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Hormonal Treatment of Benign Prostatic Hyperplasia1
HORMONAL TREATMENT OF BENIGN PROSTATIC HYPERPLASIA 1 HENRY W. E. WALTHER
AND
ROBERT M. WILLOUGHBY
Department of Urology, Louisiana State University, New Orleans
In the light of modern research it has become increasingly clear that prostatic hyperplasia can no longer be regarded as an independent entity, but that it is inseparably bound up with endocrine changes affecting the hypophysis and the gonads. We know that, following castration, the prostate and seminal vesicles become atrophic. Similar effects follow hypophysectomy. On the other hand, if we remove the testes we get an increase in size and function of the hypophysis. The inter-relationship between the testes, the secondary sex organs and the anterior pituitary gland are now clearly recognized, and we know that changes in one member of this triad are inevitably conveyed to the other members. Hence, the concept has arisen that benign prostatic hyperplasia may be the result of an endocrine imbalance. Within the last decade the possibilities of the clinical application of glandular therapy in cases of prostatic hyperplasia have engaged the attention of many serious workers, and a new literature has appeared, based on the results of animal experimentation along these lines, both in this country and in Europe. It is our purpose here to glance over this literature and to add to it a brief account of the work that we have had the opportunity to do in this interesting field. The idea that the testes have an internal secretion was.first put forward in 1889 by Brown-Sequard, who made some experiments on himself, for which he was derided by both the profession and the laity. The first worker to study the effects of active extracts of testes by the cockscomb method was Pezard, who in 1918 observed that extract from cryptorchid testes produced full comb growth in a capon. Many investigators have since taken up the study of the male sex hormone. They found that it is present in testes and also in the urine of males of practically all ages except the very young, although its quantity is diminished in old age. A quantitative test for this hormone was first devised by Gallagher and Koch in 1930. In 1931, Butenandt isolated from urine a crystalline 1 Read before the Southeastern Branch Society, American Urological Association Birmingham, November 5, 1937. 135
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HENRY W. E. WALTHER AND ROBERT M. WILLOUGHBY
hormone to which he gave the name of androsterone. So difficult was it to obtain this hormone that up to 1933 only 25 mg. of the substance had been secured. In that year Ruzicka and his co-workers succeeded in preparing androsterone from cholesterol. This was the first artificial production of a sex hormone, and was the starting point for the investigation of the relationship between chemical constitution and male hormone activity. In order to investigate the specific effect of androsterone upon the accessory male glands these workers employed the seminal vesicle and prostate tests in castrated rats. The hormone was found to have a greater effect on the prostate than on the vesicles. Lower and McCullagh in 1929 had already begun their attempts to demonstrate that prostatic hyperplasia in experimental animals may result from endocrine imbalance. They have only recently shown, after 7 years of research, that this hyperplasia can be controlled by the use of a testicular hormone. Hoskins, as long ago as 1911, had expressed the view that the pituitary gland is normally held in check by the gonads, and that when this inhibition is removed, the pituitary manifests increased activity leading to altered metabolism. If an excess of anterior pituitary gonad-stimulating hormone is introduced into the circulation, the stimulation is exerted not only on the testes but also on the prostate and seminal vesicles. In castrated animals the pituitary hormone, notwithstanding its increased quantity, is unable to prevent the atrophy of the prostate and vesicles. It is becoming clear that the testes serve as an important link between the hypophysis and the secondary sex organs. Lower and Hicken in 1931 experimented with parabiosis in 87 pairs of rats, anastomosed together in such a way as to leave a permanent artificial opening connecting the two peritoneal cavities. There was thus a free exchange of peritoneal fluids, and the intestines passed freely from • one peritoneal cavity into the other. It was observed that when a castrated rat was anastomosed to a normal male, the prostate and seminal vesicles of the ca.s trates became atrophic, while the hypophysis increased in size. In the normal partner, on the other hand, the testes, vesicles and prostate were all definitely hyperplastic, while the pituitary remained normal. When the rats were killed at the end of 30 days, the prostate in all the normal animals was found increased, both in size and in weight, from 300 to 500 per cent. The consistency of the gland was firm and solid, and the enlargement was uniform in all directions. After
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the ablation of the gonads in the castrated males, the hypophysis had increased in size and function. The excessive prehypophyseal hormone had then passed from the castrate into its normal partner, where it caused the testes to secrete an excess of sex hormones which resulted in hyperplasia of the prostate. McCullagh and Walsh in 1935 carried out similar parabiotic experiments and observed precisely similar results. It is thus seen that prostatic enlargement was produced merely by altering the endocrine system, causing hyperfunction of the pituitary gland. Lower and McCullagh demonstrated that a second testicular hormone is produced within the germinal epithelium of the tubular portion of the testes. To this they gave the name inhibin, since it was shown to have an inhibitory effect upon the pituitary. When the tubular portion of the testes deteriorates after the climacteric, the withdrawal of this inhibition would cause the gonadotropic functions of the anterior lobe to become exaggerated, which in turn would invite prostatic enlargement. Space does not allow us to dwell longer on the experimental aspect of the subject. Mention may be made, however, of the important work of Zuckerman, and of Miescher, Wettstein and Tschopp in England and Switzerland, of Moore and his co-workers, of Martine and Rocha, Hamilton, Heslin and Gilbert, and de Jongh of Amsterdam, to all of whom we are indebted for valuable communications. According to Moore the question whether the testis produces more than more than one hormone is not yet settled. From the weight of evidence, however, both clinical and experimental, it would appear that another hormonal substance is active within the testis during the florid years of every male individual's life, and that this is to be found in germinal epithelium of the tubular portion of the testis. Under normal conditions, these 2 hormones, tubular and interstitial, would work synergetically, each supplementing the other. In 1936, Owen and Cutler expressed the view that there are several possible sex hormone imbalances, and that evidence exists for at least two male and two female types of hormone, as well as regulator agents acting through or from the pituitary . It can thus be seen that accurate quantitative assays for small amounts of both the male and female hormones are essential, since this is the only way the true imbalance in sex hormones, if any, can be determined. Many authors assume today that a hypothetical substance, known as inhibin or contriun, exerts a restraining action upon the pituitary that keeps the
