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Nonoperative (Gonadotropic) Treatment of Cryptorchism
Medical Clinics of North America January, 1937. Chicago Number
CLINIC OF DR. HUGO R. RONY NORTHWESTERN UNIVERSITY MEDICAL SCHOOL NONOPERATIVE (GONADOTROPIC) TREATMENT OF CRYPTORCHISM
SINCE 1930 when Schapirol first reported successful treatment of human cryptorchism by injections of the gonadotropic principle of pregnancy urine, this type of treatment has been applied by a number of clinicians with variable results. As is frequently the case with new therapeutic procedures, the first enthusiastic reports were soon followed by expressions of skepticism and caution. In the meantime sufficient experimental and clinical material was accumulated to allow for a clearer appreciation of the possibilities and limitations of this treatment. To this end it is necessary to keep in mind some pertinent physiological and pathological data. Normally the testicles descend from the abdominal cavity through the inguinal canal into the scrotum during the seventh to eighth month of intra-uterine life; at birth both testicles are found in the scrotum. Nothing definite was known about the physiological mechanism of the descent of the testicles until 1932 when Engle2 suggested that maternal gonadotropic hormones play in important part in it. This contention is supported by the following observations: (1) The human is the only organism known in which testicular descent occurs before birth, and the human female is also the only one having gonadotropic hormones in blood circulation throughout the period of gestation. (2) A noticeable increase in the number of the interstitial cells of the testicle of the human fetus occurs one to two months before term; a similar change may be experimentally produced in immature monkeys by injections of the gonadotropic hormone of pregnancy urine. (3). In imma207
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ture monkeys and rats injections of the pregnancy urine gonadotropic honnone cause premature descent of the testicles. ( 4) An analogous phenomenon indicating effects of maternal female sex hormone is occasionally observed in newborn girls showing swelling of the major labia or breasts. These and similar other observations may be considered as sufficient evidence to indicate that in the normal fetal descent of the testicles. gonadotropic hormones of the mother are instrumental. If the testicle fails to descend before birth, it usually remains undescended until the beginning of puberty. The descent may be arrested at any point, in some cases in the abdominal cavity, more often in the inguinal canal. The arrest may be bilateral, both testicles being arrested at the same point or at different points. In the majority of the cases unilateral arrest is observed, the other testicle being in normal position. Drake 3 observed 11 cases of cryptorchism among 260 boys nine to nineteen years of age-a frequency of 42 per thousand. It has been known for many years that spontaneous descent of undescended testicles may occur at puberty, but the frequency of this phenomenon was not realized until recently. It appears that spontaneous pubertal descent occurs in the majority of cases of cryptorchism; it occurred in 9 out of 11 of Drake's cases. This is confirmed by the fact that cryptorchism is not nearly as frequent in the adult population: extensive statistics obtained on army recruits in different countries indicate an incidence of 2 to 5 per thousand. While the normal fetal descent of the testicle occurs under the influence of maternal gonadotropic hormones, late spontaneous descent in puberty is thought to be brought on by the gonadotropic hormone of the hypophysis of the individual. Histologically the undescended testicle, prepubertal or postpubertal, shows a picture similar to that of a normal prepubertal scrotal testicle. In . other words, the undescended testicle fails to supply at puberty its seminiferous tubules with normal germinal epithelium, and remains aspermic and sterile. It has been shown conclusively by Moore 4 that scrotal position.. is necessary for the normal development of the germinal
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epithelium because of the lower temperature it insures. If a mature scrotal testicle with the spermatic cord intact is placed in the abdominal cavity, soon most of the germinal epithelium degenerates and disappears; replacement of such a testicle into the scrotum is followed by regeneration of the germinal epithelium and spermatogenesis. However, the abdominal testicle may produce male sex hormone in apparently undiminished amounts, as demonstrated by Moore in experiments on guineapigs. CIassification.-Group A .-In a number of cases of human cryptorchism examination of the patient fails to disclose any additional pathology of importance. There are no signs of disturbance of the endocrine system; growth, sexual and· mental development are normal. Puberty appears in due time with all secondary sex chara<;:teristics and sexual potency. The majority of unilateral cryptorchism cases and a few of the bilateral ones belong to this category. Failure to descend may be due to causes of local anatomical nature, such as developmental error, or adhesions due to fetal peritonitis; in these cases spontaneous late descent at puberty will not occur. In other cases descent is arrested before birth because of deficiency in maternal gonadotropic hormones; late spontaneous descent frequently sets in at puberty under the stimulation of the normally functioning anterior pituitary. Clinical differentiation between these two subgroups can, as a rule, not be made before puberty. Group B.-In most cases of bilateral cryptorchism clinical examination reveals more or less marked signs of hypogonadism. The scrotum is undeveloped, the penis is infantile, the prostate and seminal vesicles are hypoplastic. The patient is more or less obese with a girdle type of fat distribution. Puberty is delayed and imperfect, or entirely missed. Late spontaneous descent rarely occurs. The undescended testicle remains not only sterile but also deficient in the production of the male sex hormone on which the development of the secondary sex characters depends. The hypogonadism is usually secondary, being due to VOL. 21-I4
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deficient gonadotropic activity of the hypophysis; it is frequently accompanied by signs of deficiency of other functions of the hypophysis, such as stunted growth, diabetes insipidus, subnormal mentality, delayed dentition, etc. The question arises whether the fetal arrest of testicular descent is also due to the pituitary deficiency. There is no evidence that the hypophysis of the fetus has any active role in the physiological mechanism of testicular descent. Furthermore, a number of cases of most severe hypopituitarism are born with scrotal testicles, even though the further development of these testicles will be seriously impaired. Accordingly, it must be assumed that the fetal arrest of descent is independent from the pituitary . failure of the patient jn cases of hypogonad cryptorchism. On the other hand, the absence of late spontaneous descent is obviously a consequence of the patient's deficient pituitary gonadotropic hormone production. In some cases cryptorchism is associated with primary hypogonadism: there is congenital idiopathic hypoplasia of the testicles, or atrophy following orchitis as a complication of mumps, etc. The gonadotropic activity of the anterior pituitary is intact in these cases. Clinically they usually present the picture of eunuchoidism with the typical body proportions and delayed union of epiphysial junctions. Differentiation between primary and secondary hypogonadism, associated with cryptorchism, may be difficult in some cases. Specificity of Gonadotropic Therapy.-Injections of gonqdotropic hormone preparations in cryptorchism have been followed in many cases by descent of one or both testicles. Some doubt has been expressed as to the specificity of this effect in view of the fact that spontaneous descent frequently occurs; the result might be merely coincidental. However, a number of observations are available which would be difficult to explain on the basis of coincidence: (1) In many cases gonadotropic therapy was followed by descent of the testicles in four- to six-year-old boys, and in some cases in eighteen- to twenty-seven-year-old men, i. e., at ages when spontaneous descent very rarely occurs. (2) Results were frequently ob-
