Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Conservative treatment of benign prostatic hyperplasia Ernesto Palanca & Wilfrido Juco To cite this article: Ernesto Palanca & Wilfrido Juco (1977) Conservative treatment of benign prostatic hyperplasia, Current Medical Research and Opinion, 4:7, 513-520, DOI: 10.1185/03007997709109342 To link to this article: http://dx.doi.org/10.1185/03007997709109342
Published online: 07 Aug 2008.
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Date: 05 November 2015, At: 17:09
Current Medical Research and Opinion
Vol. 4, No. 7, 1977
Conservative treatment of benign prostatic byperplasia
Ernest0 Palanca, M.D., F.P.C.S., F.I.C.S. and
Wilfrido Juco, M.D.
Downloaded by [Deakin University Library] at 17:09 05 November 2015
University of Santo Tomas, College of Medicine and Surgery, Manila, Philippines
Cum. Med. Res. Opin., (1977), 4, 513.
Received: 22nd October 1976
Summary A study was carried out in 30 malepatients with benignprostate hyperplasia to assess the effectivenessof treatment with a progestational agent, gestonorone caproate (200 mg), given intramuscularly every 7 days over a period of 2 to 3 months. The results showed definite subjective and objective improvement after treatment. Residual urine determination diminished significantly after therapy in 78 % of the 28 cases completing the study; uroflometry also showed improvement. There appeared to be some reduction in the degree of occlusion of the urethral lumen in at least 13 (65 %) out of 20patientsgiven follow-up cystopanendoscopy after 6 months. This result was further supported by improvement in urinaryflow rates and uroflometrograms in the same patients. The only adverse effect of treatment noted was the development of impotency in 21 patients.
Key words: Gestonoronecaproate -progestational hormones - prostatic hypertrophy
Introduction Enlargement of the prostate gland is known to occur in older men. It generally affects people past the fifth decade of life, occurring in 6 out of every 10males in this age group.’ Its incidence increasesin direct proportion to the age so that at age 65 years, autopsy findingshave shown in one series an incidence of 65 %,2 and at 85 years, 80 % of the men evaluated showed evidence of prostate hyperplasia. The prostate enlargement is a benign neoplasm which produces symptomsby causingprogressive obstruction to the urine flow.Mostly, men in the 60 to 70 years of age group13 are the ones who seek medical attention for their prostate problems. The currently accepted treatment is surgical removal, and for some time many attempts have been made to treat this tumour medically with varying degrees of S U C C ~ S S . ~ ,T ~h .i ~s paper reports on one such attempt to treat benign prostate gland hyperplastic growth with gestonoronecaproate (‘Primostat’ t), a progestogenpreparation with a depot action. It is a progestational agent with an advantage over the purely androgenic or oestrogenic preparations since it minimizes the undersirable side-effects of the latter. Chemically, gestonorone caproate is 17a-hydroxy-19-norprogesterone caproate. Its structural formula is given in Figure 1. ttrade mark, Schering AG
513
Conservative treatment of benign prostatic hyperplasia
Figure 1.
Structural formula of gestonorone caproatr CH3
I
Downloaded by [Deakin University Library] at 17:09 05 November 2015
c o
Methods and material Thirty Filipino males with signs and symptoms of prostatism for 1 year or less due to benign prostate hyperplasia were the subjects in this study. The diagnosis of benign prostate hyperplasia was confirmed only by the rectal examination findings. A tandem study was carried out in these subjects. Initially, each subject underwent a thorough evaluation. Apart from the history and physical examination findings, several ancillary tests were utilized to serve as parameters of observation on the efficiency of micturition. The ancillary tests included : (i) uroflometry, (ii) residual urine test, (iii) cystometry, (iv) cysto-urethrography, (v) excretory urography, and (vi) cystopanendoscopy. In addition, each patient had routine urinalysis and, when indicated, urine culture and sensitivity tests were carried out. After the initial evaluation, each subject was given 200 mg gestonorone caproate intramuscularlyonce every 7 days for a period of 2 to 3 months. The subject was reevaluated at monthly intervals utilizing the same parameters used in the initial study. The total period covered by the study was 6 months.
Results Out of the 30 patients included as subjects in the initial phase of the study, 2 failed to return for follow-up and hence were removed from the study (Table I). Included in the evaluation were 13 patients in the 60 to 70 years age group. Twelve patients were in the 70 to 80 years age group. There were 3 subjects below 60 years of age, while there were 2 subjects older than 80 years. The youngest was 51 years old; the oldest was 86years old. Some patients were not able to comply with the strict schedule in the protocol. Nevertheless, all but 6 had at least one re-evaluation using the complete parameters in the protocol. Only 28 patients returned for follow-upfor clinical assessment, uroflometry, residual urine determination, and cysto-urethrography. All but 2 had repeat cystopanendoscopy. Of the 28 subjects considered on test, 6 did not improve. Three of these patients underwent prostatectomy. One patient improved significantlyin his subjectiveassessment but submitted for surgery because of impotency. The only side-effect noted was impotency which affected 21 patients, 14 of whom had total impotence while 7 had partial impotence. 514
Ernest0 Palanca and Wilfrido Juco
Table I. Response to treatment of 30 patients studied Patient No.
