The Treatment of Benign Prostate Adenoma and Chronic Prostatitis: a placebo-controlled, randomized double-blind study with Prostagutt®
(Behandlung des benignen Prostataadenoms and der chronischen Prostatitis – Placebokontrollierte randomisierte Doppelblindstudie mit Prostagutt®)
V. Gabric / H. Miskic
Urological Department of the Bebro Clinic, Zagreb (Croatia) Yugoslavia
published in:
Therapiewoche 37, No. 19, May 1987
The efficacy of a six-week therapy with Prostagutt® (3 x 20 drops.per day) versus placebo was tested in a multicenter double-blind study involving 30 patients with adenoma of the prostate gland in stages II and III (group A), and 29 patients suffering from prostatitis (group B). The changes produced by therapy as found in the individual findings and symptoms were evaluated in each case according to a 4-level score; measurement data from the placebo/active substance comparison were also taken into accounbt for uroflow and residual urine. At the end of the study, the examining physician evaluated global therapy success based on a 3-level score.
The decrease in prostate size was tendentially more prominent as a result of therapy with Prostagutt® in the patients of the A and U groups than in those treated with placebo. An increase in uroflow could be established statistically for the group with the prostate adenoma as compared with the placebo effects. Residual urine findings showed a significant improvement both in group A as well as in group B; in addition, for the patients with prostatitis, the mean parameter was reduced to a statistically important degree following administration of the active substance. Furthermore, the urge to urinate, delayed start of micturition and micturitional frequency improved clearly under active substance, the differences between Prostagutt® and placebo were here significant for each group. Therefore, for the patients with prostate adenoma and/or prostatitis, a clinically recorded, statistically meaningful success of therapy with Prostagutt® was obtained at a good level using placebo as reference.
Approx. 15 % of the patients in general practices complain of micturitional difficutlies; in fact, in urological practices, those patients suffering from micturitional dysfuction comprise the majority. In the age group up to 45 years, prostatitis is generally present. In older patients, on the other hand, benign prostate hyperplasia is in the foreground (prostate adenoma in stages II and III according to Vahlensieck (9) = stages I and II in the old classification).
In the overall diagnosis of "prostatitis", however, we are only dealing with an acute bacterial or abacterial inflammation in only 20 to 30 'o of all cases; by applying antibiotics, these can be treated with good success. In the majority of patients, a so-called chronic prostatitis with congestion of the prostate gland is present; produced by a venous stasis in the pelvic region, this is either edematous or based on a dysregulation via the autonomic nervous system, whose condition has then been influenced by stress, disturbances of a sexual nature or origin, or overexposure to cold. Chronic prostatitis based on a previous microbial attack can only be established in 30 % of all cases (8).
The frequency of benign prostate hyperplasia (prostate adenoma in stages II and III) increases exponentially with age. Whereas an adenoma can only be found in a total of 10 PS of those aged 40, the incidence is already at 15 % in those aged 45 and we must assume that approx. 30 % of those aged 60 and 45 % of those aged 70 suffer from adenomas. And a prostate adenoma can be established in 95 'o of those aged over 80 (1).
However, the growth of periurethral tissue produces a functional disturbance of the bladder exit only in a third of these patients; on the other hand, even a minor enlargement of the prostate can also be accompanied by considerable difficulties.
Micturitional difficulties often only occur in phases during the initial stage of adenomal development (2). An urge to urinate, delayed start of micturition, a weakened and insufficient projection of urine as well as subsequent dripwise incontinence are then typical for stage II. Depending on the irritative state of the bladder, pollakisuria and nocturia occur. Whereas, in stage III, the functional disturbances of the detrusor sphincter mechanism in the region of the vesicular exit are in the foreground, a mechanical obstruction of the bladder oulet determine the picture in stage III. As a result of progressive vesicular atonia, a considerable formation of residual urine occurs as the bladder outlet resistance increases (9).
