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Abstract
Alpha-Receptor Antagonist Drugs
Alpha-receptor antagonists may be reversible or irreversible in their interaction with these receptors. Reversible antagonists dissociate from receptors; irreversible drugs do not. Phentolamine and tolazoline are examples of reversible antagonists. Prazosin and labetalol—drugs are used primarily for their antihypertensive effects. Several ergot derivatives are also reversible α-adrenoceptor antagonists.
Phenoxybenzamine, an agent related to the nitrogen mustards, forms a reactive ethyleneimonium intermediate that covalently binds to receptors, resulting in irreversible blockade, illustrating the effects of a reversible drug in comparison to those of an irreversible agent.
The duration of action of a reversible antagonist is largely dependent on the half-life of the drug in the body and the rate at which it dissociates from its receptor: The shorter the half-life of the drug in the body or of binding to its receptor, the less time it takes for the effects of the drug to dissipate. However, the effects of an irreversible antagonist may persist long after the drug has been cleared from the plasma. In the case of phenoxybenzamine, the restoration of tissue responsiveness after extensive α-receptor blockade is dependent on synthesis of new receptors, which may take several days. The rate of return of α1 adrenoceptor drug effect may be particularly important in patients having a sudden cardiovascular event or who become candidates for urgent surgery.
Pharmacologic Effects
Cardiovascular Effects
Because arteriolar and venous tone are determined to a large extent by α- receptors on vascular smooth muscle, α-receptor antagonist drugs cause a lowering of peripheral vascular resistance and blood pressure. These drugs can prevent the pressor effects of usual doses of α agonists; indeed, in the case of agonists with both αand β2 effects (eg, epinephrine), selective α1 receptor antagonism may convert a pressor to a depressor response. This change in response is called epinephrine reversal. (Boehm and Kubista, 2002 )
Alpha-receptor antagonists may cause postural hypotension and reflex tachycardia. Postural hypotension is due to antagonism of sympathetic nervous system stimulation ofα1 receptors in venous smooth muscle. Tachycardia may be more marked with agents that block α2-presynaptic receptors in the heart, since the augmented release of norepinephrine will further stimulate βreceptors in the heart. (Bernstein D, 2002)
Alpha1-receptor blockade of the base of the bladder and the prostate is associated with decreased resistance to the flow of urine. Individual agents may have other important effects in addition to α-receptor antagonism.
Minor effects that signal the blockade of α1 receptors in other tissues include miosis and nasal stuffiness.
Table (3) showing different alpha adrenoreceptor subtypes, their plasma half lives and the dosing. (Roehrborn and Debra , 2004)
SPECIFIC AGENTS
Phentolamine, an imidazoline derivative, is a potent competitive antagonist at both α1 and α2 receptors. Phentolamine causes a reduction in peripheral resistance through blockade of α1 receptors and possibly α2 receptors on vascular smooth muscle. The cardiac stimulation induced by phentolamine is due to sympathetic stimulation of the heart resulting from baroreflex mechanisms.
In addition to being an α1- and α2-receptor antagonist, phentolamine also inhibits responses to serotonin and may be an agonist at muscarinic and H1 and H2 histamine receptors.
Phenolamine has limited absorption after oral administration, it may reach peak concentrations within an hour after oral administration and has a half-life of about 5–7 hours. The principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia.
Ergot derivatives—eg, ergotamine, dihydroergotamine—cause reversible α-receptor blockade. However, most of the clinically significant effects of these drugs are the result of other actions; eg, ergotamine probably acts at serotonin receptors in the treatment of migraine.
Phenoxybenzamine binds covalently to α receptors, causing irreversible blockade of long duration (14–48 hours or longer). It is somewhat selective for α1 receptors but less so than prazosin. The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (H1), acetylcholine, and serotonin receptors as well as αreceptors.
Many of the adverse effects of phenoxybenzamine derive from its α-receptor-blocking action; the most important are postural hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur.
Prazosin is a piperazinyl quinazoline effective in the management of hypertension. It is highly selective for α1 receptors, having relatively low affinity for α2 receptors typically 1000-fold less potent (Walden et al, 1999). This may partially explain the relative absence of tachycardia seen with prazosin as compared to what is reported with phentolamine and phenoxybenzamine. Prazosin leads to relaxation of both arterial and venous smooth muscle due to blockade of α1 receptors. Prazosin is extensively metabolized in humans; because of metabolic degradation by the liver, only about 50% of the drug is available after oral administration. The half-life is normally about 3 hours.
Terazosin is another reversible α1-selective antagonist that is effective in hypertension; it has also been approved for use in men with urinary symptoms due to benign prostatic hyperplasia (BPH). Terazosin has high bioavailability but is extensively metabolized in the liver, with only a small fraction of unchanged drug excreted in the urine. The half-life of terazosin is 9–12 hours. (Brawer e al, 2000)
Doxazosin is efficacious in the treatment of hypertension and BPH. It differs from prazosin and terazosin in having a longer half-life of about 22 hours. It has moderate bioavailability and is extensively metabolized, with very little parent drug excreted in urine or feces. Doxazosin has active metabolites, although their contribution to the drug’s effects is probably small.
Tamsulosin is a competitive α1 antagonist with a structure quite different from that of most other α1-receptor blockers. It has high bioavailability and a long half-life of 9–15 hours. It is metabolized extensively in the liver. Tamsulosin has higher affinity for α1A and α1D receptors than for the α1B subtype. A fourth receptor subtype the alpha-1L with low affinity to prazosin has also been pharmacologically defined. Both alpha-1a and alph-1L adrenoreceptor subtypes can demonstrated as pharmacological entities in human prostatic urethra so retrograde ejaculation does not occur with prazosin while it occurs with other alpha blockers according to the affinity to alpha1-l receptor (Fukasawa et al, 1998) . The drug’s efficacy in BPH suggests that the α1A subtype may be the most important α subtype mediating prostate smooth muscle contraction. Evidence suggests that tamsulosin has relatively greater potency in inhibiting contraction in mechanism of action smooth muscle versus vascular smooth muscle, compared with other α1-selective antagonists, which have equal or greater effects in vascular smooth muscle. This finding suggests that α1A receptors are less important in mediating contraction in human arteries and veins. Furthermore, compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients.
Alfuzosin: has been used extensively in Europe since 1988 IR (2.5 mg 3 times daily) and SR (5 mg twice daily) formulations .Use of an ER formulation 10 mg once daily for BPH signs and symptoms was approved by the United States Food and Drug Administration in 2003 based on clinical trials showing improvement in irritative and obstructive urinary symptoms as well as in PFRs with ER alfuzosin compared to placebo.
Alfuzocin is an α1-selective quinazoline derivative that has also been shown to be efficacious in BPH. It has a bioavailability of about 60%, is extensively metabolized, and has an elimination half-life of about 5 hours.
Indoramin is another α1-selective antagonist that also has efficacy as an antihypertensive.
Urapidil is an α1 antagonist (its primary effect) that also has weak α2-agonist and 5-HT1A-agonist actions and weak antagonist action at β receptors. It is used in as an antihypertensive agent and for benign prostatic hyperplasia.
Labetalol has both α1-selective and β-antagonistic effects. Neuroleptic drugs such as chlorpromazine and haloperidol are potent dopamine receptor antagonists but may also be antagonists at α receptors. Their antagonism of α receptors probably contributes to some of their adverse effects, particularly hypotension. Similarly, the antidepressant trazodone has the capacity to block α1 receptors.
Yohimbine, an indole alkaloid, is an α2-selective antagonist. It has no established clinical role. Theoretically, it could be useful in autonomic insufficiency by promoting neurotransmitter release through blockade of presynaptic α2 receptors. It has been suggested that yohimbine improves male sexual function; however, evidence for this effect in humans is limited. Yohimbine can abruptly reverse the antihypertensive effects of an α2-adrenoceptor agonist such as clonidine—a potentially serious adverse drug interaction.
Patients and methods
This study is a direct comparative study on 88 patients who have LUTS secondary to benign prostatic hyperplasia (BPH) randomized into two equal groups, this study was carried out in Suez Canal University hospital in outpatient clinic of urology department ISMALIA, EGYPT between September, 2002 and October, 2005 .
The sample size was determined as following using the equation of the difference between two means (Brash; 1989).
Sample size / group = 2 δ2 (z α + z β)2 / Δ2
where :
Z α the value of standard normal distribution for type 1 error probability for two sided test ( 0.05/2) = 1.96
Z β the value of standard normal for the desired statically power 80% = 0.84
Δ the difference of Q max for patients with symptoms secondary to BPH before and after treatment = 2.4 (Boyle et al, 1996)
δ the standard deviation of Q max in treated patients = 4 (Boyle et al, 1996)
Sample size = 2 x 42(1.96+0.84)2 / (2.4)2 = 44/ group.
-Inclusion criteria :
- Age : 50 –79 years
- IPSS >8 the IPSS is a suitable, reliable, valid and sensitive instrument to measure clinical change in the population (appendix l l ).
- Obstructed peak urinary flow rate (Q max) of 15 ml /sec. or less with voided volume of 150 ml or more
- Post voiding residual urine less than 200 cc assessed by pelvic ultrasound or by invasive method by introducing a Nelaton catheter of small caliber
Exclusion criteria:
-Refractory urinary retention ( failed at least one attempt after catheter removal).
-Recurrent gross hematuria from BPH
-Marked disorders of other organ systems (including renal or hepatic insufficiency )
-Meatal stenosis
- Urethral stricture
-History of prostatectomy
- Patients unwilling to be included in the study
- Active urinary tract infection
The clinical data of the patients fulfilling the inclusion criteria will be evaluated as follow :
1-Pre-medication clinical data
Pre-trial assessment and establishing a baseline to evaluate the effect of treatment required each patient to undergo a history and symptom assessment. The severity of symptoms was assessed subjectively using the IPSS (maximum 35 points) (Cockett and Aso et al, 1993) (appendix l) and The international index of erectile function (IIEF) ,which consists of 15 items and 5 domains, (appendix l l ) is a psychometrically valid and reliable instrument for use in determining efficacy of treatment (Rosen et al, 1997).