Age
Effect on
Prostate/rectum examination Urethroscopy (clinical grade)
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Micturition Uroflometry Residual urine
12 13
75 56 63 60 60 66 63 73 64 75 51 66 12
Imp. Imp. Imp. Imp. Imp. Imp. Imp. Imp. Imp. N.C. Imp. Imp. N.C.
14 15 16 17 18 19 20 21 22 23 24 25 26 21 28 29 30
71 75 68 19 62 83 65 70 64 54 65 79 86 73 62 70 76
Imp. Imp. Dim. N.C. Imp. Imp. Inc. Dim. Imp. Imp. Dim. Dim. Imp. Imp. Dim. Dim. Imp. Imp. Dim. Dim. Imp. Imp. Inc. N.C. N.C. N.C. N.C. N.C. Imp. Imp. Dim. N.C. Imp. Imp. Dim. Dim. Lost to follow-up: did not return after 1 month N.C. N.C. Inc. N.C. Lost to follow-up: diagnosed as cancer of pancreas Imp. Imp. Dim. N.D. Imp. Imp. Dim. Dim.* Imp. Imp. Dim. N.D. hP. Imp. Dim. Dim. Imp. Imp. Dim. N.C.
1 2 3
4 5 6 7 8 9 10 11
Imp. Imp. Imp. Imp. Imp. Imp. Imp. Imp. Imp. N.C. Imp. Imp. N.C.
Dim. Dim. Dim. Dim. Dim. Dim. Dim. Dim. Dim. Inc. Dim. Dim. N.C.
.
Dim. Occl. Occl. Occl. Occl. N.C. N.C. N.C. N.C.
N.C. N.C. N.C. N.C.
I1 I I I I I I I I I I1 I1 Suprapubic prostatectomy I I
I I
I1 I1
I Tur I1 I I1 Tur I
I1 I I1
Note: Imp. =improved, Dim. =diminished, N.C. =no change or unimproved, Inc. =increased, Occl. =occlusion, N.D. =not done. *patient stopped drug treatment after 5 months because of impotency
Subjective results The symptoms of urinary frequency, weakened urinary stream and post-micturition dribbling were followed up. Details are given in Table 11. Twenty-three patients reported improvement of their urinary frequency, while 5 showed unchanged results after treatment. The urinary stream of the 23 patients also showed similar improvement. Eighteen patients reported disappearance of their dribbling, but in 10 dribbling persisted. Objective results Details of the results of the ancillary tests used as objectiveparameters of the efficiency of micturition are summarizedin Table III. 515
Conservative treatment of benign prostatic hyperplasia
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Table II. Subjective d t s after treatment: 28 patients completiogstudy Observation
No.
%
Urinaryfrequency Improved Unchanged Deteriorated
23 5
82 18
18 10
64 36
23 5
82 18
7 7 14
25 25 50
Dribbling Disappeared Unchanged Urinary stream Improved Unchanged Deteriorated Potency Good Fair Absent
Table ITI. Objectiveresults after treatment: 28 patients completing study Test
No.
%
Residual urine Improved Unchanged Deteriorated
20 6 2
71.5 21.4 7.1
22 6
78.6 21.4
13 7
65 35
15 13
53.6 46.4
Urojlometry Improved Unchanged Deteriorated Endoscopy* Diminished Unchanged
Increased Rectal examination Diminished Unchanged Increased
*not carried out in 8 patients
Residual urine determination. The patients readily submitted to this test as an outpatient procedure. All but 6 patients showed significant reduction in their residual urine as early as the third month of the clinical trial. The most remarkable result was a reduction from the initial 150 ml to 16 ml after 2 months of gestonorone caproate therapy. Two patients achieved complete emptying of their bladder. Eight had diminished their residual urine by 70% to 80%. The remaining 12 patients had an average of 30 % reduction in their residual urine. Two patients showed no change in 516
Ernest0 Palanca and Wilfrido Juco
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their amount of residual urine after therapy. Three patients manifested deterioration by showing increase in the volume of their residual urine. Uroflometry. Initially, all patients showed markedly abnormal urination pattern in their uroflometrograms. They showed prolonged micturition time with a very low flow rate. The average flow rate was 6 ml/sec in an average urine volume of 200 ml. Improvements in their voiding patterns became noticeable on the third month of the trial. O n the sixth month of the study, the averageflow rate was increased to 14 ml/sec. Twenty patients showed these improvements while 8 continued to show abnormal data. Cystopanendoscopy. Follow-up cystopanendoscopy was done at least once after completion of the therapy in 20 subjects.Thirteen showed improvementin the degree of occlusion of the lumen of the prostatic urethra as originally noted in the initial endoscopic examination. This gave the examiner the impression that the prostate gland had diminished in size. The distance from the verumontanum to the bladder neck also appeared to have relatively decreased in these patients. The degree of bladder trabeculation appeared unchanged. The endoscopicfindings correlated well with the clinical improvementand the residual urine test in all but one patient. Patient No. 15 reported subjective improvement. His endoscopic examination revealed apparent decrease in the size of his prostate. His residual urine, however, remained unchanged from the initial determination. Side-effects Impotency was the major side-effect noted in this study. Twenty-one patients experienced this problem. One submitted to prostatectomy in spite of subjective improvement in his micturition. Two patients did not complete the 3-month course of treatment because of this side-effect. Significant improvement, however, was observed even if they were just able to complete2 months of treatment. These patients returned periodically for re-evaluation. Their potency returned 2 months after gestonorone caproate was discontinued. Their urination remained efficient. These patients were included in the group who improved. Fourteen patients had total impotency,while 7 had partial impotency. These patients remained with their problem of impotency up to the 6-month period of observation. No other remarkable side-effectwas noted.