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latter from excessive output of energy. When the first signs of old age appear, this would be the principle that :first gives out; this 'pace-maker', as de Jongh has called it, fails by degrees to balance the gonadrotropic hormone of the pituitary. According to Lower, Engel and McCullagh, this, if established, agrees with Collip's conception that all hormones are buffered by antihormones. In accordance with this idea, these workers at the Cleveland Clinic found it rational to treat prostatic hyperplasia by administering the hormone inhibin. They reported that in the first 10 months they treated 40 patients with prostatic obstruction, by means of this hormone. All cases presented the typical symptoms of slowness of stream, nocturia and frequency. All types of prostatic hyperplasia were treated, but the authors feel that the soft, adenomatous hyperplasias are likely to give the best response. Each patient received orally the equivalent of about 60 grams of fresh testes daily for 3 months, after which it was reduced to a maintenance dose representing 20 grams of fresh testes daily. After critical analysis the authors consider 26, or 65 per cent, of these cases to be markedly improved to the point where they are virtually symptom free. Rectal palpation does not, however, give the impression of a reduction in size, and yet the patients feel well and suffer none of their old symptoms. The general consensus seems to be that clinical improvement of a very satisfactory kind follows recourse to this hormonal treatment. Laqueur and Van Cappellen are enthusiastic, after 3 years' use of the Dutch hormonal product, hombreol. Results were good in all but one of the latter's 12 cases. It is his opinion that only first grade cases should be thus treated, never grades 2 and 3, for which he still prefers surgical measures. Morell recommends androstine, a glandular preparation which complies with all the necessary requirements. Ampoules 'A' contain the water-soluble product and ampoules 'B' the liposoluble active principles, while androstine tablets contain both extracts. The water soluble principle 'A' provokes hyperemia of the genital organs and as a result of the improved nutrition of the testis the hormone production is increased. McCullagh has pointed out that the aqueous testicular extracts check the modification of the cells of the pituitary which appears after castration or loss of testicular function, and prevents hyperfunction of the pituitary body. This in turn would prevent excess of gonadotropic secretion, and, with it, the hyperplasia of the prostate. In contrast to the preparations which contain the so-called male hormone of the interstitial cells, an-
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drostine utilizes all the active principals of the testis. Since at the present time the exact mode of action of these principals is not clearly understood, there are certain advantages in the use of androstine. It is undeniable that whole testis extract, when given to old men with benign prostatic hyperplasia, has been shown, in some instances, to furnish relief of symptoms after prolonged medication with this hormone, without further treatment such as surgery. Bergmann reported the results of treatment in 69 cases, complaining of fatigue, insomnia, frequent and difficult micturition and perinea! discomfort. He gives a water-soluble hormone intramuscularly, first, 2 or 3 times weekly, to stimulate hypophyseal growth action until a better balance is reached; then he gives the sex hormone androstine. The injections must be given once a week over a period of time. Champy, Heitz-Boyer and Coujard are making therapeutic use of testis hormone in hyperplasia of the prostate. Like Lower and his coworkers, they point out that the favorable effect upon the dysuria often precedes the diminution of the adenoma. They think that this is due to a mucoid edema around the vessels of the verumontanum, which is normal to adult animals, missing in castrates and diminished in aged animals. Wugmeister maintains that hyperplasia of the prostate is due to a hypervirilization of the organism, which takes place during the presenile age due to a deficiency of estrogen. Female hormone that is normally present in all human beings, is withdrawn in later life, he contends, and the organism undergoes a hypervirilization resulting in prostatic hyperplasia. He administers folliculin to correct this deficit and thereby reduces gland enlargement. This view, he admits, is in complete contradiction to that of several other investigators, who con.. tend that hyperplasia of the prostate results from a deficiency in testis hormone. Wugmeister claims that large doses of estrogen should, in that case, aggravate the prostatism symptoms; but they do not; to the contrary, he says, they effect an amelioration. In 16 of 23 cases so treated, improvement was marked. It is not claimed that the results of the treatment are permanent, Thus far it appears that the symptoms tend to recur after treatment is stopped, and it is necessary to continue a maintenance dose, more or less like what is done with insulin. That the good results are not merely of a psychological nature was proved by Van Cappellen, who, to test this very point, gave some of his
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injections with no hombreol content, and got no result. The exact modus operandi with this method of treatment is not known. Lower has suggested that it is possible that insufficient time has elapsed for the changes in the size of the prostate to be apparent, though with experimental animals marked changes are noted both grossly and microscopically. Schmitz of Berlin, who has treated 42 patients with perandrentestosterone propionate-with most gratifying results, points out that these good results are made possible today by the fact that all these hormonal extracts can be made synthetically, whereas, in the past, it was impossible to give sufficient doses of the male sex hormone. Needless to add, all of this work remains experimental at the present writing. For the past two years we have been using the oral tablets and the ampoules 'A' and 'B' of androstine-a total extract (aqueous and lipoidal) of fresh whole testes of healthy bulls. During the past 12 months we have also employed perandren- a chemically pure testosterone propionate, the testosterone being synthesized from other sterols, especially cholesterol, and then esterized with propionic acid. Up to the present time, we have treated, over variable periods, 15 patients with these male sex hormone preparations. In the group are included (a) 8 patients all of whom presented symptoms of early prostatism, some complicated by prostatitis and some with an impending sexual impotency; (b) 4 patients in whom serious cardiac complications seemed to preclude any form of surgical relief; and, (c) 3 patients who refused to submit to any type of operative intervention. It is not our purpose, in reporting so small a series of cases, to give any one the impression that this form of therapy will ever replace surgery. Although in no instance did we fail to notice definite clinical improvement, our observations have not extended over a sufficient period of time to warrant any positive conclusions. As an ever-widening circle of urologists interest themselves in this fascinating field of male sex endocrinology, in its relation to benign prostatic hyperplasia, reports will be forthcoming in due time to confirm or refute the observations made in the medical literature to date. Of our series, forming the basis of this communication, we give only 3 case-reports; a tabulation of all of them would simply mean a repetition of the essentials included in those histories herein detailed. Case 1. Mr. E. W., age 68, a retired university professor, consulted us in January 1930 for frequency and difficulty in voiding. He stated that he was getting up once or twice at night and voiding 4 or S times during the day.