Data personally collected according to a pre- planned case sheet that included relevant general information about the patients. A special scoring system was designed to assess the degree of LUTS and ED.
- Examination :
a- General examination:
• blood pressure in both supine and sitting position at the first visit and one week after the start of the treatment
• abdominal examination
b- Digital rectal examination (DRE)
to evaluate :
-Anal tone ( weak, spastic, normal )
-bulbocavernosus reflex ( present, absent )
-Prostate ( size , consistency, nodule, suspicious cancer)
2-Pre medication investigations and imaging:
-urine analysis
-serum creatinine
-PSA, total and free. The percentage of free PSA is significantly lower in men with cancer prostate than men with BPH. In men with total PSA levels 4-10 ng/ml , a cutoff of 25% free PSA would have all of the cancers detected by total PSA alone, while correctly identifying an additional 31% of the patients without cancer ( Luderer et al, 1995).
-Uroflowmetry(Q max and voided volume) asking the patient to void without straining using Dantec UD 5500 MK2 .
-Pelviabdominal ultrasound .
3-Medication data:
Patients will be randomly classified into two equal groups each is 44 patients. The whole patients will be classified according to the attendance from 1 to 88, patients carrying the odd numbers will be categorized as group A while the patients carrying pair number will be group B.
Group A : will receive terazosin with l mg. starting dose at bed time for four successive days then 2 mg for 12 weeks .
Group B : will receive 5 mg. alfuzosin SR twice daily
4-Clinical outcome:
Was estimated both subjectively and objectively:
1- Objective outcome was based on the extent of improvement of Q max after 12 weeks from treatment
2- Subjectively was based on the extent of the change of IPSS after treatment
5- Study instrument:
The data were collected through the questionnaire (appendix no 1) directed to males suffering from symptoms secondary to BPH. The questionnaires were fulfilled by interviewing the patient .
Results
The 88 patients enrolled in the study were randomly divided into two equal groups, 44 patients in each group A ( patients received terazosin) and group B ( patients received alfuzosin SR).
Table 1: age distribution of both groups
Age in years Groups
A B
N % N % N %
50 – 59 years 23 52.3% 24 54.5% 43 53.4%
60 – 69 16 36.4% 12 27.3% 28 31.8%
70 – 75 5 11.4% 8 18.2% 13 14.8%
Total 44 100.0% 44 100.0% 88 100.0%
P value= 0.660 > 0.05 not statistical significant at the 0.05 level.
A- terazosin group B- alfuzosin group
Table 1 shows categorization of patients according to age group
In group A we have 23 patients ( 52.3%) aged from 50-60 years, 16 patients 36.4% aged from 60-70 years and 5 patients ( 11.4%) aged 70-75. On the other hand; group B shows 24 patients (54.5%) aged 50-60 years, 12 patients 27.3% aged 60-70 years and 8 patients (18.2%) aged 70-75. There is no statistical difference between the two groups p =.066
Table 2 shows the mean pre-treatment basic parameters of both groups ( Age, prostate size, Q.max, IPSS, QOL, , residual urine & concomitant diseases DM& HTN)
Table 2: the different study variables among both groups BEFORE
treatment
Study variables Group A Group B
Mean ±SD. Mean ±SD.
Age 60.89 6.73 60.82 7.90 .965
P.Size 47.7 11.65 46.1 7.32 .642
Qmax 9.37 3.20 9.72 2.65 .578
IPSS 16.57 5.22 16.95 5.58 .738
QOL 2.75 1.22 2.73 1.13 .928
Residual 33.7 12.91 32.8 11.37 .729
DM (n %) 5 11% 4 10% .614
HTN (n %) 4 10% 5 11% .738
Not statistically significant at the 0.05 level.
(Note) P- value of the previously mentioned parameters was calculated by the T test , while for percentage of DM& HTN in both groups by chi square test.
As shown in the table, there is no significant statistical difference between the basic parameters in both groups at base line. This confirms the reliability of constitution of both groups to begin the study and also confirms the validity of comparison of the post treatment values.
The pre and post treatment values in Q max, IPSS, QOL, prostate size and residual urine in terazosin group were illustrated in figure(1) , to assess the efficacy of terazosin
Figure 1:comparison between different study variables in patients
received terazosin
Not statistically significant at the 0.05 level
As shown in the figure, there is an obvious improvement in urine flow in patients who received terazosin as there is statistically significant difference between the mean Q max post treatment in comparison to the base line value, P<0.045. There is highly statistically significant differences between pre and post treatment scores of IPSS, QOL, P value 0.002 and 0.0001 respectively.
While no statistically differences in prostate volume and residual volume of urine post treatment regarding to the figures pre-treatment P= 0.633
On the other hand the different parameters in group B.( the patients who received alfuzosin SR) to assess the efficacy of alfuzosin either by objective measurements taken before and after the treatment period were the maximum flow rate Q max , residual urine & prostate size and subjective measurements of IPSS and QOL taken before and after treatment period. This is shown in figure (2) that there are highly statistically significant improvement in Q.max , IPSS and QOL, while there were no significant change in prostate volume and residual urine volume
Figure (2) The change from the baseline after treatment in Alfuzosin
Not statistically significant at the 0.05 level
Figure (3) shows direct comparison between the two groups on the effect of the basic parameters after the treatment. Although the Q max and IPSS before treatment were similar in both groups as shown in table 2 before, the figure shows the improvement in Q max and IPSS is
statistically better in patients who received terazosin than in patients received alfuzosin SR, P= 0.045 and 0.025 respectively
While no significant statistical difference between the two groups in the degree of improvement of QOL, prostate size and residual urine
P=0.549, 0.704 and 0.964 respectively
Figure 3: Comparison between both groups variables AFTER
Treatment
Not statistically significant at the 0.05 level
The safety of terazosin and alfuzosin were evaluated in table 3
Table (3) adverse events
Adverse events Group A Goup B P value
Dizziness 6 (13.9) 4 (9.1) 0.451
Asthenia 4 (9.1) 1(2.3) 0.192
Headache 5 (11.4) 8(8.2) 0.812
Postural hypotension 3 (6.9) 1(2.3) 0.31
Not statistically significant at the 0.05 level
The table shows that 6 patients in the terazosin group had dizziness in comparison to 4 patients in alfuzosin group but there is no statistical difference between the two groups P = 0.451. Four patients in the terazosin group suffered from asthenia while 1 patient in alfuzosin group had asthenia.Three patients in the terazosin group versus 1 patient in the alfuzosin group had a symptomatic orthostatic hypotension which defined as 20 mmHg or more decrease in systolic blood pressure
But there was no statistical difference between the two groups P=0.31
Fig (4) categorization of the study population according to sexual function
.
The figure tells us that 37 patients are within normal ,10 mild ,7 moderate, 8 moderate to sever and 2 patients have sever to complete erectile dysfunction according to IEFF
Age, IIEF,Prostate size and IPSS
The correlation beween the age and the IPSS and the correlation between the age and prosate size are presented as scattergrams(Fig. 5,6). The statistical analysis using Pearson correlation coefficient revealed some correlation between age and the IPSS r=0.128 and little correlation between age and prostate size r=0.115
Fig. 5 Scattergram demonstrate the correlation between the age and the IPSS. The statistical analysis using Pearson correlation coefficient revealed some correlation between age and the IPSS r=0.128
Fig. 6 Scattergram demonstrate the correlation between the age and the prostate size. The statistical analysis using Pearson correlation coefficient revealed little correlation between age and the IPSS r=0.115
The correlation beween the IIEF and the IPSS is presented as scattergram (Fig. 7). The statistical analysis using Pearson correlation coefficient revealed strong correlation between IIEF and the IPSS r=0.306
Fig. 7 Scattergram demonstrate the correlation between the IIEF and IPSS. The statistical analysis using Pearson correlation coefficient revealed strong correlation between age and the IPSS r=0.115
pvalue=0.014 statistically significant at the 0.05 level
Natural History and Prognosis of Benign Prostatic Hyperplasia
There continues to be ongoing discussion regarding the timing of when treatment for LUTS should be implemented. It is generally agreed that treatment should be considered when the LUTS significantly affects quality of life, but there is also some concern that outlet obstruction may affect the structural basis of how the bladder functions over the long term. In a study by Levin et al,1999) bladder biopsies were examined in men with outlet obstruction and symptomatic BPH and compared with age-matched men with no urologic dysfunction. There were significant changes in bladder function caused by BPH. They included (1) decreased ability of the sarcoplasmic reticulum to store and release calcium and (2) mitochondrial dysfunction. These cellular functional changes raise some issues about how extensively LUTS patients should be evaluated and when to initiate treatment. A Japanese study by Inui et al,1999) examined histologic changes in the bladder, bladder hypertrophy, and BPH. In this study, 26 men underwent urodynamic evaluation and bladder ultrasound to estimate bladder weight preoperatively. A significant correlation between the ultrasound estimated bladder weight and preoperative measurement of bladder wall compliance (ie, the ability of the bladder to store a normal amount of urine at low pressure) was found. It appeared that this increase in bladder weight and decrease in compliance was caused by an increased deposition of connective tissue (collagen) caused by infravesical obstruction (ie, BPH). These results indicate the importance of identifying those men with LUTS who are at risk for progressive change in bladder function (ie, the development of poor bladder wall compliance). This loss of bladder elasticity places these individuals at significant risk for upper urinary tract deterioration and may permanently alter bladder function.
Traditionally, detailed urodynamics studies are used to determine the presence or absence of obstruction from the prostate and to quantitate the severity of the obstruction if present. Urodynamics may be useful in identifying those men with LUTS who are at risk for renal damage (due to persistent high pressure in the bladder during filling, known as poor compliance) or those with extremely high-grade outlet obstruction as determined by plotting the pressure-flow study results on a pressure flow nomogram. Most clinicians agree that a urodynamics study before LUTS treatment should be reserved for ”complex” cases and is generally not needed for ”routine” cases of LUTS because the presence of outlet obstruction due to BPH is not correlated with prostate size, the amount of postvoid residual urine, or the cystoscopic appearance of the prostate gland (Leach, 1999).
