Spermatogenic Activity Test (S.A. T.) for Evaluation of Fertility in Cryptorchidism

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1 Spermatogenic Activity Test (S.A. T.) for Evaluation of Fertility in Cryptorchidism PINCHAS CZERNIAK, M.D., and JOSEPH ITELSON, M.D. IN RECENT YEARS, the problem of the relationship of cryptorchidism to fertility has received considerable attention It has been su.ggested that prolonged extrascrotal residence of the testes may result often in sterility. Histologic studies5 6 performed on the human undescended testes have shown that abnormal development began when the patient was 7 years old, and when he was 1, there was manifest pathologic maturation leading to infertility with azoospermia at pubertal age. In 1961, a test for examination of the spermatogenic activity in man, the Spermatogenic Activity Test (S.A.T.), was proposed. 2 A tracer dose of p32 is injected intravenously and the trans-scrotal beta-radiation examined in vivo on each testis separately, 1, 2, 3, 4, 6, 8, and 1 days after the injection. The spermatogenic activity of each testis can be thus established on the basis of the determined uptake curves. The radiation exposure of the testicles was only 8-13 mrad per test, an amount nearly equal to the yearly background exposure. The purpose of this study was to establish the value of the S.A.T. for control of spermatogenic potentiality in cases of cryptorchidism. METHOD AND MATERIAL The method of S.A.T. examination has been previously reported in detail. 2-4 Currently we simplify the technique and eliminate the examination of the ethmoidal region, examining only the testicular radiation. Figure 1 shows the three types of received curves (S.A.T. positive with a From the Department of Radiotherapy and Isotopes, Tel-Aviv University Medical School, Tel-Hashomer Hospital, and the Department of Endocrinology, Central Clinic of the Sick Fund, Petah-Tiqva, Israel. Supported by a grant from the James picker Foundation, National Institute of Science (Section of Radiology). Dr. Feller of Hasharon Hospital (Medical Center Beilinson, Petah-Tiqva) performed the surgery referred to in this work. 135

2 136 CZERNIAK & ITELSON FERTILITY & STERILITY plateau on Days 3-5, S.A.T. negative without a plateau, and S.A.T. infantile with a low plateau on Days 7-1). S.A.T. was performed in 28 cases of cryptorchidism in boys aged from 7 to 14 years. Clinical data in these 28 cases are shown in Table 1. In most cases the test was done before and after orchidopexy. In patients with postoperative hormonal treatment, the results of the therapy were also controlled by the S.A.T. In some subjects with negative S.A.T. the semen was examined and the urine concentration of gonadotropin was measured. RESULTS The results of examination in 12 representative cases are summarized below. Case l. H.I., Hosp. No. 9615, an 8-year-old boy with retractile testes, was treated with 5 lu. of chorionic gonadotropin intramuscularly, 2 times a week for 8 weeks (February-March, 1962). In September 1962, the testes were in the scrotum. S.A.T. performed in June 1963 showed a normal plateau on the fourth day (Fig. 2). Case 2. S.A., Hosp. No. 6951, an ll-year-old boy, had spontaneous descent of his testes at the age of 9 years. Present examination revealed normal morphology 1"1 II)... II) :r z... «'".. :> N Q. 1"1 'I :; TIME(OAYS) 5 TIME (DAYS) 1 12 Fig. 1. Typical curves of the Spennatogenic Activity Test (S.A.T.). A indicates positive curves; B, negative curves; C, infantile curves; and D, combination of A, B, and C for comparison. o 5 TIME(nAYS) 1 :; TIME (DAYS) 1 12

