Chapter 9. Benign Prostate Disorders


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Chapter 9. Benign Prostate Disorders

  1. 1. Chapter 9. Benign Prostate Disorders INTRODUCTION The prostate is an organ linked inextricably with the endocrine system. During the development of the prostate, epithelium and mesenchyme are under the control of testicular androgens, and interact to form an organised secretory organ. Furthermore, many of the disease processes are attributed to, and therapies aimed at the manipu- lation of, the endocrine system. The gland resides in the true anatomical pelvis and forms the most proximal aspect of the urethra. It has been stated that the prostate gland is the male organ most commonly afflicted with either benign or malignant neoplasms [1]. Therefore, it is an organ with which every physician and surgeon need be familiar. We will focus on benign prostatic hyperplasia (BPH), the most prevalent of benign disorders affecting the prostate. EMBRYOLOGY The development, growth and cytodifferentiation of the prostate are androgen de- pendent and occur via reciprocal mesenchymal-epithelial interactions, the latter re- ferring to a cell-cell interaction initiated during embryonic periods in which mes- enchyme (undifferentiated connective tissue) induces epithelial development, while the epithelium reciprocally induces mesenchymal differentiation [2]. In the developing prostate, urogenital sinus mesenchyme acting under the influence of testicular androgens induces ductal morphogenesis, the expression of epithelial androgen receptors, regulates epithelial proliferation and specifies the expression of prostatic-lobe specific secretory proteins. Reciprocally, the developing prostatic ep- ithelium induces the differentiation and morphological patterning of smooth muscle in the urogenital sinus mesenchyme [2]. In the prostate, it is traditional to consider androgens as promoters of growth, while activin and TGFβ are regarded as potent growth inhibitors These factors do not act independently, however, and cross-talk occurs between the signalling pathways at a sub-cellular level [3]. The first step in development of the prostate begins with the urogenital sinus mes- enchyme signalling to the epithelium, causing it to form epithelial buds. Androgens then induce bud elongation, branching and epithelial differentiation [3]. Prenatally, the androgen receptor (AR) is expressed only in the mesenchyme, not in the ep- ithelium. Initial epithelial development is thus controlled via paracrine interactions where activation of stromal androgen receptors stimulates growth factors and in- duces growth in adjacent prostatic epithelial cells [4]. At the 5th week, the mesonephric (Wolffian) duct opens onto the lateral surface of the urogenital sinus and gives rise to the ureteric bud (Figure 1). By the 7th week, the growth of the urogenital sinus involves the progressive incorporation of the terminal part of the mesonephric duct into the wall of the urogenital sinus. They eventually open into the Mullerian tubercle, which is the future veru montanum of the prostate. At their termination, the paramesonephric (Mullerian) ducts fuse and are surrounded by the mesonephric ducts. At 10 weeks, prostatic epithelial buds begin to arise from the circumference of the urethra, around the orifice of the paramesonephric ducts. They develop predominantly on the posterior surface of the junction of the mesonephric ducts, forming two levels, above and below them [5]. 1
  2. 2. Chapter 9. Benign Prostate Disorders Figure 1. The embryological origin and development of the prostatic urethra and the prostate (adapted from Delmas [5]). During the fetal period at about 6 months, multiple outgrowths arise from the pro- static portion of the urethra, particularly the posterior surface of the urethra, and grow into the surrounding mesenchyme. Glandular epithelium of the prostate dif- ferentiates from the endodermal cells of the urethra, and the associated mesenchyme into which the outgrowths grow differentiates into the dense stroma and smooth muscle fibres of the prostate. In contrast, the outgrowths situated on the anterior sur- face regress and are replaced by fibromuscular tissue. This region becomes the future anterior commissure of the prostate [5, 6]. 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 ejac- ulatory ducts. It is the zone which usually gives rise to inflammatory processes (eg prostatitis). 2
  3. 3. Chapter 9. Benign Prostate Disorders 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 di- aphragm [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]). The Prostate “Capsule” It is widely accepted that an anatomically incomplete Denonvilliers’ fascia exists in the region of the apex and some authors have questioned if an apical margin is a true positive margin because the “capsule” of the prostate is deficient at the apex. Another important factor is the ‘detrusor apron’, a continuation of the anterior bladder wall with the pubis, which constitutes a large portion of the anterior fibromuscular stroma . This stroma covers the entire anterior and anterolateral surface of the glandular prostate, Kiyoshima and colleagues have extensively studied the prostate anatomy in 79 spec- imens to determine if a capsule does exist[11]. They found that Denonvilliers’ fas- cia and the prostatic capsule adhered tightly at the center of the posterior aspect in 77 cases (97%). A smooth transition from the prostatic capsule to the anterior fibro- muscular stroma was observed in all cases. No prostatic capsule was independently recognized at the anterior aspect in around 90% of cases because the prostatic tissue was not distinct from the anterior fibromuscular stroma. In most cases (85%), the lat- eral pelvic fascia connected and fused with the anterior fibromuscular stroma, and covered the outermost regions of the lateral and anterior surfaces. Also, the lateral pelvic fascia and the prostatic capsule were separated by adipose tissue in 41 cases (52%), whereas they adhered in 38 cases (48%).[11] In summary, there is a thickening of the periphery of the prostate that some may regards as a “capsule”, but it is neither 3
  4. 4. Chapter 9. Benign Prostate Disorders complete nor consistent amongst prostates and in many cases is difficult to discern from surrounding fascial layers. Neurovascular anatomy The autonomic nerves from the pelvic (inferior hypogastric) plexus supply the prostate. The plexus may be found two finger breadths lateral to the third anterior sacral foramina, lying deep to a line drawn from third sacral vertebra, the conventional level of the recto-sigmoid junction, and the palpable posterior superior surface of the pubic symphysis[12]. The prostatic “capsule” is covered by numerous nerve fibers and ganglia, which form a true periprostatic nerve network[13]. A study of twenty autopsied prostates of different age (forties, fifties, sixties and seventies) and not having cancer has given insight into the more general neuranatomy of the prostate[14]. Most densely innervated was the prostate region bordering on the neurovascular bundles (as discussed above), followed by the regions close to the seminal vesicles and posterior capsule. Innervation was found to be relatively low at the apex, dense in the inner zones and most rich in the outer regions. The peripheral zone was more densely innervated than the transitional zone, while least innervation was found in BPH tissue. A further finding was that a decrease in nerve density across all zones was demonstrated with increasing patient age. Derived from the hypogastric plexus are the neurovascular bundles travelling adja- cent to (and within Denovilliers’ fascia) laterally on the prostate up to and including the apex. The role of these nerves in erectile function have been explored widely, particularly by Walsh[15-17] in the context of radical retropubic prostatectomy for cancer. The original assumption was that this neurovascular bundle is gathered at the rectolateral side of the prostate[18]. However, research at several institutions in Australia has demonstrated that the autonomic neurovascular bundles extend later- ally around the prostate and converge toward the apex but are in fact not a single nerve but a plexus that has many divisions scattered throughout Denovilliers’ fascia, including medially towards the midline[19, 20]. It has been stated that one fifth to one quarter of nerves can be found along the ventral circumference of the prostatic cap- sule[18] and that only around half of prostates will have a definitive neurovascular bundle (in addition to the more scattered nerves as discussed)[11]. HISTOLOGY The prostate consists of stromal and epithelial elements. Smooth muscle cells, fibrob- lasts and endothelial cells are in the stroma and the epithelial cells are secretory cells, basal cells and neuroendocrine cells (Figure 3). 4
  5. 5. Chapter 9. Benign Prostate Disorders Figure 3. Histology of a prostate gland affected by benign prostatic hyperplasia. The columnar secretory cells are tall with pale to clear cytoplasm. These cells stain positively with prostate specific antigen[21]. Basal cells are less differentiated than secretory cells and so are devoid of secretory products such as prostate-specific anti- gen (PSA)[22]. Finally, neuroendocrine cells are irregularly distributed throughout ducts and acini, with a greater proportion in the ducts .The prostate has the greatest number of neuroendocrine cells of any of the genitourinary organs[23]. Glands are structured with open and closed cell types with the open type facing the inside of the duct having a monitoring role over its contents. Most cells contain serotonin but other peptides present include somatostatin, calcitonin, gene-related peptides and katacalcin[21]. The cells co-express PSA and prostatic acid phosphatase. Their func- tion is unclear but it is speculated that these cells are involved with local regulation by paracrine release of peptides[21].Prostatic ducts and acini are distinguished by ar- chitectural pattern at low power magnification. The prostate becomes more complex with ducts and branching glands arranged in lobules and surrounded by stroma with advancing age 5