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The urine showed an occasional pus cell and an occasional colon bacillus. By rectal palpation the prostate gland was moderately enlarged, soft and movable. The prostatic secretion showed 1 plus pus. The phthalein test for one hour read 60 per cent. The blood pressure was 125/100. He was receiving treatment from an opthalmologist for vitreous opacities. For years he had been treated for myocardial weakness with a distinct mitral blow. The patient was very nervous, couldn't sleep well at night and found it impossible to concentrate. His memory was failing him. It was clearly evident that although he had the symptoms of early prostatism with some 12 ounces residual, he was in no shape to undergo any type of surgical relief. We gave him gentle rectal massage of the prostate gland weekly. This gave him some relief. We gave him 0.03 gm. to 0.06 gm. intramuscular injections of androstine, 3 times a week over a period of 2 months. This was followed by administering 0.075 gm. androstine tablets orally; in the beginning he received 1 tablet 3 times a day. After 2 weeks the dose was increased to 2 tablets 3 times a day. At the time the androstine therapy was begun, he was getting up 3 or 4 times at night to void. Within a month after the hormonal therapy was begun, this nocturnal frequency was decreased to 1 nightly voiding and often he did not get up at all. The urinary stream improved. This was not all. Soon after the injections were begun (without any suggestions from us as to what the treatment would do for him) he found that he could concentrate easier, his memory became more keen, his appetite increased and he slept better at night. This patient is still under observation and most comfortable. He takes androstine tablets by mouth, 2 morning and night, 2 or 3 times a week. He comes to the office once or twice a month for an androstine hypodermic injection. Upon rectal examination, the prostate gland, now free of infection, is the same size as it was when we began hormonal treatment in 1935, but as stated above his symptoms have ameliorated. Cystoscopy has not been done. His_residual urine is nil. To illustrate the point that this medication must be continued over an indefinite period, we might say that during the past summer this patient had to go to one of the New England States, for several weeks, to visit a brother who was quite ill. He left the city in such a rush that he failed to take his tablets along with him and he was 3 weeks without any medicine. When he returned to the city he was getting up 3 or 4 times at night to void with a return of all the symptoms of which he had originally complained. His injections of androstine were resumed every other day, plus the oral administration of androstine tablets, 2 morning and night every other day, and the aggravation subsided promptly . Case 2. Mr. C. G. G., age 62, a minister, consulted us in February 193with all the classic symptoms of early prostatism. He was getting up 3 to 4 times every night to void and had to empty his bladder at least 6 to 10 times
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HENRY W . E . WALTHER AND ROBERT M. WILLOUGHBY
during the day. He stated that the difficulty in starting the stream was gradually becoming more noticeable. He refused to consider any surgical procedure, owing to the fact that he had been told in Boston that his heart was in bad shape. He was of an intensely nervous temperament. He had no appetite, was losing weight and strength. The urine showed no albumin or sugar, but revealed 1 plus pus and one plus colon bacilli. His blood pressure was 90/60. The phthalein test for 1 hour was 65 per cent. The prostate per rectum revealed a type 2 enlargement, the gland being soft and movable. The secretion showed two plus pus. There was no residual urine. He was given with a rectal massage once a week, followed every time by an installation of weak silver nitrate. Within 3 months the infection in the gland had disappeared and his blood pressure now read 115/75. The frequency and difficulty were slightly relieved. We then started injections of 0.03 gm. to 0.06 gm. androstine every other day for 2 months. Within 2 weeks of the initial injection of androstine he began to show improvement. After he had been on the injections for a month we began giving him 0.075 gm. androstine tablets by mouth, 2 morning and night. The oral treatment was continued steadily for 3 months, at the end of which time he was getting up to void at night only once or twice and during the day about 3 times. Weekly rectal massage was continued throughout this period. He reports to the office about once a month, and is perfectly satisfied with the progress he has made under male sex gland therapy. He takes at present 2 androstine tablets daily ; possibly once or twice a month he comes in for an intramuscular injection. He is still under observation. Case 3. Mr. A. B., age 56, a farmer by occupation, was first seen by us in June 1935, complaining of frequency, burning and difficulty at voiding. He was getting up 4 or 5 times at night and voiding as often as 12 times during the day. There were 4 ounces of residual urine which showed considerable pus and colon bacilli. The prostate per rectum revealed type 3 enlargement, the gland being soft and movable. The secretion showed 3 plus pus. The phthalein test read 35 per cent for an hour. The blood pressure was 145/100. Rectal massage was given weekly, each time followed with an installation of weak silver nitrate solution. We suggested that his home physician give him intramuscular injections of 0.03 gm. to 0.06 gm. androstine 3 times a week. He received no oral medication. Within a month he showed marked improvement. He was not getting up at all at night and voided normally throughout the day. The inflammatory swelling in the prostate subsided but the gland was still clinically hyperplastic and the residual was still 4 ounces. Cystoscopy was not done. He is at present receiving androstine injections about twice a week.
