Treatment of Defective Spermatogenesis tvith Human Gonadotropins

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1 Treatment of Defective Spermatogenesis tvith Human Gonadotropins W. Z. POLISHUK, M.D., Z. PALTI, M.D., and A. LAUFER, M.D. TREATMENT of male sterility due to defective spermatogenesis is not satisfactory. Mter the successful results in induction of ovulation with human gonadotropins,! 4 we hoped that similar treatment in cases of defective spermatogenesis might improve our results. One of the common mistakes in this field is to regard azoospermia and oligospermia as a single clinicopathologic entity. Testicular biopsy and the estimation of FSH levels in the urine 3.6 have permitted the classification of these cases into those representing pituitary or testicular failures. However, in many cases there is little correlation between sperm count and testicular biopsy findings. 6 In most cases of oligospermia, FSH titration gives normal values. The use of gonadotropin therapy in azoospermia and oligospermia is expected to give good results in cases with low FSH titration values. This would naturally limit the use of pituitary hormones to a small number of cases. The introduction into clinical use of human gonadotropins raised the hope of improving our results in the treatment of oligo- and azoospermia also in cases in which FSH values were normal. It was hoped that excess human gonadotropins (FSH and ICSH) might stimulate to higher activity the germinal epithelium also in patients with normal FSH values, thus improving sperm count and quality. MATERIAL AND METHOD This report concerns 23 patients sent to our Ma]e Sterility Clinic for investigation and treatment. Most were admitted for 2 days' hospital study, which includes a general examination, routine urinalysis, studies of blood morphology and chemistry, X-ray of sella turcica, and assays of P.B.I. and urinary 17 -ketosteroids and FSH, as well as testicular biopsy. From the Department of Pathology, Hadassah University Hospital, Jerusalem, and the Male Sterility Clinic, Gynecological Department, Rothschild Hospital, Haifa, Israel. 127

2 128 POLISHUIt ET AL. FERTILITY & STERILITY The cases studied were divided into 3 groups according to the clinical findings: azoospermia (6 cases), oligospermia of different grades ( 14 cases), and hypokinesis with normal sperm count and morphology (3 cases). Testicular biopsy was performed in 17 cases: 4 in which there was tubular atrophy and fibrosis, 1 in which tubuli were lined by Sertoli cells only, 4 of spermatogenic arrest, 2 of "mixed type" pattern, where tubules with arrest of spermatogenesis or hypospermatogenesis are mingled with tubules lined by Sertoli cells only, and 7 of hypospermatogenesis. Treatment was given in 3 dose schedules: 1. Human menopausal gonadotropin (HMG, Pergonal 500*) was given for its FSH activity, in doses of 300 mg. (IRP), 3 times weekly for 2 weeks, followed by twice-weekly injections from Days of treatment, a total of 4800 mg. In addition, human chorionic gonadotropin (HeG, Pregnylt) was given for its LH-like activity, in doses of 24,000 u. of HeG. This course of treatment was given in 4 cases. 2. Pergonal was given in 150-mg. doses every 2 days, and Pregnyl in 1500-U. doses once weekly, a total of mg. of IRP HMG and 52,000-63,000 HeG U. This treatment lasted between 70 and 84 days, and was given to 14 patients. 3. Pergonal was given in 150-mg. doses every 2 days for doses, with Pregnyl, 2500 U., once a week. This amounted to a total of 1800 mg. IRP HMG and 10,000 U. of HeG. This treatment was given to 8 patients. RESULTS The results of semen analysis reported in Table 1 were those shortly before treatment and the highest value obtained during and in the immediate follow-up period. Azoospermia Of the 6 cases with azoospermia, in only 1 did we find an improvement, with the appearance of spermatozoa of good motility in the ejaculate. The repeated testicular biopsy showed a regenerative spermatogenic process (Table 1). Case Report. RY., aged 35, married for 10 years, had primary sterility due to oligospermia. This patient was sent to our clinic in 1962 after having received various treatments, including Gestylt and Pregnyl. His sperm count had slowly decreased during this period until it reached azoospermia. Because of repeated findings of azoospermia during 12 months, he was reinvestigated. *Cutter Laboratories, Berkeley, Calif. torganon Inc., West Orange, N. J.