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served within two weeks of treatment. (3) In some cases descent occurred during treatment but the testicle again retracted into the inguinal canal or abdominal cavity shortly after the injections were discontinued. A second course of injections brough,t the testicle down again. ( 4) Cases were observed that were previously operated on, the testicle being placed in the scrotum; subsequent retraction occurred; gonadotropic treatment was followed by descent. In view of such observations it is safe to say that descent of cryptorchid testicles may be the direct result of gonadotropic therapy. Indications for Gonadotropic Therapy.-Obviously, gonadotropic treatment is indicated in all cases belonging to Group B, although favorable results are not always obtained. Why treatment fails in some patients of this group is difficult to say. Possibly, in some cases, local anatomical causes exist in addition to the deficiency of the anterior pituitary. In primary hypogonadism (eunuchoidism) the lesion of the cryptorchid testicle. may be so severe as to obviate response to the strongest gonadotropic stimulation. In other cases the intensity or duration of the treatment might have been insufficient. In some patients belonging to Group A gonadotropic treatment is doomed to failure because of the presence of anatomical obstacle. In other cases of this group treatment is superfluous as descent will spontaneously occur at puberty. Only in a relatively small number of cases is hormonal treatment both necessary and successful. Unfortunately, the nature of the case is not, as a rule, recognizable before puberty. Accordingly, correct indication for hormone therapy can hardly be made when the patient is seen before puberty. If cryptorchism persists in the presence of more or less marked pubertal changes, a trial with hormone therapy is indicated. Failure of this therapy may be considered as evidence of anatomical obstruction and indication for surgical interference. Postoperative hormonal treatment-following orchiopexyhas been advocated to insure against possible retraction of the testicle (Spence and Scowen5 ).
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At what age should treatment be started? Cryptorchism is an abnormal condition at any age and it might seem logical to attempt to correct it as early as possible. In fact, several clinicians expressed this opinion and a number of four- to tenyear-old successfully treated children are on record. It is not quite clear to me what is to be gained by producing testicular descent artificially at this early age unless some special indication, such as local pain, or hernia exists. For cases of Group B with marked genital dystrophy (undeveloped scrotum and penis) advisability of early treatment may be a matter of opinion: the testicle in these patients is not only undescended but hypoplastic as well; chances for spontaneous late correction are slight. Yet, even in these cases treatment at the normal beginning of puberty--eleven to thirteen years-rather than earlier appears to be the logical procedure. For Group A early treatment is hardly justified. As I mentioned before, a normal prepubertal undescended testicle does not differ histologically and functionally from a normal prepubertal scrotal testicle, and scrotal position becomes of great importance for the structure and function of the testicle only with the onset of puberty. In patients of Group A, general development, including sexual development proceeds normally whether the testicle is in the scrotum or in the abdomen. Furthermore, in many instances spontaneous descent occurs at puberty. Accordingly, there is no reason why one should not wait with treatment of patients of this group until puberty is well established, at fourteen or fifteen. It is probably not advisable to wait much longer. I have found no report in the literature of successful treatment of patients older than eighteen, belonging to this group. Some Technical Details of Hormone Therapy.-Most authors used preparations of the pregnancy urine gonadotropic hormone (prolan, anterior pituitary-like substance). Others used extracts made from the anterior lobe of the hypophysis. There is no evidence that either one is superior. In the prese\1ce-
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Injections of the pregnancy urine gonadotropic hormone are given daily or every other day subcutaneously or intramuscularly, 100 to 300 rat units each time. The duration of treatment and the total amount of the hormone administered varies greatly. In some cases a few hundred units given within two weeks prove sufficient. In other cases (Group B) treatment was continued for over a year with a total amount of 20,000 or more units injected. It is probably safe to say that if the injection of 10,000 units fails to produce any change, further treatment at that time is not likely to succeed. In such cases it may be advisable to undertake a second course of injections starting a few months later, as suggested by Spence and Scowen. 5 They quote the work of Sellye et al./ who have shown that after prolonged administration of gonadotropic hormone virgin female rats become temporarily insensitive to the hormone. Repetition of treatment_ is also indicated when the testicle which has descended after a course of injections, later retracts into its previous position. As a rule, treatment is discontinued as soon as the testicle reaches the bottom of the scrotum, although in cases associated with sexual infantilism it may be necessary to continue hormonal treatment over a longer period. By-effects of Hormone Therapy.-In some cases mild to moderate pain is complained of in the groin of the affected side during treatment. This does not necessitate interruption of treatment as the pain soon subsides. After the testicle has descended it is usually smaller than normal but soon reaches normal proportions. Enlargement beyond the normal for the patient's age is not produced even when treatment is continued with large doses. The same is true for the scrotum and penis. Precocious secondary sex characteristics-such as pubic hair, mutation of voice, etc.-in children treated before puberty were not observed, except by Dorff7 who gave very large amounts of the hormone (as much as 46,000 units). N either is enlargement of the prostate or of the breasts of the patients reported, although Geschickter et al. 8 reported such effects in monkeys treated with large amounts of pregnancy urine hormone.