This case is clearly one of early hyperplasia with a supraimposed prostatitis. The infection has been controlled and the symptoms of pros-
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tatism are no longer giving him trouble. He is not adverse to surgery but it does not appear indicated at the present time. He will be kept under observation. The oldest patient in our series was 75 years and the youngest 46. AU have been observed in private office practice. None had gone to the stage of complete retention (with advanced fibrotic changes); such cases we feel are obviously surgical. In all 15 cases treated, the residual either diminished perceptibly or disappeared. Nocturia was the symptom to show prime improvement; also, all cases experienced less difficulty at voiding. Prostatic massage, etc., was also given in many cases. Regarding dosage, the tablets of androstine contain 0.075 gram of orchitic extract or 8 grams of fresh gland. The ampules of androstine contain 1.5 cc of either the hydrosoluble (0.06 gm.) or the liposoluble (0.03 gm.) principles and are given alternately. The 1 cc ampules of perandren contain 5 mgs. of synthetically prepared chemically pure testis hormone corresponding to 250 International Units. In no single instance have we noted any untoward reaction. More clinical investigation is needed over a longer period of time, before this point can be determined. As Lower observes, it is possible that many such patients might improve under ordinary conditions without this form of medication, but if this be true, he archly remarks, then too many patients with this type of prostatic hypertrophy have been operated upon in the past. The authors wish to express thanks to the Ciba Pharmaceutical Products, Inc, for their cooperation in supplying experimental material for this study. SUMMARY
Prostatic hyperplasia can no longer be regarded as an independent entity; it is inseparably bound up with endocrine changes affecting the pituitary and the testis. In early prostatism, or where, for some serious physical disability in any type of prostatic obstruction, surgery seems inadvisable, the newer male sex hormones should be given conscientious trial. The disadvantage of this mode of treatment is that, like insulin, we must continue a maintenance dose; therefore, contact with the patient is necessary over an indefinite period and massage is usually indicated. Preparations of androsterone and testosterone propionate, for oral and intramuscular use, are available for such therapy. Using these substances, 15 cases of benign prostatic hyperplasia have
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been treated by us during the past two years with clinical improvement of symptoms.
Whitney Bank Bldg., New Orleans, La. REFERENCES BERGMANN: Prostatic hypertrophy as a definite endocrine problem. J. Missouri State Assn., 119-121, 1937. BROWN-SEQUARD: Compt. rend. Soc. d. biol. d. Paris, ser. 9, 1: 415,420,430,454, 1889. BuTENANDT: Ueber die chemische untersuchung der sexual-hormone. Ztschr. f. ang. Chem., 44: 905, 1931. CHAMPY, HEITZ-BOYER AND CouJARD: L'action des hormones sexuelles sur la prostate. Bull. de l'Acad. med., Paris, 118: 45-121, 1937. CoLLIP: Recent advances in physiology of anterior pituitary. J. Mt. Sinai Hosp., 1: 28, 1934. DEJOGH: Paradoxe wirkungen von follikehormon (menformon) bei mannlichen tieren. Arch. internat. de pharmacodyn. et de therap., 60: 348, 1935. GALLAGHER AND KOCH: Quantitative assay for testicular hormone by comb growth reaction. J. Pharmacol. and Exp. Therapy. 40: 327, 1930. HAMILTON, HESLIN AND GILBERT: Effect of female sex hormone on male. J. Urol., 37: 725732, 1937. HOSKINS : Inter-relation of organs of internal secretion. IL The pituitary. Am. J. Med. Sci., 141: 535, 1911. LAQUEUR: Behandlung der prostathypertrophie mit mannlichem hormon (hombreol) . Schweiz. med. Wchnschr., 64: 1116, 1934. LOWER: Use of contruin in treatment of benign prostatic hypertrophy. Surg. Clin. North Amer., August 1936. LOWER AND HICKEN : Experimental research by parabiosis, showing hypophyseal-gonadal influence on growth and development of prostate gland. J. Urol., 28: 601, 1932. LOWER AND McCuLLAGH: Endocrine therapy of benign prostatic hypertrophy. Med. Clin. North Amer. 19: May 1936. LOWER, ENGEL AND McCuLLAGH: Summary of experimental research on control of benign prostatic hypertrophy and preliminary clinical report. J. Urol., 34: 670, 1935. MARTINS AND ROCHA: Regulatio·n of hypophysis by testicle and some problems of sexual dynamics. Endocrinology, 16: 421, 1931. McCuLLAGH: Dual activity of testes. Science, 76: 19-20, 1932. MCCULLAGH AND WALSH: Experimental hypertrophy and atrophy of prostate gland. Endocrinology, 19: 466, 1935. MIESCHER, WETTSTEIN AND TSCHOFF : Activation of male sex hormones. Biochem. J., 30: 1970, 1936. MooRE: Glandular Physiology and Therapy. 1935, Chicago. Chapter 18, A. M.A. MoRREL : Therapeutische erfahrungen mit einem neuen vollextrakt aus aus mannlichen keimdrusen (androstine). Deut. med. Wchnschr., n5. 40, p. 1516, 1934. OWEN AND CUTLER: Sex hormones and prostatic hypertrophy. Am. J. Cancer, 27: 1936. PEZARD: Le conditionnement physiologique des caracteres sexuels secondaires chez Jes oiseaux. Bull. biol. de la France e de la Belgique, 62: 1-176, 1918. RuzICKA: Male sex hormones. J. Chem. Education, 13: No. 1, Jan., 1936. SCHMITZ : Erfahrungen mit dem neuen synthetischen testeshormon-praparat perandren. Deutsch. med. Wchnschr., nr. 6, p. 230, 1937. VAN CAPELLEN : Versuch einer therapie mit sexualhormon im besonderen mannlichem hormon (hombreol) bie prostatahypertrophie. D eutsch. med. Wchnschr., 69: 726-728, 1933. WuGMEISTER: Le traitement, de l'hypertrophie de la prostate par doses massives de la folliculine. Paris med., 1: 535, 1937. ZUCKERMAN: Inhibitory effect of testosterone proprionate on experimental prostatic hypertrophy. Lancet, 2: 1259-1262, 1936.
