Benign prostate hyperplasia

節錄自http://www.endotext.org/male/male9/male9.html

ANATOMY

According McNeal’s model of the prostate [7], four different anatomical zones may be distinguished that have anatomo-clinical correlation (Figure 2):

1) The peripheral zone : is the area forming the postero-inferior aspect of the gland and represents 70% of the prostatic volume. It is the zone where the majority (60-70%) of prostate cancers form.

2) The central zone : represents 25% of the prostate volume and contains the ejaculatory ducts. It is the zone which usually gives rise to inflammatory processes (eg prostatitis).

3) The transitional zone : this represents only 5% of the total prostatic volume. This is the zone where benign prostatic hypertrophy occurs and consists of two lateral lobes together with periurethral glands. Approximately 25% of prostatic adenocarcinomas also occur it this zone.

4) The anterior zone : predominantly fibromuscular with no glandular structures.

The prostate weighs approximately 20g by the age of 20 and has the shape of an inverted cone, with the base at the bladder neck and the apex at the urogenital diaphragm [8].The prostatic urethra does not follow a straight line as it runs through the centre of the prostate gland but it is actually bent anteriorly approximately 35 degrees at the verumontanum (where the ejaculatory ducts joins the prostate) [9].

Figure 2. 1= Peripheral Zone, 2= Central Zone, 3= Transitional Zone, 4= Anterior Fibromuscular Zone. B= Bladder, U= Urethra, SV= Seminal Vesicle (adapted from Algaba[10]).

Testosterone

Prostatic epithelial cells express the androgen receptor[31]. From the beginning of embryonic differentiation to pubertal maturation and beyond, androgens are a prerequisite for the normal development and physiological control of the prostate[32]. Androgens also help maintain the normal metabolic and secretory functions of the prostate. They are also implicated in the development of benign prostatic hyperplasia (BPH) and prostate cancer. Androgens do not act in isolation and other hormones and growth factors are being investigated[33].

Androgens also interact with prostate stromal cells which release soluble paracrine factors that are important in the growth and development of the prostate epithelium [4]. These paracrine pathways may be critical in regulation of the balance between proliferation and apoptosis of prostate epithelial cells in the adult[33].

The appropriate balance between testosterone and its 5 α reduced metabolites are key to normal prostate physiology (note the metabolic pathways for androgen metabolism are described in the Chapter 2 on Androgens by D Handelsman). The metabolism of testosterone to dihydrotestosterone (DHT) and its aromatisation to estradiol are recognised as the key events in prostatic steroid response.

Figure 5. Conversion of testosterone to dihydrotestosterone (DHT) by 5α-reductase

Testosterone, to be maximally active in the prostate, must be converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase (Figure 5)[34]. DHT has a much greater affinity for the androgen receptor than does testosterone [35, 36]. DHT is about twice as potent as testosterone in studies of rats at equivalent androgen cconcentrations[37].DHT due to its greater affinity for the androgen receptor may have effects intraprostatically independent of serum fluctuations in serum testosterone levels. [35, 36].

The impact of serum androgen manipulation on prostate tissue hormone levels in normal men is unknown. Studies of men with prostate cancer have suggested that prostatic androgens are preserved in the setting of castration. Tissue androgens might stimulate prostate growth, producing adverse clinical consequences.[38] In a small study of healthy subjects, despite a 94% decrease in serum T with medical castration, intraprostatic T and dihydrotestosterone levels remained 20-30% of control values, and prostate cell proliferation, apoptosis, and androgen-regulated protein expression were unaffected. [38] Future therapies may need to take such findings into account if they are reproduced.

DHT concentrations may remain similar to those in young men in the prostate of elderly men, despite the fact that serum testosterone levels may decline with age[34]. In the prostate, the total level of testosterone is 0.4 ng/g and the total of DHT is 4.5 ng/g[39]. The total concentration of testosterone in the blood (18.2nnmol/L[27]) is approximately 10 times higher than that of DHT. Circulating DHT, by virtue of its low serum plasma concentration and tight binding to plasma proteins, is of diminished importance as a circulating androgen affecting prostate growth.