Benign prostatic hyperplasia (BPH) frequently has a significant detrimental impact on a patient’s quality of life. If the disease is left untreated, it may progress in severity, leading to recurrent bladder infections, bladder calculi, and acute urinary retention (AUR) necessitating surgical treatment (Kirby, 2000).
One of the first studies conducted by (Garraway et al, 1991), surveyed men from the Forth Valley area of Scotland. The study involved a survey of 705 men, 214 of whom underwent transrectal ultrasonography. The researchers defined BPH as a prostate gland in excess of 20 g with a reduced urinary peak flow (<15 mL/s) in the presence of urinary dysfunction symptoms and no evidence of malignancy. They suggested that approximately 14% of men aged 40 to 50 years might have BPH. The study also reported that as many as 43% of men >60 years old might have BPH- a surprising finding that created a stir in the urology community. Approximately half of the men >60 years old who had BPH noted that the disease interfered with activities of daily living.
Some urologists believe that every patient with AUR should undergo a trial without a catheter. The catheter–inserted to empty residual urine– is removed to see if patients can reestablish micturation on their own.? One study has reported a 72% failure rate for trial without a catheter (Taube and Gajraj, 1989). In he other hand a trial without a catheter can be traumatic, because recatheterization may be required. There may also be a delay and discomfort involved in accomplishing recatheterization and because of this (Kirby, 2000) mentioned that men who develop AUR often require emergency surgery, with its attendant risk of morbidity and mortality.
BPH is not always associated with AUR and does not always progress in every patient. This was first observed in 1969 by in a study of 212 men with BPH having a mean age of 70 years and presenting with LUTS or AUR. A follow-up at 4 to 7 years revealed that nearly half of the men (29 of 60) who did not have surgery no longer had symptoms of BPH (Craigen et al, 1961). Another study followed patients with LUTS for 5 years. Of 107 patients, only 16 who did not undergo surgery considered their condition to have deteriorated. Ten of the 107 patients were treated surgically and 52% were considered to be unchanged, whereas 32% were thought to show improvement in their symptoms (Ball et al, 1981).
Risk Factors for Disease Progression
(Arrighi et al, 1990) identified urinary symptoms that are more likely to be associated with BPH with progression to AUR and prostate surgery in the Baltimore Longitudinal Study of Aging. They identified three risk factors: a change in the size and force of the urinary stream, a sensation of incomplete bladder emptying, and an enlarged prostate on digital rectal examination. Patients with a greater number of risk factors were more likely to experience AUR or require prostate surgery. The presence of one risk factor was associated with a 9% risk of AUR or prostate surgery, which increased to 16% in those with two risk factors, and 37% in patients with three risk factors. Age is a very important independent determinant of risk. A man aged 70 years who has all three of the risk factors has an 11-fold greater risk of progressing to AUR or requiring prostate surgery compared with a man who has the same three risk factors and is only 40 years old.
The Olmsted County Study -a population-based longitudinal study- has provided a wealth of epidemiologic data on BPH and its natural history. This study included more than 2,000 randomly selected men aged 40 to 79 years with no prior disease that could affect urinary function. Peak urinary flow rates measured in 2,113 of these men showed decreasing rates with advancing age. This decrease corresponds to a reduction of approximately 2 ml/s for each decade. There is a corresponding increase in prostate size (0.6 mg/year). Men with enlarged prostates (>40 gm) are three times more likely to have elevated LUTS. They are also twice as likely to be bothered by these symptoms and twice as likely to experience interference with normal daily activities. Men who have a prostate (>30 gm) in volume are at a three times greater risk of developing AUR compared with men who have smaller prostates (Cliute et al, 1993; Girman et al, 1993; Guess et al, 1995).
Effect of Treatment on Disease Progression
Until recently, there were few treatment options available to those suffering from LUTS. The predominant therapy was observation, complimented by reassurance, reduction of evening intake of fluids, and pelvic floor exercises, until symptoms became severe enough to warrant surgery.
There are now pharmacologic alternatives to surgery, encouraging males to seek treatment earlier in the course of the disease. They include alpha1 adrenergic blockers and 5-alpha-reductase inhibitors (finasteride). These two groups of drugs are active in reducing symptoms and partly relieving bladder outlet obstruction and may alter the progression of BPH, 5α-Reductase inhibitors (including finasteride) and alpha-adrenergic antagonists.
In the randomized Finasteride Long-term Efficacy and Safety Study, the risk of patients progressing to TURP or AUR was decreased by approximately 50% in 3,040patients with moderate to severe BPH treated with the 5α-reductase inhibitor finasteride 5mg/day for 4 years, compared with placebo. 8% of placebo patients and only 4% of finasteride patients underwent TURP. Likewise, 7% of patients in the placebo progressed to AUR requiring catheterization compared with only 3% in the finasteride group. a 57% reduction in risk with the study drug (McConnell et al, 1998).
Similarly, in a nonrandomized open-label trial incorporating 13,228 men with BPH treated with the α-blocker alfuzosin and studied over a 3-year period, only 9 patients (0.3%) experienced AUR (Lukacs et al, 1998).
A recent randomized trial found that the α1-blocker alfuzosin is useful for the treatment of acute urinary retention (AUR) and for subsequent maintenance. 360 patients with AUR underwent emergency catheterization and were randomized blindly to alfuzosin, 10 mg, a day or placebo for three days ”Alfuzosin 10 mg daily increased the likelihood of successful TWOC in men with a first episode of spontaneous AUR and should be continued beyond the acute phase, as it reduced the need for BPH surgery during a six-month treatment period and the editorialist suggests that these results are generalizable to other alpha blockers (Barclay, 2005; McNeill et al, 2005).
Transurethral resection of the prostate (TURP) was shown to be more effective than watchful waiting in the Veterans Affairs Cooperative Study which compared these two approaches in patients with moderate BPH. In that study, 280 patients were randomized to the surgery group and 276 to the watchful waiting group. Over a 3-year follow-up period, 47 patients (17%) in the watchful waiting group experienced treatment failure. Surgery was necessary in 11 of the men in the watchful waiting group because of high residual urine, 8 because of LUTS, and 5 because of AUR. In contrast, only one patient who underwent TURP developed subsequent AUR. The impact of symptom severity is demonstrated by the increased risk of crossover: the higher the symptom score at the time patients entered the watchful waiting group, the greater the risk of crossover to surgery. Men with high symptom scores had a two-fold greater risk of crossover to surgery (Wasson et al, 1995).
Alpha-blockers may improve LUTS symptoms both in men with urodynamically proven outlet obstruction and in those without obstruction. Up to 90% of obstructed men will respond to alpha-blockers vs a 70% response rate for those men without urodynamically proven obstruction (Jeon et al, 1999).
Potential treatment outcome predictors for BPH include age, symptom severity and frequency, bothersomeness of symptoms, peak flow rate, prostate size, prostate-specific antigen (PSA) level, etc. Of these, prostate size is the factor that has been studied in detail (Kirby, 1999). A meta-analysis has been conducted on six randomized clinical trials, which compared treatment with finasteride to placebo over one year: Prostate size, as determined by either transrectal ultrasonography or magnetic resonance imaging, varied at baseline by 50%, (37-60 ml). Stratification of patients according to prostate size demonstrated convincingly that the response to treatment with finasteride was dependent on baseline prostate volume, that is the larger the prostate, the greater the improvement in peak flow rate and symptom score . Overall, the greatest response to finasteride treatment was seen in patients with baseline prostate volumes greater than 40 ml (Boyle et al, 1996).
An important component of any therapy is compliance. In a study by Olson and colleagues (1999) 46 men were followed for 48 months while treated with terazosin (an alpha-blocker). The authors found that terazosin was well-tolerated in doses of 10 to 20 mg/day and that improvement in the American Urological Association’s BPH symptom score was well-maintained for up to 48 months of treatment. The most common side effects from the terazosin treatment were dizziness, which occurred in 32% of men, and asthenia, which occurred in 29%. About 12% of men discontinued therapy each year during the 4-year follow-up period, with approximately 50% of men with LUTS completing the study.
Although providing the highest likelihood of relief of both prostatic symptoms and urodynamic obstruction, surgical intervention for BPH with procedures such as TURP can have a significant impact on the patient’s sexual function. Rates of erectile dysfunction as high as 14.0% have been reported following, TURP (Bolt et al, 1987), as well as retrograde ejaculation rates of 68%. (Richman, 1995). (Petsch and Schulze, 1999) examined sexual dysfunction in 68 men following TURP. Postoperatively, one third of the men developed difficulty in sexual function though their urinary symptoms had improved. The researchers emphasized how important it is to discuss the possibility of experiencing sexual dysfunction prior to performing a TURP.Moreover, evidence suggests that surgery for BPH carried out as an emergency for AUR carries greater morbidity than elective TURP (Malone , 1988; Higgins et al, 1991).
Vicentini and colleagues (1996) presented a unique study examining the outcomes in symptomatic men with large prostates (average 63g) treated with open prostatectomy and followed for up to 26 months after surgery. Excellent resolution of symptoms and well-maintained urodynamic improvement in flow rates and voiding pressures occurred postoperatively that the authors suggested that open prostatectomy should be considered the new ”gold standard” of surgery modalities for the treatment of LUTS.
The cost of disease progression to AUR is a painful and distressing condition associated with a significant morbidity and requiring hospitalization, catheterization and often surgery. The costs associated with treatment of AUR can be substantial. A recent study from the UK reviewing the surgical outcome in 3966 men undergoing prostatectomy found that nearly a third of men (31%) presented in AUR. These group of patients were also at higher risk of developing complications and death more than men who underwent elective prostatectomy. These differences were only partly accounted for by renal impairment, age and co-morbidity (Pickard et al, 1998).
Prostate Anatomy
Prostate Size, Shape, and Configuration
The normal prostate weighs 18 g; measures 3 cm in length, 4 cm in width, and 2 cm in depth. The prostate has been ascribed many different shapes (Fig. 1) including conical, spheroidal, “croissant-shaped” and “doughnut-shaped”. Depending upon age and probable genetic factors, there is a wide range of prostate size, shape, and configuration. Prostates of the teenager may have strikingly different shapes. With aging, adenofibromatous hyperplasia (AFH) becomes the primary determinant of any subsequent lobar configuration resulting in the production of lateral, middle, and even anterior lobes. This is readily apparent both endo-scopically and in the enucleated adenomata from suprapubic prostatectomies (Myers, 1994).