AND
ROBERT M. WILLOUGHBY
Department of Urology, Louisiana State University, New Orleans
In the light of modern research it has become increasingly clear that prostatic hyperplasia can no longer be regarded as an independent entity, but that it is inseparably bound up with endocrine changes affecting the hypophysis and the gonads. We know that, following castration, the prostate and seminal vesicles become atrophic. Similar effects follow hypophysectomy. On the other hand, if we remove the testes we get an increase in size and function of the hypophysis. The inter-relationship between the testes, the secondary sex organs and the anterior pituitary gland are now clearly recognized, and we know that changes in one member of this triad are inevitably conveyed to the other members. Hence, the concept has arisen that benign prostatic hyperplasia may be the result of an endocrine imbalance. Within the last decade the possibilities of the clinical application of glandular therapy in cases of prostatic hyperplasia have engaged the attention of many serious workers, and a new literature has appeared, based on the results of animal experimentation along these lines, both in this country and in Europe. It is our purpose here to glance over this literature and to add to it a brief account of the work that we have had the opportunity to do in this interesting field. The idea that the testes have an internal secretion was.first put forward in 1889 by Brown-Sequard, who made some experiments on himself, for which he was derided by both the profession and the laity. The first worker to study the effects of active extracts of testes by the cockscomb method was Pezard, who in 1918 observed that extract from cryptorchid testes produced full comb growth in a capon. Many investigators have since taken up the study of the male sex hormone. They found that it is present in testes and also in the urine of males of practically all ages except the very young, although its quantity is diminished in old age. A quantitative test for this hormone was first devised by Gallagher and Koch in 1930. In 1931, Butenandt isolated from urine a crystalline 1 Read before the Southeastern Branch Society, American Urological Association Birmingham, November 5, 1937. 135
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HENRY W. E. WALTHER AND ROBERT M. WILLOUGHBY
hormone to which he gave the name of androsterone. So difficult was it to obtain this hormone that up to 1933 only 25 mg. of the substance had been secured. In that year Ruzicka and his co-workers succeeded in preparing androsterone from cholesterol. This was the first artificial production of a sex hormone, and was the starting point for the investigation of the relationship between chemical constitution and male hormone activity. In order to investigate the specific effect of androsterone upon the accessory male glands these workers employed the seminal vesicle and prostate tests in castrated rats. The hormone was found to have a greater effect on the prostate than on the vesicles. Lower and McCullagh in 1929 had already begun their attempts to demonstrate that prostatic hyperplasia in experimental animals may result from endocrine imbalance. They have only recently shown, after 7 years of research, that this hyperplasia can be controlled by the use of a testicular hormone. Hoskins, as long ago as 1911, had expressed the view that the pituitary gland is normally held in check by the gonads, and that when this inhibition is removed, the pituitary manifests increased activity leading to altered metabolism. If an excess of anterior pituitary gonad-stimulating hormone is introduced into the circulation, the stimulation is exerted not only on the testes but also on the prostate and seminal vesicles. In castrated animals the pituitary hormone, notwithstanding its increased quantity, is unable to prevent the atrophy of the prostate and vesicles. It is becoming clear that the testes serve as an important link between the hypophysis and the secondary sex organs. Lower and Hicken in 1931 experimented with parabiosis in 87 pairs of rats, anastomosed together in such a way as to leave a permanent artificial opening connecting the two peritoneal cavities. There was thus a free exchange of peritoneal fluids, and the intestines passed freely from • one peritoneal cavity into the other. It was observed that when a castrated rat was anastomosed to a normal male, the prostate and seminal vesicles of the ca.s trates became atrophic, while the hypophysis increased in size. In the normal partner, on the other hand, the testes, vesicles and prostate were all definitely hyperplastic, while the pituitary remained normal. When the rats were killed at the end of 30 days, the prostate in all the normal animals was found increased, both in size and in weight, from 300 to 500 per cent. The consistency of the gland was firm and solid, and the enlargement was uniform in all directions. After
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the ablation of the gonads in the castrated males, the hypophysis had increased in size and function. The excessive prehypophyseal hormone had then passed from the castrate into its normal partner, where it caused the testes to secrete an excess of sex hormones which resulted in hyperplasia of the prostate. McCullagh and Walsh in 1935 carried out similar parabiotic experiments and observed precisely similar results. It is thus seen that prostatic enlargement was produced merely by altering the endocrine system, causing hyperfunction of the pituitary gland. Lower and McCullagh demonstrated that a second testicular hormone is produced within the germinal epithelium of the tubular portion of the testes. To this they gave the name inhibin, since it was shown to have an inhibitory effect upon the pituitary. When the tubular portion of the testes deteriorates after the climacteric, the withdrawal of this inhibition would cause the gonadotropic functions of the anterior lobe to become exaggerated, which in turn would invite prostatic enlargement. Space does not allow us to dwell longer on the experimental aspect of the subject. Mention may be made, however, of the important work of Zuckerman, and of Miescher, Wettstein and Tschopp in England and Switzerland, of Moore and his co-workers, of Martine and Rocha, Hamilton, Heslin and Gilbert, and de Jongh of Amsterdam, to all of whom we are indebted for valuable communications. According to Moore the question whether the testis produces more than more than one hormone is not yet settled. From the weight of evidence, however, both clinical and experimental, it would appear that another hormonal substance is active within the testis during the florid years of every male individual's life, and that this is to be found in germinal epithelium of the tubular portion of the testis. Under normal conditions, these 2 hormones, tubular and interstitial, would work synergetically, each supplementing the other. In 1936, Owen and Cutler expressed the view that there are several possible sex hormone imbalances, and that evidence exists for at least two male and two female types of hormone, as well as regulator agents acting through or from the pituitary . It can thus be seen that accurate quantitative assays for small amounts of both the male and female hormones are essential, since this is the only way the true imbalance in sex hormones, if any, can be determined. Many authors assume today that a hypothetical substance, known as inhibin or contriun, exerts a restraining action upon the pituitary that keeps the