DISEASE MANIFESTATIONS OF BPH

Lower Urinary Tract Symptoms (LUTS)

Lower urinary tract symptoms (LUTS) suggestive of BPH are highly prevalent and the majority of LUTS in men is produced by BPH, but may be contributed to by a variety of conditions (Fig. 5). LUTS are traditionally divided into voiding or obstructive and storage or irritative symptoms (Table 2). Voiding symptoms are more common, however it is storage symptoms that are most bothersome and have a greater impact on a patient's life[72, 73]. The prevalence of clinical BPH rises with age and approximately 25% of men age 40 or over will suffer from LUTS.

Table 2. Lower Urinary Tract Symptoms

Voiding or Obstructive Symptoms	Storage or Irritative Symptoms
Hesitancy Poor stream Intermittent stream Straining to pass urine Prolonged micturition Sense of incomplete bladder emptying Terminal dribbling	Urinary frequency Urgency Urge incontinence Nocturia

Table 4. A Summary of Diagnosis and Treatment Options in BPH

EVALUATION of LUTS

ESSENTIAL History Digital Rectal Exam (DRE) Urinalysis Serum creatinine PSA, if > 10 year life expectancy International Prostate Symptom Score (IPSS) or AUA symptom index SELECTED Uroflowmetry Imaging – especially if haematuria , UTI , urolithiasis Post Void Residual (PVR) estimation +/-Pressure flow studies +/-Cystoscopy

TREATMENT OPTIONS

MEDICAL THERAPY Phytotherapy Alpha blockers 5 alpha reductase inhibitors SURGERY Transurethral resection of the Prostate (TURP) Transurethral Incision of the Prostate (TUIP) Open prostatectomy Laser prostatectomy/treatment Others viz., TUMT, HIFU, TUNA

International Prostate Symptom Score (IPSS)

The American Urologic Association (AUA) Symptom Index was developed as a standardised instrument to assess the degree of bladder outlet obstruction in men [98]. It is widely used and consists of seven questions that assess emptying, frequency, intermittency, urgency, weak stream and straining with each graded with a score of 0-5. Total score ranges 0-35. The index categorises patients as:

1. Mild (Score 7)
2. Moderate (Score 8-19)
3. Severe (20-35).

The International Prostate Symptom Score (I-PSS) is a modification of the AUA Symptom Index adding a single question assessing the quality of life or bother score based on the patient’s perception of the problem (Figure 8)[114]. Both the AUA and I-PSS questionnaires, although not specific for BPH, prostate volume, urinary flow rate, post-void residual volume or bladder outlet obstruction, have been validated and are sensitive enough to be to be used in the evaluation of symptoms and selection of treatment[115-117]. Many would argue that the bother score is the primary determinant of whether or not a patient proceeds to further treatment.

Figure 8. International Prostate Symptom Score (I-PSS) Sheet[118, 119]

Urodynamics

Urodymanics is a general term for a collection of investigations useful in quantifying the activity of the lower urinary tract during micturition[126]. Complete pressure-flow urodynamics are complex and usually involves fluoroscopy, video recording, bladder and rectal pressure measurement, as well as an assessment of urine flow. The simplest urodymamics are pressure-flow studies, requiring only voiding into a measuring device to obtain flow rates, and may easily be done in the office setting.
With regard to the investigation and diagnosis of conditions underlying LUTS, when considering inexpensive, safe and completely reversible treatments, one may opt to avoid urodynamics studies initially. However, when considering irreversible, expensive or potentially morbid therapy, such studies are considered mandatory. Many patients will not have urodynamics studies based on the first premise above[126]. However, in reality, many surgeons and physicians will have simple pressure-flow studies easily available and will perform these as part of an initial consultation. More complex studies require time and are costly, and so should be reserved for particular situations as discussed below.