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The question whether the testicle, which has descended into the scrotum in response to hormonal therapy, becomes fertile cannot be answered directly at this time. Some indirect evidence is available. Thus it is known that bilateral undescended testicles brought down into the scrotum by surgical orchiopexy may become fertile (MacCollum9 ). Brosius and Schaffer10 reported a case of bilateral testicular atrophy with complete aspermia following orchitis as a complication of mumps, in which gonadotropic hormone therapy repeatedly produced extensive spermatogenesis. Huberman ll and Dorff7 noticed marked improvement of mental development and enuresis nocturna in some of their cases treated for cryptorchism. Accelerated growth is sometimes observed. It appears that when the gonads mature under gonadotropic treatment, they exert a stimulating influence on growth, probably by way of the anterior lobe growth-promoting apparatusP Gonadotropic treatment has no effect on the obesity associated with genital dystrophy. The obesity and the type of fat distribution usually persist even after complete correction of cryptorchism and sexual underdevelopment. Neither is there any definite change in basal metabolism. A unique observation of enuresis, polydipsia and glycosuria appearing during. gonadotropic treatment for cryptorchism in a thirty-month-old child is reported by Koplin13; all symptoms disappeared after three weeks following the termination of treatment. This may be considered as another· reason against gonadotropic therapy at early age. PRESENTATION OF CASES
Case I.-This boy is now thirteen years old. He is normally developed. Both testicles are in the scrotum; their size is normal for his age. He was a normal boy when I saw him first about a year ago, except for a unilateral cryptorchism. The left half of the scrotum was empty, as was the left inguinal canal. We gave him injections of 200 units antuitrin-S three times a week. After the sixth injection the left testicle de-
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scended into the scrotum and soon reached the size of the right testicle. I have no doubt that the gonadotropic therapy was instrumental in the descent of this testicle, although it is quite possible that descent would have occurred by this time, or later, without any therapy. We now believe that such cases do not need treatment before they reach their fourteenth or fifteenth year. Case H.-This boy is twelve and one-half years old. He has bilateral cryptorchism; no trace of the testicles can be found on physical examination. Otherwise he,is normally developed in every way. We have started with gonadotropic therapy five months ago, giving him daily injections of 100 units antuitrin-S. On the tenth day I found the right testicle in the scrotum, the left testicle in the inguinal canal. After waiting for four weeks without noticing further change, we gave him again daily injections of the same substance and amount. Two weeks later both testicles were in the scrotum. He has received altogether 2400 units of the hormone. Now he returns with both testicles retracted into the abdominal cavity. Another course of injections would probably bring these testicles down again, and with continued treatment they might stay in the scrotum permanently. But we might as well wait for a year or two without treating this patient. In the meantime the testicles may spontaneously descend. If this will not occur, we will then try another course of hormon~ injections. Small amounts of the hormone will probably suffice at that time to insure permanent result. Case 111.-Two years ago this patient presented a typical picture of adiposogenital dystrophy. He was then thirteen years old, his height was 63 inches, his weight 123 pounds. The scrotum and penis were markedly underdeveloped; a tiny structure, of the size of a small pea, was found in the left half of the scrotum; the right half of the scrotum and the right inguinal canal were empty. He had an average intelligence. His basal metabolism was -26 per cent. His bone development was two years advanced as indicated by x-ray pictures of his hands and
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lower arms, a finding which is not infrequently associated with genital underdevelopment. Gonadotropic treatment was started in March, 1934. He received daily injections of antuitrin-S, 100 units each time for thirty days. At the end of this period I found both testicles in the scrotum; they were not larger than small peas. After four weeks we gave another course of 20 injections in the same way as before. After another month we tried an anterior pituitary gonad-stimulating preparation, prephysin, which was given in daily injections, 25 units each, for six weeks. Altogether he received 11,200 units of antuitrin-S and 1050 units of prephysin. There was no further change, and we decided to wait for a while. About a half year later, in May, 1935, the right testicle was much larger, of the size of a cherry, the left remained as small as it was. The penis and scrotum have shown some development, and there was some pubic hair. It appeared that he was entering puberty and we again decided against interference. As you can see from his present state, this was justified. The appearance of his external genital organs is now almost normal: both testicles in scrotum, the right testicle is of normal size and consistency, the left is somewhat smaller and softer. The penis is of normal size, and there is pubic hair present. His voice is in mutation. His height is now 68 inches, weight 131 pounds, basal metabolic rate -20 per cent. We believe that the prompt descent of the right testicle, after one month's treatment, was due to the gonadotropic therapy. Whether this therapy was also instrumental in bringing about his puberty is open to question. We have in our care another boy, now eighteen years old who five years ago was a typical case of adiposogenital dystrophy and who at fifteen entered puberty and eventually showed perfect genital development, without any treatment whatsoever. Undoubtedly, in some cases of adiposogenital dystrophy spontaneous adjustment occurs at puberty. As you see, the patient is still obese, and I may add that his ,tYf'e of fat distribution, thought to be characteristic for adiposo-
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genital dystrophy, is quite the same as it was two years ago when he was sexually infantile. This indicates that the hypogonadism is not the cause of the obesity with which it is so frequently associated.
