as the irrigant. The basic principle of the technique consists of retrograde enucleation of the prostate and fragmentation of the enucleated tissue to allow its elimination through the operating channel of the resectoscope .

Conclusions

Laser prostatectomy should be advised for patients who are:

· receiving anticoagulant medication

· unfit for TURP (side-fire or ILC)

· wanting to maintain ejaculation (side-fire or ILC)

· holmium laser prostatectomy is a viable alternative to TURP and irrespective of any anatomical configuration.

Transrectal high-intensity focused ultrasound (HIFU)

Procedure

A beam of ultrasound can be brought to a tight focus at a selected depth within the body, thus producing a region of high energy density within which tissue can be destroyed without damage to the overlying or intervening structures. If the site-intensity is set below the tissue cavitation threshold, the predominant therapeutic effect is the induction of heat. This technique is known as high-intensity focused ultrasound (HIFU). The source for HIFU is a piezoceramic transducer, which has the property of changing its thickness in response to an applied voltage. Theoretically the prostate can be ablated by HIFU via a transabdominal or transrectal route. In clinical use, however, only transrectal HIFU devices are applied for the indication of BPH.

Clinical data are only available for one device, the Sonablate®. This system uses the same 4.0 MHz transrectal transducer for imaging and therapy. The focal length (2.5-4.0 cm) is dependent upon the

crystal used. The site intensity can be varied from 1.260 to 2.200 W/cm2. Within the HIFU beam focus, an ellipsoidal tissue volume approximately 2 mm in diameter and 10 mm in length is destroyed. In order to create a clinically useful volume of necrosis, a multiplicity of laterally or axially displaced individual lesions is generated by physical movement of the sound-head. The histological effect of transrectal HIFU therapy using the Sonablate® on the canine and human prostate has been studied in detail

Conclusions

Transrectal HIFU therapy is the only technique that provides non-invasive tissue ablation; however, general anaesthesia or at least heavy intravenous sedation is required. Improvement of urinary symptoms is in the range 50-60% and Qmax increases by a mean of 40-50%. Long-term efficacy is limited, with a treatment failure rate of approximately 10% per year.

Transurethral needle ablation (TUNA®)

Procedure
The TUNA® device delivers low-level, radio-frequency energy to the prostate via needles inserted transurethrally

Conclusions
TUNA® is a simple and safe technique and can be performed under local anaesthesia in a significant number of patients. It results in an improvement of urinary symptoms in the range 50-60% and Qmax increases by a mean of 50-70%.



Transurethral microwave therapy (TUMT)

The microwave thermotherapy principle

Microwave thermotherapy devices consist of a treatment module that contains the microwave generator with a temperature measurement system and a cooling system. A treatment catheter is connected to the module and inserted into the prostatic urethra. The main difference between the devices available is the design of the urethral applicator. Apart from differences in the construction of the catheter, the characteristics of the applicators differ, significantly affecting the heating profile. The similarity in catheter construction consists of the presence of a microwave antenna positioned in the tip of the catheter just below the balloon. Fluid channels surrounding the catheter provide urethral cooling. Also incorporated in the catheter are one or more temperature sensors that differ in the way in which they measure temperature.

Conclusions

· High-energy TUMT produces significant subjective and objective improvement, with sustained and durable long-term results.

· Morbidity after TUMT consists mainly of the need for catheter drainage after treatment due to urinary retention.

· High-energy TUMT is associated with improved objective results compared with low-energy TUMT, but with increased morbidity.