  6. 6. Chapter 9. Benign Prostate Disorders Figure 4. Diagram outlining the structure of the prostate gland with regard to ducts, glandular cells and their relationship to blood vessels. PHYSIOLOGY At present, there is only limited knowledge of all of the secretory products of the prostate and how this relates to reproduction and infertility. However, the main role of the prostate as a male reproductive organ is to produce prostatic fluid, which ac- counts for up to 30 per cent of the semen volume. Sperm motility and nourishment are aided by the prostatic fluid constituents and the environment they create. . Pro- static fluid is a thin, milky alkaline fluid containing citric acid, calcium, zinc, acid phosphatase and fibrinolysin among its many constituents (Table 1)[24]. Prostate spe- cific antigen (PSA) is also a constituent found in prostatic secretions. During ejacu- lation, α-adrenergic stimulation results in transport of the seminal fluid containing sperm from the ampulla of the vas deferens into the posterior urethra[25]. Interest- ingly, abnormal growth of the prostate is only experienced by humans and dogs and why other mammals are spared is a mystery[26]. Table 1. The composition of human semen (adapted from Ganong17) Colour White, opalescent Specific Gravity 1.028 pH 7.35-7.50 Volume 3ml SPECIFIC COMPONENTS OF SEMEN Gland/Site Volume in ejaculate Features Testis/Epididymis 0.15ml (5%) Average approximately 80 million/ml Seminal Vesicle 1.5-2ml (50-65%) Fructose (1.5-6.5 mg/ml)Phosphorylcholine Ergothioneine Ascorbic acid Flavins Prostaglandins Bicarbonate 6
  7. 7. Chapter 9. Benign Prostate Disorders Prostate 0.6-0.9ml (20-30%) ProstateSpermineCitric AcidCholes- terol,phospholipidsFibrinolysin, fibrinogenaseZincAcid phosphateaseProstate- specific Bulbourethral Glands < 0.15ml (<5%) Clear mucus ENDOCRINE CONTROL OF PROSTATIC GROWTH It is becoming clear that intraprostatic signalling systems are important for the reg- ulation of cell proliferation and extracellular matrix production in prostatic stroma. Central to this premise is the balance between factors such as tumour growth fac- tor β 1 (TGFb1), that induces extracellular matrix production, suppresses collagen breakdown and cell proliferation and factors such as fibroblast growth factor 2 and insulin-like growth factors that are mitogenic in the stromal compartment[28].Other endocrine pathways are being investigated and there is experimental data suggesting an abnormality in the insulin-like growth factor axis playing a role in the pathogene- sis of BPH[29]. Other data has emerged on the relationship between connective tissue growth factor (CTGF) expression and fibronectin (FN) synthesis after transforming growth factor- β-1 (TGF-β1) stimulation in human prostate stromal cells. CTGF appears to play a crucial role in extracellular matrix production as a TGF-β1 downstream mediator in human prostate stromal cells, suggesting that CTGF blockade is likely to be a thera- peutic target against benign prostatic hyperplasia.[30] Testosterone Prostatic epithelial cells express the androgen receptor[31]. From the beginning of embryonic differentiation to pubertal maturation and beyond, androgens are a pre- requisite 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 hyperpla- sia (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. 7
  8. 8. Chapter 9. Benign Prostate Disorders 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[26]. Estrogen A role for estrogens in the prostate pathology of the ageing male appears likely with accumulating evidence that estrogens, alone or in combination with androgens, are involved in inducing aberrant growth and/or malignant change. Animal mod- els have supported this hypothesis in the canine model, where estrogens “sensitize” the ageing dog prostate to the effects of androgen[40]. The evidence is less clear in humans. Estrogens in the male are predominantly the products of peripheral arom- atization of testicular and adrenal androgens[41]. While the testicular and adrenal production of androgens declines with ageing, levels of total plasma oestradiol do not decline. This has been ascribed to the increase in fat mass with ageing (the pri- mary site of peripheral aromatization) and to an increased aromatase activity with ageing. However, free or bioavailable estrogens may decline due to an increase in sex hormone binding globulin, which could translate to lower intraprostatic levels of the hormone. The potentially adverse effects of oestrogens on the prostate may be due to a shift in the intra-prostatic estrogen:androgen ratio with ageing. Estrogen, which acts through estrogen receptors (ER) α and β, has been implicated in the pathogenesis of benign and malignant human prostatic tumors[42-44]. As stated 8
  9. 9. Chapter 9. Benign Prostate Disorders above benign prostatic hyperplasia is thought to originate in the transitional zone (TZ) and prostate cancer the peripheral zone (PZ) of the prostate. Receptor stud- ies have found ER-α and ER-β types distributed in human normal and hyperplas- tic prostate tissues, using in situ hybridization and immunohistochemistry. ER-α ex- pression was restricted to stromal cells of the PZ. In contrast, ER-β was expressed in the stromal and epithelial cells of PZ as well as TZ. These findings suggest that estrogen may play a crucial role in the pathogenesis of benign prostatic hyperpla- sia through ER-β[43]. Investigations are ongoing and could result in a new range of therapies directed against BPH and prostate cancer. Dietary phytoestrogens (in soy and other vegetables) or selective estrogen receptor modulators are currently being investigated with regard to their role in the development of BPH and prostate can- cer[41]. Such ER modifiers may oppose some of the effects of natural oestrogen by modulating ER receptors, thus reducing the local impact of androgens that need ac- tive ER receptors, effectively making them anti-androgenic compounds however this requires more investigation[45]. Benign Prostatic Hyperplasia (BPH) Benign Prostatic Hyperplasia (BPH) is an age-related and progressive neoplastic con- dition of the prostate gland[46]. BPH may only be defined histologically. BPH in the clinical setting is characterised by lower urinary tract symptoms (LUTS, see Table 2). There is no causal relationship between benign and malignant prostatic hypertro- phy[47]. Clinically apparent BPH represents a considerable health problem for older men, due to the negative effects it has on quality of life (QOL). A recent study has demonstrated an overall prevalence of 10.3%, with an overall incidence rate of 15 per 1000 man-years, increasing with age (3 per 1000 at age 45-49 years, to 38 per 1000 at 75-79 years). For a symptom free man at age 46, the risk of clinical BPH over the com- ing 30 years, if he survives, is 45%[48]. The true prevalence and incidence of clinical BPH will vary according to the criteria used to describe the condition. It is crucial to acknowledge that LUTS can exist without signs of BPH – as the symptoms can be caused by variations in the sympathetic nervous stimulation of prostatic smooth muscle, variability of prostatic anatomy (viz., enlarged median lobe of the prostate), and the variable effects of bladder physiology from the obstruction and aging. There have been several studies demonstrating the fact that clinical BPH is a progres- sive disease. The Olmsted county study[49] showed that with each year there were deteriorations in symptom scores, peak flow rates, and increases in prostate volumes based on transrectal ultrasound scanning (TRUS). The risk of acute urinary retention (AUR) increased with flow rates below 12 ml/sec and with glands greater than 30ml. Studies have also demonstrated that those with larger prostates (>40 ml) and with serum PSA greater than 1.4 ng/ml were more likely to develop acute urinary reten- tion[50]. Treatment however has changed with the advent of effective non-surgical therapies. Between 1992-1998 there has been a significant lengthening of the period between first diagnosis of LUTS secondary to clinical BPH and surgery, associated with the earlier and increased use of specific medical treatments [51]. From the pa- tients perspective the goals of therapy are to improve quality of life, reduce symp- toms, and avoid surgery while ensuring safety from the complications of BPH [52]. Risk Factors for BPH The only clearly defined risk factors for BPH are age and the presence of circulating androgens. BPH does not develop in men castrated before the age of forty [53]. But other factors may influence the prevalence of clinical disease. These include: 9