3 VOL. 18, No.1, 1967 GONADOTROPINS IN SPERMOPATHY 129 The patient was 178 cm. tall and weighed 62 kg., with normal external genitalia. Physical examination and routine urine and blood studies were essentially normal. The value for P.B.I. was 7.2 gm.%; for 17-ketosteroids, 11.5 mg.jl.; and for FSH, less than 25 R.U.jL. Testicular biopsy showed small tubules with a thin basal membrane lined with Sertoli cells only. No spermatogenesis was present. Leydig cells had normal distribution (Fig. 1). Fig. 1. Before treatment with Pergonal: Seminiferous tubules of various size, lined by Sertoli cells only. No spermatogenesis present. (H & E, X 87) The patient received 150 mg. IRP HMG in 10 doses. Repeated semen analysis showed 1-2 million spermatozoa per cubic centimeter, 80% of which were motile. On repeated testicular biopsy (Fig. 2), the histological picture varied from area to area (Fig. 3). In some areas the tubules were atrophic and fibrotic. In other areas the tubules were small and shrunken with a thickened basal membrane lined with Sertoli cells only, but in the lumen some spermatocytes were present. A third group of tubules, also rather small, with a thickened and fibrotic wall, showed complete spermatogenesis and few spermatozoa. A further 15 injections of HMG were given and there was a further rise in his sperm count (5 millionj cc.) with 40% motility. This patient is receiving further treatment. Oligospermia In the group with oligospermia (Table 1) we found improvement in sperm count and motility in 4 patients (Cases 2, 9, 11, and 12). The wife of one of these (Case 12) became pregnant and delivered an apparently normal child. Improvement in only motility was observed in 2 cases (Cases 1 and 6) and an increase in sperm count alone in 1 case (Case 8). In 2 cases (Cases 4 and 5) there was a reduction in number of spermatozoids and their motility. In 2 others (Cases 6 and 13) there was a reduction in number and in 1 case a reduction in motility only (Case 7).

4 TABLE 1. Results of Treatment with HMG and HCG Semtln analysi8 Before treatment After treatment Dosage Age Motility Motility HMG oaslj Initials (years) Million/cc. (%) Million/cc. (%) (mg.irp) HOG Testicular biopsy AZOOSPERMIA 1 S.T ,000 R: arrested spenniogenesis; L: atrophy and fibrosis 2 A.M ,000 3 RS ,500 Arrest of spenniogenesis 4 RI ,500 Sertoli cells only D.D ,500 Atrophy 6 S.B ,500 Atrophy OLIGOSPERMIA 1 R.H ,500 H ypospenniogenesis 2 S.A ,000 Hypospenniogenesis, Sertoli cells ---..,.., ~ ~ " 0;; ROOO ~oooo H vnosnenniol!enesis

5 ~ :S.A. ~\:J 0 lu..1u ;::oq, q,<>uu ;::o<>,uuu nypusperrnlugenesls, "ertoli cells 3 C.A ,000 Rypospenniogenesis 4 A.I ,500 Arrest at spennatocytes II 5 T.M ,000 Rypospenniogenesis 6 C.B ,000 Mixed type 7 M.C ,500 8 P.R ,000 Rypospenniogenesis 9 M.Z , B.M , T.I ,000 12* C.N , R.I , A.A ,000 HYPOKINESIS 1 B.I ,000 Arrest of spenniogenesis 2 Y.M M.A ,000 Nonnal spenniogenesis *Pregnancy occurred.