Discussion Benign growth within the prostate gland has long been recognized by medical practitioners. Although its exact aetiology is obscure, its nature as an obstructive uropathy in the distal urinary tract is generally accepted. The prostate enlargement provides a progressive increase in the resistance to the urinary flow and subsequently makes voiding incomplete. With significant obstruction, the patient is unable to completely empty his urinary bladder, leaving a considerable amount of residual urine. With progressive prostate gland enlargement, increasingocclusion of the prostatic urethal 517
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Conservative treatment of benign prostatic hyperplasia
lumen occurs. Eventually, the patient may go into an agonizing urinary retention, failing to urinate in spite of a full bladder. Guyen4 proposed that benign prostate enlargement in the elderly is part of a compensatory hypertrophy of the gland in response to arteriosclerotic changes. Other writers have proposed sexual act indiscretion as the principal predisposing factor to prostate gland hypertrophy, and some advance the theory that infection is the aetiological factor causing progressive fibrosis of the prostate gland. All of these, however, have been disproved by other investigators. What is generally accepted is that benign prostate enlargement in the elderlymale is a neoplastic growth composed of glandular, fibrous and muscular tissues which, because of hyperplastic proliferation, stimulates this mass to enlarge causing the true prostate gland to be pushed outwards and be compressed into a thin rim against the prostate capsule.8 The most attractive theory is the endocrine theory which proposes that the aetiologic factor in benign prostate hyperplasia is endocrine imbalance in the aged male, the nature and mechanism of which is not exactly known. Certain reports, notably those of Lower and McCullah,’ tend to support this theory. The studiesof hug gin^,^ where he demonstrated the degeneration of the anterior lobes of the prostate after prolonged administration of oestrogen, tends to favour hormone as a casual factor in this disease. Huggins also noted that prostate gland enlargement did not occur among eunuchs. The attraction offered by the role of endocrineimbalancein the aetiology of benign prostate hyperplasia led many investigators to explore this area further. Various progestational agents have been tried to treat prostate gland hyperplasia.Among the various compounds tried were megestrol acetate,10 cyproterone,16 norgestrel,’ 1 and hydroxyprogesterone caproate.5 These studies produced equivocal results. Encouraging results were reported by Geller et al.,5 Scott and Wade16 and Lebech and Nordentoft. l o On the other hand, the studies of Weinbergla and Wolfe and Madsen’g showed apparent refractoriness of prostatic hyperplasia to these agents. Our current study has shown deiinite objective and subjective improvements in our patients. They reported not only subjective improvements of their prostatism, but these comments appeared to be supported by the application of the parameters utilized in our protocol. Residual urine determination showed significantdiminution after therapy in 78% of the cases. Uroflometry likewise showed improvement. Finally, there appeared to be some reduction in the degreeof occlusion of the urethral lumen during the follow-upcystopanendoscopyon the sixth month of the study. This was noted in at least 13 (65 %) out of 20 patients. This result was further supported by the improvement in the flow rates and uroflometrograms of these same patients. Cystometry and cysto-urethrographyfailed to give significant information, contrary to what was originally expected. The majority of the subjects were unable to void satisfactorily to show contrast visualization of their urethra. The studies of Thumannl7 also showed the unreliability of the cysto-urethrogram in the estimation of the weight of prostate gland enlargement.This objective data correlated well with the subjective improvements reported by our patients. The only adverse effect of gestonorone caproate therapy noted in our serieswas the development of impotency in 21 out of 28 patients on test. This side-effect proved troublesome to them: one 518
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Ernest0 Palanca and Wilfrido Juco