  10. 10. Chapter 9. Benign Prostate Disorders Genetics Clinical BPH appears to run in families. If one or more first degree relatives are af- fected, an individual is at greater risk of being afflicted by the disorder [54]. In a study by Sanda et al [55] the hazard-function ratio for surgically treated BPH amongst first degree relatives of the BPH patients as compared to controls was 4.2 (95% CI, 1.7 to 10.2). The incidence of BPH is highest and starts earliest in blacks than Caucasians and is lowest in Asians [47]. Interestingly, despite having larger prostate glands, the age-adjusted risk of BPH was the same for blacks as for whites (RR = 1.0, 95% Cl 0.8- 1.2) [56]. Furthermore, in an Asian population, men presenting with BPH are likely to have higher symptom scores than blacks or Caucasians [57]. Diet Diet has been reported as a risk factor for the development of BPH. Large amounts of vegetables and soy products in the diet may explain the lower rate of BPH in the orient when compared to westernized countries. In particular, certain vegetables and soy are said to be high in phyto-oestrogens, such as genestin, that have ant- androgenic effects by an as yet determined mechanism on the prostate in vitro [58]. The study of migrant populations with their heterogeneous exposures to the en- vironment, increases the probabilities of identifying potential risk factors for BPH. Therefore, the association of alcohol, diet, and other lifestyle factors with obstructive uropathy was investigated in a cohort of 6581 Japanese-American men, examined and interviewed from 1971 to 1975 in Hawaii. After 17 years of follow-up, 846 inci- dent cases of surgically treated obstructive uropathy were diagnosed with BPH. Total alcohol intake was inversely associated with obstructive uropathy (P < 0.0001). The relative risk was 0.64 (95% confidence interval: 0.52-0.78) for men drinking at least 25 grams of alcohol per month compared with nondrinkers. Among the 4 sources of alcohol, a significant inverse association was present for beer, wine, and sake, but not for spirits. No association was found with education, number of marriages, or cigarette smoking. Increased beef intake was weakly related to an increased risk (p = 0.047), while no association was found with the consumption of 32 other food items in the study [59]. Other Risk Factors It has not been possible to delineate any other risk factors for BPH such as coronary artery disease, liver cirrhosis or diabetes mellitus. There is also no causal relationship between prostatic malignancy and benign hyperplasia [47]. PATHOPHYSIOLOGY OF BPH Natural History BPH is a histological diagnosis but its clinical manifestations occur after growth has occurred to such a degree and in such a strategic location within the gland, namely the transitional zone, that it impairs bladder emptying and results in LUTS. One can therefore consider the natural history of BPH as involving three phases: (i) The pathological or first phase of BPH is asymptomatic and involves a progression from microscopic to macroscopic BPH. Microscopic BPH will develop in almost all men if they live long enough but in only about half will progress to macroscopic BPH. This would suggest that additional factors are necessary to cause microscopic to progress to macroscopic BPH [60]. The pathological phase involves development of hyperplastic changes in the transitional zone of the prostate [61]. 10
  11. 11. Chapter 9. Benign Prostate Disorders (ii) The clinical or second phase of BPH involves the progression from pathological to ‘clinical BPH’ which is synonymous with the development of LUTS. Only about one half of patients with macroscopic BPH progress to develop clinical BPH [60]. BPH consists of mechanical and dynamic components and it is these components that are responsible for the progression from pathological to clinical BPH [62]. In clinical BPH, the ratio of stroma to epithelium is 5: 1 whereas in the case of asymptomatic hyperplasia the ratio is 2.7:1. A significant contribution is therefore made by stroma to the infravesical obstruction of BPH [63]. While there is wide variability in prostate growth rates on an individual level, prostate volume appears to increase steadily at about 1.6% per year in randomly selected community men [64]. (iii). There is probably a third phase, during which clinical BPH progresses. This pro- gression may be defined as a deterioration of clinical variables such as lower urinary tract symptoms (LUTS), health-related quality of life and peak flow rate, increased prostate size, or unfavourable outcomes such as acute urinary retention and BPH- related surgery [65]. However, there is evidence from longitudinal studies[49, 66], and to a lesser extent from the placebo arms of large controlled studies[67, 68], that clinical BPH is a progressive disease. Symptom worsening is by far the most fre- quently occurring progression event. Identifying those patients at risk of BPH pro- gression is crucial to optimize their management [65]. Aetiology Several theories have been proposed to explain the etiology of the pathological phase of BPH. The major theories include the hypotheses that pathological BPH is due to[69-71]: 1) Dihydrotestosterone (DHT) hypothesis- a shift in prostatic androgen metabolism that occurs with aging, which leads to an abnormal accumulation of di- hydrotestosterone, thus producing the enlarged prostate. This is supported by the fauilure of BPH development in men castrated before puberty. 2) Embryonic reawakening theory- assumes a reawakening of the embryonic induc- tion potential of prostatic stroma. In summary, a change in the prostatic stromal- epithelial interaction that occurs with aging occurs, which leads to an inductive effect on prostatic growth. 3) Stem cell theory featuring an increase in the total prostatic stem cell number and/or clonal expansion of the stem cells into amplifying and transit cells that occurs with aging. 4) Inflammatory theory- Prostatic inflammation may contribute to prostate growth due to the induction of cell growth due to the presence of inflammatory markers and agents stimulating 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 va- riety 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 approxi- mately 25% of men age 40 or over will suffer from LUTS [74]. 11
  12. 12. Chapter 9. Benign Prostate Disorders Figure 6. Conversion of testosterone to dihydrotestosterone (DHT) by 5α-reductase Table 2. Lower Urinary Tract Symptoms Voiding or Obstructive Symptoms Storage or Irritative Symptoms • Hesitancy • Urinary frequency • Poor stream • Urgency • Intermittent stream • Urge incontinence • Straining to pass urine • Nocturia • Prolonged micturition • Sense of incomplete bladder emptying • Terminal dribbling In the past, LUTS suggestive of bladder outflow obstruction (BOO) secondary to BPH were referred to as ‘prostatism’, once other causes such as a urinary tract infection or 12
  13. 13. Chapter 9. Benign Prostate Disorders prostate cancer were excluded. The pathology behind the symptoms was thought to be obstruction due to prostatic gland enlargement alone. However, today it is recog- nised that voiding/obstructive symptoms result from direct urinary flow obstruction whilst storage/irritative symptoms appear to be due to secondary bladder dysfunc- tion [76]. This concept has been further refined in that obstructive symptoms are thought to result not only from mechanical obstruction due to glandular enlargement, but also dynamic obstruction secondary to contraction of the smooth muscle of the prostate, urethra and bladder neck. This dynamic obstruction is a result of sympathetic ner- vous system mediated stimulation of α-1adrenoceptors. Storage symptoms appear to be caused by detrusor instability related to detrusor muscle changes in response to obstruction, such as bladder wall hypertrophy and collagen deposition in the blad- der[77, 78]. The role of adrenoceptor subtypes in the bladder in this process is cur- rently being investigated. Adrenoceptors may be further sub-divided into α 1Aand α 1Dsubtypes, with α 1Apredominant in the prostate and α 1D in the bladder. Thus blockade of α 1Amay be necessary for reduction of obstruction whereas the blockade of α 1Dmay be required to relieve storage symptoms [79] (see below). New research has also suggested that the aetiology of LUTS related to BPH is even more complex than outlined above with extra-prostatic mechanisms such as bladder wall ischaemia and changes in the central nervous system being implicated [80]. Nor- mal lower urinary tract function is complex, and theoretically any disruption of the pathway for micturition (Figure 7 below) may lead to LUTS [81]. It is also worth noting the relationship between LUTS and sexual dysfunction, with sexual dysfunction being highly prevalent in men with LUTS [82]. By sexual dys- function, we refer to decreased libido, erectile dysfunction, decreased ejaculation and other ejaculation disorders. Kassabian [83] expands on the relationship and agrees with Leilefeld et al [84] in suggesting that the relationship is coincidental and both are common in the ageing male. 13
  14. 14. Chapter 9. Benign Prostate Disorders Figure 7. Normal micturition pathways (reproduced with permission from Physi- ology and pathophysiology of lower urinary tract symptoms, Drugs of Today, Vol 37, p. 7, Michel MC [81]). COMPLICATIONS Table 3. Summary of Common Complications of BPH 1. Urinary retention 2. Recurrent Urinary Tract Infections 3. Bladder Calculi 4. Haematuria 5. Secondary bladder instability 6. Renal Impairment 14