3 VOL. 18, No.1, 1967 CRYPTORCHIDISM 137 TABLE 1. Clinical Data in 28 Cases of Cryptorchidism (No. of Patients) Age (year,q) Total Total No Undescended testes Unilateral Bilateral Treatment None or honnonal Operative Operative and hormonal Spermatogenic activity Fertile Sterile of the testes. The normal maturity was confirmed by an S.A.T. showing a plateau on the fourth day. Case 3. P.R., Hosp. No. 2432, was 24 years old and infertile. He was operated upon at the age of 11 because of undescended testes. The testes are in the scrotum, but are very small. Laboratory findings were of azoospermia, high gonadotropin excretion (F.S.H. 12 M.V.j24 hr.), and S.A.T. negative. A testicular biopsy confirmed the diagnosis. Case 4. B.M., Hosp. No. 627, was 26 years old and sterile. Bilateral orchidopexy had been performed when he was 14. Present examination revealed norma] morphology of the testicles. Laboratory findings were of azoospermia, an F.S.H. level of 6 M.V.j24 hr., and S.A.T. negative (Fig. 3). After administration of 1 I. V. of chorionic gonadotropin 3 times weekly for 8 weeks, there was no change in S.A.T. No spermatozoa were found in the ejacul!l,te, verifying the diagnosis. Case 5. H.C., Hosp. No. 6385, was an 8-year-old boy with undescended testes. Treatment with 5 LV. of chorionic gonadotropin 3 times weekly for 2 months was uneffective. Additional similar therapy 8 months later was also without results. Orchidopexy was done on the left testicle when the patient was 9 years and 6 months old, and on the right testicle when he was 1 years and 3 months. S.A.T. performed 1 month after the second operation showed a normal plateau in the curve for the left testis, and a small plateau for the right testis (Fig. 4). Case 6. K.A., Hosp. No. 654, was an 8-year-old boy with a cryptorchid right testicle. Administration of chorionic gonadotropin in total doses of 14, LV. in 1958 and 24, L U. in 1959, was without beneficial result. In 1961, orchidopexy was performed (the patient was then 1 years and 6 months). The right testis was normal in size and consistency after the operation, but an S.A.T. re-

4 138 CZERNIAK & ITELSON FERTILITY & STERILITY vealed a pathologic curve, contrary to a normal plateau, for the left testicle (Fig. 5). Case 7. K.Z., Hosp. No. 7774, was a 9-year-old boy with cryptorchid testes. In 1961 he was treated with 5 LU. of chorionic gonadotropin 3 times weekly for 2 months, which treatment was repeated 1 year later. Examination in March 1962 showed the right testicle in the scrotum, and the left testicle undescended. Orchidopexy was performed July 1962 (the patient was then over 1 years old). The testis operated upon remained small, and did not change in the following 5 months. The pathologic spermatogenic maturity of this testicle was confirmed by S.A.T., which was negative for the left and positive for the right side. Case 8. G.A., Hosp. No. 6984, an 8-year-old boy with an undescended right testicle, received 12, I.U. of chorionic gonadotropin in 1959 and 16, in <f) Ui 8 6 a. ::J c j! eft "-,,, right "' Time (days) 1 II> t;.& c 6... a. " ::J c right "- E 4 "- lefr'o- CI "b.. 2 ' II> 8 +- a. ::J 4.E CI "'a Time (days) 1 6 Co ::J C 4 "".E CI ", Il. 2 - Fig. 2. SAT curves obtained in Case 1. Fig. 3. SAT curves obtained in Case 4. Fig. 4. SAT curves obtained in Case 5. Fig. 5. SAT curves obtained in Case 6.

5 VOL. 18, No.1, 1967 CRYPTORCHIDISM Therapy was unsuccessful and orchidopexy was performed in July 196, when the patient was gt. An S.A.T. in December 1961 showed a normal plateau for the left testis and no plateau for the right one. Then he was given injections 3 times weekly of 5 I. U. of chorionic gonadotropin, for 2 months. Amelioration was observed: the testis became larger. An S.A.T. in July 1962 revealed a very small plateau for the right side. We have had no further opportunity to follow up the spermatogenic activity in this case. Case 9. H.M., Hosp. No. 692, was a 1-year-old boy with undescended testes. After the administration of chorionic gonadotropin (1 I.U. 3 times weekly for 2 months), the testes descended into the scrotum. Their size proved normal. But an S.A.T. performed 6 weeks later (April 1961, when the boy was 12 years old) gave negative results (Fig. 6, top). Additional treatment with chorionic gonadotropin (total dosage 16, I.U.) was beneficial and a control S.A.T. showed a normal plateau for both testes (Fig. 6, bottom). Case 1. D.M., Hosp. No. 7125, had had a left orchidopexy at the age of 11 years (August 1961). On examination in January 1962; the left testis was found to be small, and the right one of normal morphology. An S.A.T. was infantile for the right and negative for the left side (Fig. 7, top). After treatment with 1 L U. of chorionic gonadotropin 3 times weekly (total dosage 15, I. U. ), a control S.A.T. was performed (March 1963): a normal plateau in the curves for the both testes was found (Fig. 7, bottom). The left testicle is now completely normal in size and consistency. Case 11. B.N., Hosp. No , was a 1-year-old boy with undescended testes. Orchidopexy was performed on the right side in July 1963 and on the left side in July In addition the patient received chorionic gonadotropin treatment, to a total dose of 18, I.U. after the first operation and 24, I.U. after the second. An S.A.T. was performed in December 1964; results were positive for both sides. Case 12. N.E., Hosp. No. 95, was a 12-year-old boy with an undescended left testis and a retractile right one. After administration of 1 I.U. of chorionic gonadotropin 3 times weekly (total dosage 18, L U. ), we found the testes in the scrotum. But in spite of normal morphology of the testicles, an S.A.T. was negative (Fig. 8, top). Additional therapy with chorionic gonadotropin was given (total dose 24, LU.) and a control S.A.T. showed a normal plateau for either side (Fig. 8, bottom). DISCUSSION The S.A.T. examinations show that in the human at the age of lo years, normal spermatogenic activity exists and therefore a plateau appears on the third to fifth day in the uptake curve after the administration of p32