Urinary Flow Rate (Uroflowmetry)

Uroflowmetry is considered by some as the single most useful urodynamic technique for the assessment of obstructive uropathy. The purpose of the uroflow examination is to record one or more micturitions that are representative of the patient’s usual voiding pattern. Therefore, more than one micturition is often required and it is necessary to confirm with the patient if the flow was better, worse or about the same as their normal pattern, otherwise intra-individual variability may lead to false assumptions[127]. The study may be performed in the office or as part of other urodynamic studies in the laboratory or operating suite.
Figure 9 indicates the most common urinary flow parameters measured. Of these, the peak flow rate is the most closely correlated with the extent of outflow obstruction (Table 10). Total voiding time is prolonged in obstruction and has a reduced Qmax. Poor detrusor contractility is impossible to distinguish from bladder outflow obstruction on uroflowmetry so other urodynamics investigations such as a cystometry are indicated.

Figure 9. Uroflowmetry in a normal individual- diagram above and actual reading below.

Figure 10. Abnormal patterns of uroflowmetry: A) This is likely to represent the flowmetry pattern of a patient with bladder outlet obstruction. The maximum flow reached is around 10ml/sec and the flow rate is prolonged. A diagnosis cannot be made from this reading alone but is certainly characteristic of someone with obstructed voiding and having normal detrusor muscle function. B) This pattern of intermittent flow usually represents abdominal straining in an attempt to overcome outflow obstruction. The peak flow rate may be normal or high, especially if outlet resistance is reduced.

Table 10. Interpretation of Uroflowmetry Results

Flow rate- Qmax	Interpretation
>15ml/sec	Unlikely to be significant obstruction
<10ml/sec	Likely to be significant obstruction or weak detrusor activity
10-15ml/sec	Equivocal

Urodynamics- presssure-flow studies

Various measurements may be used to define detrusor pressures (e.g. Abram-Griffiths nomogram) and urethral sphincter pressures as an aid to diagnosis in specific circumstances. This is relevant in patients with LUTS who have had a stroke (or other neurologic disease) where bladder function may have sensory deficits or unstable detrusor contractions, that may need alternate management. Nevertheless, detrusor instability is not considered a negative factor with respect to the outcome of BPH surgery[111], provided it is adequately managed. Some have even suggested that the detection of detrusor instability in patients with LUTS is only of minor diagnostic importance[128].

There is no evidence that pressure-flow studies should be mandatory prior to surgical (or medical) intervention. However, prior to transurethral resection of the prostate (TURP) it has been recommended that the following patients undergo pressure-flow studies:

1. Previous unsuccessful invasive treatment of LUTS
2. Elderly men (>80 years old), because of the risk of alternate pathology other than bladder outlet obstruction and operative morbidity
3. Younger men (less than 50 years old) because of the risk of retrograde ejaculation and alternate diagnosis
4. Neurogenic bladder suspected
5. Previous radical pelvic surgery
6. Post void residual of greater than 300ml (not on one reading)

MEDICAL THERAPY FOR BPH

The first line of medical treatment is an α-blocker, as the majority of patients treated have a prostate volume of less than 40ml. 

1. Prazosin (titrated up to 5mg day) 
2. Alfuzosin (5 mg bid or10 mg daily) 
3. Terazosin (2-10mg)  
4. Tamsulosin (0.4 mg once daily dose) 
5. Doxazosin (4-12mg/day) 

PS. In a meta-analysis, all α ₁-adrenoceptor antagonists seem to have similar efficacy in improving symptoms and flow rates. The difference between α 1-adrenoceptor antagonists is related to their side effect profile. Overall, alfuzosin and tamsulosin appear to be better tolerated than doxazosin, terazosin and prazosin

PS2. Compared to finasteride (5 α-reductase inhibitor), the α-blockers have a more rapid onset of action, are effective independent of prostate size, and show greater improvements in symptom scores but similar improvements in flow rate improvements