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latter from excessive output of energy. When the first signs of old age appear, this would be the principle that :first gives out; this 'pace-maker', as de Jongh has called it, fails by degrees to balance the gonadrotropic hormone of the pituitary. According to Lower, Engel and McCullagh, this, if established, agrees with Collip's conception that all hormones are buffered by antihormones. In accordance with this idea, these workers at the Cleveland Clinic found it rational to treat prostatic hyperplasia by administering the hormone inhibin. They reported that in the first 10 months they treated 40 patients with prostatic obstruction, by means of this hormone. All cases presented the typical symptoms of slowness of stream, nocturia and frequency. All types of prostatic hyperplasia were treated, but the authors feel that the soft, adenomatous hyperplasias are likely to give the best response. Each patient received orally the equivalent of about 60 grams of fresh testes daily for 3 months, after which it was reduced to a maintenance dose representing 20 grams of fresh testes daily. After critical analysis the authors consider 26, or 65 per cent, of these cases to be markedly improved to the point where they are virtually symptom free. Rectal palpation does not, however, give the impression of a reduction in size, and yet the patients feel well and suffer none of their old symptoms. The general consensus seems to be that clinical improvement of a very satisfactory kind follows recourse to this hormonal treatment. Laqueur and Van Cappellen are enthusiastic, after 3 years' use of the Dutch hormonal product, hombreol. Results were good in all but one of the latter's 12 cases. It is his opinion that only first grade cases should be thus treated, never grades 2 and 3, for which he still prefers surgical measures. Morell recommends androstine, a glandular preparation which complies with all the necessary requirements. Ampoules 'A' contain the water-soluble product and ampoules 'B' the liposoluble active principles, while androstine tablets contain both extracts. The water soluble principle 'A' provokes hyperemia of the genital organs and as a result of the improved nutrition of the testis the hormone production is increased. McCullagh has pointed out that the aqueous testicular extracts check the modification of the cells of the pituitary which appears after castration or loss of testicular function, and prevents hyperfunction of the pituitary body. This in turn would prevent excess of gonadotropic secretion, and, with it, the hyperplasia of the prostate. In contrast to the preparations which contain the so-called male hormone of the interstitial cells, an-
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drostine utilizes all the active principals of the testis. Since at the present time the exact mode of action of these principals is not clearly understood, there are certain advantages in the use of androstine. It is undeniable that whole testis extract, when given to old men with benign prostatic hyperplasia, has been shown, in some instances, to furnish relief of symptoms after prolonged medication with this hormone, without further treatment such as surgery. Bergmann reported the results of treatment in 69 cases, complaining of fatigue, insomnia, frequent and difficult micturition and perinea! discomfort. He gives a water-soluble hormone intramuscularly, first, 2 or 3 times weekly, to stimulate hypophyseal growth action until a better balance is reached; then he gives the sex hormone androstine. The injections must be given once a week over a period of time. Champy, Heitz-Boyer and Coujard are making therapeutic use of testis hormone in hyperplasia of the prostate. Like Lower and his coworkers, they point out that the favorable effect upon the dysuria often precedes the diminution of the adenoma. They think that this is due to a mucoid edema around the vessels of the verumontanum, which is normal to adult animals, missing in castrates and diminished in aged animals. Wugmeister maintains that hyperplasia of the prostate is due to a hypervirilization of the organism, which takes place during the presenile age due to a deficiency of estrogen. Female hormone that is normally present in all human beings, is withdrawn in later life, he contends, and the organism undergoes a hypervirilization resulting in prostatic hyperplasia. He administers folliculin to correct this deficit and thereby reduces gland enlargement. This view, he admits, is in complete contradiction to that of several other investigators, who con.. tend that hyperplasia of the prostate results from a deficiency in testis hormone. Wugmeister claims that large doses of estrogen should, in that case, aggravate the prostatism symptoms; but they do not; to the contrary, he says, they effect an amelioration. In 16 of 23 cases so treated, improvement was marked. It is not claimed that the results of the treatment are permanent, Thus far it appears that the symptoms tend to recur after treatment is stopped, and it is necessary to continue a maintenance dose, more or less like what is done with insulin. That the good results are not merely of a psychological nature was proved by Van Cappellen, who, to test this very point, gave some of his
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injections with no hombreol content, and got no result. The exact modus operandi with this method of treatment is not known. Lower has suggested that it is possible that insufficient time has elapsed for the changes in the size of the prostate to be apparent, though with experimental animals marked changes are noted both grossly and microscopically. Schmitz of Berlin, who has treated 42 patients with perandrentestosterone propionate-with most gratifying results, points out that these good results are made possible today by the fact that all these hormonal extracts can be made synthetically, whereas, in the past, it was impossible to give sufficient doses of the male sex hormone. Needless to add, all of this work remains experimental at the present writing. For the past two years we have been using the oral tablets and the ampoules 'A' and 'B' of androstine-a total extract (aqueous and lipoidal) of fresh whole testes of healthy bulls. During the past 12 months we have also employed perandren- a chemically pure testosterone propionate, the testosterone being synthesized from other sterols, especially cholesterol, and then esterized with propionic acid. Up to the present time, we have treated, over variable periods, 15 patients with these male sex hormone preparations. In the group are included (a) 8 patients all of whom presented symptoms of early prostatism, some complicated by prostatitis and some with an impending sexual impotency; (b) 4 patients in whom serious cardiac complications seemed to preclude any form of surgical relief; and, (c) 3 patients who refused to submit to any type of operative intervention. It is not our purpose, in reporting so small a series of cases, to give any one the impression that this form of therapy will ever replace surgery. Although in no instance did we fail to notice definite clinical improvement, our observations have not extended over a sufficient period of time to warrant any positive conclusions. As an ever-widening circle of urologists interest themselves in this fascinating field of male sex endocrinology, in its relation to benign prostatic hyperplasia, reports will be forthcoming in due time to confirm or refute the observations made in the medical literature to date. Of our series, forming the basis of this communication, we give only 3 case-reports; a tabulation of all of them would simply mean a repetition of the essentials included in those histories herein detailed. Case 1. Mr. E. W., age 68, a retired university professor, consulted us in January 1930 for frequency and difficulty in voiding. He stated that he was getting up once or twice at night and voiding 4 or S times during the day.