Case IV.-This boy was first seen fourteen months ago when he was fourteen years old. He had bilateral cryptorchism. The small and empty scrotum was in peculiar contrast to the large penis. There was no pubic hair. A slight but definite gynecomastia was present. He was undersized, his height being 57 inches. He was obese, weighing 118 pounds. There was marked delay in dentition. His intelligence was definitely subnormal. Basal metabolic rate was ---,-6 per cent. I classified the case as a cretinoid. Starting in February, 1935, he received 5600 units of antuitrin-S and 250 units of prephysin within three months. At the end of this period a cherry-size testicle was found in the right side of the scrotum; the left testicle was still missing. Pubic hair appeared. In September, 1935, we gave another course of injections, 1400 units of antuitrin-S in three weeks. There was no immediate change, but a half year later, now, the right testicle is of normal size, in the scrotum, and the left testicle about half as large, in the inguinal canal. His height is 61 inches, a growth of 4 inches in fourteen months, which is rather remarkable in view of his slow growth before. His weight is 122 pounds. The gynecomastia is hardly noticeable now. There is no apparent change in his mental capacity. Case V.-This young man is twenty-one years old. He was admitted to the clinic two years ago. He complained of severe nosebleeds and extensive subcutaneous hemorrhages which were found to be due to thrombocytopenic purpura. In addition, he had a unilateral cryptorchism. The right testicle, penis, prostate, pubic hair, and sexual manifestations were normal; the left testicle, of the size of a cherry, was found in the middle of the inguinal canal. Four thousand units of antuitrin-S were administered within two months, without noticeable effect. Half a year later 11,000
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units of antuitrin-S were injected within four months. As you see, the cryptorchism persists. We may conclude that in this case an anatomical obstruction exists which cannot be eliminated except by surgical intervention.
Case VI.-You will recognize this case by inspection as that of eunuchoidism. He is thirty-three years old. He is tall and obese with a female type of fat distribution. His extremities are relatively long, the trunk relatively short. There is very little pubic hair and no body hair; he shaves once in two weeks. The penis and scrotum are infantile, the prostate is hardly palpable. There is a scar in the right inguinal region; he was operated on that side for cryptorchism at thirteen, unsuccessfully; there is no trace of the right testicle. In the left inguinal canal a small firm structure, of the size of a navy bean is palpable. He complains bitterly of his greatly impaired sexual ability. We have given this patient in the past two years 27,000 units of antuitrin-S and 1000 units of prephysin. He noticed occasional slight pain in the left groin, faster growth of facial hair, and more frequent sexual manifestations. But the testicle is as small as it was before, and remains in the inguinal canal. We advise orchiopexy to be followed immediately by gonadotropic therapy. This may help if viable testicular tissue is still present in the structure palpable in the inguinal canal. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. ·13.
BmLlOGRAPHY Schapiro, B.: Deutsche Med. Woch., 56: 1605, 1930. Engle, E. T.: Endocrinology, 16: 506, 1932. Drake, C. B.: J. A. M. A., 102: 759, 1934. Moore, C. R.: Am. J. Obst. Gynec., 29: 1, 1935. Spence, A. W., and Scowen, E. F.: Lancet, 229: 1335, 1935. Sellye, H., Collip, J. and Thompson, D. L.: Proc. Soc. Exp. BioI. Med., 31: 566, 1934. Dorff, G. B.: Am. J. Dis. Child.,. 50: 649, 1429, 1935. Geschickter, C. F., Lewis, D. and Hartman, C. G.: Cancer, 21: 828, 1934. MacCollum, D.W.: Arch. Surg., 31: 290, 1935. Brosius, W. L. and Schaffer, R. L.: J. A. M. A., 101: 1227, 1933. Huberman, J.: J. Pediat., 7: 759, 1935. Rony, H. R.: Ill. Med. J., 66: 234, 1934. Koplin, H.: J. A. M. A., 106: 374, 1936.