6 132 POLISHUK ET AI.. FERTILITY & STERILITY Hypokinesis In the group of cases of hypokinesis (Table 1) there was a definite improvement in 1 case, slight improvement in another, and no change in the third. DISCUSSION Attempts to stimulate spermatogenesis have been made with various hormones. When no general or local conditions are found to account for Fig. 2. After treatment with Pergonal: Irregular size of seminiferous tubules. Basal membrane is thickened. Note presence of spermatogenesis in some tubules; rare spermatozoa are present. (H & E X 350) Fig. 3. Similar area to that in Fig. 2. Note presence of few spermatozoa. (H & E, X 350)

7 VOL. 18, No.1, 1967 GONADOTROPINS IN SPEll.MOPATHY 133 reduced spermiogenesis, the use of gonadotropins seems logical. Failure of this type of therapy in the past has been considered as due to the formation of antibodies to the animal proteins contained in the FSH preparations used. 7 The introduction into clinical use of HPG and HMG was found effective in cases of amenorrhea and azoospermia due to hypopituitarism. 2, 5,8 However, also in cases of normal FSH values and anovulation, treatment with gonadotropins (HMG and HCG) induced ovulation. By analogy, this type of treatment was applied in male sterility, in cases of azoospermia and oligospermia with normal FSH levels. There is little doubt that the two conditions that will favor good results are: ( 1 ) low FSH values, indicating pituitary hypofunction, and (2) tubules that are able to respond to FSH stimulation. The favorable results observed, in the 1 case reported above, represented by the improvement in sperm count as well as by the presence of spermatogenesis in the biopsy specimen, seem to be the direct effect of human gonadotropin stimulation. This is supported by the fact that the patient did not respond to previous treatments, and by the time relationship between gonadotropin treatment and the changes in the tubules. With acceptance of the principle that the biopsy specimen represents the over-all picture of the testicular histopathology, the change that occurred in the second biopsy further supports our view that the changes found are due to the HMG administered. With the doses of FSH and LH employed in this study, the results were generally disappointing (Table 2). The duration of treatment with FSH was determined according to the view that the spermatogenic cycle lasts about 64 days.9 We did not find any correlation between any of the schedules of treatment used and the results obtained. SUMMARY 1. Human gonadotropins were used in 23 cases of male sterility: 6 cases of azoospermia, 14 cases of oligospermia, and 3 cases of hypokinesia. TABLE 2. Summary of Seminal Changes after Treatment with HMG and HCG No. of Increased Decreased No Condition cases No lcc. Motility Both No lcc. Motility Both change Azoospermia Oligospermia Hypokinesis TOTAL

8 134 POLISHUK ET AL. FERTILITY & STERILITY In all cases the FSH titration value in the urine was within normal limits. 2. The gonadotropins used were human menopausal gonadotropin (HMG) for its FSH activity, and human chorionic gonadotropin (HCG) for its LH-like activity. Three dose schedules were studied: (1) 4800 mg. of HMG and 24,000 U. of HCG given during 50 days of treatment; (2) mg. of HMG and 52,000-63,000 U. of HCG given during days; and (3) 1800 mg. of HMG and 10,000 U. of HCG given in a 24-day period. 3. Of the 6 cases of azoospermia, in only 1 was there improvement in semen analysis and in the histologic picture of the testes. In that case, reported in detail, the testes had tubules lined with Sertoli cells only. In the group with oligospermia (14 cases) an increased sperm count was found in 4 cases, in 1 of which pregnancy ensued. Of the 3 cases of hypokinesis, there was definite improvement in sperm motility in With the doses of HMG and HCG employed in this study, the results were generally disappointing. We feel that more favorable results would be expected in cases indicative of pituitary hypofunction. Department of Obstetrics and Gynecology Hadassah University Hospital Jerusalem, Israel REFERENCES 1. GEMZELL, G, DICZFALUSY, K, and TILLINGER, K. G. J Clin Endocr 18: 1333, GEMZELL, C., and KJESSLER, H. Lancet 1:644, '3. JOEL, C. J. Harefuah 41:82, LUNENFELD, B. J Int Fed Gynec Obstet 1:153, MACLEOD, J., PAZIANOS, A., and RAY, B. S. Lancet 1:1196, NELsoN, W. O. Evaluation of testicular function. Presented at Michigan State University Centennial Symposium, STERGARD, K Acta Endocr 90 (Suppl): 235, POLISHUK, W. Z., PALTI, Z., RABAu, K, LUNENFELD, B., and DAVID, A. J Obstet Gynaec Brit Comm 72:778, HELLER, C. G., and CLERMONT, Y. Science 140:184,1963.