Micturitional difficulties also occur at times in patients suffering from a prostate congestion in the con‑
perplasia and for the therapy of chronic prostatitis (5, 10, 11). This urological preparation contains extracts from Populus tremuloides, Urtical dioica and the fruits
of Sabal serrulata. The therapeutical application of the total extract in the conditions cited is primarily based on their decongestive and antiedematous effect. Apart from their antiphlogistic and mildly diuretic active components, a tonic effect on vesical muscles and a spasmolytic effect on the neck of the bladder are particularly desirable.
The present controlled study deliberately tests the efficacy of the preparation both in chronic prostatitis as well as in prostate adenoma in its early stages. The
question as to objective changes in clinical findings is here of equal value to the medical assessment of these changes in the findings obtained and in an evaluation of the degree to which symptoms are prominent.
The study carried out on a multicenter basis at the PLIVA Research Institute included 59 (male) patients. Two patient groups comprising 30 and 29 patients respectively were formed according to the central diagnoses of prostate adenoma in stages II and III or suspected recurrence of prostate adenoma (following prostatectomy or transurethral prostate electroresection) and prostatitis by itself.
The patients with prostate adenoma as major diagnosis were assigned to to group A and the patients with chronic prostatitis as main dignosis under exclusion of prostate adenoma to group B. In accordance with a randomization process, 15 patients received active substance and 15 received placebo in group A, and 15 the active substance and 14 placebo in group B.
Table 1 gives general patient data, i.e. number, age and weight as broken down in the respective groups. Table 2 shows the major and accompanying diagnoses in the context of urinary tract disturbances before treatment. Patients with stage IV prostate adenoma or with bacterial forms of prostatitis, cystitis and urethritis were not admitted to the study.
Method and aoolication
Patients in groups A and B each received 20 drops of Prostagutt° 3 times per diem before meals, or placebo as control substance, over a period of 6 weeks. Therapy of previous medication was discontinued for at least 10 days prior to the study in patients with previous conservative therapy of disturbances of the urinary tract.
No other treatment was conducted capable of having an effect on the findings or symptoms to be assessed during the trial. The therapy of other concomitant diseases such as e.g. diabetes, cardiac insufficiency, arterial hypertension, uremia and lumbar ischialgia etc. could also be carried out during this study.
The following findings and changes conditioned by treatment were obtained in all patients before and after the 6
weeks of therapy and evaluated according to a scale whereby 1 - no change, 2 = improvement and 3 = normal: rectal findings after palpation, uroflow, residual urine and protein/sediment.
In addition, a series of symptoms were assessed before and after treatment, i.e. urge to urinate, delayed start of micturition, pain when urinating, pains at end of micturition, micturitional frequency over 24 hours.
Changes in the extent or degree of symptoms after therapy were evaluated according to the 4 categories: 0 = aggravation, 1 = no change, 2 = improvement and 3 = disappearance of symptoms.
Immediately following the treatment, the effect of therapy was assessed by the physician according to the 3 categories: 1 = no success, 2 = satisfactory and 3 = good success.
We used the t test for statistical checking of the measurement data obtained for relevant differences between treatment with placebo and active substance: the assessment of statistical differences as regards therapy score rating was according to the Mantel-Hanszel Test.
Roe„1Fe
Rectal findings (Fig. 1)
In group a with prostate adenoma, rectal findings were assessed as satisfactorily improved after 6 weeks of therapy with Prostagutt® (mean score 2.1). Normalization was obtained in five cases. In 3 of the 4 patients with‑
out treatment success, a recurrent adenoma was suspected. However, the results after administration of active substance were not significant in spite of a mean value of 0.5 points above placebo.
In group B as well, i.e. where patients principally had chronic prostatitis under exclusion of prostate adenoma as diagnosis, the mean score in the active substance group was at 2.1. In spite of this, the difference of + 0.6 points scored between 'active substance and placebo is agin not sufficient to confirm a statistically significant advantage for the active substance.
Nevertheless, a regression/subsidence in prostate size was clearly obtainable after therapy with Prostagutt® in over 50 % of the cases concerned.