patient even decided to undergo an operation, and some unilaterally discontinued their treatment. In 1965, Geller et aZ.6 followed the effect of a similar compound by observing the histologic changes in the prostate glands through repeated biopsies. He was able to demonstrate, by light and electron microscopy,a reduction in the cellular structure of the prostate in as many as one-halfof the cases who received hormone. Certainly this report further supports our current findings of a decrease in the size of the prostate utilizing the various parameters in our protocol. No attempt was made to determine the mechanism of action of the drug on trial, this study concentratingmore on the effects of gestonorone caproate, both subjective and objective, on the efficiency of urination. Apart from showing that urinary function improved after gestonorone caproate therapy, we were also able to gather evidence that tends to show that the main effect of the drug is directly on the hyperplastic gland causing it to decrease in size. It is acknowledged that there were several limitations in this clinical trial, notably, that the follow-up period of 6 months was short. In addition, this study lacked a double-blind feature so we are unable to comment on the report of Clarke,’ who reported spontaneous subjective improvement in 60 % of his patients followed for 5 years with no specific treatment. Lastly, this study involved a relatively small number of cases not necessarily representative of patients with benign prostate hyperplasia. Moreover, the majority of our subjects had early prostate gland problems, as shown by the clinical grades of their prostate enlargement and the relatively small volume of their residual urine. Although no definite conclusion can be drawn from our clinical trial, the authors consider that the results of this study have fulfilled the criteria for this drug to be considered as an effective agent in the short-term treatment of benign prostate hyperplasia. Gestonorone caproate (‘Primostat’) proved to be effective in our patients with early and small gland enlargement (Grade I), and in patients with residual urine of less than 150 ml. It is realized, however, that more patients and a longer period of study are necessary before the true value of this drug as a medical treatment in benign prostate hyperplasia is finally confirmed.
Acknowledgement This study was made possible by a grant from Berlimed Phil. Corp.
References 1. Clarke, R., (1937). The prostate and endocrine. Br. J. Urol., 9,254-271. 2. Deming, C. L., (1940). The development of prostatic hyperplasias. Surg. Gynecol. Ubstet., 70,588-594. 3. Deming, C. L., Jenkins, R. H., and van Wagenenen, G., (1935). Further studies in the endocrinological relationships of prostatic hypertrophy. The effect of castration on the sub-urethral glands in the posterior urethra. J. Urol., 34,678-685. 4. Guyen, J. C. F., (1903). “wens Cliniques sur les Maladies des Voies Urinaries.” Baillere, Paris. 519
Conservative treatment of benign prostatic hyperplasia
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5. Geller, J., Angrist, A., Nakao, K., and Newman, H., (1969). Therapy with progestational agents in advanced benign prostatic hypertrophy. J.A.M.A., 210,1421-1427. 6. Geller, J., Bora, R., Roberts, T., Newman, H., Lin, A., and Silva, R., (1965). Treatment of benign prostatic hypertrophy with hydroxy-progesterone caproate. J.A.M.A., 193, 121-128. 7. Huggins, C., (1947). The etiology of benign prostatic hypertrophy. Bull. N. Y. Acad. Med., 23,696-704. 8. Huggins, C., and Stevens, R. A., (1940). Effect of castration on benign hypertrophy of prostate in man. J. Urol., 43,705-714. 9. Huggins, C., and Webster, W. O., (1948). Duality of human prostate in response to estrogen. J. Urol., 59, 258-266. 10. Lebech, P. E., and Nordentoft, E. L., (1967). A study of endocrine function in the treatment of benign prostatic hypertrophy with megestrol accrate. Acta Obstet. Gynecol. S c a d . , 46, Suppl. 9, 25-38. 11. Littleton, P., Fotherby, K., and Dennis, K. J., (1968). Metabolism of norgestrel in man. J. Endocrinol., 42, 591-598. 12. Lower, W. E., and McCullah, (1935). Summary of an experimental research on the control of benign prostatic hyperplasia and a preliminary clinical report. J. Urol., 34,670-677. 13. Moore, R. A., (1943). Benign hypertrophy of the prostate. A morphological study. J. Urol., 50, 680-710. 14. Moore, R. A., and McLellan, A. M., (1938). A histological study of the sex hormones of the human prostate. J. Urol., 40,641-657. 15. Palanca, E. A., (1968) The surgical treatment of prostaticobstruction Philipp.J. Surg. Spec., 23, No. 6. 16. Scott, W. W., and Wade, J. C., (1969). Medical treatment of benign nodular prostate hyperplasia with cyproterone acetate. J. Urol., 101,81-85. 17. Thumann, R. C., Jnr., (1951). Estimation of weight of byperplastic prostate from cystourethrography. Am. J. Roentgenol., 65,593-595. 18. Weinberg, S. R., (1968). Refractoriness of prostatism to hydroxy-progesterone caproate (Delalutin) therapy. J. Urol., 100, 57-58. 19 Wolfe, H , and Madsen, P. O., (1968). Treatment of benign prostate hypertrophy with progestational agent - a preliminary report. J. Urol., 99, 780-785.