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The urine showed an occasional pus cell and an occasional colon bacillus. By rectal palpation the prostate gland was moderately enlarged, soft and movable. The prostatic secretion showed 1 plus pus. The phthalein test for one hour read 60 per cent. The blood pressure was 125/100. He was receiving treatment from an opthalmologist for vitreous opacities. For years he had been treated for myocardial weakness with a distinct mitral blow. The patient was very nervous, couldn't sleep well at night and found it impossible to concentrate. His memory was failing him. It was clearly evident that although he had the symptoms of early prostatism with some 12 ounces residual, he was in no shape to undergo any type of surgical relief. We gave him gentle rectal massage of the prostate gland weekly. This gave him some relief. We gave him 0.03 gm. to 0.06 gm. intramuscular injections of androstine, 3 times a week over a period of 2 months. This was followed by administering 0.075 gm. androstine tablets orally; in the beginning he received 1 tablet 3 times a day. After 2 weeks the dose was increased to 2 tablets 3 times a day. At the time the androstine therapy was begun, he was getting up 3 or 4 times at night to void. Within a month after the hormonal therapy was begun, this nocturnal frequency was decreased to 1 nightly voiding and often he did not get up at all. The urinary stream improved. This was not all. Soon after the injections were begun (without any suggestions from us as to what the treatment would do for him) he found that he could concentrate easier, his memory became more keen, his appetite increased and he slept better at night. This patient is still under observation and most comfortable. He takes androstine tablets by mouth, 2 morning and night, 2 or 3 times a week. He comes to the office once or twice a month for an androstine hypodermic injection. Upon rectal examination, the prostate gland, now free of infection, is the same size as it was when we began hormonal treatment in 1935, but as stated above his symptoms have ameliorated. Cystoscopy has not been done. His_residual urine is nil. To illustrate the point that this medication must be continued over an indefinite period, we might say that during the past summer this patient had to go to one of the New England States, for several weeks, to visit a brother who was quite ill. He left the city in such a rush that he failed to take his tablets along with him and he was 3 weeks without any medicine. When he returned to the city he was getting up 3 or 4 times at night to void with a return of all the symptoms of which he had originally complained. His injections of androstine were resumed every other day, plus the oral administration of androstine tablets, 2 morning and night every other day, and the aggravation subsided promptly . Case 2. Mr. C. G. G., age 62, a minister, consulted us in February 193with all the classic symptoms of early prostatism. He was getting up 3 to 4 times every night to void and had to empty his bladder at least 6 to 10 times
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during the day. He stated that the difficulty in starting the stream was gradually becoming more noticeable. He refused to consider any surgical procedure, owing to the fact that he had been told in Boston that his heart was in bad shape. He was of an intensely nervous temperament. He had no appetite, was losing weight and strength. The urine showed no albumin or sugar, but revealed 1 plus pus and one plus colon bacilli. His blood pressure was 90/60. The phthalein test for 1 hour was 65 per cent. The prostate per rectum revealed a type 2 enlargement, the gland being soft and movable. The secretion showed two plus pus. There was no residual urine. He was given with a rectal massage once a week, followed every time by an installation of weak silver nitrate. Within 3 months the infection in the gland had disappeared and his blood pressure now read 115/75. The frequency and difficulty were slightly relieved. We then started injections of 0.03 gm. to 0.06 gm. androstine every other day for 2 months. Within 2 weeks of the initial injection of androstine he began to show improvement. After he had been on the injections for a month we began giving him 0.075 gm. androstine tablets by mouth, 2 morning and night. The oral treatment was continued steadily for 3 months, at the end of which time he was getting up to void at night only once or twice and during the day about 3 times. Weekly rectal massage was continued throughout this period. He reports to the office about once a month, and is perfectly satisfied with the progress he has made under male sex gland therapy. He takes at present 2 androstine tablets daily ; possibly once or twice a month he comes in for an intramuscular injection. He is still under observation. Case 3. Mr. A. B., age 56, a farmer by occupation, was first seen by us in June 1935, complaining of frequency, burning and difficulty at voiding. He was getting up 4 or 5 times at night and voiding as often as 12 times during the day. There were 4 ounces of residual urine which showed considerable pus and colon bacilli. The prostate per rectum revealed type 3 enlargement, the gland being soft and movable. The secretion showed 3 plus pus. The phthalein test read 35 per cent for an hour. The blood pressure was 145/100. Rectal massage was given weekly, each time followed with an installation of weak silver nitrate solution. We suggested that his home physician give him intramuscular injections of 0.03 gm. to 0.06 gm. androstine 3 times a week. He received no oral medication. Within a month he showed marked improvement. He was not getting up at all at night and voided normally throughout the day. The inflammatory swelling in the prostate subsided but the gland was still clinically hyperplastic and the residual was still 4 ounces. Cystoscopy was not done. He is at present receiving androstine injections about twice a week.
