U NDUE DELAY in the treatment of cryptorchidism will, in my opmlon,

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1 Delayed Treatment of Cryptorchidisnt with Subsequent Infertility L. STUART SCOTT, M.D., CH.M., F.R.C.S. (EDIN.), F.R.C.S. (GLAsc.) U NDUE DELAY in the treatment of cryptorchidism will, in my opmlon, inevitably lead to a higher-than-necessary incidence of sterility or severe subfertility. There is experimental evidence in animals 35 that the depleted germinal epithelium which results from artificial cryptorchidism is still capable of regeneration, provided the testis is returned to the scrotum before degeneration is complete. Although there is clinical evidence in man~~ that correctly timed treatment of cryptorchidism considerably reduces the subsequent incidence of subfertility, it has been suggested that subsequent development after orchidopexy can take place only in those parts of the germinal tissues that have not already degenerated. 17 In the past 10 years the author has personally examined over 4000 patients at a male subfertility clinic; of these patients, 3.5% had a history of treated or untreated cryptorchidism. TYPES OF CRYPTORCHIDISM Three entirely different types of cryptorchidism are recognizable; as each will require a different form of treatment, a careful initial clinical examination is of the utmost importance. Retractile Testes Retractile (or migratory) testes are normal gonads that, due to powerful cremasteric action, tend to lie principally in the superficial inguinal pouch. As this pouch is merely an upward extension of the scrotal compartment, these testes can, with patience, be manipulated back into the scrotum. Previous histological studies 27 revealed that retractile testes show no difference from their scrotal counterparts in capacity for spermatogenesis. From the Male Sub fertility Clinic, Department of Urology, Victoria Infirmary, Glasgow, Scotland. 782

2 VOL.IB, No.6, 1967 TREATMENT OF CRYPTORCHIDISM 7B3 Ectopic Testes Ectopic testes are gonads that, having completed a normal migration down the length of the inguinal canal, are prevented from entering the scrotum by a fascial barrier created by fusion of Scarpa's fascia to the symphysis pubis; 19 instead, they become diverted laterally into the groin, where they lie superficial to the external oblique aponeurosis. Undescended Testes Undescended (or retained) testes are gonads that have either partially or completely failed to negotiate a passage through the inguinal canal. Previous histological studies in my own clinic 18 showed degeneration of the germinal epithelium in retained testes to be more widespread than in ectopic testes; we postulated that the fertility potential following treatment should be subsequently poorer in this group when compared with that of treated ectopic testes. EFFECTS ON SPERM COUNT The study group consisted of 21 patients with unilateral, untreated, retained testes (Group 1); 11 with unilateral, untreated ectopic testes (Group 2); and 9 with bilateral, untreated retractile testes (Group 3). Comparison of these subjects' sperm counts was made with those of a control group of 2500 consecutive patients attending my subfertility clinic. The latter patients had no cryptorchidism or other known factor in their past or present histories. Of the patients in Group 1 and Group 2, 46% and 48%, respectively, were either sterile or quite severely subfertile, compared with only 11% of those Fig. 1. Patients with spenn counts under 1 million/ ce.: % with severely impaired spermatogenesis. % so ~ Unilateral undescended lei Unilateral ectopic 111[] Bilateral retractile Other Fertility Clinic patients in Group 3 and 10% of the controls (Fig. 1). Thus, retractile testes had no adverse effect on fertility, but failure to treat unilateral ectopic and unilateral retained testes frequently resulted in infertility. This is due to the fact that the apparently normal, opposite, scrotal testis is frequently ab-