520
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Conservative treatment of benign prostatic hyperplasia Ernesto Palanca & Wilfrido Juco To cite this article: Ernesto Palanca & Wilfrido Juco (1977) Conservative treatment of benign prostatic hyperplasia, Current Medical Research and Opinion, 4:7, 513-520, DOI: 10.1185/03007997709109342 To link to this article: http://dx.doi.org/10.1185/03007997709109342
Published online: 07 Aug 2008.
Submit your article to this journal
Article views: 3
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Download by: [Deakin University Library]
Date: 05 November 2015, At: 17:09
Current Medical Research and Opinion
Vol. 4, No. 7, 1977
Conservative treatment of benign prostatic byperplasia
Ernest0 Palanca, M.D., F.P.C.S., F.I.C.S. and
Wilfrido Juco, M.D.
Downloaded by [Deakin University Library] at 17:09 05 November 2015
University of Santo Tomas, College of Medicine and Surgery, Manila, Philippines
Cum. Med. Res. Opin., (1977), 4, 513.
Received: 22nd October 1976
Summary A study was carried out in 30 malepatients with benignprostate hyperplasia to assess the effectivenessof treatment with a progestational agent, gestonorone caproate (200 mg), given intramuscularly every 7 days over a period of 2 to 3 months. The results showed definite subjective and objective improvement after treatment. Residual urine determination diminished significantly after therapy in 78 % of the 28 cases completing the study; uroflometry also showed improvement. There appeared to be some reduction in the degree of occlusion of the urethral lumen in at least 13 (65 %) out of 20patientsgiven follow-up cystopanendoscopy after 6 months. This result was further supported by improvement in urinaryflow rates and uroflometrograms in the same patients. The only adverse effect of treatment noted was the development of impotency in 21 patients.
Key words: Gestonoronecaproate -progestational hormones - prostatic hypertrophy
Introduction Enlargement of the prostate gland is known to occur in older men. It generally affects people past the fifth decade of life, occurring in 6 out of every 10males in this age group.’ Its incidence increasesin direct proportion to the age so that at age 65 years, autopsy findingshave shown in one series an incidence of 65 %,2 and at 85 years, 80 % of the men evaluated showed evidence of prostate hyperplasia. The prostate enlargement is a benign neoplasm which produces symptomsby causingprogressive obstruction to the urine flow.Mostly, men in the 60 to 70 years of age group13 are the ones who seek medical attention for their prostate problems. The currently accepted treatment is surgical removal, and for some time many attempts have been made to treat this tumour medically with varying degrees of S U C C ~ S S . ~ ,T ~h .i ~s paper reports on one such attempt to treat benign prostate gland hyperplastic growth with gestonoronecaproate (‘Primostat’ t), a progestogenpreparation with a depot action. It is a progestational agent with an advantage over the purely androgenic or oestrogenic preparations since it minimizes the undersirable side-effects of the latter. Chemically, gestonorone caproate is 17a-hydroxy-19-norprogesterone caproate. Its structural formula is given in Figure 1. ttrade mark, Schering AG
513
Conservative treatment of benign prostatic hyperplasia
Figure 1.
Structural formula of gestonorone caproatr CH3
I
Downloaded by [Deakin University Library] at 17:09 05 November 2015
c o
Methods and material Thirty Filipino males with signs and symptoms of prostatism for 1 year or less due to benign prostate hyperplasia were the subjects in this study. The diagnosis of benign prostate hyperplasia was confirmed only by the rectal examination findings. A tandem study was carried out in these subjects. Initially, each subject underwent a thorough evaluation. Apart from the history and physical examination findings, several ancillary tests were utilized to serve as parameters of observation on the efficiency of micturition. The ancillary tests included : (i) uroflometry, (ii) residual urine test, (iii) cystometry, (iv) cysto-urethrography, (v) excretory urography, and (vi) cystopanendoscopy. In addition, each patient had routine urinalysis and, when indicated, urine culture and sensitivity tests were carried out. After the initial evaluation, each subject was given 200 mg gestonorone caproate intramuscularlyonce every 7 days for a period of 2 to 3 months. The subject was reevaluated at monthly intervals utilizing the same parameters used in the initial study. The total period covered by the study was 6 months.