The urethra represents the primary reference point, dividing the prostate into an anterior fibromuscular (30% of the prostate volume) and a posterior glandular portion (70% of the prostate volume). Passage of the urethra through the prostate usually is accompanied by variable anterior angulation just superior to the seminal colliculus or verumontanum (veru). Usually there is “roughly 350” of the pre-urethral angulation but occasionally there is no angulation, or the angulation approaches 900 (Myers, 1991).
Zonal Anatomy
The urethra divides the prostate into anterior fibromuscular and posterior glandular portions. The ejaculatory ducts pass through the prostate in a line parallel to the plane of the distal urethral segment and empty through the veru into the distal segment. The glandular prostate is divided into four distinct regions; peripheral zone, central zone, transition zone, and periurethral gland region. Each of these distinct four regions is bounded or centered on either the urethra and/or the ejaculatory ducts (McNeal et al, 1988).
Fig. 2: Zonal anatomy of the prostate. The transition zone surrounds the urethra proximal to the ejaculatory ducts. The central zone surrounds the ejaculatory ducts and projects under the bladder base. The peripheral zone constitutes the bulk of the apical, posterior, and lateral aspects of the prostate. The anterior fibromuscular stroma extends from the bladder neck to the striated urethral sphincter (McNeal et al, 1988).
• Anterior Fibromuscular Stroma: The anterior fibromuscular stroma (AFMS) represents almost all of the non-glandular tissue of the prostate. It consists of a thick sheet of tissue covering the entire anterior surface of the prostate and hiding the urethra and glandular portions of the prostate from view anteriorly. The AFMS contains the prostatic isthmus (isthmus prostatae, anterior commissure). It is composed mainly of smooth muscle that is continuous proximally with the detrusor fibers of the anterior bladder wall. These fibers sweep distally from the bladder neck and fan out laterally, covering the entire anterior and anterolateral surface of the glandular prostate (McNeal, 1988).
• Peripheral Zone: The peripheral zone constitutes about 75% of the glandular tissue of the normal prostate. It surrounds the urethra along and distal to the veru, and it ducts drain into the urethral segment between the veru and the apex. The peripheral zone is a frequent site (approximately 70 percent) of origin for carcinoma and does not give rise to benign hyperplasia (Epstein et al, 1993).
• Central Zone: The central zone accounts for nearly 25 percent of the glandular tissue in the normal prostate. It surrounds the ejaculatory ducts throughout their course through the prostate. 10 percent of prostate cancers arise from the central zone, meanwhile, benign hyperplasia does not occur within the central zone (McNeal, 1988).
• Transition Zone: The transition zone comprises two small lobules on either side of the proximal urethral segment just lateral to the periprostatic sphincter and anterior to the peripheral zone. The ducts of the transition zone empty into the posterolateral recesses of the urethral wall above and in continuity with the ducts of the peripheral zone (McNeal, 1988). Transition zone constitutes 5 to 10 percent of the glandular tissue of the prostate in a young man. It is the site of origin of benign prostatic hyperplasia and is also the site of origin of approximately 20 percent of carcinoma (Fleshner and Fair, 1997).
• Periurethral Glands: They constitute less than one percent of all prostate glandular tissue and are embedded in the smooth muscle wall of the urethra entirely within the preprostatic sphincter. Their ducts open out to the posterolateral recesses of the proximal urethral segment. These glands can be the site of development of benign hyperplasia, giving rise to a so-called large middle lobe (McNeal et al, 1988).
Basic Surgical Anatomy
• Surfaces and Relations: The prostate is commonly thought of as having a “base” against the bladder and an “apex” distally. The area in contact with levator muscle defines the lateral surfaces. The anterior surface depends on the length of the anterior commissure. The area in contact with the rectovesical septum (Denonvilliers’ fascia) situated between prostate and rectum defines the posterior somewhat triangular surface (Hinman, 1993).
Figure 3: Coronal section of the male pelvis; relations of the prostate (Hinman , 1993).
• Pelvic Fascias: The pelvic fascias originate from the retroperitoneal connective tissue that line the body wall and invest the pelvic organs. The parietal layer consists of fascia covering the levator muscles, while the visceral layer covers the urinary bladder and prostate. Fusion of the parietal and visceral layers forms a fascial condensation that runs from the pubis to the ischial spine bilaterally adjacent to prostate, known as the tendinous fascial arch of the pelvis (Myers, 1994).
• Pubovesical Ligaments and Ventral Vascular Complex: The ”puboprostatic ligaments” are ligamentous attachments to the pubis. They are condensations of the endopelvic fascia that extend to the bladder neck. Laterally, the fascial condensations are dense and are continuous with the fascial tendinous arch of the pelvis (Myers, 1991).
• Denonvilliers’ Fascia: Denonvilliers’ fascia covers the posterior surface of the prostate. It begins at the apex, where it is least distinct, and extends cephalad, becoming thicker at the prostate base and seminal vesicles. This fascia anatomically separates the prostate from the rectum (Cummings, 2000). It is continuous laterally with para-rectal fascia posteriorly and lateral pelvic fascia anteriorly (Kourambas et al, 1998).
• Prostatic Capsule: The prostatic capsule is not a true one, rather it is a condensation of gland-free fibromuscular tissue that encases the prostatic parenchyma, incorporates vascular channels and neural elements, and blends inseparably on the inside with fibromuscular stroma of the prostatic parenchyma. This covering (capsule) is 0.5mm thick, except where the gland joins the bladder, where it increases to a thickness of 2mm. The capsule is thin on the posterior aspect and thickest in anterior Medline where it blends inseparably with the underlying ventral (anterior commissure, isthmus, anterior lobe) part of the prostate. The outer limit of the prostatic capsule is not sharply delineated. It is represented by the irregular interface with outlying fibro-adipose tissue of the periprostatic fascia (prostatic sheath) on the anterior and lateral surfaces, and its fusion with Denonvillier’s fascia posteriorly (Hinman, 1993). This prostatic sheath is a much thicker fibrous covering than the capsule. It envelops the prostate completely and constitutes the so-called prostatic lodge, formed by an adventitious fibrovascular covering because it contains within its walls the vascular and nerve columns from the hypogastric plexus (Gil-Vernet, 1996).
• Arterial Supply: The inferior vesical artery branches out to supply the seminal vesicles and the base of the bladder and prostate. The prostatic branches divide into urethral and capsular branches. The capsular branch runs between the leaves of the parietal (levator) fascia and visceral (prostatic) fascia along the posterior lateral border of the prostate (Cummings, 2000).
• Venous Drainage: A rich plexus of veins encompasses the prostate gland between the true fibrous capsule of the gland and the lateral prostatic fascia. It forms the dorsal venous complex (Santorini plexus) that runs along the puboprostatic ligaments and is visible landmarks on TRUS.
Venous drainage from the prostate moves from the Santorini plexus eventually into the internal iliac vein. The prostatic venous plexus communicates freely with the extradural venous (Batson plexus), which is thought to be factor in the spread of prostate cancer (Hinman, 1993).
• Deep Dorsal Vein Complex: The apex of the prostate is nestled in the dorsal vein complex. from this complex a multitude of veins emanates that travel in different directions. One division of veins exits posteriorly to become the pudendal veins. Another exits posterolaterally to the apex to accompany the neurovascular bundle on each side. Finally, a major division is spread anterolaterally over the urethra, prostate-urethral junction, and the prostate itself (Myers, 2001).
• Lymphatics of the Prostate: The prostate has a rich lymphatic plexus surrounding the gland and a wide-meshed subcapsular plexus. The prostate lymphatics drain into periprostatic subcapsular network, from which three groups of ducts originate: the ascending, from the cranial gland, running to the external iliac nodes; the lateral, running to the hypogastric nodes; the posterior, from the caudal gland, running towards the lateral and sub-aortic sacral nodes of the promontory (Gil-Vernet, 1996).
• Innervation of the Prostate: The parasympathetic visceral efferent preganglionic sacral fibers (S2¬-S4) and the sympathetic thoracolumbar fibers (T1-1¬L2) through the presacral and hypogastric neural plexuses form the pelvic plexus, which is located posterior and lateral to the tip of the seminal vesicle. Branches to the membranous urethra and corpus cavernosa run with the capsular artery and associated venous tributaries, and together constitute the neurovascular bundles (Reiner and Walsh, 1979). The neurovascular bundle (NVB) is a discrete structure lying at the posterolateral edge of the prostate, beneath the lateral pelvic fascia at the lateral edge of the Denonvilliers’ fascia. At the level of the sphincteric urethra, the NVB run at the 3- and 9-o’clock positions. These fibers branch in the prostatic plexus and then travel with the prostatic vascular pedicles, located at the posterolateral aspect of the prostatic base, between the rectum and prostate (Myers, 1994)
Conclusion and Recommendations
This clinical trial showed that both alfuzosin SR formulation and terazosin are effective in the treatment of patients with LUTS suggestive of BPH, regardless of prostate size.
Terazosin has better efficacy in improving IPSS and Qmax than alfuzosin S.R.
Terazosin 2 mg in incremental dose and alfuzosin S.R 5 mg twice daily are tolerable and has no serious side effects in the treatment of BPH.
Titration of terazosin is recommended to avoid serious side effects while no need for dose titration with alfuzosin. Because the therapeutic effect and adverse events associated with alpha blockers are dose dependent, we recommend the use of minimal doses that can achieve significant clinical improvement.
There is significant relationship between the severity of LUTS and the degree of ED and the improvement of IPSS over all patients in both groups are associated with significant improvement in the IIEF.