CLINIC OF DR. HUGO R. RONY NORTHWESTERN UNIVERSITY MEDICAL SCHOOL NONOPERATIVE (GONADOTROPIC) TREATMENT OF CRYPTORCHISM
SINCE 1930 when Schapirol first reported successful treatment of human cryptorchism by injections of the gonadotropic principle of pregnancy urine, this type of treatment has been applied by a number of clinicians with variable results. As is frequently the case with new therapeutic procedures, the first enthusiastic reports were soon followed by expressions of skepticism and caution. In the meantime sufficient experimental and clinical material was accumulated to allow for a clearer appreciation of the possibilities and limitations of this treatment. To this end it is necessary to keep in mind some pertinent physiological and pathological data. Normally the testicles descend from the abdominal cavity through the inguinal canal into the scrotum during the seventh to eighth month of intra-uterine life; at birth both testicles are found in the scrotum. Nothing definite was known about the physiological mechanism of the descent of the testicles until 1932 when Engle2 suggested that maternal gonadotropic hormones play in important part in it. This contention is supported by the following observations: (1) The human is the only organism known in which testicular descent occurs before birth, and the human female is also the only one having gonadotropic hormones in blood circulation throughout the period of gestation. (2) A noticeable increase in the number of the interstitial cells of the testicle of the human fetus occurs one to two months before term; a similar change may be experimentally produced in immature monkeys by injections of the gonadotropic hormone of pregnancy urine. (3). In imma207
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ture monkeys and rats injections of the pregnancy urine gonadotropic honnone cause premature descent of the testicles. ( 4) An analogous phenomenon indicating effects of maternal female sex hormone is occasionally observed in newborn girls showing swelling of the major labia or breasts. These and similar other observations may be considered as sufficient evidence to indicate that in the normal fetal descent of the testicles. gonadotropic hormones of the mother are instrumental. If the testicle fails to descend before birth, it usually remains undescended until the beginning of puberty. The descent may be arrested at any point, in some cases in the abdominal cavity, more often in the inguinal canal. The arrest may be bilateral, both testicles being arrested at the same point or at different points. In the majority of the cases unilateral arrest is observed, the other testicle being in normal position. Drake 3 observed 11 cases of cryptorchism among 260 boys nine to nineteen years of age-a frequency of 42 per thousand. It has been known for many years that spontaneous descent of undescended testicles may occur at puberty, but the frequency of this phenomenon was not realized until recently. It appears that spontaneous pubertal descent occurs in the majority of cases of cryptorchism; it occurred in 9 out of 11 of Drake's cases. This is confirmed by the fact that cryptorchism is not nearly as frequent in the adult population: extensive statistics obtained on army recruits in different countries indicate an incidence of 2 to 5 per thousand. While the normal fetal descent of the testicle occurs under the influence of maternal gonadotropic hormones, late spontaneous descent in puberty is thought to be brought on by the gonadotropic hormone of the hypophysis of the individual. Histologically the undescended testicle, prepubertal or postpubertal, shows a picture similar to that of a normal prepubertal scrotal testicle. In . other words, the undescended testicle fails to supply at puberty its seminiferous tubules with normal germinal epithelium, and remains aspermic and sterile. It has been shown conclusively by Moore 4 that scrotal position.. is necessary for the normal development of the germinal
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epithelium because of the lower temperature it insures. If a mature scrotal testicle with the spermatic cord intact is placed in the abdominal cavity, soon most of the germinal epithelium degenerates and disappears; replacement of such a testicle into the scrotum is followed by regeneration of the germinal epithelium and spermatogenesis. However, the abdominal testicle may produce male sex hormone in apparently undiminished amounts, as demonstrated by Moore in experiments on guineapigs. CIassification.-Group A .-In a number of cases of human cryptorchism examination of the patient fails to disclose any additional pathology of importance. There are no signs of disturbance of the endocrine system; growth, sexual and· mental development are normal. Puberty appears in due time with all secondary sex chara<;:teristics and sexual potency. The majority of unilateral cryptorchism cases and a few of the bilateral ones belong to this category. Failure to descend may be due to causes of local anatomical nature, such as developmental error, or adhesions due to fetal peritonitis; in these cases spontaneous late descent at puberty will not occur. In other cases descent is arrested before birth because of deficiency in maternal gonadotropic hormones; late spontaneous descent frequently sets in at puberty under the stimulation of the normally functioning anterior pituitary. Clinical differentiation between these two subgroups can, as a rule, not be made before puberty. Group B.-In most cases of bilateral cryptorchism clinical examination reveals more or less marked signs of hypogonadism. The scrotum is undeveloped, the penis is infantile, the prostate and seminal vesicles are hypoplastic. The patient is more or less obese with a girdle type of fat distribution. Puberty is delayed and imperfect, or entirely missed. Late spontaneous descent rarely occurs. The undescended testicle remains not only sterile but also deficient in the production of the male sex hormone on which the development of the secondary sex characters depends. The hypogonadism is usually secondary, being due to VOL. 21-I4
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deficient gonadotropic activity of the hypophysis; it is frequently accompanied by signs of deficiency of other functions of the hypophysis, such as stunted growth, diabetes insipidus, subnormal mentality, delayed dentition, etc. The question arises whether the fetal arrest of testicular descent is also due to the pituitary deficiency. There is no evidence that the hypophysis of the fetus has any active role in the physiological mechanism of testicular descent. Furthermore, a number of cases of most severe hypopituitarism are born with scrotal testicles, even though the further development of these testicles will be seriously impaired. Accordingly, it must be assumed that the fetal arrest of descent is independent from the pituitary . failure of the patient jn cases of hypogonad cryptorchism. On the other hand, the absence of late spontaneous descent is obviously a consequence of the patient's deficient pituitary gonadotropic hormone production. In some cases cryptorchism is associated with primary hypogonadism: there is congenital idiopathic hypoplasia of the testicles, or atrophy following orchitis as a complication of mumps, etc. The gonadotropic activity of the anterior pituitary is intact in these cases. Clinically they usually present the picture of eunuchoidism with the typical body proportions and delayed union of epiphysial junctions. Differentiation between primary and secondary hypogonadism, associated with cryptorchism, may be difficult in some cases. Specificity of Gonadotropic Therapy.-Injections of gonqdotropic hormone preparations in cryptorchism have been followed in many cases by descent of one or both testicles. Some doubt has been expressed as to the specificity of this effect in view of the fact that spontaneous descent frequently occurs; the result might be merely coincidental. However, a number of observations are available which would be difficult to explain on the basis of coincidence: (1) In many cases gonadotropic therapy was followed by descent of the testicles in four- to six-year-old boys, and in some cases in eighteen- to twenty-seven-year-old men, i. e., at ages when spontaneous descent very rarely occurs. (2) Results were frequently ob-