Uroflow (Fig. 2)
After treatment with Prostagutt®, the uroflow value increased by 4.1 ml/sec in the prostate adenoma group. This increase is statistically significant compared with the slight reduction in uroflow by 0.8 ml/s after application of placebo. Significant results are also obtained under therapy with Prostagutt® in a before/after assessment of therapy success as compared with placebo medication. After administering Prostagutt® findings were improved or normalized in 10 out of 14 cases.
The results shown by the uroflow measurement values and the relative assessment of therapy success in this category of findings yield, for the B group, no statistically significant difference in the comparison between active substance and placebo: the 6 weeks of treatment improved
the uroflow in the same way.
Residual urine (Fig. 3)
The residual urine values in the A group sank after treatment with active substance by 5.7 ml. Compared with the increase in residual urine values after placebo by 4.8 ml, this reduction is not significant statistically. Nevertheless, this favorable change in results gives reason for us to speak of a clinically relevant improvement in findings. The difference in the mean score values of 0.8 points in favor of the active medication is important by comparison with placebo: the score value distributions differ from each significantly. In the placebo comparison in each case, significant results speaking in favor of treatment with Prostagutt° are found in group B, both in relation to the measurement values for residual urine as well as in the light of therapy assessment. At all events it is notable that, after administration of this medicament, findings were validated as normal in 11 out of 14.cases. This assessment correlates with the drastic reduction of residual urine values in the active substance group by 27 ml: residual urine is here still only at 3.6 ml after treatment.
A significantly better assessment of urine findings (mean score 2.6 + 0.76) compared with patients in the placebo group (mean score 1.5 + 0.9) was only found in patients of group B recieving therapy with active substance.
The urge to urinate (Fig. 4)
In group A, the sensation of having to pass water after treatment with Prostagutt° is reduced in a round 60 % of all cases, the symptom is no longer complained of in two cases. Under the administration of placebo, the symptom generally remained unchanged in its level of markedness. The mean assessment score of 1.9 points after therapy with active substance is situated clearly below the ra ting of 0.9 score points after placebo. The comparison between active medication and placebo in the context of score value distribution is statistically significant.
The difference in therapy rating between active substance and placebo in groupB speaks even more clearly in favor of treatment with the medication here tested: treatment with Prostagutt® produced a total subsidence of the urge to urinate as a symptom in 50 'a of the cases, and an improvement was recognizable in half of the patients involved. The score value distributions for active substance
and placebo are different statistically to a highly significant extent.
Delayed start of micturition (Fig. 5)
The mean score for evaluation of therapy with the medicament tested in this study is higher than that after application of placebo by comparison in the A group, and even more in the B group. The difference between the active substance and the placebo in the score value distributions is significant in each case for both groups. Success of treatment with Prostagutt° is particularly recognizable in group B; here, the symptom no longer appears in 40 '; of the cases concerned after the 6 weeks of therapy.
Pain during micturition and pains on termination of micturition (Fig. 6)
Where these two symptoms are involved, the patient groups were too small in each case for a statistical analysis of
therapy results. Nevertheless, a good response to treatment with active substance was found, particularly in the patients of group B. cturitional frequency (Fig. 7)
Both in the A and the B groups, the frequency of micturition decreased as treatment progressed and therefore as a
result of it. In each group as well, the drop in the number of times patients needed to pass water (i.e. the micturitional frequency as a rating) was clearly more pronounced and significantly much greater in those having received the active substance than in those where placebo
was administered.
Therapy success in the physicians' assessments
The global assessment given by the physicians at the end of the study as regards actual success produced a clear decision, both in the'A and B groups, in favor of the active medication as compared with the placebo: here the assessment was slightly more favorable in the case of the B group than where the corresponding treatment of the patients in the A group was concerned.
Summary and discussion
At present, the causal therapy of prostate adenoma simply involves surgical removal or electroresection of hyper-plastic prostate tissue. However, in many patients suf‑
fering from a stage II to stage III prostate adenoma (9),
surgery is not or not yet indicated. This is where sym‑
ptomatic conservative therapy has a place.
We have had good therapeutical experience in patients complaining of prostate hyperplasia due to the good prostatotropic effects of Prostagutt®, a plant-based pharmaceutical (phytopharmaceutical compound). We have also applied this preparation with good success in therapy of non-bacterial chronic prostatitis.