In men with larger prostates (greater than 40cc), finasteride alone or in combination with an α-blocker would be appropriate. Patients who are likely to respond to finasteride will do so at the same relative magnitude as an α-blocker, but it will take a longer period of time (months as opposed to weeks). This is likely to be a reduction in 20-30% symptoms and a 1-2ml per second increase in urinary flow[195]. Side-effect profiles of medical treatments are also important, as discussed above. For example, with regard to sexual function, tamsulosin has an increased risk of retrograde ejaculation and finasteride increases sexual dysfunction [83]. These may be important factors in choosing therapies. 

Finasteride and Dutasteride

Finasteride was the first of these to be trialled in humans and was shown to decrease DHT levels[187]. It acts on the type 2 isoenzyme of 5-α reductase and has been the only available 5 α-reductase inhibitor. Dutasteride is also available and it blocks both isoenzymes of 5 α-reductase[169, 188]. Dutasteride shows a 60-fold greater inhibition of the type 1 isoenzyme compared with finasteride and is also active against the type 2 isoform [34, 169]. Further studies are needed to gain a more clear understanding of any clinically significant differences between dutasteride and finasteride[188]. Finasteride reduces serum DHT levels by 65-70% and prostatic levels by 85-90%, although the intraprostatic levels of testosterone are reciprocally elevated.
Because 5-α reductase inhibitors work by reducing prostatic tissue volume, baseline prostate size has a significant impact on the efficacy of 5-α reductase inhibitors, with larger glands (>50cc) more likely to respond[189, 190]. After treatment for one year, there is a significant decrease (17-30%) in total gland size with the greatest size reduction in the periurethral component of the prostate (with finasteride), which has the greatest impact on obstructive symptoms [87], [191, 192]. Both transition and peripheral zone volumes are equally affected by dutasteride.[193] There is a 60-70% decrease in DHT concentration , 25% decrease in prostate volume , a 13-30% symptom score reduction vs placebo 4-20% , flow rate improvement of 7-20% vs placebo 3-15%. Furthermore, there were more pronounced changes with larger prostates > 40cc , decreased libido in 10% , ejaculatory dysfunction 7.7% and impotence (15.8%) , they reduced risk of AUR (50%) and the need for surgery (30%).
There is some evidence that patients on finasteride experience fewer serious complications associated with the progression of BPH compared with those prescribed an α blocker, such as acute urinary retention or undergoing BPH-related surgery, but more prospective data is needed[194]. Adverse events associated with finasteride include decreased libido, ejaculation disorders and erectile dysfunction but overall are uncommon, with approximately 4% of patients discontinuing treatment for such events[169, 195]. Finasteride has also developed a role in the treatment of BPH-related haematuria although its role in reduction of perioperative bleeding is not well defined [93, 169].


Table 16. A Brief Summary from Larger Series Comparing Treatment Outcomes.

Treatment	Evidence
MEDICAL
5 α-reductase inhibitors
Finasteride	2 point reduction in IPSS vs placebo 0.7 points [93, 178] Qmax improved 1.4ml/sec compared to placebo 0.3 [178]
Dutasteride	5.5 point improvement in AUA-SS [179]
α-blockers
Tamsulosin	IPSS reduced by 3 points compared to placebo at 6/12 Qmax improved 1.4ml/sec compared to placebo at 6/12 [180]
Terazosin	IPSS reduced 2.2 points over placebo IPSS [128] Qmax improved 1.4 mL/s compared with placebo
SURGERY
TURP	Reduction 4.5 points symptom score versus watchful waiting Qmax improved 6 ml/sec versus 0.4 watchful waiting [154]
Laser	Noncontact: IPSS improved by 2.5 pointsQmax improved 3.18 ml/sec Contact: IPSS improved 2.9 pointsNd-YAG Qmax improved 1.91 ml/sec164HoLRP Comparable to TURP [164]