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served within two weeks of treatment. (3) In some cases descent occurred during treatment but the testicle again retracted into the inguinal canal or abdominal cavity shortly after the injections were discontinued. A second course of injections brough,t the testicle down again. ( 4) Cases were observed that were previously operated on, the testicle being placed in the scrotum; subsequent retraction occurred; gonadotropic treatment was followed by descent. In view of such observations it is safe to say that descent of cryptorchid testicles may be the direct result of gonadotropic therapy. Indications for Gonadotropic Therapy.-Obviously, gonadotropic treatment is indicated in all cases belonging to Group B, although favorable results are not always obtained. Why treatment fails in some patients of this group is difficult to say. Possibly, in some cases, local anatomical causes exist in addition to the deficiency of the anterior pituitary. In primary hypogonadism (eunuchoidism) the lesion of the cryptorchid testicle. may be so severe as to obviate response to the strongest gonadotropic stimulation. In other cases the intensity or duration of the treatment might have been insufficient. In some patients belonging to Group A gonadotropic treatment is doomed to failure because of the presence of anatomical obstacle. In other cases of this group treatment is superfluous as descent will spontaneously occur at puberty. Only in a relatively small number of cases is hormonal treatment both necessary and successful. Unfortunately, the nature of the case is not, as a rule, recognizable before puberty. Accordingly, correct indication for hormone therapy can hardly be made when the patient is seen before puberty. If cryptorchism persists in the presence of more or less marked pubertal changes, a trial with hormone therapy is indicated. Failure of this therapy may be considered as evidence of anatomical obstruction and indication for surgical interference. Postoperative hormonal treatment-following orchiopexyhas been advocated to insure against possible retraction of the testicle (Spence and Scowen5 ).
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HUGO R. RONY
At what age should treatment be started? Cryptorchism is an abnormal condition at any age and it might seem logical to attempt to correct it as early as possible. In fact, several clinicians expressed this opinion and a number of four- to tenyear-old successfully treated children are on record. It is not quite clear to me what is to be gained by producing testicular descent artificially at this early age unless some special indication, such as local pain, or hernia exists. For cases of Group B with marked genital dystrophy (undeveloped scrotum and penis) advisability of early treatment may be a matter of opinion: the testicle in these patients is not only undescended but hypoplastic as well; chances for spontaneous late correction are slight. Yet, even in these cases treatment at the normal beginning of puberty--eleven to thirteen years-rather than earlier appears to be the logical procedure. For Group A early treatment is hardly justified. As I mentioned before, a normal prepubertal undescended testicle does not differ histologically and functionally from a normal prepubertal scrotal testicle, and scrotal position becomes of great importance for the structure and function of the testicle only with the onset of puberty. In patients of Group A, general development, including sexual development proceeds normally whether the testicle is in the scrotum or in the abdomen. Furthermore, in many instances spontaneous descent occurs at puberty. Accordingly, there is no reason why one should not wait with treatment of patients of this group until puberty is well established, at fourteen or fifteen. It is probably not advisable to wait much longer. I have found no report in the literature of successful treatment of patients older than eighteen, belonging to this group. Some Technical Details of Hormone Therapy.-Most authors used preparations of the pregnancy urine gonadotropic hormone (prolan, anterior pituitary-like substance). Others used extracts made from the anterior lobe of the hypophysis. There is no evidence that either one is superior. In the prese\1ce-
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Injections of the pregnancy urine gonadotropic hormone are given daily or every other day subcutaneously or intramuscularly, 100 to 300 rat units each time. The duration of treatment and the total amount of the hormone administered varies greatly. In some cases a few hundred units given within two weeks prove sufficient. In other cases (Group B) treatment was continued for over a year with a total amount of 20,000 or more units injected. It is probably safe to say that if the injection of 10,000 units fails to produce any change, further treatment at that time is not likely to succeed. In such cases it may be advisable to undertake a second course of injections starting a few months later, as suggested by Spence and Scowen. 5 They quote the work of Sellye et al./ who have shown that after prolonged administration of gonadotropic hormone virgin female rats become temporarily insensitive to the hormone. Repetition of treatment_ is also indicated when the testicle which has descended after a course of injections, later retracts into its previous position. As a rule, treatment is discontinued as soon as the testicle reaches the bottom of the scrotum, although in cases associated with sexual infantilism it may be necessary to continue hormonal treatment over a longer period. By-effects of Hormone Therapy.-In some cases mild to moderate pain is complained of in the groin of the affected side during treatment. This does not necessitate interruption of treatment as the pain soon subsides. After the testicle has descended it is usually smaller than normal but soon reaches normal proportions. Enlargement beyond the normal for the patient's age is not produced even when treatment is continued with large doses. The same is true for the scrotum and penis. Precocious secondary sex characteristics-such as pubic hair, mutation of voice, etc.-in children treated before puberty were not observed, except by Dorff7 who gave very large amounts of the hormone (as much as 46,000 units). N either is enlargement of the prostate or of the breasts of the patients reported, although Geschickter et al. 8 reported such effects in monkeys treated with large amounts of pregnancy urine hormone.