Results Out of the 30 patients included as subjects in the initial phase of the study, 2 failed to return for follow-up and hence were removed from the study (Table I). Included in the evaluation were 13 patients in the 60 to 70 years age group. Twelve patients were in the 70 to 80 years age group. There were 3 subjects below 60 years of age, while there were 2 subjects older than 80 years. The youngest was 51 years old; the oldest was 86years old. Some patients were not able to comply with the strict schedule in the protocol. Nevertheless, all but 6 had at least one re-evaluation using the complete parameters in the protocol. Only 28 patients returned for follow-upfor clinical assessment, uroflometry, residual urine determination, and cysto-urethrography. All but 2 had repeat cystopanendoscopy. Of the 28 subjects considered on test, 6 did not improve. Three of these patients underwent prostatectomy. One patient improved significantlyin his subjectiveassessment but submitted for surgery because of impotency. The only side-effect noted was impotency which affected 21 patients, 14 of whom had total impotence while 7 had partial impotence. 514
Ernest0 Palanca and Wilfrido Juco
Table I. Response to treatment of 30 patients studied Patient No.
Age
Effect on
Prostate/rectum examination Urethroscopy (clinical grade)
Downloaded by [Deakin University Library] at 17:09 05 November 2015
Micturition Uroflometry Residual urine
12 13
75 56 63 60 60 66 63 73 64 75 51 66 12
Imp. Imp. Imp. Imp. Imp. Imp. Imp. Imp. Imp. N.C. Imp. Imp. N.C.
14 15 16 17 18 19 20 21 22 23 24 25 26 21 28 29 30
71 75 68 19 62 83 65 70 64 54 65 79 86 73 62 70 76
Imp. Imp. Dim. N.C. Imp. Imp. Inc. Dim. Imp. Imp. Dim. Dim. Imp. Imp. Dim. Dim. Imp. Imp. Dim. Dim. Imp. Imp. Inc. N.C. N.C. N.C. N.C. N.C. Imp. Imp. Dim. N.C. Imp. Imp. Dim. Dim. Lost to follow-up: did not return after 1 month N.C. N.C. Inc. N.C. Lost to follow-up: diagnosed as cancer of pancreas Imp. Imp. Dim. N.D. Imp. Imp. Dim. Dim.* Imp. Imp. Dim. N.D. hP. Imp. Dim. Dim. Imp. Imp. Dim. N.C.
1 2 3
4 5 6 7 8 9 10 11
Imp. Imp. Imp. Imp. Imp. Imp. Imp. Imp. Imp. N.C. Imp. Imp. N.C.
Dim. Dim. Dim. Dim. Dim. Dim. Dim. Dim. Dim. Inc. Dim. Dim. N.C.
.
Dim. Occl. Occl. Occl. Occl. N.C. N.C. N.C. N.C.
N.C. N.C. N.C. N.C.
I1 I I I I I I I I I I1 I1 Suprapubic prostatectomy I I
I I
I1 I1
I Tur I1 I I1 Tur I
I1 I I1
Note: Imp. =improved, Dim. =diminished, N.C. =no change or unimproved, Inc. =increased, Occl. =occlusion, N.D. =not done. *patient stopped drug treatment after 5 months because of impotency
Subjective results The symptoms of urinary frequency, weakened urinary stream and post-micturition dribbling were followed up. Details are given in Table 11. Twenty-three patients reported improvement of their urinary frequency, while 5 showed unchanged results after treatment. The urinary stream of the 23 patients also showed similar improvement. Eighteen patients reported disappearance of their dribbling, but in 10 dribbling persisted. Objective results Details of the results of the ancillary tests used as objectiveparameters of the efficiency of micturition are summarizedin Table III. 515
Conservative treatment of benign prostatic hyperplasia
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Table II. Subjective d t s after treatment: 28 patients completiogstudy Observation
No.
%
Urinaryfrequency Improved Unchanged Deteriorated
23 5
82 18
18 10
64 36
23 5
82 18
7 7 14
25 25 50
Dribbling Disappeared Unchanged Urinary stream Improved Unchanged Deteriorated Potency Good Fair Absent
Table ITI. Objectiveresults after treatment: 28 patients completing study Test
No.