Multicenter randomized double-blind placebo conrolled trials of alpha-1 adrenorecepor blockers are powered to show differences in efficacy but not in safety. Since these agents are generally well tolerated (Lepor et al,1992; Lepor 1995; Fawzy et al, 1995; Roehrborn et al, 1996; Buzelin et al, 1997; Lepor 1998; Roehrborn 2001) larger sample sizes are required to distinguish differences in their side effects. The incidences of adverse events must be interpreted relative to their effectiveness, since the efficacy and tolerability of alph-1 adrenoreceptor blockers are both dose dependant.
Aim of the work
• Assessment of efficacy and safety of terazosin and alfuzosin in the treament of BPH
• Evaluation of the relationship between ED and the severity of LUTS
• Evaluation of the effect of alpha blockers on ED
Study questions
Is terazosin more effective than alfuzosin in the treatment of BPH?
Is there a relation between LUTS and ED?
Clinical Aspects and Workup of
Benign Prostatic Hyperplasia (BPH)
Benign prostatic hyperplasia (BPH) is one of the most common medical conditions and the most common benign neoplasm affecting older men (Nicke and Roehrborn, 2000). Histologic evidence of BPH occurs in 50% of men by the age of 50 years, 70% of men over 70 years old and in up to 90% of men by age 80 years. It is affecting the quality of life (QOL) for approximately one third of men older than 50 years (Abrams, 1995; Wasson et al, 1995; Nicke and Roehrborn, 2000).
Furthermore, untreated BPH may lead to a number of medical complications, most notably acute urinary retention (AUR), gross hematuria, repeated urinary tract infections, obstructive uropathy, bladder calculi, and renal failure on rare occasions (Nicke and Roehrborn, 2000).
The interpretation of lower urinary tract symptoms is fraught with difficulty. Symptoms can be categorised into filling symptoms and voiding symptoms, previously known as irritative and obstructive symptoms, even though there is generally little ”irritation” in the lower urinary tract in such patients and the so called obstructive symptoms show no statistical association with urodynamically proved bladder outlet obstruction. Only the concurrence of the symptoms of urgency and urge incontinence give any clue to an individual patient’s bladder dysfunction. A patient with both these symptoms has a high chance (85%) of having detrusor instablility (detrusor contractions during bladder filling which the patient is unable to inhibit) (Abrams, 1995).
Symptom questionnaires only measure symptoms at a particular time, and do not have any diagnostic importance. Indeed, the international prostate symptom score (IPSS) (appendix ), a validated questionnaire gives identical readings in men with and without obstruction (Abrams et al, 1993). The only way that benign prostatic obstruction can be diagnosed accurately is by urodynamic studies (Abrams, 1995).
LUTS refer to a complex of irritative and obstructive voiding symptoms that are exceedingly common in both aging men and women. Thus, LUTS are neither prostate nor sex specific. These symptoms may or may not be associated in an individual male patient with prostate enlargement, estimated either by digital rectal examination (DRE) or measured by transrectal ultrasonound (TRUS) or magnetic resonance imaging (MRI). Furthermore, such prostate enlargement may or may not be associated with BOO as validated by a reduction in peak urinary flow rate (Q¬max) and/or urodynamically proven obstruction. Lastly, LUTS, prostate enlargement, and obstruction may or may not be associated with or related to benign stromoglandular hyperplasia of the prostate, referred to as BPH (Nicke and Roehrborn, 2000).
Garraway and Kirby (1994) in The Forth Valley, Scotland, study was the first to examine in detail the degree to which BPH affects a patient’s quality of life (QOL). They ranked the symptoms of BPH by order of impact beginning with the most bothersome: lack of sleep, anxiety/worry, reduced mobility, interference with leisure activities. interference with usual daily activities, and compromised sense of well-being.
The short term impact of acute urinary retention (AUR), which is frequently seen in patients with BPH are devastating, characterized by the sudden onset of painful, distressing symptoms that require hospitalization. patients often experience a long-term loss of confidence due to anxiety over the possibility of a subsequent episode (Kirby, 2000).
LUTS has a negative association with physical and mental aspects of health. Mild symptoms impaired health status to some degree; severe symptoms, however, were associated most strongly with health status. The strongest associations that may prompt men to seek medical attention are energy/fatigue and general health perception (Roberts et al, 1997).
Clinically lower tract obstruction is associated with voiding difficulties (eg, hesitancy, decreased force of urinary stream, straining to void, postvoid dribbling, sensation of inadequate emptying, double voiding). Frequency (especially nocturia) is a sign of inadequate emptying, necessitating an increased number of urination episodes. Significant long-term obstruction usually leads to urinary urgency and urge incontinence. Suprapubic fullness or pain indicates urinary retention. Dysuria and cloudy urine suggest an infectious process. Depending on the etiology of obstruction, hematuria can be present. In lower tract obstruction, a palpable bladder indicates urinary retention. Digital rectal examination may reveal benign or malignant prostate enlargement (AUA Practice Guidelines Committee, 2003).
Accurate and early diagnosis of BPH leads to better treatment outcomes and predetermines the treatment choice. These guidelines have defined a series of tests as mandatory, optional, or recommended and not recommended and are presented in table 2.
Initial Evaluation
The initial evaluation should include a detailed medical history, with particular attention given to the urinary tract and comorbid conditions that may influence or complicate treatment. Uncontrolled diabetes mellitus, urinary tract infection, neurogenic bladder, urethral strictures, bladder cancer and medications that can increase obstructive urinary symptoms include tricyclic antidepressants and other anticholinergic agents, diuretics, narcotics, and first-generation antihistamines and decongestants (common cold medications) may cause symptoms similar to those in BPH (Dull et al, 2002).
The physical examination should include a digital rectal examination to check for size, palpable nodules, induration, or irregularities associated with malignancy or infection. An irregularity that is suspicious for cancer requires a discussion of the patient’s preferences for further investigation (Denis, 1995).
All patients with suspected BPH should undergo dipstick urinalysis testing or microscopic urinalysis to screen for infection or hematuria, and a serum creatinine determination to evaluate renal function. In addition, prostate-specific antigen (PSA) testing may be offered to patients at risk for prostate cancer who prefer to be screened for the malignancy (Dull et al, 2002).
Prostate specific-antigen
PSA is a single 34 kilodalton (Kda) chain glycoprotein of 237 amino acids and 4 carbohydrate side chains. It is produced by the prostatic epithelium and is a normal component of human ejaculate. Its functionis to cause protein lysis resulting in liquefaction of the ejaculate .The half life of PSA was determined to be 3.2+_0.1 days.Because of the long half life of this glycoprotein , It may take several weeks to return to basal line levels after prostatic manipulation or to undetectable level after radical prostatectomy.
Effect of prostatic manipulation on PSA
• DRE and prostatic massage : DRE has no effect on PSA while prostatic massage has minimal effects
• TRUS, TRUS guided biopsy and TURP : TRUS has no effect on serum PSA level. In contrast TRUS-biopsy causes an immediate elevation in serum PSA of 7.9ng/ml and requires a median of 15 days to return to base line levels. TURP causes a median elevation un PSA of 5.9ng/ml and a median of 17 days is required to return to base line (Oesterling et al, 1993)
• Catheterizaion and cystoscopy : atraumatic catheterization has no significant effect on serum PSA level, as it is unlikely to disrupt prostatic epithelium . Neither flexible nor rigid cystoscopy significantly change serum PSA(Oesterling et al, 1993)
Age adjusted PSA increase :Age adjusted PSA determination were introduced as a means to improve cancer detection sensitivity . Age specific PSA reference ranges are shown in table (1) (Oesterling et al, 1993).
Table 1. Age specific reference ranges for PSA
Age(years) Serum PSA range (ng/ml)
40-49 0.-2.5
50-59 0.0-3.5
60-69 0.0-4.5
70-79 0.0-6.5
Effect of BPH vs. prostate cancer on PSA
• Normal prostate tissue contributes on average 0.07 ng/ml per gram of tissue to the serum PSA concentration .The corresponding value for BPH tissue is 0.21 ng/ml, and for cancerous tissue, it is 2.5 ng/ml
Table 2. Recommended assessments for the diagnosis of BPH(Jean et al, 2001)
________________________________________
Assessment EAU recommendations
________________________________________
Digital rectal examination mandatory
International prostate symptom score recommended
Creatinine measurementa *a recommended
Flow rates recommended
Post void residual urine volume recommended
Prostate-specific antigen optional
Renal ultrasound optional
Bladder ultrasound optional
Transrectal ultrasonography optional
Voiding charts optional
Urodynamics *b optional
Endoscopy optional
________________________________________
*a Or renal ultrasound.
*b Straightforward cases.
Imaging of the Urinary Tract
The imaging modality used for patients with LUTS should provide an image of the urinary tract and demonstrate the morphological effects of prostate pathology on the lower and/or upper urinary tract.
Transrectal ulrasound first performed in 1963, its importance is more clear in evaluation of suspicious prostates with subsequent use in biopsy when indicated.
Indications of TRUS-guided biopsy(Aboseif 1995)
• PSA greater than 4.0 ng/ml
• Abnormal DRE
• Presence of high grade prostatic intraepithelial neoplasia or atypia
• Palpable abnormality or increasing PSA after definitive therapy (radical prostatectoy, radiation therapy, cryotherapy and so forth)
Intravenous urography (IVU) or sonography and plain films are the procedures routinely used for imaging the upper urinary tract, prior to prostate surgery (Koch et al, 1996) . However, these guidelines recommend a renal ultrasound as the imaging modality for the upper urinary tract. Imaging of the lower urinary tract with a urinary bladder voiding cysto-urethrogram gives limited urodynamic information and is not recommended in the routine diagnostic workup of elderly men with LUTS. A retrograde urethrography gives indirect information on the effect of benign prostatic enlargement on adjacent structures; it is not recommended here. The prostate is viewed to assess size and shape and the presence of an occult carcinoma and for tissue characterization. Imaging of the prostate can by done by transabdominal ultrasound, TRUS, computed tomograpy, and magnetic resonance imaging (Scheckowitz et al, 1995) . TRUS has been documented as the most accurate way to calculate the size of the prostate (Aarnink et al, 1998) . It is necessary to calculate prostate size when surgery and medical and thermotherapy are considered as treatment options.