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RUGO R. RONY
The question whether the testicle, which has descended into the scrotum in response to hormonal therapy, becomes fertile cannot be answered directly at this time. Some indirect evidence is available. Thus it is known that bilateral undescended testicles brought down into the scrotum by surgical orchiopexy may become fertile (MacCollum9 ). Brosius and Schaffer10 reported a case of bilateral testicular atrophy with complete aspermia following orchitis as a complication of mumps, in which gonadotropic hormone therapy repeatedly produced extensive spermatogenesis. Huberman ll and Dorff7 noticed marked improvement of mental development and enuresis nocturna in some of their cases treated for cryptorchism. Accelerated growth is sometimes observed. It appears that when the gonads mature under gonadotropic treatment, they exert a stimulating influence on growth, probably by way of the anterior lobe growth-promoting apparatusP Gonadotropic treatment has no effect on the obesity associated with genital dystrophy. The obesity and the type of fat distribution usually persist even after complete correction of cryptorchism and sexual underdevelopment. Neither is there any definite change in basal metabolism. A unique observation of enuresis, polydipsia and glycosuria appearing during. gonadotropic treatment for cryptorchism in a thirty-month-old child is reported by Koplin13; all symptoms disappeared after three weeks following the termination of treatment. This may be considered as another· reason against gonadotropic therapy at early age. PRESENTATION OF CASES
Case I.-This boy is now thirteen years old. He is normally developed. Both testicles are in the scrotum; their size is normal for his age. He was a normal boy when I saw him first about a year ago, except for a unilateral cryptorchism. The left half of the scrotum was empty, as was the left inguinal canal. We gave him injections of 200 units antuitrin-S three times a week. After the sixth injection the left testicle de-
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scended into the scrotum and soon reached the size of the right testicle. I have no doubt that the gonadotropic therapy was instrumental in the descent of this testicle, although it is quite possible that descent would have occurred by this time, or later, without any therapy. We now believe that such cases do not need treatment before they reach their fourteenth or fifteenth year. Case H.-This boy is twelve and one-half years old. He has bilateral cryptorchism; no trace of the testicles can be found on physical examination. Otherwise he,is normally developed in every way. We have started with gonadotropic therapy five months ago, giving him daily injections of 100 units antuitrin-S. On the tenth day I found the right testicle in the scrotum, the left testicle in the inguinal canal. After waiting for four weeks without noticing further change, we gave him again daily injections of the same substance and amount. Two weeks later both testicles were in the scrotum. He has received altogether 2400 units of the hormone. Now he returns with both testicles retracted into the abdominal cavity. Another course of injections would probably bring these testicles down again, and with continued treatment they might stay in the scrotum permanently. But we might as well wait for a year or two without treating this patient. In the meantime the testicles may spontaneously descend. If this will not occur, we will then try another course of hormon~ injections. Small amounts of the hormone will probably suffice at that time to insure permanent result. Case 111.-Two years ago this patient presented a typical picture of adiposogenital dystrophy. He was then thirteen years old, his height was 63 inches, his weight 123 pounds. The scrotum and penis were markedly underdeveloped; a tiny structure, of the size of a small pea, was found in the left half of the scrotum; the right half of the scrotum and the right inguinal canal were empty. He had an average intelligence. His basal metabolism was -26 per cent. His bone development was two years advanced as indicated by x-ray pictures of his hands and
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RUGO R. RONY
lower arms, a finding which is not infrequently associated with genital underdevelopment. Gonadotropic treatment was started in March, 1934. He received daily injections of antuitrin-S, 100 units each time for thirty days. At the end of this period I found both testicles in the scrotum; they were not larger than small peas. After four weeks we gave another course of 20 injections in the same way as before. After another month we tried an anterior pituitary gonad-stimulating preparation, prephysin, which was given in daily injections, 25 units each, for six weeks. Altogether he received 11,200 units of antuitrin-S and 1050 units of prephysin. There was no further change, and we decided to wait for a while. About a half year later, in May, 1935, the right testicle was much larger, of the size of a cherry, the left remained as small as it was. The penis and scrotum have shown some development, and there was some pubic hair. It appeared that he was entering puberty and we again decided against interference. As you can see from his present state, this was justified. The appearance of his external genital organs is now almost normal: both testicles in scrotum, the right testicle is of normal size and consistency, the left is somewhat smaller and softer. The penis is of normal size, and there is pubic hair present. His voice is in mutation. His height is now 68 inches, weight 131 pounds, basal metabolic rate -20 per cent. We believe that the prompt descent of the right testicle, after one month's treatment, was due to the gonadotropic therapy. Whether this therapy was also instrumental in bringing about his puberty is open to question. We have in our care another boy, now eighteen years old who five years ago was a typical case of adiposogenital dystrophy and who at fifteen entered puberty and eventually showed perfect genital development, without any treatment whatsoever. Undoubtedly, in some cases of adiposogenital dystrophy spontaneous adjustment occurs at puberty. As you see, the patient is still obese, and I may add that his ,tYf'e of fat distribution, thought to be characteristic for adiposo-
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genital dystrophy, is quite the same as it was two years ago when he was sexually infantile. This indicates that the hypogonadism is not the cause of the obesity with which it is so frequently associated.