  15. 15. Chapter 9. Benign Prostate Disorders Urinary Retention (Acute and Chronic) As prostate volume increase with age, the likelihood of acute urinary retention (AUR) and symptom severity both increase while urinary flow rates fall. In one study of more than 2000 men, those with a maximum urinary flow rate (Qmax) <12 ml/s had a 4 times greater risk for AUR than did men with a Qmax >12ml/s [85]. AUR is usu- ally painful and necessitates the insertion of a per urethral indwelling or suprapubic urinary catheter. If the urinary retention is not dealt with in a timely fashion, the detrusor muscle becomes distended and damaged, contributing to poor detrusor function and an in- ability to adequately empty the bladder. The retention of urine becomes painless over time, and the sequelae of retained urine such as recurrent UTI, calculi and renal im- pairment may develop. Furthermore, a situation of overflow incontinence may develop whereby the bladder automatically empties once the volume reached exceeds its new, larger capacity. The passage of urine is typically uncontrolled, and this may often be the first presentation for someone with advanced BPH. The bladder remains full despite the emptying, which is only partial. In situations of chronic retention, there is no guarantee that by relieving the bladder outflow obstruction, the detrusor will return to normal functioning. These patients often need to use intermittent self catheterisation or have permanent drainage to keep their bladder empty and to reduce damage to the upper urinary tract, even after definitive treatment for BPH. Recurrent lower Urinary Tract Infection (UTI) Perhaps the best host defence against infection in the lower urinary tract is the nor- mal flow of urine and bladder emptying that accompanies normal urinary tract func- tioning. In BPH, bladder outflow obstruction results in disruption of this mechanism with retention and pooling of urine in the bladder, giving organisms the opportunity to multiply rather than be flushed out. Despite this logical assumption, there is little evidence in the literature to support this theory. Nevertheless, men with significant clinical BPH are probably at risk of UTI, and men with UTI should be assessed for signs of BPH. Bladder Calculi (stones) In developed countries, the most prevalent cause of bladder calculi is bladder out- let obstruction owing to BPH [86].Of those who undergo prostate surgery for BPH, approximately 2% of all patients are found to have bladder stones [87]. Stones oc- cur in this situation due to urinary stasis combined with high urinary solute con- centrations, which leads to crystal precipitation [88]. Chronic infection with urease- producing organisms may predispose to the development of stones and rarely stones pass from the upper tract to act as a nidus in the bladder [88] . Bladder calculi as- sociated with BPH remain an absolute indication for transurethral resection of the prostate (TURP)[89, 90] because of the risk or recurrence of stone formation. How- ever, the necessity of surgery is being challenged by the expanding use of medical management in treating BPH [90]. Haematuria The incidence of haematuria with BPH is uncertain however, in a retrospective re- view of almost 4000 patients undergoing TURP, Mebust et al [89] noted that haema- turia was an indication for surgery in 12% of patients. It is hypothesised that BPH, with its increased acinar and stromal cell proliferation, stimulates increased vascular- ity via angiogenesis. These new and prolific vessels may be easily disrupted leading 15
  16. 16. Chapter 9. Benign Prostate Disorders to recurrent bleeding [91].This is supported by Foley et al [92] who found the mi- crovessel density to be higher in those patients with BPH having haematuria after histological studies. It is also hypothesised that 5-α reductase inhibitors may reduce angiogenesis and theoretically, reduce prostate bleeding. Thus finasteride, has been suggested as an option in treating the problem of haematuria[93-95]. Detrusor (Bladder) Instability The definition of detrusor instability is the development of a detrusor contraction which exceeds 15cm H 2O at a bladder volume of less than 300ml [96]. Detrusor instability is not a specific term related to BPH, but implies LUTS secondary to a detrusor problem. These symptoms are normally storage related and consist of ur- gency, frequency, urge incontinence and nocturia. In BPH, the normal dynamics of the bladder are altered due to detrusor muscle stretching as a result of retention of urine and contraction against an obstructed outlet. Although not completely under- stood, some of the detrusor instability may be related to changes at the adrenoceptors level, rather than just from obstruction and its consequences alone. In normal blad- der physiology, β-adrenoceptors are believed to be involved in the relaxation of the bladder during storage of urine [80]. In some patients, however, the administration of noradrenaline leads to contraction of the detrusor muscle which may be blocked by α-1 adrenoceptor antagonist [97]. This implies the presence of α-adrenoceptors in the detrusor muscle in at least some patients. Furthermore, α-adrenoceptor antagonists have been shown to relieve storage and voiding symptoms in men without obstruc- tion and storage symptoms in women[80, 98-101]. α adrenoceptor subtypes in the human bladder are predominantly of the α 1Dand α 1Atype. In animal models, the α 1D receptors become more abundant with obstruction[102], and it may be speculated that this is the case in humans and that these receptors, once up-regulated, play a role in storage symptoms [80]. Renal insufficiency Renal insufficiency results from obstructive uropathy secondary to the bladder out- let obstruction of BPH. In an analysis of patients receiving treatment for BPH, 13.6% (range 0.3-30%) had renal insufficiency [87]. Certainly, an abnormal creatinine is an indication to further investigate the upper urinary tract with imaging. Obviously, other concurrent causes of renal insufficiency need to be excluded. Those patients with renal insufficiency undergoing surgery are at increased risk (25%) of postoper- ative complications such as acute renal failure and urosepsis compared to patients without (17%) insufficiency [89]. Elevated Prostate Specific Antigen (PSA) As BPH is a true hyperplasia, more cells produce a greater amount of PSA[103]. It has been suggested that many PSA elevations detected and investigated in clinical prac- tice may in fact be due to BPH leading Stamey to controversially argue that PSA is a better marker of BPH than of prostate cancer[103, 104]. One approach to distinguish the two conditions when PSA is elevated is to perform a free-to-total PSA ratio: more free PSA than complexed PSA suggests BPH rather than prostate cancer. A ratio of around 20% or greater for free PSA is considered more likely to represent BPH than cancer[105]. PSA is discussed further in the investigations section below. Quality of Life In terms of complications of BPH, quality of life (QOL) issues have gained more at- tention since the landmark paper of Girman et al over a decade ago[106]. They high- 16
  17. 17. Chapter 9. Benign Prostate Disorders lighted in their study of several thousand men that moderate to severe urinary symp- toms have a significant impact on men’s lives in terms of degree of bother, worry, interference with daily living, and psychological well-being. The impact of BPH on QOL has been highlighted in many recent studies[107, 108] and such studies con- tinue to be important in raising awareness of BPH in the community and the ability of men to seek treatment for BPH. Comprehensive surveys of men, such as the Men in Australia Telephone Survey (MATeS), provide contemporaneous data that men are interested in their health and the QOL impact of problems such as LUTS secondary to BPH[109, 110]. HISTORY A comprehensive medical history must be evaluated and should include the use of a voiding diary, the International Prostate Symptom Score and a discussion of the role of prostate specific antigen (PSA) testing[111]. An outline of the evaluation and treatment options for LUTS is shown in Table 4 and is discussed in greater depth below[112, 113]. Previous urological disease should be documented including previ- ous urological surgery, UTI, bladder or renal calculi, renal disease and penoscrotal pathology. Any risk factors for surgery such as diabetes mellitus, immunosuppres- sion, ischaemic heart disease, respiratory problems, smoking as well as a comprehen- sive list of medications should be noted. In particular, the use of antihypertensives must be noted as any α-blocker treatment initiated could potentially cause severe hypotension. As discussed in the section on differential diagnosis, consideration needs to be given to neurologic causes of voiding dysfunction such as stroke or Parkinson’s disease. Table 4. A Summary of Diagnosis and Treatment Options in BPH EVALUATION of LUTS 17
  18. 18. Chapter 9. Benign Prostate Disorders ESSENTIAL 1. History 2. Digital Rectal Exam (DRE) 3. Urinalysis 4. Serum creatinine 5. PSA, if > 10 year life expectancy 6. International Prostate Symptom Score (IPSS) or AUA symptom index SELECTED 1. Uroflowmetry 2. Imaging – especially if haematuria , UTI , urolithiasis 3. Post Void Residual (PVR) estimation 4. +/-Pressure flow studies 5. +/-Cystoscopy TREATMENT OPTIONS MEDICAL THERAPY 1. Phytotherapy 2. Alpha blockers 3. 5 alpha reductase inhibitors SURGERY 1. Transurethral resection of the Prostate (TURP) 2. Transurethral Incision of the Prostate (TUIP) 3. Open prostatectomy 4. Laser prostatectomy/treatment 5. Others viz., TUMT, HIFU, TUNA International Prostate Symptom Score (IPSS) The American Urologic Association (AUA) Symptom Index was developed as a stan- dardised 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, 18