Voiding Charts
Voiding charts (diaries) are simple to complete and can provide useful objective clinical information. Recording a 24-hour frequency volume chart prior to initial consultation helps identify patients with idiopathic nocturia or excessive fluid intake. There is no standard frequency volume chart, but the 7-day chart of Abrams and Klevmark is the simplest (Abrams and klevmark B ,1996).
Postvoid Residual Urine Volume
Postvoid residual urine volume measurement is recommended in these guidelines. It should be calculated by measurement of the bladder height, width, and length obtained by transabdominal ultrasonography. This is a simple, accurate, and non-invasive method (Griffiths et al, 1986).
Urodynamic Studies
Flow Rates: Uroflowmetry is recommended as a diagnostic assessment in the workup of patients with LUTS and an obligatory test prior to patients receiving surgical treatment. It is a simple, non-invasive test that can reveal abnormal voiding. Flow rate machinery provides information on voided volume, maximum flow (Qmax), average flow (Qave) and time to Qmax, and this information should be interpreted by the physician to exclude artefacts (Witjes et al, 1998) . Serial flows (two or more) are recommended to get a representative flow test (Qmax). Obstruction can only be diagnosed with a pressure flow test; however, flow rates should be interpreted with caution, as elderly patients with LUTS have age-related urodynamic changes (Madersbacher et al, 1996).
Pressure-flow studies: are regarded as an additional diagnostic test in these guidelines. Flow rates only determine the probability of obstruction, whereas pressure-flow studies can categorize the degree of obstruction and identify patients in whom a low flow rate may be due to a low-pressure detrusor contraction. These guidelines recommend that pressure-flow studies remain optional tests in straightforward cases, presenting for the first time with LUTS. These studies are the most useful investigation available for the purpose of counseling patients regarding the outcome of surgical therapies for BPH. The International Continence Society nomogram should be used for the diagnosis of obstruction in order to standardize data for comparative purposes (Griffiths et al, 1997).
Endoscopy
A urethrocystoscopy is the standard endoscopic procedure used for evaluating the lower urinary tract (urethra, prostate, bladder neck, and bladder). It can provide information as to the cause, size, and severity of obstruction, patency of bladder neck, prostatic occlusion of the urethra, and estimated prostate size. It can confirm causes of outflow obstruction and eliminate intravesical abnormalities. It is recommended as an optional diagnostic test in these guidelines; however, it should be performed if patients are to receive surgical treatment (Larsen et al,1991).
Recommended Guidelines for the Diagnosis of BPH (Jean et al, 2001)
(1) Among all the different urinary symptom score systems currently available, the use of the I-PSS is recommended because of its world-wide distribution and use.
(2) In patients undergoing investigation for LUTS, the minimal requirement is to assess the upper urinary tract function by a creatinine measurement and or an ultrasonographic examination.
(3) There is consensus that if imaging of the upper urinary tract is performed, ultrasonography is the method of choice.
(4) Imaging of the upper urinary tract is recommended in patients with LUTS with:
• History of or a current urinary tract infection
• History of urolithiasis
• History of urinary tract surgery
• History of urothelial tumor (including IVU)
• Haematuria (including IVU)
• Urinary retention
(5) Routine imaging of the urinary bladder cannot be recommended as a diagnostic test in the workup of patients with LUTS. Ultrasound of the bladder, however, is a valuable diagnostic tool for the detection of bladder diverticula or bladder stones.
(6) Routine imaging of the urethra is not recommended in the diagnostic workup of patients with LUTS.
(7) DRE is a minimal requirement in patients undergoing investigation for LUTS.
(8) The method of choice for the determination of the prostate volume is ultrasonography, preferably via the transrectal route. However, imaging of the prostate by transabdominal ultrasound and TRUS is optional.
(9) The prostate size should be assessed when considering open prostatectomy and transurethral incision of the prostate (TUI), and prior to finasteride therapy.
(10) If the voided volume is <150 ml or the Qmax is >15 ml/s, pressure-flow studies should be considered before surgical intervention, particularly in elderly men. Pressure flow studies should be considered for patients prior to surgical treatment in the following subgroups:
• Younger men (e.g., <50 years of age)
• Elderly patients (>80 years of age)
• Post void residual urine volume c300 ml
• Suspicion of neurogenic bladder dysfunction
• After radical pelvic surgery
• Previous unsuccessful invasive treatment
(11) Measurement of residual urine volume is a recommended test in the assessment of patients with LUTS suggestive of benign prostatic obstruction.
(12) Endoscopy is recommended as a guideline at the time of surgical treatment to rule out other pathology and to assess the shape and size of the prostate which may have an impact on the treatment modality chosen.
Development of the Prostate
During midgestation, the primitive urogenital sinus is separated from the terminal region of the hindgut through the division of the cloaca by the urorectal septum. The most rostral region (vesico-urethral part) of the primitive urogenital sinus forms the urinary bladder, whereas the most caudal region (phallic part) forms the penile urethra. The prostate gland originates from the intermediate region, known as the pelvic part (Timms et al, 1999).
Five epithelial buds form in a paired manner on the posterior side of the urogenital sinus on both sides of verumontnum, and they then invade the mesenchyme to form the prostate. The top pairs of buds form the inner zone of the prostate and appear to be of mesoderm in origin; the lower buds form the outer zone of the prostate and appear to be of ectoderm origin. These two zones of the prostate develop as concentric circles around the urethra. The long branched ducts on the outside form the thick outer layer of the true prostate gland. The center portion contains the mucosal and submucosal glands and the ejaculatory ducts as well as the small remnant of the müllerian duct, utriculum prostaticus, which forms the small prostatic utricle (Timms et al, 1999).
The first endodermal buds develop from the lining of the urogenital sinus at around the 10th week of development. The secretion of testosterone by the embryonic testes stimulates the growth and development of the prostate, resulting in the lengthening, arborization and canalization of the prostatic ducts. By 12 weeks the branching ductal network consists of five distinct groups; posterior, lateral (two), anterior and middle lobes. The ducts of the posterior lobe originate from the floor of prostatic urethra distal to the openings of the ejaculatory ducts and grow posteriorly. The epithelial buds of the two lateral lobes branch lateral to the veru. The ducts of middle lobe originate on the posterior urethra proximal to the openings of the ejaculatory ducts. The anterior lobe buds branch anterior to the veru and is prominent until the 16th week and then involutes by the 22-week. The distinct boundaries between the five prostate lobes cannot be identified after 2.5 months (Timms et al, 1999).
Three stages of prostate development are recognized. During the bud stage (20-30 weeks), the buds at the ends of the ducts are simple, solid, and cellular and contain no lumina. The bud-tubule stage (31-36 weeks) is characterized by small collection of cellular buds and acini in both the inner and peripheral zones. With lumen formation basal cells are located along the perimeters of developing acini and ducts, a location found in the postnatal, prepubertal, and adult prostate glands. The histomorphogenesis of the fetal prostate further develops into the acinotubular stage (37-42 weeks), in which distinct acinotubular gland clusters arie from tubules with distinct lumina. At birth, the majority of the acini are lined with squamous epithelium metaplasia and scattered secretory activity and cyst formation. This stimulation is believed to be under the control of residual maternal steroids, and there is a postnatal involution phase that occurs over the first 5 months following birth (Tanagho,1982 ).
Management of Benign Prostatic Hyperplasia
The primary outcome in patients with of AUA symptom score of 8 to 30 was disease progression, defined by an increase in the symptom score of at least 4 points over the base-line score, acute urinary retention, renal insufficiency, recurrent urinary tract infection, or urinary incontinence (McConnell et al, 2003).
Based on the validated American Urological Association (AUA) symptom scale, AUA guidelines recommend watchful waiting for patients with mild symptoms (symptom scores of 0 to 7). Medical management is generally the first recommendation for patients with symptom scores greater than 7, if they are bothered by symptoms (AUA Practice Guidelines Committee, 2003).
WATCHFUL WAITING
Watchful waiting is appropriate in patients with a low AUA symptom score (zero to seven) because studies have shown that medications are not significantly more effective than placebo in these patients.1 However, follow-up monitoring is important, because spontaneous exacerbations and remissions of BPH (even without treatment) can occur. Patients with higher AUA symptom scores should be given information on appropriate treatment options (McConnell, 1994).
Table no. (4) Treatment options for patients with moderate
to severe symptoms of benign prostatic hyperplasia
Watchful Waiting
Medical Therapies
Alpha-adrenergic blockers
Alfuzosin
Doxazosin
Tamsulosin
Terazosin
5 Alpha-reductase inhibitors
Dutasteride*
Finasteride
Combination therapy (alpha blocker and 5 alphareductase inhibitor)* †
Minimally Invasive Therapies
TherMatrx™*
Transurethral needle ablation
UroLume® stent‡
Surgical Therapies
Transurethral resection of the prostate
Transurethral electrovaporization
Transurethral incision of the prostate
Transurethral holmium laser resection/enucleation
Transurethral laser vaporization
Transurethral laser coagulation (e.g., visual laser ablation)
Open prostatectomy
*Recommendations based on randomized, controlled trialsnot included in the outcomes tables.
†The Panel assumes that the combination of any effective alpha blocker and 5 alpha-reductase inhibitor probably produces a comparable benefit. However, the best-tested combination is doxazosin and finasteride. The safety of specific combinations other than finasteride plus doxazosin, terazosin, and alfuzosin has not been assessed.
‡Recommended for a subset of patients
Medical Treatment of BPH
While transurethral resection of the prostate (TURP) was once the mainstay of treatment for BPH, less invasive treatment options, including minimally invasive, mostly heat-based therapies as well as pharmacotherapies and phytotherapies, have become popular, largely because clinically significant subjective improvements can be obtained with fewer side effects (Bruskewitz, 1999). Furthermore, medical therapy is a viable option for men who may not be candidates for surgery, and it can be more cost-effective. Reflecting the shift toward less invasive therapy, the annual number of prostatectomies performed has decreased by approximately 30%, (Lowe et al, 1995).