6 1Kr-.--r-'--r-.--'-'--r-' '----' ----,-i---;---t" U> 4.l!! 2 en.l!!.a. :> j S N "h. - >l! "TV 2 t I I I I I O Time (days) 6 en 4 en 2 ", ght ''-... "' :-: left. OL, L--L L- :> K)O -r--r-r-i:rt-rt-rt-rl 2 N "'.. 8 ' 6 41 ',- 2 1 I I I I I Time (days)... " I en '* 4 2 >.a. :> N "h. ' >l! o OI-L--L o 2 Time (days) Fig. 6. SAT curves obtained in Case 9. At top, after operation and before treabnent. At bottom, after treabnent. Fig. 7. SAT curves obtained in Case 1. At top, after orchidopexy. At bottom, after. additional treabnent. Fig. 8. SAT curves obtained in Case 12. At top, with undescended testes after first treabnent. At bottom, after additional treabnent. 8

7 VOL. 1N 1, 1967 CRYPTORCHIDISM 141 (Cases 1 and 2). These results agree with the histological picture of normal testicular biopsy specimens. Histological studies clearly demonstrated that (1) the maturation of testes begins at the age of 7 years, and (2) pathologic maturation is observed in the tubules, tubular walls, and connective interlobular tissue in the undescended testis, at the age of 1 years. 5,11 These abnormal maturations are related to the extrascrota] position of the testes 6 and are responsible for infertility. In Cases 3 and 4, orchidopexy was performed at the ages of 11 and 14 years, respectively, and those patients were found to be infertile at the ages of 24 and 26, respectively. Their ejaculates were azoospermic, the urinary gonadotropin level was high, and the S.A.T. remained negative. The S.A.T. examinations proved that the maturity of the undescended testis is defective after the age of 9 years. In Case 5, orchidopexy was performed at the age of 9 years and 5 months, and at the age of 1 years and 3 months. The S.A.T. gave a normal picture. But in Cases 6 and 7, in which the operations were done at the age of 1 years 6 months and 1 years 2 months, the S.A.T. was negative for the testicles operated upon, but positive in the noncryptorchid testes of the same patients. Gross et al. concluded from their results, based on observations of more than 17 undescended testes, that "the optimal age for surgical therapy is around 9 or 1 years and can be started without hesitation."7,8 The results of our examinations confirm their findings. Follow-up studies of our patients strongly suggest the importance of a postoperative hormonal treatment with chorionic gonadotropin in boys with negative S.A. T. results (without plateau or with a very small plateau). The treatment was in most cases beneficial if started not too long after the orchidopexy. Cases 9, 1, 11, and 12 illustrate the normalization, due to the hormonal therapy, of the spermatogenic activity. In Case 1, orchidopexy was performed at the age of 11 years. The testicle was very small with a negative S.A. T. Prolonged treatment with chorionic gonadotropin was successful, as proved by the repeated S.A. T. and by clinical examinations. It is worth mentioning that this therapy can be of value sometimes at the age of 12 years, as demonstrated in Case 12. The same good results with additional therapy after operation were obtained by Lelong et al. Several investigators have demonstrated that an apparently normal testicle, operated upon after the age of 1 years, does not prove fertile. Semen analyses for 13 patients of this group revealed azoospermia in 1 cases, and the biopsies showed absence of spermatozoa. 1, 13 In our observations, Patients 6, 9, and 12, whose testes were in the scrotum after the age of 1 years, showed negative S.A.T. in spite of completely norma]