  19. 19. Chapter 9. Benign Prostate Disorders 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 <61603>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] EXAMINATION General appearance is of importance, especially in identifying those with neurologi- 19
  20. 20. Chapter 9. Benign Prostate Disorders cal disease (eg. past stroke, Parkinson’s disease) or other major co-morbidities (obe- sity, severe osteoarthritis, diabetes) that may impact on treatment or further inves- tigation. An abdominal examination should identify those in marked urinary reten- tion, any abnormal masses and previous surgical scars. A careful assessment of the scrotum and its contents as well as the penis is also warranted to exclude any other pathology. The digital rectal examination (DRE) is important in identifying prostatic abnormalities, including clinically apparent prostate carcinoma[120]. Prostate size, texture and tenderness should all be assessed, as should anal tone. Any nodules should be carefully noted. Constipation may also be a contributing factor to urinary retention and anal tone should also be recorded. DIFFERENTIAL DIAGNOSIS OF BPH It is important to acknowledge that the diagnosis of BPH often relies on surrogate measures until a histological diagnosis is confirmed. These range from clinical (symp- tom scores), physiological (uroflowmetry), anatomical (prostatic volume on DRE or TRUS) and biochemical (PSA values) measurement. Although all of these measure- ments capture some component of BPH, none of them is specific for BPH[121] which is itself a histological diagnosis. Surrogate measures are likely to represent a con- tinuum of disease severity without the existence of a threshold. Thus, differential diagnoses need to always be considered and where appropriate, excluded. In table 5 below, some of the more obvious differential diagnoses are listed, but will not be examined in detail. Table 5. Differential diagnoses for LUTS Inflammatory Conditions 1. Urinary Tract Infection 2. Prostatitis 3. Bladder Calculi 4. Interstitial Cystitis 5. Tuberculous Cystitis Neoplastic Conditions 1. Prostate cancer 2. Bladder transitional cell carcinoma (usually CIS) 3. Urethral cancer 20
  21. 21. Chapter 9. Benign Prostate Disorders Neurological Conditions 1. Parkinson’s disease 2. Stroke 3. Multiple Sclerosis 4. Cerebral Atrophy 5. Shy-Drager Syndrome Other Causes of Urinary Obstruction 1. Urethral stricture 2. Severe phimosis 3. Bladder neck dyssynergia 4. External sphincter dyssynergia PROSTATITIS Prostatitis is a common condition that must be excluded from other causes of LUTS and is a common cause of visits to primary care physicians and urologists. It may present as an acute bacterial infection or may be chronic, occasionally progressing to a debilitating illness. In practice, the clinical diagnosis of prostatitis depends on the history and physical examination, but there is no characteristic physical finding or diagnostic laboratory test. Patients with prostatitis experience considerable mor- bidity and may remain symptomatic for many years. Unfortunately, there is limited understanding of the pathophysiology and optimal treatment for most patients. Prostatitis has been sub-classified and an abbreviated version is in table 6. Table 6. The National Institute of Health (USA) Consensus Classification of Pro- statitis Syndromes 1. Acute bacterial prostatitis 2. Chronic bacterial prostatitis 3. Chronic prostatitis/chronic pelvic pain syndrome a. Inflammatory b. Non-inflammatory 4. Asymptomatic inflammatory prostatitis 21
  22. 22. Chapter 9. Benign Prostate Disorders Acute Prostatitis. Clinical features suggestive of acute prostatitis (Type 1, in Table 6 above) include dy- suria and urinary frequency as well as perineal pain (Table 7). Systemic symptoms such as fever, rigors, myalgia and sweats are often a feature. On examination, the pa- tient is normally febrile, and may be overtly septic depending on the infection sever- ity. A digital rectal exam finds an extremely tender prostate which is often intolerable to the patient. An abscess is occasionally palpated. Table 7. Clinical symptoms in prostatitis (adapted from Lobel94) Genital symptoms 1. Dribbling 2. Inguinal pain 3. Testicular pain 4. Retropubic pain 5. Perineal pain 6. Urethral Burning General Symptoms 1. Backache 2. Sweating 3. Tiredness 4. Cold feet Investigations should include a mid-stream urine sample for microscopy, culture for bacteria, and antibiotic sensitivity. The most common organisms are typical uropathogenic bacteria such as Escherichia coli. Blood cultures for bacteria and antibiotic sensitivity should also be considered. Prostatic massage is usually contraindicated in patients with acute prostatitis due to pain and the risk of precipitating sepsis. A treatment regime is highlighted in Table 8. If there is failure to respond to therapy, evaluation for a prostatic abscess using a tran-srectal ultrasound scan or computed tomography scan may be required. If necessary, perineal or transurethral drainage of an abscess may be undertaken. At least 4 weeks of antibiotic therapy is recommended in all patients to try to prevent chronic bacterial prostatitis. Following resolution of acute prostatitis, the urinary tract should be investigated for any structural problems[123, 124]. Table 8. Treatment of Acute Prostatitis 22
  23. 23. Chapter 9. Benign Prostate Disorders 1. Hydration 2. Rest and hospitalisation if severe 3. Empirical therapy with antibiotic until urine culture and sensitivities available 4. For patients requiring parenteral therapy antibiotics covering the likely organisms: broad spectrum cephalosporins, for example, cefuroxime, cefotaxime, or ceftriaxone plus gentamicin 5. Oral treatment according to sensitivitiesQuinolones, such as ciprofloxacin or norfloxacin For patients intolerant of, or allergic to, quinolones: trimethoprim or co-trimoxazole; 6. Analgesics, such as non-steroidal anti-inflammatory drugs Suprapubic catheterisation if catheterisation needed – per urethral catheters may precipitate abscess formation Chronic Prostatitis As the presentation may be localised to the genital region or non-specific (see Table 7) a careful history and examination along with specialised diagnostic tests are needed to identify this condition. Investigations may involve prostatic massage to express or- ganisms and/or white blood cells for analysis. Urine sample collection is often done in phases to aid in the localisation process: first void urethral urine; mid-stream blad- der urine; post-prostatic massage sample. Urine microscopy and quantitative culture is then undertaken. Semen analysis for excessive white blood cell numbers may also be indicative of chronic prostatitis. A serum prostate specific antigen measurement may be undertaken and is often raised, especially in acute prostatitis or in an ac- tive phase of chronic prostatitis. Trans-rectal ultrasound is considered but not rec- ommended to differentiate the different forms of chronic prostatitis. Urinary tract lo- calisation procedures (culture of first void urethral urine; mid-stream bladder urine; post-prostatic massage samples of urine correlating to urethra, bladder and prostate) although theoretically correct, are often not used in clinical practice[123, 124]. The various classifications of chronic prostatitis are listed in Table 6. Patients with chronic bacterial prostatitis (type II prostatitis) experience recurrent episodes of bac- terial urinary tract infection caused by the same organism, usually E. coli, another Gram-negative organism, or enterococcus. Between symptomatic episodes of bac- teriuria, lower urinary tract cultures can be used to document an infected prostate gland as the focus of these recurrent infections. Acute and chronic bacterial prostati- tis represent the best understood, but least common, prostatitis syndromes[123, 124]. Unfortunately, more than 90% of symptomatic patients have chronic prostatitis/chronic pelvic pain syndrome (type III). This term recognizes the limited understanding of the causes of this syndrome for most patients and the possibility that organs other than the prostate gland may contribute to this syndrome. Urological pain (normally in the perineum or associated with voiding or intercourse) is now recognised as a primary component of this syndrome. Active urethritis, urogenital cancer, urinary tract disease, functionally significant urethral stricture, or neurological disease affecting the bladder must be excluded. Patients with the inflammatory subtype (type IIIA) of chronic prostatitis/chronic pelvic pain syndrome have leukocytes in their expressed prostatic secretions post prostate massage urine or in semen. 23