The quantitative study results here communicated only confirm our experience. 6 weeks of treatment with this medication improves and normalizes palpation findings of a prostate gland which has become enlarged and in part painfully responsive to pressure where patients suffering from BPH (benign prostate hyperplasia) and prostatitis were involved. This recognizable and noticable improve‑
ment in findings is, however, not significant statistically when compared with placebo, so that the problems involved in an objective assessment of these findings will have to remain under discussion'as far as conservate treatment of the symptoms described is concerned. Nevertheless the fact is still decisive for patients with BPH that uroflow values could be improved to a significant exent under therapy with Prostagutt®. These rose from
10.5 ml/sec to 14.6 ml/sec. We also assess a noticable tendency to reduce residual urine after treatment with this medicament as an improvement relating to therapy, which cannot be recognized where placebo is concerned. When one consideres these results in connection with the significant reduction in the micturitional urge and the improvement of the symptom of delayed start of micturition versus placebo, one can validate Prostagutt® as an effective therapeutical agent. A subsidence/reversal in the symptoms micturitional pain and pains on termination of micturition also support this assessment. The reduction in daily micturitional frequency after administration of the active substance means a marked relief for
the patients involved. From a total point of view, the
efficacy of the preparation is principally to be found in relation to micturitional complaints.
Apart from the only tendential improvement of findings from rectal palpation in an enlarged and generally painful prostate of the medicament tested in chronic prostatitis, application of the, medicament in cases of chronic prostatitis must here be assessed as being positive. The reduction in subjective cimplaints, ie.e the urge to pass water and delayed start of micturition are also to be en‑
sured statistically. In this set of symptoms comprising chronic prostatis, which are pathogenetically very manifold, therapy does relieve prostatopathic complaints, so that a treatment with the decongestively acting extract
is to be recommended.
We should also not go without mentioning that, in the 5 patients manifesting both BPH as well as signs of a chronic prostatitis, rectal findings became normal in 3 cases and the uroflow increased to values around 20 ml/sec in all 5 patients.
It was possible to improve or totally eliminate the symptoms termed urge to urinate and delayed start of micturition in most cases. By contrast to the above successes, however, the two patients in whom BPH was coupled with chronic prostatitis showed no success at all after 6 weeks of therapy.
On behalf of the authors: Prof. Dr. med. V. Gabric,
Bebro Clinic, Urological Department,
Krispaticeva 12,
Y-4100 Zagreb
(Croatia) Yugoslavia
Literature
Bruhl P.: Benigne Prostatahyperp(asie
(BHP). Therapiewoche 35, 3629-3637 (1985)
Eger B.: Das Prostataadenom. Biomed 4 (1984)
Melchior D.: Vier Fragen zum Thema Prostatahyperplasie. (Incerview). Therapiewoche 32, 4236-4237 (1982) Neugebauer W., R. Komm, J. Sokeland: Zystitis. Dusch. Aruebl. 17, 1097-1104 (1980) ‑
Rugendorff E..R, H.-J. Schneider, C.G. Rohrborn: Ergebnisse einer randomisierten Doppelblindstudie Ober die Behandlung der benignen Prostatahyperplasie mit Proscagutt vs. Beta-Sitosterin. extracta urologica 9, 115-118(1986)
Schilcher H.: Phytopharmaka zur Thera‑
ev words:
Prostate adenoma
Prostatitis Prostagutt®
pie von Prostacaerkrankungen. Zschr. angew. Phytocher. 2, 14-19 (1981)
[7] Sturm W., I.J. Marx: Prostatitis — Diagnostik and Therapie. Munch. med. Wschr. 128, 160-163 (1986)
(8] Vahlensieck E.W.: Vortrag auf dem 3. Prostata-Workshop ,,Proscatakongescion and Prostacicis". Frankfurt 19. Januar 1985. Aus: Prostacitis — jeder Form die richcige Therapie. Selecta (Suppl.) Heft 5 (1985)
[9] Vahlensiec'.< E.W.: Konservative Behandlung der benignen Prostatahyperplasie (BPH). Therapiewoche 35, 4031-4040 (1985)