3 784 SCOTT FERTILITY & STERILITY normal (as established by testicular biopsy). The author drew attention to this generally unaccepted concept some years ago,27.28 and at a recent Amsterdam symposium on cryptorchidism a number of other investigators confirmed such findings There can be little doubt that many testes fail to descend because they are inherently abnormal. We have no means of telling, before treatment, which will improve and which will not-although it is clear that subsequent infertility can be prevented in many cases, provided the correct treatment is given at the correct age OPTIMUM AGE FOR TREATMENT The factor of optimum age (which I believe to be of utmost importance) is an extremely controversial one in considering initiation of treatment. A tabulation of opinions follows..tl 'Uthority Thomson and Hecke134 Kimbrough and Reedlli Nicole and Spindler23 Robinson and Engle25 Hinman13 Handll Gross and Jewett9 Paatela et al.24 Drake5 Age (yr.) < The experimental work of Nelson 22 in rats, and of Charny2 in human beings, suggests that the amount of tubular damage is proportional to the duration of the cryptorchidism, although Bergstrand 1 places more emphasis on the degree of nondescent before treatment. At first consideration, therefore, it would seem logical to treat all cryptorchid boys as soon as the diagnosis is made. Unfortunately, the solution is not so simple. McNab1!) has pointed out that gonadotrophin therapy in the early years of life may induce the development of unwelcome, precocious secondary sex characteristics, and it has also been noted 12 that orchidopexy at this age is technically more difficult to perform and also more likely to produce vascular trauma. On the other hand, Knauth 16 found that, following Olchidopexy after the age of 10 years, 22% of his patients were subsequently subfertile and 56% were either sterile or very severely subfertile. At puberty, and without treatment, many testes will descend spontaneously-with a peak incidence around the twelfth year Although my own previous studies and those of others3 showed clearly that late spontaneous descent up to the tenth year had no adverse effect on spermato-

4 VOL. 18, No.6, 1967 TREATMENT OF CRYPTORCHIDISM 785 genesis, there is ample evidence in Fig. 1 to suggest that undue delay in treatment may cause serious malfunction. Table 1 shows the findings in 38 cryptorchid testes from testicular biopsies taken from boys whose family doctors had waited until "puberty" before referring them to me for treatment. Tests showed that 5% of these testes still had prepubertal solid tubules, while 45% had no evidence of spermatogenesis-the tubules being lined only by Sertoli cells. A further 50% showed maturation arrest at various levels of spermatogenesis. In none of these "pubertar cryptorchid testes were spermatids or mature spermatozoa identified. This suggests that it is a mistake to leave cryptorchid testes untreated until the onset of puberty, even though one can be confident that some will still descend at a later date, without treatment. INDICATIONS FOR TREATMENT As retractile testes are usually perfectly normal gonads, it is illogical to treat them at all. Since no amount of hormonal stimulation can break down the fascial barriers that prevent ectopic testes from entering the scrotum, surgical treatment will always be indicated for this type of mal descent. Treatment of retained testes creates a bigger problem for consideration, and opinions are still divided among the sole use of gonadotrophins, the sole use of surgery, and a combination of both. Charny2 suggests that some of these testes failed to descend because of secondary (pituitary) hypogonadism, and in such cases spontaneous descent can be anticipated around puberty-when there is a natural increase in the amount of circulating gonadotrophins. These are also testes in which descent can be accomplished at an earlier age by artificial gonadotrophic stimulation. Since no known test can distinguish these cases before treatment, it would seem logical to administer gonadotrophins to all patients with retained testes TABLE 1. Biopsy Findings in 38 ''Pubertal'' Testes Level of spermatogenesis reached Patient a.qe No. of Solid Sertoli Spermato- Sr.ermato- (yr.) cases tubules only gonia cytes '

5 786 SCOTT FERTILITY & STERILITY (before resorting to surgery). Against this concept, however, it has been found 6 9 that testicular atrophy may occasionally occur when gonadotrophin administration has ceased, and atrophy of the opposite, scrotal testis has also been described. 2o 21 CONCLUSIONS There now seems to be little doubt that unilateral cryptorchidism, whether due to ectopy or true nondescent, frequently leads to subsequent subfertility if not treated. The presence of one testis in the scrotum is no guarantee that it, too, is not abnormal (as established by histologic examination). Retractile testes require no treatment at all; these are normal gonads and spermatogenesis is not affected by their occasional unusual position. Although late spontaneous descent of retained testes can frequently be anticipated at the onset of puberty, such descent is also frequently associated with degenerative changes in the seminal tubules. This corroborates the findings of Robinson,25 who noted that, after orchidopexy during puberty, few testes develop normally. W. W. Scott's studies 32 suggest that treatment in the early years of life has no evident advantage. My own studies show that delay up to-but not beyond-the tenth year has no adverse effect. Taken together, these conclusions suggest that any boy with cryptorchid testes which are not retractile, not associated with a congenital hernia, and not fixed in an ectopic position, should have a course of gonadotrophin therapy in the hope of accelerating descent before puberty. This treatment should be given about the ninth year; if descent does not take place within 3 months of the injections, early surgical intervention is clearly indicated. 5, The Grove Whitecraigs, Glasgow Scotland REFERENCES 1. BERGSTRAND, C. G., and QVIST, O. Late prognosis in patients operated on for bilateral cryptorchidism. Hormoon (Oss)3:9, CHARNY, C. W. Spermatogenic potential of undescended testes. J Urol 83:697, CHARNY, C. "V., and WOLGIN, W. The management of cryptorchidism. Surg Gynec Obstet 102:177, DOEPFMER, R. Frequency of cryptorchidism in adults, and the importance of unilateral cryptorchidism in fertility. Hormoon (ass) 3:4, DRAKE, C. B. Treatment of cryptorchidism. lama 163:626, EISENSTADT, J. S. Imperfect descent of the testis and its management. Surg Glin N Amer 30: 141, GASSER, G., and HOLZNER, J. H. Testicular biopsy in unilateral retention with its therapeutic consequences. Hormoon (ass) 3:4, 1964.