  24. 24. Chapter 9. Benign Prostate Disorders In contrast, patients with the non-inflammatory subtype of chronic prostatitis (type III B) have no evidence of inflammation. In essence, they have no evidence of active infection nor of inflammation on available investigative techniques taken at a par- ticular point in time. Repeat investigations are therefore done to be sure adequate sampling has been undertaken. This condition may be difficult to treat and requires intensive counselling, information and reassurance to the patient to be successfully managed[124]. Finally, asymptomatic inflammatory prostatitis (type IV) is diagnosed in patients who have no history of genitourinary tract pain complaints. It is often an inciden- tal finding on prostatic biopsy done for other reasons (eg a raised PSA). Treatment is usually not required. Treatment of chronic prostatitis All patients should have investigations as outlined above. A summary of treatment options is included (Table 9).Those patients with chronic prostatitis secondary to bacterial infection (type II) require a prolonged course of antibiotics (often up to 3 months) and should then be re-cultured to ensure eradication of the organism. Some urologists argue that these patients should also have investigation of their urinary tract by way of cystoscopy and at minimum, an ultrasound to ensure no anatomical abnormality that may be responsible. Patients with asymptomatic prostatitis (IV) require no treatment but those with the inflammatory (IIIA) and non-inflammatory (IIIB) are more difficult. Patients with type IIIA disease have excessive leucocytosis in their specimens but no bacteria. However, because their symptoms may be due to a pathogen that is difficult to isolate, a further course of antibiotics (6-12 weeks) with coverage of chlamydia and ureaplasma[122] is indicated. If this antibiotic course is not therapeutic, then concentration should be focus on anti-inflammatory medications (which may be used in conjunction with the course of antibiotics). If anti-inflammatory treatment fails, then patients should be treated as below, for type IIB. Current treatment for Type IIIB patients requires multiple therapies. Triple therapy with high dose α-blocker (3 month minimum), analgesia and muscle relaxant (benzo- diazepines).Initially, a narcotic analgesic should be changed to a non-steroidal anti- inflammatory (NSAID) if a response occurs after 2 weeks. The NSAID should be continued for at least 6 weeks, but stopped if there is no response at 2 weeks. If the triple treatment fails, other avenues must be explored, including biofeedback, relax- ation exercises psychotherapy and lifestyle changes (soft cushions, cease bike-riding). The focus is on improving quality of life and minimising symptoms, not curing the disease[122]. Table 9. Management and Treatment of Chronic Prostatitis 24
  25. 25. Chapter 9. Benign Prostate Disorders 1. Oral and written patient education 2. Pharmacological treatment for chronic bacterial prostatitis chosen according to antimicrobial sensitivities Quinolones, such as: ciprofloxacin; ofloxacin; norfloxacin For those allergic to quinolones: minocycline; doxycycline; trimethoprim; co-trimoxazole 3. Other treatments for chronic bacterial prostatitis: radical transurethral prostatectomy or total prostatectomy in carefully selected patients. 4. Empirical Treatments for chronic abacterial prostatitis 5. Treat as for chronic bacterial prostatitis with a quinolone or tetracycline 6. Alpha Blockers: terazosin, alfuzosin 7. Non-steroidal anti-inflammatory drugs 8. Stress management. Referral for psychological assessment as appropriate; diazepam. Note: benzodiazepines are considered but not recommended in clinical practice because of dependency 9. Adequate follow-up and counselling, often with professional support 10. Cernilton (pollen extract) 11. Bioflavonoid quercetin 12. Transurethral microwave thermotherapy Note: allopurinol (chronic abacterial prostatitis) is considered but further studies are needed before recommending it. INVESTIGATIONS of LUTS As outlined by Tubarro et al[111], the aim of investigations for LUTS should be three- fold: (1) to evaluate the possible relationship between prostatic enlargement, lower urinary tract symptoms and signs of bladder outlet obstruction; (2) to quantify the severity of benign prostatic enlargement-related symptoms and signs and (3) to rule out the presence of a prostate cancer. Urinalysis Urinalysis is used to screen for urinary tract infection as a cause of LUTS in order to identify those with microscopic or macroscopic haematuria. A formal urine culture may be undertaken if the analysis was suspicious for infection. Post-void residual urine volume (PVRU) Although there is a high degree of intra-individual variation in the PVRU it may still provide valuable information with regard to bladder emptying. It may not dis- tinguish adequately between bladder outlet obstruction or poor detrusor function 25
  26. 26. Chapter 9. Benign Prostate Disorders and the United States guidelines on BPH suggest it is an optional investigation be- cause of this variability [87] . Greater than 300ml is considered a potential risk factor for upper urinary tract dilatation and renal impairment[125]. The PVRU does have the advantage of being used as a monitoring investigation in those opting for non- surgical therapy for BPH. It is readily and quickly performed in the office or hospital setting using portable ultrasound equipment. Serum Creatinine Most guidelines on investigation of BPH recommend this investigation and an elevated serum creatinine would be an indication to evaluate the upper urinary tract[113]. Upper Urinary Tract Imaging Urinary tract ultrasound or computerised tomography are appropriate modalities. Most would consider upper tract imaging as mandatory if haematuria was present and recommend it if there was a history of urolithiasis, urinary tract infection or renal insufficiency. Intravenous pyelography still has a role in certain cases, as other modal- ities do not outline the anatomy of the collecting system with such definition[111]. 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, expen- sive 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 nec- essary 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 assump- tions[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 obstruc- tion on uroflowmetry so other urodynamics investigations such as a cystometry are indicated. 26
  27. 27. Chapter 9. Benign Prostate Disorders 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 27
  28. 28. Chapter 9. Benign Prostate Disorders made from this reading alone but is certainly characteristic of someone with ob- structed voiding and having normal detrusor muscle function. B) This pattern of intermittent flow usually represents abdominal straining in an attempt to over- come 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 ejacula- tion and alternate diagnosis 4. Neurogenic bladder suspected 5. Previous radical pelvic surgery 6. Post void residual of greater than 300ml (not on one reading)[129] Urethrocystoscopy The performance of this investigation depends on patient history and proposed sur- gical intervention. It is necessary where there is a history of microscopic or macro- scopic haematuria to exclude bladder tumours or stones. A history of urethral stric- tures, bladder tumours or prior lower urinary tract surgery should also prompt this investigation. Surgeons may also use urethroscystoscopy when planning different surgical treatments or invasive therapies. 28
  29. 29. Chapter 9. Benign Prostate Disorders Transrectal ultrasound scanning (TRUS) Compared to TRUS, methods of determining prostate size such as DRE, urethrocys- toscopy and retrograde urethrography are poor[130]. It is often conducted in unison with biopsies of the prostate for suspected carcinoma, but is also a useful tool for assessing the size of an enlarged prostate so that the best mode of management may be undertaken, such as open versus endoscopic surgery. Two planes of measurement are needed to mainatain accuracy and reproducibility with a common formula used being: W x W x H x pi/6.[131] The amount of prostate actually protruding into the bladder (i.e median lobe) on ultrasound may also be important in predicting response to medical treatment after an episode of retention (more protrusion, increased risk of failing trial of void).[132] Serum Prostate Specific Antigen (PSA) Currently PSA is not recommended as part of the diagnostic workup for BPH and it is currently used in the context of case finding, staging, treatment response and monitoring of prostate cancer in patients.[133-135] It may have a role in population based-screening for prostate cancer in the future once larger studies mature.[135] An interesting observation by Stamey and colleagues from 1317 consecutive men under- going radical prostatectomy at Stanford University during the past 20 years has been the reduction in size of prostate cancers identified by PSA testing 1983. Thus, with downward stage migration, a PSA taken in today’s environment now likely repre- sents benign prostate enlargement rather than prostate.[104] Following on from this, recommendations have been made concerning the role of PSA in the patient with BPH [136]. This statement acknowledged that PSA levels are used as part of the decision-making process in men presenting with LUTS in the context of excluding prostate cancer and thus testing for it would be part of any consultation in any case. As outlined previously, distinguishing the two conditions when PSA is elevated may be aided by a free-to-total PSA ratio. A ratio of around 20% or greater for free PSA is considered more likely to represent BPH than cancer[105]. Furthermore, the consensus panel contended that PSA may be used as a surrogate for prostate volume and potentially a biomarker for disease progression (as it increases along with patient symptoms and deciding who may benefit from medical treatment. For example, it was emphasised that men with a PSA of ≥1.5ng/ml should be con- sidered to be at increased risk of BPH progression. To support such assumptions in a practical sense in men with BPH, those with a higher PSA have been found to benefit greatest from 5 α-reductase treatment (along with those men having larger prostates) [137]. More data on such uses of PSA in men with BPH is likely to emerge in the future. TREATMENT OF BPH- OVERVIEW The primary aim of any treatment for BPH in the vast majority of men is to relieve bothersome obstructive and irritative symptoms[138] (Table 2). Treatment is often undertaken on an elective basis for such patients. Those in whom complications of BPH occur have treatment done urgently as a matter of course. A range of treatment options are available and may be tailored to the needs of every individual, taking into account their disease manifestations, success rates of treatment, possible compli- cations and patient preference. There is persistent deterioration in BPH symptom severity and an increase in prostate volume, risk of acute urinary retention and need for prostatic surgery overall in un- treated patients with BPH over time.[139] Much of the evidence for such progression in BPH has arisen from large community studies such as those discussed below (Sec- tion 9.20). In addition, such studies have demonstrated a cumulative incidence in 29