Case IV.-This boy was first seen fourteen months ago when he was fourteen years old. He had bilateral cryptorchism. The small and empty scrotum was in peculiar contrast to the large penis. There was no pubic hair. A slight but definite gynecomastia was present. He was undersized, his height being 57 inches. He was obese, weighing 118 pounds. There was marked delay in dentition. His intelligence was definitely subnormal. Basal metabolic rate was ---,-6 per cent. I classified the case as a cretinoid. Starting in February, 1935, he received 5600 units of antuitrin-S and 250 units of prephysin within three months. At the end of this period a cherry-size testicle was found in the right side of the scrotum; the left testicle was still missing. Pubic hair appeared. In September, 1935, we gave another course of injections, 1400 units of antuitrin-S in three weeks. There was no immediate change, but a half year later, now, the right testicle is of normal size, in the scrotum, and the left testicle about half as large, in the inguinal canal. His height is 61 inches, a growth of 4 inches in fourteen months, which is rather remarkable in view of his slow growth before. His weight is 122 pounds. The gynecomastia is hardly noticeable now. There is no apparent change in his mental capacity. Case V.-This young man is twenty-one years old. He was admitted to the clinic two years ago. He complained of severe nosebleeds and extensive subcutaneous hemorrhages which were found to be due to thrombocytopenic purpura. In addition, he had a unilateral cryptorchism. The right testicle, penis, prostate, pubic hair, and sexual manifestations were normal; the left testicle, of the size of a cherry, was found in the middle of the inguinal canal. Four thousand units of antuitrin-S were administered within two months, without noticeable effect. Half a year later 11,000
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HUGO R. RONY
units of antuitrin-S were injected within four months. As you see, the cryptorchism persists. We may conclude that in this case an anatomical obstruction exists which cannot be eliminated except by surgical intervention.
Case VI.-You will recognize this case by inspection as that of eunuchoidism. He is thirty-three years old. He is tall and obese with a female type of fat distribution. His extremities are relatively long, the trunk relatively short. There is very little pubic hair and no body hair; he shaves once in two weeks. The penis and scrotum are infantile, the prostate is hardly palpable. There is a scar in the right inguinal region; he was operated on that side for cryptorchism at thirteen, unsuccessfully; there is no trace of the right testicle. In the left inguinal canal a small firm structure, of the size of a navy bean is palpable. He complains bitterly of his greatly impaired sexual ability. We have given this patient in the past two years 27,000 units of antuitrin-S and 1000 units of prephysin. He noticed occasional slight pain in the left groin, faster growth of facial hair, and more frequent sexual manifestations. But the testicle is as small as it was before, and remains in the inguinal canal. We advise orchiopexy to be followed immediately by gonadotropic therapy. This may help if viable testicular tissue is still present in the structure palpable in the inguinal canal. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. ·13.
BmLlOGRAPHY Schapiro, B.: Deutsche Med. Woch., 56: 1605, 1930. Engle, E. T.: Endocrinology, 16: 506, 1932. Drake, C. B.: J. A. M. A., 102: 759, 1934. Moore, C. R.: Am. J. Obst. Gynec., 29: 1, 1935. Spence, A. W., and Scowen, E. F.: Lancet, 229: 1335, 1935. Sellye, H., Collip, J. and Thompson, D. L.: Proc. Soc. Exp. BioI. Med., 31: 566, 1934. Dorff, G. B.: Am. J. Dis. Child.,. 50: 649, 1429, 1935. Geschickter, C. F., Lewis, D. and Hartman, C. G.: Cancer, 21: 828, 1934. MacCollum, D.W.: Arch. Surg., 31: 290, 1935. Brosius, W. L. and Schaffer, R. L.: J. A. M. A., 101: 1227, 1933. Huberman, J.: J. Pediat., 7: 759, 1935. Rony, H. R.: Ill. Med. J., 66: 234, 1934. Koplin, H.: J. A. M. A., 106: 374, 1936.