The two major classes of medication available for BPH include alpha-adrenergic receptor blockers (eg, doxazosin, terazosin, alfuzosin, tamsulosin) and 5-alpha-reductase inhibitors (ie, finasteride). While it is commonly believed that alpha-adrenergic receptor blockers work by relaxing the smooth muscle around the bladder neck, the prostate adenoma and capsule, and the prostatic urethra, it has become quite clear that other factors (eg, induction of apoptosis) may trigger the symptomatic improvement associated with this class of medication ( Chon et al, 1999). 5-Alpha-reductase inhibitors work primarily by blocking the conversion of testosterone to dihydrotestosterone (DHT), thus inducing relative androgen withdrawal in the prostate, resulting in shrinkage of the prostate gland (McConnell et al, 1998).
Alpha-Adrenergic Receptor Blockers
The rationale for alpha-adrenergic receptor blockers in the management of BPH is rooted in research indicating that prostate smooth muscle mediates BOO via an alpha-adrenergic receptor-mediated mechanism, the suggestion being that alpha-adrenergic receptor antagonists relax prostate smooth muscle, thereby improving LUTS associated with BPH. Smooth muscle tissue in the prostate, prostatic capsule, and bladder neck was shown to respond to sympathetic innervation by the alpha-adrenergic receptor antagonist norepinephrine. In vivo studies confirmed that approximately half of total urethral pressure in men with BPH is regulated by an alpha-adrenergic receptor-mediated mechanism (Nicke and Roehrborn, 2000).
Phenoxybenzamine, a nonselective alpha1/alpha2-adrenergic receptor antagonist, was the first alpha-adrenergic receptor blocker to be evaluated for BPH. Despite symptom and urinary flow improvements, the use of this agent in BPH is limited because of its association with cardiovascular and central nervous system side effects related to nonselective alpha-adrenergic receptor blockade (eg, dizziness, asthenia, palpitations) (Caine et al, 1981). Studies reported that patients treated with the antihypertensive agent prazosin, a short-acting, selective, alpha1-adrenergic receptor antagonist, experienced less urinary frequency and incontinence (Thien et al, 1978), which led them to speculate on its potential use in the management of BPH. Despite efficacy and a better side-effect profile than phenoxybenzamine (Chapple et al, 1992).
Since the introduction of prazosin and phenoxybenzamine, research has been driven to develop selective alpha1-adrenergic receptor antagonists with fewer side effects and a longer duration of action. Selective, long-acting alpha-adrenergic receptor blockers include the quinazoline derivatives terazosin, doxazosin and Alfuzosin and the sulfonamethylamine tamsulosin. Another new alpha-adrenergic receptor blocker, fiduxosin, is undergoing phase III testing and has been found to be highly selective for the alpha1A- and alpha1D-adrenergic receptors, while having virtually no affect on the alpha1B-adrenergic receptor. That is, this agent selectively targets those receptor subtypes believed to have the greatest role in LUTS due to BPH. The clinical significance of this uroselectivity remains uncertain (Nicke and Roehrborn, 2000).
Efficacy
Terazosin: Terazosin is a selective alpha1-adrenergic receptor blocker originally developed for the treatment of hypertension. The safety and efficacy of terazosin as an antihypertensive have been well established (Luther, 1986), and numerous studies have evaluated its effectiveness in the management of symptomatic BPH (Elhilali, et al, 1996; Roehrborn, et al, 1996).
The largest clinical trial of terazosin, the Hytrin Community Assessment Trial (HYCAT), was a 1-year, double-blind, placebo-controlled, multicenter study of over 2000 men with an AUA Symptom score of 13 or more and a Qmax of less than 15 mL/sec. Fifty-five percent of terazosin-treated men enrolled in this study (mean baseline AUASI = 20.1) experienced a clinically significant reduction in symptoms (35% reduction in AUASI score) compared with only 28% of placebo-treated men. Overall, terazosin-treated men experienced an average 37.8% reduction in AUASI score compared with an 18.4% reduction seen in the placebo arm. Similarly, Qmax improved by an average of 2.2 ± 0.5 mL/sec from baseline (9.6 mL/sec, both groups) for terazosin-treated men vs. only 0.8 ± 0.5 mL/sec for placebo-treated men. The most commonly reported treatment-emergent side effects among terazosin-treated men in this study included dizziness (11.7% vs 5.8% for placebo; P < .001) and asthenia (7.5% vs 2.9% for placebo; P < .001). A total of 19.7% of terazosin-treated men withdrew from the trial due to adverse events compared with 15.2% of placebo-treated men. Treatment response was maintained for the duration of this 1-year study. An extension study of 494 men showed that these effects were maintained for 42 months. It should be noted that only 47 men were evaluable at the study endpoint. This is the largest published, long-term data set for treatment of BPH with an alpha-adrenergic receptor blocker (Lepor et al, 1995).
Terazosin has a sufficient half-life to permit convenient once-daily dosing and must be titrated to avoid first-dose effects (eg, dizziness, syncope). Terazosin is initiated at 1-mg daily doses at bedtime and titrated to 5 mg/day or 10 mg/day over a period of 1-2 weeks to achieve desired improvement (Nicke and Roehrborn, 2000).
Doxazosin: Like terazosin, doxazosin is a selective alpha1-adrenergic receptor antagonist originally developed as an antihypertensive. The efficacy and safety of doxazosin for the management of hypertension has been studied in both placebo-controlled and comparative studies (Daae and Westlie, 1998). Of particular note, the investigators of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a large, double-blind study comparing antihypertensive medications, prematurely terminated the doxazosin arm of this study of 24,335 patients with hypertension and at least 1 coronary artery disease risk factor because doxazosin was shown to be associated with a higher risk for combined cardiovascular disease (CVD) events, particularly congestive heart failure, than the reference agent chlorinthalidone. This finding has put into question the rationale for using an alpha-adrenergic receptor antagonist for the ”2 for 1” effect on both BPH and hypertension (ALLHAT Collaborative Research Group, 2000).
Doxazosin is an effective and well-tolerated long-term therapy for the reduction of LUTS in men with BPH. Statistically and clinically significant changes in hypertensive men were observed; however, no changes in blood pressure were observed for normotensive men (Fawzy, et al 1995). However, doxazosin may cause statistically significant changes in blood pressure in normotensive men (Nicke and Roehrborn, 2000). ALLHAT, however, raises important concerns regarding the safety of alpha-adrenergic receptor blockers as antihypertensive agents (ALLHAT Collaborative Research Group, 2000).
Doxazosin can be initiated with 1-mg/day doses and titrated over a period of 1-2 weeks to a maximum dose of 8 mg/day. Titration reduces the risk for first-dose cardiovascular effects. In most studies, symptom improvement was observed within 2 weeks (Nicke and Roehrborn, 2000).
Alfuzosin: Alfuzosin 10 mg, administered without dose titration, provides effective relief from the symptoms of benign prostatic hyperplasia with no additional benefit from a 15-mg dose (Roehrborn, 2001).
Alfuzosin was seen to be significantly more effective than placebo in improving the symptoms and peak urinary flow rate. The mean change in the International Prostate Symptom Score from baseline at endpoint was -3.6 and -3.4 with alfuzosin 10 mg and 15 mg, respectively, compared with -1.6 with placebo (alfuzosin 10 mg versus placebo, P = 0.001; alfuzosin 15 mg versus placebo, P = 0.004). The median increase in the peak urinary flow rate was +1.1 mL/s and +1.0 mL/s with alfuzosin 10 mg and 15 mg, respectively, compared with 0.0 mL/s with placebo (P = 0.0006 versus placebo for both dose groups). The patients’ quality of life also significantly improved with both alfuzosin doses. Overall, alfuzosin at both doses was well tolerated. The incidence of orthostatic hypotension as determined by systematic blood pressure measurements with both doses of alfuzosin was similar to placebo. No clinically relevant ejaculation disorders were observed with alfuzosin. It is well tolerated from a cardiovascular viewpoint and is not associated with abnormal ejaculation (Roehrborn, 2001).
There is no significant changes in blood pressure with alfuzosin compared with placebo, including in elderly and hypertensive patients (Roehrborn et al,2003).
de Reijke and Klarskov (2004) randomized 210 men with moderate to severe lower urinary tract symptoms (LUTS) to receive doxazosin 1-8 mg once daily or alfuzosin 5-10 mg divided in two or three daily doses for 14-weeks. The differences between the treatment groups were statistically significant in favour of doxazosin (total IPSS, P = 0.036; irritative symptoms, P = 0.049). The improvement between groups was also significantly different for postvoid residual urine volume, at 8.6 and 8.9 mL for doxazosin and alfuzosin, respectively (P = 0.002). Improvements in mean and maximum urinary flow rates were similar for both treatments, at + 1.5 and + 1.2, and + 2.8 and + 2.5 mL/s, respectively. Doxazosin and alfuzosin were both well tolerated, with most all-cause adverse events reported as mild or moderate. Doxazosin 6.1 mg/day produced significantly greater improvements than alfuzosin 8.8 mg/day in total and irritative urinary symptom scores and postvoid residual urine volume in men with moderate to severe LUTS.
Sexual adverse events in terms of abnormal ejaculation were rare and occurred in 0.6% of patients in a series of 473 patients receiving alfuzosin for 12weeks (Roehrborn et al, 2003), and reported no specific sexual dysfunction including ejaculation disorder using alfuzosin 10 mg once-daily.
Tamsulosin: The selective alpha1a-adrenergic receptor blocker tamsulosin was developed only for BPH and does not have an effect on hypertension. Research indicates that the alpha1a-adrenergic receptor is the predominant receptor subtype within the prostate stromal elements (Price et al, 1993). Tamsulosin has a 7- to 38-fold greater affinity for the alpha1a-adrenergic receptor vs the alpha1b, suggesting that it is a more ”uroselective” agent than terazosin or doxazosin (Wilde and McTavish, 1996). The clinical significance of this uroselectivity remains uncertain.
The long-term efficacy of tamsulosin on symptoms has been demonstrated in a 53-week, double-blind, placebo-controlled extension study. Seventy-eight percent and 81% of men treated with tamsulosin 0.4 and 0.8 mg/day, respectively, demonstrated a ≥25% improvement in AUASI symptom score compared with 59% of placebo-treated men. This effect was maintained for the duration of the study. The percentages of men experiencing an improvement in Qmax > 3 mL/sec were 39%, 40%, and 22% for the tamsulosin 0.8 mg/day, tamsulosin 0.4 mg/day, and placebo groups, respectively (Lepor, 1998).