  30. 30. Chapter 9. Benign Prostate Disorders severity of symptoms (LUTS) and a decrease in urinary flow rate (Qmax) in men not treated for BPH. Some groups of men who are more likely to experience disease progression have risk factors such as: 1. Prostate volume- large baseline volume 2. Age- older at higher risk 3. Qmax- poor maximum urinary flow rate 4. PSA- higher levels increasing risk 5. Increased symptom severity [136, 139, 140] In summary the physician can predict the risk of progression from the patient’s clin- ical profile based on the parameters immediately above. After predicting risk, the most appropriate treatment should be established by balancing the benefits of treat- ment against the possible risks and bother resulting from adverse events[140]. Such assumptions on parameters for BPH progression have recently been challenged in reviewing the large community Olmstead County study data , but further analysis from large cohorts would be needed to refute their value.[141] For a sixty year old man, over a lifetime, there is approximately a one in four risk of developing acute urinary retention [142] and almost a third will require BPH-related surgery[143]. However, BPH is a slowly progressing condition with the average de- cline in peak urine flow rate of 0.2ml/sec/year and an average increase in prostate volume of 1-2cc per year. Larger prostates tend to suffer faster growth rates.[144]. Hence the primary aim of any treatment for BPH in the vast majority of men is to relieve bothersome obstructive and irritative symptoms that developps slowly over time [138] (table 3). Treatment is often undertaken on an elective basis for such pa- tients. Conversely, those in whom complications of BPH occur have treatment done urgently as a matter of course. A range of treatment options are available and may be tailored to the needs of every individual, taking into account their disease mani- festations, success rates of treatment, possible complications and patient preference. WATCH AND WAIT/LIFESTYLE CHANGE Many men who presenting with LUTS are often seeking a full assessment of their prostatic health rather than immediate treatment of symptoms that may not be ex- ceptionally bothersome. People with mild symptoms may wish to pursue lifestyle changes as a way of improving their quality of life but with the option of review if such measures fail or symptoms worsen. Furthermore, when an adequate history is taken, hidden agendas such as fear of prostate cancer may even be revealed and fears allayed. Often drinking habits may be responsible for symptoms such as nocturia, where con- siderable fluid volumes are consumed in the evening. Reducing fluid intake may diminish nocturia and evening urgency. Furthermore, caffeine and alcohol acting as diuretics, can further exacerbate LUTS. Simple shifts in daily fluid intake may fulfil patient expectations and result in satisfactory outcomes. Voiding diaries are useful for making patients aware of drinking habits and may be the catalyst for initiating and monitoring changes. Bladder retraining (by using timed voiding, strengthening pelvic floor exercises and monitoring oral intake) is also an option in some individu- als, once a voiding diary has been examined. Medications may also play a role with LUTS. Measures such as diuretic restriction in evenings often prevents nocturia and frequency, provided the diuretic can be taken earlier in the afternoon. It is important to discuss options with the patient and that they are made aware that the possibility of damage to their upper urinary tract or to the detrusor muscle may result if their symptoms deteriorate and they do not seek medical attention. 30
  31. 31. Chapter 9. Benign Prostate Disorders PHYTOTHERAPY FOR BPH Phytotherapy, or the use of plant extracts, is becoming widely used in the manage- ment of many medical conditions including BPH (Table 11)[145]. Often these agents are promoted to aid “prostatic health” and a significant proportion of men try them. Factors also contributing to their widespread use include the perception that they are supposedly ”natural” products; the presumption of their safety (although this is not adequately proven); their alleged potential to assist in avoiding surgery, and even the unproven claim that they may prevent prostate cancer. The widespread availability of these products (without prescription) in vitamin shops, supermarkets, pharmacies and over the internet has contributed to their usage and reflects the demand for these phytotherapeutic agents. The mechanisms of action are poorly understood but have been proposed to be (1) anti-inflammatory, (2) inhibitors of 5α-reductase, and more recently (3) through alteration in growth factors[146]. Phytotherapy although promising, lacks long-term, good quality clinical data[147]. Nevertheless, because there is a large placebo effect associated with treatment of voiding symptoms, the use of herbal products that have few or no side effects may be a reasonable first-line approach for many patients[148]. However, patients should be counselled that the efficacy, mechanisms of action and long term effects of these agents are not known and they must be aware of the limitations before proceed- ing[149]. The most popular phytotherapeutic agents are extracted from the seeds, barks and fruits of plants. Products may contain extracts from one or more plants and different extraction procedures are often used by manufacturers. Thus the composition and purity of any one product may differ even if they both originated from the same plant. Basic research on one product may not be easily transferred to another making the gathering of data and giving of advice difficult[150]. [Table 11, TBD] Saw Palmetto Berry (Serenoa repens) Extracts from the berries of the American dwarf palm (saw palmetto) are the most popular and widely available plant extracts used to treat symptomatic BPH today[151, 152]. At least eight possible mechanisms of action for saw palmetto have been advocated including anti-androgenic properties, anti-inflammatory properties and the induction of apoptosis to name a few[150]. It is most commonly believed that saw palmetto works as a naturally occurring 5 α reductase inhibitor, blocking the conversion of testosterone to dihydrotestosterone (see below in medical therapies section), as demonstrated in several in vitro studies [148, 153-156]. Thus, saw palmetto may be expected to reduce prostate size. However, this is not the case in several trials using saw palmetto in men with BPH[157, 158]. The only trial to show in vivo effects of saw palmetto involved needle biopsies of the prostate gland, before and after treatment with saw palmetto or placebo. Although the mechanism is unclear, there was a significant increase in prostatic epithelial contraction in the saw palmetto group[159]. In a meta-analysis of 18 randomised studies relating to saw palmettto extracts, almost 3000 men with BPH were studied and the authors concluded that “the evidence sug- gests that saw palmetto improves urologic symptoms and flow rates but that further research is needing using standardised preparations to determine long term effec- tiveness”[145]. When analysing flow rate and symptom score alone from this meta- analysis, the effect of seronoarepens was to increase the flow rate by a further 2.28 ml/sec (standard error SE 0.29) over placebo which gave an increase of 1.09 ml/sec (SE 0.45). Serenoarepens also reduced the IPSS by 4.7 (SE 0.41), which is comparable to that found with finasteride and tamsulosin[160]. Many studies are currently un- derway to try and further delineate the role of saw palmetto extracts. One such study by Hruby et al. monitored progression rates in men with mild symptoms of blad- der outflow obstruction (IPSS<8) receiving serenoa repens and found that they were 31