%
Residual urine Improved Unchanged Deteriorated
20 6 2
71.5 21.4 7.1
22 6
78.6 21.4
13 7
65 35
15 13
53.6 46.4
Urojlometry Improved Unchanged Deteriorated Endoscopy* Diminished Unchanged
Increased Rectal examination Diminished Unchanged Increased
*not carried out in 8 patients
Residual urine determination. The patients readily submitted to this test as an outpatient procedure. All but 6 patients showed significant reduction in their residual urine as early as the third month of the clinical trial. The most remarkable result was a reduction from the initial 150 ml to 16 ml after 2 months of gestonorone caproate therapy. Two patients achieved complete emptying of their bladder. Eight had diminished their residual urine by 70% to 80%. The remaining 12 patients had an average of 30 % reduction in their residual urine. Two patients showed no change in 516
Ernest0 Palanca and Wilfrido Juco
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their amount of residual urine after therapy. Three patients manifested deterioration by showing increase in the volume of their residual urine. Uroflometry. Initially, all patients showed markedly abnormal urination pattern in their uroflometrograms. They showed prolonged micturition time with a very low flow rate. The average flow rate was 6 ml/sec in an average urine volume of 200 ml. Improvements in their voiding patterns became noticeable on the third month of the trial. O n the sixth month of the study, the averageflow rate was increased to 14 ml/sec. Twenty patients showed these improvements while 8 continued to show abnormal data. Cystopanendoscopy. Follow-up cystopanendoscopy was done at least once after completion of the therapy in 20 subjects.Thirteen showed improvementin the degree of occlusion of the lumen of the prostatic urethra as originally noted in the initial endoscopic examination. This gave the examiner the impression that the prostate gland had diminished in size. The distance from the verumontanum to the bladder neck also appeared to have relatively decreased in these patients. The degree of bladder trabeculation appeared unchanged. The endoscopicfindings correlated well with the clinical improvementand the residual urine test in all but one patient. Patient No. 15 reported subjective improvement. His endoscopic examination revealed apparent decrease in the size of his prostate. His residual urine, however, remained unchanged from the initial determination. Side-effects Impotency was the major side-effect noted in this study. Twenty-one patients experienced this problem. One submitted to prostatectomy in spite of subjective improvement in his micturition. Two patients did not complete the 3-month course of treatment because of this side-effect. Significant improvement, however, was observed even if they were just able to complete2 months of treatment. These patients returned periodically for re-evaluation. Their potency returned 2 months after gestonorone caproate was discontinued. Their urination remained efficient. These patients were included in the group who improved. Fourteen patients had total impotency,while 7 had partial impotency. These patients remained with their problem of impotency up to the 6-month period of observation. No other remarkable side-effectwas noted.
Discussion Benign growth within the prostate gland has long been recognized by medical practitioners. Although its exact aetiology is obscure, its nature as an obstructive uropathy in the distal urinary tract is generally accepted. The prostate enlargement provides a progressive increase in the resistance to the urinary flow and subsequently makes voiding incomplete. With significant obstruction, the patient is unable to completely empty his urinary bladder, leaving a considerable amount of residual urine. With progressive prostate gland enlargement, increasingocclusion of the prostatic urethal 517
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lumen occurs. Eventually, the patient may go into an agonizing urinary retention, failing to urinate in spite of a full bladder. Guyen4 proposed that benign prostate enlargement in the elderly is part of a compensatory hypertrophy of the gland in response to arteriosclerotic changes. Other writers have proposed sexual act indiscretion as the principal predisposing factor to prostate gland hypertrophy, and some advance the theory that infection is the aetiological factor causing progressive fibrosis of the prostate gland. All of these, however, have been disproved by other investigators. What is generally accepted is that benign prostate enlargement in the elderlymale is a neoplastic growth composed of glandular, fibrous and muscular tissues which, because of hyperplastic proliferation, stimulates this mass to enlarge causing the true prostate gland to be pushed outwards and be compressed into a thin rim against the prostate capsule.8 The most attractive theory is the endocrine theory which proposes that the aetiologic factor in benign prostate hyperplasia is endocrine imbalance in the aged male, the nature and mechanism of which is not exactly known. Certain reports, notably those of Lower and McCullah,’ tend to support this theory. The studiesof hug gin^,^ where he demonstrated the degeneration of the anterior lobes of the prostate after prolonged administration of oestrogen, tends to favour hormone as a casual factor in this disease. Huggins also noted that prostate gland enlargement did not occur among eunuchs. The attraction offered by the role of endocrineimbalancein the aetiology of benign prostate hyperplasia led many investigators to explore this area further. Various progestational agents have been tried to treat prostate gland hyperplasia.Among the various compounds tried were megestrol acetate,10 cyproterone,16 norgestrel,’ 1 and hydroxyprogesterone caproate.5 These studies produced equivocal results. Encouraging results were reported by Geller et al.,5 Scott and Wade16 and Lebech and Nordentoft. l o On the other hand, the studies of Weinbergla and Wolfe and Madsen’g showed apparent refractoriness of prostatic hyperplasia to these agents. Our current study has