In general, tamsulosin tends to be associated with cardiovascular adverse events (eg, orthostatic hypotension, dizziness, lightheadedness, fatigue, asthenia) to a lesser degree than alpha1-adrenergic receptor blockers developed as antihypertensives (eg, doxazosin, terazosin). Tamsulosin does not require titration. For most men, 0.4 mg/day is an adequate dose; however, the 0.8 mg/day dose can be administered if adequate improvement is not achieved with the lower dose. Treatment-emergent side effects, particularly abnormal ejaculation, were more common among men treated with tamsulosin 0.8 mg/day compared with those men treated with tamsulosin 0.4 mg/day (Nicke and Roehrborn, 2000).
Selection Criteria
The short-term efficacy on symptom relief of the selective alpha1-adrenergic receptor blockers in the management of BPH has been well established. Selective alpha1-adrenergic receptor blockers provide rapid symptom relief, with partial symptom relief observed in as little as 1 week. Full therapeutic benefit is observed with alpha-adrenergic receptor blockers after 2-3 months of treatment. alpha-adrenergic receptor blockers are recommended for all patients who seek immediate symptom relief, including men with small prostates. In general, men with BPH treated with these products experience a 30%-40% symptom reduction and a 16%-25% improvement in Qmax (Djavan and Marberger, 1999).
Although these agents have comparable efficacy in regard to LUTS, there are important differences among the cardiovascular safety and tolerability profiles of alpha-adrenergic receptor blockers. In general, those agents that are more effective for treating hypertension (ie, doxazosin, terazosin) are more likely to affect blood pressure in normotensive men with BPH than tamsulosin. In controlled studies, DROPout rates for tamsulosin were comparable to placebo. In the case of doxazosin and terazosin, 4%-10% more men treated with these agents DROPped out compared with placebo-treated men. Doxazosin and terazosin require titration to avoid first-dose cardiovascular side effects (ie, syncope), whereas tamsulosin does not require titration. Each agent has a unique side-effect profile. If a patient finds 1 particular side effect intolerable, another agent may be considered. However, patients who are incompletely responding to one of the alpha-adrenergic receptor blockers are not likely to respond with significantly better symptomatic improvement to another alpha-adrenergic receptor blocker. Thus, patients who are not adequately responding to 1 agent should be offered other treatment alternatives (Nicke and Roehrborn, 2000).
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Summary
Benign prostatic hyperplasia (BPH) is the most common benign neoplasm in men, the incidence increases with increasing age. Although not a life-threatening condition, BPH can significantly affect quality of life.
Benign prostatic hyperplasia may be associated with benign prostatic obstruction (BPO) which can result in lower urinary tract symptoms (LUTS) and is nowadays referred as LUTS suggestive of BPO.
Lower urinary tract symptoms can be brought by the static component of BPH ; the increased prostatic mass compresses and inhibits urinary flow. LUTS also can arise throughout the dynamic component BPO; increased smooth muscle tone in the prostate and prostatic urethra by stimulation of alpha adrenoreceptors in the lower urinary tract.
A significant number of patients with BPH will respond to α-adrenoreceptors (AR) antagonists with symptom. As prostatic α- ARs are considered to mediate the dynamic component of obstruction, it is natural that these receptors have been assumed to mediate at least part of the symptoms.
Alph-1 adrenoreceptors are members of the larger family of G protein-coupled receptors (GPCRs) ; cDNA encoding nine total AR subtypes (three alph-1AR,i.e.alpha-1a, alpha 1-b,alpha-1d ).A fourth receptor subtype the alpha-1L with low affinity to prazosin has also been pharmacologically defined. Both alpha-1a and alph-1L adrenoreceptorsubtypes can demonstrated as pharmacological entities in human prostatic urethra. A three alpha-2 ARs,alpha-2a alpha-2b, alpha-2c and three beta ARS beta 1,2,3),in addition to three alph-1 AR
subtypes, four splice variants of the human α1a- AR have been shown to exist (α1a/A-1, α1a/A-2 , α1a/A-3 , α1a/A-4 )
Although both alpha-1 and alpha-2 adrenoreceptors are found in the prostate prostatic smooth muscle tone is mediated primarily by alpha-1 adrenoreceptors.
This study is a direct comparative study carried on 88 patients who have LUTS secondary to benign prostatic hyperplasia (BPH) randomized into two equal groups, and carried out in SUEZ CANAL UNIVERSITY hospital in outpatient clinic of urology department ISMALIA, EGYPT between September, 2002 and October, 2005 .
Patients were randomly classified into two equal groups
Group A : patients who received terazosin with l mg. starting dose at bed time for four successive days then 2 mg for 12 weeks .
Group B : patients who received 5 mg. alfuzosin SR twice daily
Clinical outcome was estimated both subjectively and objectively:
Objective outcome was based on the extent of improvement of Q max after 12 weeks from treatment
Subjectively was based on the extent of the change of IPSS after treatment
Histology of normal Prostate
The normal prostate is composed of glands and stroma. The glands are seen in cross section to be rounded to irregularly branching. These glands represent the terminal tubular portions of long tubuloalveolar glands that radiate from the urethra. Two cell layers line the glands: an outer low cuboidal layer and an inner later of tall columnar mucin-secreting epithelium. These cells project inward as papillary projections. The fibromuscular stroma between the glands accounts for about half of the volume of the prostate.
As males age, there are more likely to be small concretions within the glandular lumina, called corpora amylacea, that represent laminated concretions of prostatic secretions. The glands are normally separated by stroma. The prostate is surrounded by a thin layer of connective tissue that merges with surrounding soft tissues, including nerves. There is no distinct capsule (McNeal et al, 1988)
Prostate Epithelium
Prostate epithelial cell types:
(i) Secretory cells: are tall (10 to 12 μm) columnar secretory epithelial terminally differentiated cells. Their morphologic structure and abundant secretory granules that stain abundantly with PSA, acid phosphates, and other enzymes easily distinguish them. These tall columnar cells appear like rows resting next to each other, connected by cell adhesion molecules and with their base attached to a basement membrane through integrin receptors. The nucleus is at the base just below a clear zone of abundant Golgi apparatus, and the upper cellular periphery is rich in secretory granules and enzymes. The apical plasma membrane facing the lumen possesses microvilli, and secretions move out into the open collecting spaces of the acinus. These epithelial cells ring the periphery of the acinus and produce secretions into the acini, which drain into the ducts that connect to the urethra. In androgen ablation, the typical secretory cells decrease by 90% in total numbers, become cuboidal, and shrink by 80% in cell volume and 60% in cell height (de Voogt et al, 1987). At the molecular level, luminal secretory cells are characterized by their expression of androgen receptor, as well as cytokeratins 8 and 18 and the cell surface marker CD57 (Liu et al, 1997).
(ii) Basal cells: In contrast to secretory epithelial cells, basal cells are much smaller and less abundant in number and comprise less than 10% of prostatic epithelial cells. These small cells are not columnar, are more round with little cytoplasm, and contain large, irregularly shaped nuclei. They are less differentiated and almost devoid of secretory products such as acid phosphatase. They are always resting on the basement membrane, forming a continuous layer and appear wedged between the bases of adjacent tall columnar epithelial cells. The plasma membrane is rich in ATPase, suggesting that these cells maybe involved in active transport. They are rich in 5-nm tonofilaments and stain brightly with anti-keratin antibodies. They were mistaken as myoepithelial cells, but they are not rich in actin and myosin (McNeal et al., 1988; ). Basal cells can also be distinguished phenotypically from secretory cells, because they uniquely express specific cytokeratins, including keratins 5 and 14 as well as CD44 as well as low levels of androgen receptor (although this is controversial), but do not produce prostatic secretory proteins, and lack expression of secretory markers such as PSA and prostate-specific acid phosphatase (De Marzo et al, 1998; Liu et al, 1997). Consistent with a possible stem cell function, basal cells also express factors that protect from DNA damage, such as the free-radical scavenger glutathione (GSTpi) and the anti-apoptotic gene Bcl2 (De Marzo et al, 1998).
(Ш) Neuroendocrine cells:
Significant populations of neuroendocrine cells, also known as an endocrine–paracrine or amine precursor uptake and decarboxylation (APUD) also reside among the more abundant secretory epithelium in the normal prostate gland. Neuroendocrine cells of the prostate are part of a much larger neuroendocrine regulatory system. Better-known elements of this regulatory system are neuroendocrine cells of the gastrointestinal tract, lung, thyroid (C cells), and pancreatic islets of Langerhans (Di Sant’Agnese and Cockett, 1994). They are found in the epithelium of the acini and in ducts of all parts of the gland as well as in the urothelium of the prostatic urethral mucosa. There are three types of prostate neuroendocrie cells, with the major type containing both serotonin and thyroid stimulating hormone (TSH). The two minor cell types contain calcitonin and somatostatin. These cells bring about their regulatory activity by the secretion of hormonal polypeptides or biogenic amines such as serotonin that is a common marker for these cells. These cells display hybrid epithelial/neural/endocrine characteristics, has long dendritic processes with nerve-like varicosities, and has open (apical processes extending to the glandular lumen) and closed subtypes (Di Sant’Agnese and deMesy, 1984). It is likely that neuroendocrine cells of the prostate regulate both growth and exocrine secretory activity. In addition, neuroendocrine cells may regulate each other. The long dendritic processes suggest a paracrine regulation of adjacent epithelial cells, and evidence demonstrating that these neuroendocrine cell processes often make contact with each other, as well as the presence of a calcitonin receptor on subsets of neuroendocrine cells, including calcitonin-secreting cells, suggests both paracrine and autocrine regulation of neuroendocrine cells by other neuroendocrine cells (Di Sant’Agnese and Cockett, 1994)
Fig. (5) Structure of prostatic acinus. (from Kirchheim D. Histochemistry. In: Hinman F Jr, ed. Benign prostatic hypertrophy. New York: Springer-Verlag, 1983)