This case is clearly one of early hyperplasia with a supraimposed prostatitis. The infection has been controlled and the symptoms of pros-
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tatism are no longer giving him trouble. He is not adverse to surgery but it does not appear indicated at the present time. He will be kept under observation. The oldest patient in our series was 75 years and the youngest 46. AU have been observed in private office practice. None had gone to the stage of complete retention (with advanced fibrotic changes); such cases we feel are obviously surgical. In all 15 cases treated, the residual either diminished perceptibly or disappeared. Nocturia was the symptom to show prime improvement; also, all cases experienced less difficulty at voiding. Prostatic massage, etc., was also given in many cases. Regarding dosage, the tablets of androstine contain 0.075 gram of orchitic extract or 8 grams of fresh gland. The ampules of androstine contain 1.5 cc of either the hydrosoluble (0.06 gm.) or the liposoluble (0.03 gm.) principles and are given alternately. The 1 cc ampules of perandren contain 5 mgs. of synthetically prepared chemically pure testis hormone corresponding to 250 International Units. In no single instance have we noted any untoward reaction. More clinical investigation is needed over a longer period of time, before this point can be determined. As Lower observes, it is possible that many such patients might improve under ordinary conditions without this form of medication, but if this be true, he archly remarks, then too many patients with this type of prostatic hypertrophy have been operated upon in the past. The authors wish to express thanks to the Ciba Pharmaceutical Products, Inc, for their cooperation in supplying experimental material for this study. SUMMARY
Prostatic hyperplasia can no longer be regarded as an independent entity; it is inseparably bound up with endocrine changes affecting the pituitary and the testis. In early prostatism, or where, for some serious physical disability in any type of prostatic obstruction, surgery seems inadvisable, the newer male sex hormones should be given conscientious trial. The disadvantage of this mode of treatment is that, like insulin, we must continue a maintenance dose; therefore, contact with the patient is necessary over an indefinite period and massage is usually indicated. Preparations of androsterone and testosterone propionate, for oral and intramuscular use, are available for such therapy. Using these substances, 15 cases of benign prostatic hyperplasia have
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been treated by us during the past two years with clinical improvement of symptoms.
Whitney Bank Bldg., New Orleans, La. REFERENCES BERGMANN: Prostatic hypertrophy as a definite endocrine problem. J. Missouri State Assn., 119-121, 1937. BROWN-SEQUARD: Compt. rend. Soc. d. biol. d. Paris, ser. 9, 1: 415,420,430,454, 1889. BuTENANDT: Ueber die chemische untersuchung der sexual-hormone. Ztschr. f. ang. Chem., 44: 905, 1931. CHAMPY, HEITZ-BOYER AND CouJARD: L'action des hormones sexuelles sur la prostate. Bull. de l'Acad. med., Paris, 118: 45-121, 1937. CoLLIP: Recent advances in physiology of anterior pituitary. J. Mt. Sinai Hosp., 1: 28, 1934. DEJOGH: Paradoxe wirkungen von follikehormon (menformon) bei mannlichen tieren. Arch. internat. de pharmacodyn. et de therap., 60: 348, 1935. GALLAGHER AND KOCH: Quantitative assay for testicular hormone by comb growth reaction. J. Pharmacol. and Exp. Therapy. 40: 327, 1930. HAMILTON, HESLIN AND GILBERT: Effect of female sex hormone on male. J. Urol., 37: 725732, 1937. HOSKINS : Inter-relation of organs of internal secretion. IL The pituitary. Am. J. Med. Sci., 141: 535, 1911. LAQUEUR: Behandlung der prostathypertrophie mit mannlichem hormon (hombreol) . Schweiz. med. Wchnschr., 64: 1116, 1934. LOWER: Use of contruin in treatment of benign prostatic hypertrophy. Surg. Clin. North Amer., August 1936. LOWER AND HICKEN : Experimental research by parabiosis, showing hypophyseal-gonadal influence on growth and development of prostate gland. J. Urol., 28: 601, 1932. LOWER AND McCuLLAGH: Endocrine therapy of benign prostatic hypertrophy. Med. Clin. North Amer. 19: May 1936. LOWER, ENGEL AND McCuLLAGH: Summary of experimental research on control of benign prostatic hypertrophy and preliminary clinical report. J. Urol., 34: 670, 1935. MARTINS AND ROCHA: Regulatio·n of hypophysis by testicle and some problems of sexual dynamics. Endocrinology, 16: 421, 1931. McCuLLAGH: Dual activity of testes. Science, 76: 19-20, 1932. MCCULLAGH AND WALSH: Experimental hypertrophy and atrophy of prostate gland. Endocrinology, 19: 466, 1935. MIESCHER, WETTSTEIN AND TSCHOFF : Activation of male sex hormones. Biochem. J., 30: 1970, 1936. MooRE: Glandular Physiology and Therapy. 1935, Chicago. Chapter 18, A. M.A. MoRREL : Therapeutische erfahrungen mit einem neuen vollextrakt aus aus mannlichen keimdrusen (androstine). Deut. med. Wchnschr., n5. 40, p. 1516, 1934. OWEN AND CUTLER: Sex hormones and prostatic hypertrophy. Am. J. Cancer, 27: 1936. PEZARD: Le conditionnement physiologique des caracteres sexuels secondaires chez Jes oiseaux. Bull. biol. de la France e de la Belgique, 62: 1-176, 1918. RuzICKA: Male sex hormones. J. Chem. Education, 13: No. 1, Jan., 1936. SCHMITZ : Erfahrungen mit dem neuen synthetischen testeshormon-praparat perandren. Deutsch. med. Wchnschr., nr. 6, p. 230, 1937. VAN CAPELLEN : Versuch einer therapie mit sexualhormon im besonderen mannlichem hormon (hombreol) bie prostatahypertrophie. D eutsch. med. Wchnschr., 69: 726-728, 1933. WuGMEISTER: Le traitement, de l'hypertrophie de la prostate par doses massives de la folliculine. Paris med., 1: 535, 1937. ZUCKERMAN: Inhibitory effect of testosterone proprionate on experimental prostatic hypertrophy. Lancet, 2: 1259-1262, 1936.