6 VOL. 18, No.6, 1967 TREATMENT OF CRYPTORCHIDISM GIABOLA, A. The undescended testicle; therapeutic aspects from the standpoint of reproductive life. Hormoon (Oss) 3:7, GROSS, R K, and JEWETT, T. C. Surgical experiences from 1222 operations for undescended testicle. lama 160:634, GUILLON, G., and SEGUY, E. Cryptorchidism and infertility. Hormoon (Oss) 3:5, HAND, J. R Treatment of undescended testicle and its complications. lama 164: 1185, HELLINGA, G. Fertility after hormonal or surgical treatment for bilateral cryptorchidism. Hormoon (Oss) 3:7, HINMAN, F. Optimum time for orchidopexy in cryptorchidism. Fertil Steril 6: 206, JOHNSON, W. W. Cryptorchidism. lama 113:25, KIMBROUGH, J. C., and REED, J. F. Treatment of undescended testicles. lama 163:621, KNAUTH, H., and POTEMPA, J. Cryptorchidism and fertility. Urol Int 15:77, LELONG, M. P., PETIT, P., CANLORBE, J., CENDRON, P., BORNICHE, S., GOTIDER, R., and LANGE, J. Our experiences of the treatment and future of cryptorchids. Hormoon (Oss) 3:5, MACK, W. S., SCOTT, L. S., SMITH, M. F., and LENNOX, B. Ectopic testis and true undescended testis; a histological comparison. 1 Path Bact 82:439, McNAB, G. H. Maldescent of the testicle. 1 Roy CoIl Surg Edinb 1:126, MAITLAND, A. I. L. Maldescent of the testicle. Glasgow Med 1 34: 170, MIMPRISS, T. W. Cryptorchidism. Brit 1 Urol24:23, NELSON, W. O. Effect of cryptorchidism in the rat, and non-descent of the testis in man. Rec Progr Hormone Res 6:29, NICOLE, R, and SPINDLER, B. Prognosis as to fertility following operations for cryptorchidism in children. Hormoon (Oss) 3:6, PAATELA, M. H., HORTLING, C. J., JOHANSSON, A., CHAPELLE, R, and SULAMAA, M. A follow-up study of 200 operated cases of cryptorchidism. H omldon (Oss ) 3:9, ROBINSON, J. N., and ENGLE, K T. Some observations on the cryptorchid testis. 1 Urol 71:726, SCOTT, L. S. The subfertile man; a study of certain aspects. M.D. TheSis, University of Glasgow, SCOTT, L. S. Unilateral cryptorchidism; subsequent effects on fertility. 1 Reprod Fertil 2:54, SCOTT, L. S. Fertility in cryptorchidism. Pmc Roy Soc Med 55: 1047, SCOTT, L. S. Use and abuse of Gonadotrophins in Cryptorchidism. Hormoon (Oss) 15:1, SCOTT, L. S. Rational treatment of cryptorchidism designed to produce maximum fertility. Presented at Sterility Conference, Venice, Italy, June, SCOTT, L. S. Gelm-cell degeneration subsequent to delayed treatment of cryptorchidism. Hormoon (Oss) 3:4, SCOTT, W. W. Undescended testis. (Editorial.) Lancet 2:989, SCIDRREN, C. Histology of undescended testicle and the spermatogram of hormone-treated and surgical-treated patients with mal-descent. Hormoon (Oss) 3:6, THOMSON, W. O.,and HECKEL, N. J. Endocrine treatment of cryptorchidism. JAMA.117:1953, ",TANGENSTEEN, O. H. Undescended testis; an experimental and clinical study. Arch Surg 14:663, 1927.