8 142 CZERNIAK & ITELSON FERTILITY & STERILITY morphology of the testes. In the light of results with the S.A.T., these hoys received hormonal treatment with subsequent normalizatiton of spermatogenic potentiality. It can be concluded from these studies that the S.A.T. should be performed for every boy whose testes descend after the age of 9 years, spontaneously or after orchidopexy. SUMMARY The Spermatogenic Activity Test (S.A.T.) gives a tme picture of.,permatogenic potentiality, making unnecessary biopsy with histologic study of the maturation state of the testicle. The results of S.A.T. demonstrate clearly that there is a spermatogenic deficiency in the undescended testicle after the age of 9 years. In cases of infertility with azoospermia, observed in adults who underwent orchidopexy after the age of 1 years, the S.A.T. remains negative. The S.A.T. should be performed for all boys whose testes descend after the age of 9 years, whether spontaneously or after orchidopexy. In cases of defective spermatogenic activity additional treatment with chorionic gonadotropin can be efficient, as evidenced by normalization of the S.A.T. Normal morphology of the testis is no proof of fertility. The verification of the S.A.T. shows the real state of spermatogenic potentiality and provides guidance in the planning of hormonal therapy for patients with negative S.A.T. in spite of normal size of the testicle. Department of Radiotherapy and Isotopes Tel-Aviv University Medical School Tel-Hashomer Hospital Israel REFERENCES 1. CARVER, 1. H. Bilateral orchidopexy and fertility. Proc Roy Soc Med 51:328, CZERNIAK, P. p32-studies of spennatogenesis in man: establishment of a spennato genic activity test. Amer 1 Roentgenol 8:327, CZERNIAK, P., and ROTEM, J. Spennatogenic Activity Test (S.A.T.) in man. Harefuah 61:189, CZERNIAK, P. "Duration of Spennatogenesis in Man as Studied by P32." In Radioisotopes in Animal Biology (Vol. 2). Acad. Press, London, 1962, p DE LA BALZE, F. A., MANCINI, R. A., ARRILAGA, F., ANDRADA, 1. A., VILAR,., GURTMAN, A. 1., and DAVIDSON, O. W. Puberal maturation of the nonnal human testis. A histologic study. 1 Clin Endocr 2:266, DE LA BALZE, F. A., MANCINI, R. A., ARRILAGA, F., ANDRADA, 1. A., VILAR,., GURTMAN, A. 1., and DAVIDSON, O. W. Histologic study of the undescended human testis during puberty. 1 Clin Endocr 2:286, GROSS, R. E., and IEWETT, T. C. Surgical experiences from 1222 operations for undescended testis. lama 16:634, 1956.

9 VOL. 18, No.1, 1967 CRYPTORCHIDISM GROSS, R. E., and REPROGLE, R. Z. Treabnent of the undescended testis. Opinions gained from 1767 operations. Postgrad Med 34:226, HAND, I. R. Fertility expectancy following prolonged extrascrotal residence of the testes. Fertil Steril 1: 15, KNAUT, H., and POTEMPA, I. Hodenretention und Fertilitiit. UrolInt 15:77, LAUFER, A. Cryptorchidism. Harefuah 51:18, LELONG, M., PETIT, P., CANLORBE, P. L'ectopie testiculaire. Sem Hop Paris 34: 2487, MACK, W. S. (in discussion) Bilateral orchidopexy and fertility. Proc Roy Soc Med 51:328, ROBINSON, I. N., and ENGLE, E. T. Some observations on the cryptorchoids testis. JUral 71 :726, Southeastern Regional Center for Trophoblastic Neoplasms The Department of Obstetrics and Gynecology, Duke University Medical Center, announces the establishment of the Southeastern Regional Center for Trophoblastic Neoplasms. This Center is sponsored by a Health Service Project Grant Award from the Department of Health, Education, and Welfare, Division of Chronic Diseases. This project in Cancer Control is established for the purpose of providing urinary gonadotropin assays and consultative assistance to physicians, to aid in evaluation of patients who have or are suspected of having abnormalities in trophoblastic tissue growth. As begun on Sept. 3, 1966, physicians desiring gonadotropin assays for patients with such placental abnormalities as molar degeneration, hydatidiform mole, syncytial endometritis, chorioadenoma destruens, and choriocarcinoma may call or write the Center at Duke University Medical Center, Durham, N. C. (Area Code 919, ). Roy T. PARKER, M.D. C. D. CHRISTIAN, M.D. CHARLES B. HAMMOND, M.D.