(10] Wolf E.: Konservacive Behandlung des Prostataadenoms (Stadium I and II) nit Prostasuct. Therapiewoche 34, 4593-4594 (1984)
[II] Wolf E.: Offene Studie zur konservativen Behandlunz des Prostataadenoms. Therapiewoche 30.2244-2251 (1980)
ADULT UROLOGY CME ARTICLE
SAW PALMETTO (Serenoa repens) IN MEN WITH LOWER URINARY TRACT SYMPTOMS: EFFECTS ON URODYNAMIC
PARAMETERS AND VOIDING SYMPTOMS
GLENN S. GERBER, GREGORY P. ZAGAJA, GREGORY T. BALES,
GERALD W. CHODAK, AND BARBARA A. CONTRERAS
ABSTRACT
Objectives. To assess the effects of saw palmetto on voiding symptoms and urodynamic parameters in men with lower urinary tract symptoms (LUTS) presumed secondary to benign prostatic hyperplasia (BPH). Methods. Fifty men with previously untreated LUTS and a minimum International Prostate Symptom Score (IPSS) of 10 or greater were treated with a commercially available form of saw palmetto (160 mg twice per day) for 6 months. The initial evaluation included measurement of peak urinary flow rate, postvoid residual urine volume, pressure-flow study, and serum prostate-specific antigen (PSA) level. Patients completed an IPSS, serum PSA was determined, and flow rate was measured every 2 months during the course of the study. A urodynamic evaluation was repeated at the completion of the 6-month trial.
Results. The mean IPSS (±SD) improved from 19.5 ± 5.5 to 12.5 ± 7.0 (P <0.001) among the 46 men who completed the study. Significant improvement in the symptom score was noted after treatment with saw palmetto for 2 months. An improvement in symptom score of 50% or greater after treatment with saw palmetto for 2, 4, and 6 months was noted in 21% (10 of 48), 309'0 (14 of 47), and 46% (21 of 46) of patients, respectively. There was no significant change in peak urinary flow rate, postvoid residual urine volume, or detrusor pressure at peak flow among patients completing the study. No significant change in mean serum PSA level was noted.
Conclusions. Saw palmetto is a well-tolerated agent that may significantly improve lower urinary tract symptoms in men with BPH. However, we were unable to demonstrate any significant improvement in objective measures of bladder outlet obstruction. Placebo-controlled trials of saw palmetto are needed to evaluate the true effectiveness of this compound. UROLOGY 51: 1003-1007, 1998. © 1998, Elsevier
Science Inc. All rights reserved.
The use of phytotherapeutic agents, also known as plants or plant extracts, in the treatment of men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) varies widely in different parts of the world.' In some European countries, plant extracts are the most commonly recommended initial treatment for men with voiding symptoms, and patients are reimbursed for the cost of these agents by health
This worh was supported by a grant from Nutraceutica[ Corp., Ogden, Utah.
From the Section of Urology, Department of Surgery. University of Chicago Pritzher School of Medicine, Chicago, Illinois
Reprint requests: Glenn S. Gerber, M.D., University of Chicago, Section of Urology MC 6038, 584I South Maryland Avenue, Chicago, IL 60637
Submitted: October 14, 1997, accepted (with revisions): December17,1997insurance companies.' By contrast, few American physicians recommend natural compounds in the treatment of men with LUTS, although many Americans use these agents because they are available without a prescription.2 Serenoa repens, or saw palmetto, is the most commonly used natural compound in the treatment of men with voiding symptoms secondary to BPI-I.1 This agent is derived from the berry of the American dwarf palm tree and has not been associated with any significant toxicity.3 In a variety of European clinical trials, the use of saw palmetto in men with LUTS has led to significant subjective and objective improvement.4-7 In general, however, these studies are flawed by the - inclusion of limited numbers of men, brief study periods of 30 days or less, inadequate assessment of objective changes in bladder outlet obstruction, and/or failure to use standardized symptom ques‑
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