  32. 32. Chapter 9. Benign Prostate Disorders significantly reduced as compared to patients on watchful waiting and a matched group of patients on placebo. One third of patients on watchful waiting and placebo progressed over the study period suggesting that phytotherapy may be an option in patients at risk for progression, defined as having a PSA > 1.5 ng/mL and an enlarged transitional zone volume (>25ml) on TRUS[161]. In summary, saw palmetto studies have shown improved symptom scores compared to placebo but generally no change in flow rates[162]. Overall there is a real paucity of well performed, adequately powered, and placebo controlled trials in the use of phytotherapy in clinical BPH. It is generally well tolerated at a dose of 320 mg/day, but its efficacy has not been compared with α blockers regarding efficacy, and has not been shown to reduce complications of BPH with long term use. Finally the product quality and purity cannot always be assured. A recent randomised controlled study by Bent et al has mounted a strong argument against the use of saw palmetto extract for symptomatic BPH.[163] The trial com- pared 160mg of saw palmetto extract against placebo in 225 men with moderate to severe LUTS. The follow-up period was 12 months with changes in symptom index and flow rates as end points with saw palmetto being no better than placebo and in fact flow rate deteriorated (0.42ml/min) and there was a negligible improvement in symptom index of 0.68 points in the saw palmetto group. One particular extract of saw palmetto, (Permixon, Pierre Fabre Medicament, Castres, France), has had all of its clinical data assessed in a meta analysis[164].This included all 14 randomized clinical trials and three open-label trials, involving 4280 patients. In the randomized controlled trials, the mean placebo effect on peak urinary flow rate was an increase of 1.20 mL/s. The estimated effect of saw palmetto was a further increase of 1.02 mL/s (P = 0.042). Further, a mean reduction symptom score (IPSS) for saw palmetto was 4.78. In summary, saw palmetto studies have shown modestly improved symptom scores compared to placebo but generally no change in flow rates[162, 163]. Overall there is a paucity of well performed adequately powered, placebo controlled trials in the use of phytotherapy in LUTS/BPH. It is generally well tolerated at a dose of 320 mg/day, but has not been compared with α blockers regarding efficacy, and has not been shown to reduce complications of BPH with long term use. The product quality and purity of saw palmetto cannot always be assured. This is continually raised as an issue[165] along with the recommended dosage required, and such differences need to be resolved if comparisons across studies are ever to be made. African plum tree (Pygeum africanum) Extracts come from the bark of the African plum tree. It is hypothesised, based on in vitro observation, that it acts on the prostate through inhibition of fibroblast growth factors, has anti-estrogenic effects and inhibits chemotactic leukotrienes. No strong clinical data exists of its efficacy although trials are in progress[146, 149]. Pumpkin Seed (Cucurbita pepo) Dried or fresh seeds have been taken to relieve symptoms. Phytosterols are thought to be amongst the active compounds. Side effects have not been reported but evidence is lacking with no current clinical trials[166]. Rye Pollen (Secale cereale) This is prepared from rye grass pollen extract. In a systematic review summarizing evidence from randomised and clinically controlled trials[138], rye pollen was found to be well tolerated but only achieved modest improvement in symptom outcomes 32
  33. 33. Chapter 9. Benign Prostate Disorders and did not significantly improve objective measures such as peak and mean uri- nary flow rates. Again, several mechanisms of action have been proposed including an improvement in detrusor activity, a reduction in prostatic urethral resistance, in- hibition of 5 α-reductase activity and an influence on androgen metabolism in the prostate[167]. Other extracts South African Star Grass (Hypoxis rooperi), Opuntia (Cactus flower), stinging nettle and Pinus (Pine flower) have also been studied and used, however the data num- bers are small and the types of trials do not allow conclusions to be drawn at this stage[146]. MEDICAL THERAPY FOR BPH In 1986 Caine[168] proposed that infravesical obstruction in men with symptomatic BPH comprised both static and dynamic components. The static component of ob- struction is related primarily to the mechanical obstruction caused by the enlarging prostatic adenoma whereas the dynamic component is principally determined by the tone of the prostatic smooth muscle. Two avenues for pharmacotherapy have there- fore evolved, namely shrinking the prostate tissue or relaxing the smooth muscle of the prostate. Medical therapy is now first-line treatment for most men with symp- tomatic benign prostatic hyperplasia[169]. They are non-invasive, reversible, cause minimal side effects, and significantly improve symptoms [90, 170]. Prostatic smooth muscle tone is under the influence of the autonomic nervous sys- tem. Thus any pharmacologic agent that may interfere with the functioning of this system could alter resistance in smooth muscle tone. There are 3 main components to clinically significant BPH: static, dynamic and de- trusor muscle components as outlined above. The dynamic component is associ- ated with an increase in smooth muscle tone of the prostate. These smooth mus- cle cells contract under the influence of noradrenergic sympathetic nerves, thereby constricting the urethra[171].Prostatic tissue contains high levels of both α 1and α 2 adrenoceptors – 98% of the α 1adrenoceptors are associated with stromal elements of the prostate[172]. Thus α 1-receptor blockers relax smooth muscle, resulting in re- lief of bladder outlet obstruction that enhances urine flow [96]. Different subtypes of α 1receptors have been identified with α 1Athe predominant. Two α 1A-adrenoceptors generated by genetic polymorphism have been identified with different ethnic distri- butions but similar pharmacologic properties [46]. It was demonstrated in 1978 that phenoxybenzamine, a nonselective α 1/α 2blocker, was effective in relieving the symptoms of BPH[173]. Side effects were significant and included dizziness and palpitations. Many of the side effects of the α-blockers were mediated by α 2-receptors[174].Thus, α 1selective antagonists such as terazosin, dox- azosin and prazosin and were developed that had fewer side effects than phenoxy- benzamine [76]. Doxazosin, alfuzosisn and terazosin have gained favour in clinical practice because they are longer acting than prazosin. Due to side effects, many α 1 selective antagonists need to be titrated and are often started at the lowest dose and built up over time to the maximal dose or a dose where clinical effects are satisfactory. Prazosin (titrated up to 5mg day) has been shown to significantly increase flow rates by 36-59% compared to placebo 6-28% but 17% of men discontinued the drug due to side effects such as dizziness (21%), headache (14%), syncope (3.4%) and retrograde ejaculation (13%). Alfuzosin (5 mg bid or10 mg daily) has shown symptom score reduction of 31-65% (compared to placebo 18-39%) and flow rate increases of 22-54% (compared to placebo 10-30%). Hence the results were similar to those of prazosin but with only 33
  34. 34. Chapter 9. Benign Prostate Disorders 3-7% discontinuations due to dizziness (3-7%), headache (1-6%) and syncope (<1 %)[175, 176]. Terazosin (2-10mg) had a symptom score reduction of 40-70% (compared to placebo 16-58%) and improved flow rates 19-40% (placebo 5-46%). Between 9-15 % of men discontinued the drug, related to dizziness (10-20%), headache (1-7%), asthenia (7- 10%), syncope (0.5-1.0%) and postural hypotension (3-9%). Thus terazosin was effec- tive and superior to placebo in reducing symptoms and increasing the peak urinary flow rate. The effect of terazosin on the peak urinary flow rate was apparent in stud- ies as soon as 8 weeks of therapy. Most importantly, the effect of terazosin on symp- toms and peak urinary flow rate was independent of the baseline prostate size for the range of prostate volumes reported[177]. Tamsulosin (0.4 mg once daily dose) is a selective α blocker for the α 1Asubtype which predominates in the human prostate, 12 times greater affinity for the receptors in the prostate than in the aorta thereby reducing side effects mediated through blood ves- sels receptors such as in the aorta. Symptom score were reduced by 20-50% ( placebo 18-30%), flow rates improved 20-45% ( placebo 5-15%) but only 3-7% of men discon- tinued drug because of dizziness (3-20%), headache (3-20%), syncope (0.3%) and ret- rograde ejaculation 5-10%. The rate of retrograde ejaculation was much higher than alfuzosin but the blood pressure lowering side effects are less with tamsulosin[178]. Doxazosin (4-12mg/day) is a selective α 1-adrenoceptor antagonist, and produced a significant increase in maximum urinary flow rate (2.3 to 3.6 ml. per sec) at doses of 4 mg, 8 mg and 12 mg, and in average flow rate compared with placebo. The in- crease in maximum flow rate was significantly greater than placebo within 1 week of initiating therapy and the drug significantly decreased patient-assessed total, ob- structive and irritative BPH symptoms. Blood pressure was significantly lower with all doxazosin doses compared with placebo. Adverse events, primarily mild to mod- erate in severity, were reported in 48% of patients on doxazosin compared to 35% on placebo, with only 11% discontinuing treatment (a similar number to placebo). The main side effects were dizziness (15-24%), headache (12%) and hypotension (5-8%) and abnormal ejaculation (0.4%)[179, 180]. In a meta-analysis, all α 1-adrenoceptor antagonists seem to have similar efficacy in improving symptoms and flow rates[181]. 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[182]. 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. It is important to understand most studies show symptom score improvements of 2-3 points and flow rate improvements of 1-2 ml/sec. Table 12. Commonly Used Alpha-Blockers Nonselective alpha blockers • Phenoxybenzamine • Nicergoline • Thymoxamine Selective alpha1 blockers • Prazosin • Alfuzosin 34