shown deiinite objective and subjective improvements in our patients. They reported not only subjective improvements of their prostatism, but these comments appeared to be supported by the application of the parameters utilized in our protocol. Residual urine determination showed significantdiminution after therapy in 78% of the cases. Uroflometry likewise showed improvement. Finally, there appeared to be some reduction in the degreeof occlusion of the urethral lumen during the follow-upcystopanendoscopyon the sixth month of the study. This was noted in at least 13 (65 %) out of 20 patients. This result was further supported by the improvement in the flow rates and uroflometrograms of these same patients. Cystometry and cysto-urethrographyfailed to give significant information, contrary to what was originally expected. The majority of the subjects were unable to void satisfactorily to show contrast visualization of their urethra. The studies of Thumannl7 also showed the unreliability of the cysto-urethrogram in the estimation of the weight of prostate gland enlargement.This objective data correlated well with the subjective improvements reported by our patients. The only adverse effect of gestonorone caproate therapy noted in our serieswas the development of impotency in 21 out of 28 patients on test. This side-effect proved troublesome to them: one 518
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Ernest0 Palanca and Wilfrido Juco
patient even decided to undergo an operation, and some unilaterally discontinued their treatment. In 1965, Geller et aZ.6 followed the effect of a similar compound by observing the histologic changes in the prostate glands through repeated biopsies. He was able to demonstrate, by light and electron microscopy,a reduction in the cellular structure of the prostate in as many as one-halfof the cases who received hormone. Certainly this report further supports our current findings of a decrease in the size of the prostate utilizing the various parameters in our protocol. No attempt was made to determine the mechanism of action of the drug on trial, this study concentratingmore on the effects of gestonorone caproate, both subjective and objective, on the efficiency of urination. Apart from showing that urinary function improved after gestonorone caproate therapy, we were also able to gather evidence that tends to show that the main effect of the drug is directly on the hyperplastic gland causing it to decrease in size. It is acknowledged that there were several limitations in this clinical trial, notably, that the follow-up period of 6 months was short. In addition, this study lacked a double-blind feature so we are unable to comment on the report of Clarke,’ who reported spontaneous subjective improvement in 60 % of his patients followed for 5 years with no specific treatment. Lastly, this study involved a relatively small number of cases not necessarily representative of patients with benign prostate hyperplasia. Moreover, the majority of our subjects had early prostate gland problems, as shown by the clinical grades of their prostate enlargement and the relatively small volume of their residual urine. Although no definite conclusion can be drawn from our clinical trial, the authors consider that the results of this study have fulfilled the criteria for this drug to be considered as an effective agent in the short-term treatment of benign prostate hyperplasia. Gestonorone caproate (‘Primostat’) proved to be effective in our patients with early and small gland enlargement (Grade I), and in patients with residual urine of less than 150 ml. It is realized, however, that more patients and a longer period of study are necessary before the true value of this drug as a medical treatment in benign prostate hyperplasia is finally confirmed.
Acknowledgement This study was made possible by a grant from Berlimed Phil. Corp.
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5. Geller, J., Angrist, A., Nakao, K., and Newman, H., (1969). Therapy with progestational agents in advanced benign prostatic hypertrophy. J.A.M.A., 210,1421-1427. 6. Geller, J., Bora, R., Roberts, T., Newman, H., Lin, A., and Silva, R., (1965). Treatment of benign prostatic hypertrophy with hydroxy-progesterone caproate. J.A.M.A., 193, 121-128. 7. Huggins, C., (1947). The etiology of benign prostatic hypertrophy. Bull. N. Y. Acad. Med., 23,696-704. 8. Huggins, C., and Stevens, R. A., (1940). Effect of castration on benign hypertrophy of prostate in man. J. Urol., 43,705-714. 9. Huggins, C., and Webster, W. O., (1948). Duality of human prostate in response to estrogen. J. Urol., 59, 258-266. 10. Lebech, P. E., and Nordentoft, E. L., (1967). A study of endocrine function in the treatment of benign prostatic hypertrophy with megestrol accrate. Acta Obstet. Gynecol. S c a d . , 46, Suppl. 9, 25-38. 11. Littleton, P., Fotherby, K., and Dennis, K. J., (1968). Metabolism of norgestrel in man. J. Endocrinol., 42, 591-598. 12. Lower, W. E., and McCullah, (1935). Summary of an experimental research on the control of benign prostatic hyperplasia and a preliminary clinical report. J. Urol., 34,670-677. 13. Moore, R. A., (1943). Benign hypertrophy of the prostate. A morphological study. J. Urol., 50, 680-710. 14. Moore, R. A., and McLellan, A. M., (1938). A histological study of the sex hormones of the human prostate. J. Urol., 40,641-657. 15. Palanca, E. A., (1968) The surgical treatment of prostaticobstruction Philipp.J. Surg. Spec., 23, No. 6. 16. Scott, W. W., and Wade, J. C., (1969). Medical treatment of benign nodular prostate hyperplasia with cyproterone acetate. J. Urol., 101,81-85. 17. Thumann, R. C., Jnr., (1951). Estimation of weight of byperplastic prostate from cystourethrography. Am. J. Roentgenol., 65,593-595. 18. Weinberg, S. R., (1968). Refractoriness of prostatism to hydroxy-progesterone caproate (Delalutin) therapy. J. Urol., 100, 57-58. 19 Wolfe, H , and Madsen, P. O., (1968). Treatment of benign prostate hypertrophy with progestational agent - a preliminary report. J. Urol., 99, 780-785.
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