- Email: [email protected]
Fertility in Cryptorchidism: An Experimental Model
0022-534 7/86/1361-0214$02.00/0 Vol. 136, July
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1986 by The Williams & Wilkins Co.
FERTILITY IN CRYPTORCHIDISM: AN EXPERIMENTAL MODEL KLAUS-PETER JUENEMANN, BARRY A. KOGAN*
AND
MOHAMED H. ABOZEID
From the Department of Urology, University of California School of Medicine, San Francisco, California
ABSTRACT
Because the long-term efficacy of treatment for cryptorchidism is difficult to evaluate in humans, we developed an animal model to study the effects of cryptorchidism on fertility. Sprague-Dawley rats were treated within the first few days of life to create either mechanical or endocrinological cryptorchidism. The ability to father offspring was used as a measure of fertility. Significant differences in fertility between rats with bilateral cryptorchidism and controls were observed, regardless of whether the cause was mechanical or endocrinological. Rats with unilateral cryptorchidism were significantly less fertile than those that underwent unilateral orchiectomy. Further development of this model will permit prospective evaluation of different treatment modalities in cryptorchidism. Although cryptorchidism has been recognized for thousands of years considerable investigation has failed to date to elucidate the mechanism of infertility in patients with cryptorchidism.1 Furthermore, there is no clear-cut evidence that current treatment modalities improve fertility. Since human studies of this condition are fraught with difficulties an animal model was developed to gain more insight into this problem. MATERIALS AND METHODS
We separated 67 newborn Sprague-Dawley rats into 2 major groups according to the cause of cryptorchidism-mechanical or endocrinological. Each group was split into subgroups, including control series, to elucidate the effects of different types of cryptorchidism on fertility. Mechanical cryptorchidism. Mechanical cryptorchidism was simulated by suturing the testis of newborn rats in its intraabdominal position. The 2 to 5-day-old rats were anesthetized with 0.075 to 0.39 mg. sodium pentobarbital (according to age on the day of operation) administered intraperitoneally. The animal was placed in a supine position and a transverse incision of about 1 cm. was made in the lower abdomen just above the base of the penis. Through this approach the as yet undescended testicle was identified on either side and sutured in its intra-abdominal position with 6-zero polyester fiber. Skin closure was performed with 8-zero polyglycolic acid. Four subgroups were formed with 10 rats in each group (except for group 4, which had 9 rats): 1) controls-only sham operations were performed (that is the testicles were exposed but left untouched), 2) bilateral mechanical cryptorchidismboth testes were sutured in their intra-abdominal positions, 3) unilateral mechanical cryptorchidism-only the right testis was sutured and 4) unilateral orchiectomy-the right testis was removed. Endocrinological cryptorchidism. The second major group consisted of rats with hormonally induced cryptorchidism to simulate the effect of endocrinological abnormality on testicular maturation and descent. The technique used was that of Rajfer and Walsh, that is daily subcutaneous injections of 17{3estradiol in sesame oil for 30 days, beginning 2 days after birth. 2 Four subgroups were formed: 1) controls-9 male rats were injected for 30 days with sesame oil alone, starting 2 days after Supported in part by grants from the Committee on Research of the Academic Senate and from the Research Evaluation and Allocation Committee, University of California, San Francisco, California, and by an award from B. Braun Stiftung, Melsungen, Federal Republic of Germany. * Requests for reprints: Department of Urology, U-518, University of California, San Francisco, California 94143. 214
birth with 0.1 ml. for 10 days, then 0.2 ml. for days 11 through 20 and 0.3 ml. for days 21 through 30, 2) full dose 17(3estradiol-9 rats were injected for 30 days with estradiol, starting with 0.01 mg. in 0.1 ml. sesame oil for 10 days, then 0.02 mg. in 0.2 ml. for the next 10 days and 0.03 mg. in 0.3 ml. sesame oil for days 21 through 30 (in 3 rats injection was continued for 30 more days, increasing the dosage of 17(3estradiol and sesame oil every 10 days by 0.01 mg. and 0.1 ml., respectively, until a dosage of 0.06 mg. in 0;6 ml. was reached on days 51 through 60), 3) full dose 17(3-estradiol, short course-5 rats were injected with 0.01 mg. estradiol in 0.1 ml. oil for 7 days only and 4) half dose 17(3-estradiol-5 rats were injected with half of the amount of estradiol (0.005 to 0.015 mg.) for 30 days, according to the schedule for group 2. When the rats were mature (64 to 66 days old), each male rat was mated with 2 female rats that previously had produced at least 1 litter. After 24 days the female rats were sacrificed and the number of all fetuses as well as the mean weight were determined. Differences among groups in the number of female rats impregnated were analyzed with a chi-square technique, while differences in litter size and mean weight were analyzed with a 1-sided t test. RESULTS
Mechanical cryptorchidism. The control rats (sham operation) had normal testes that descended after they were approximately 21 days old. One control rat died during examination at the age of 58 days. The rats that were operated on had intraabdominal unilateral or bilateral cryptorchidism without any further complications. Those rats undergoing unilateral orchiectomy were otherwise normal. The results of fertility proved by the ability to father offspring are shown in the table. After mating with control rats, 85 per cent of the female rats became pregnant within 24 days (in 3 cases 1 of the female rats had just delivered on day 24). One of the 10 control rats failed in paternity, while a second produced pregnancy in 1 of 2 female rats only. Bilateral cryptorchidism prevented paternity in all cases. Compared to controls, this difference was statistically significant (p <0.001). All of the rats with unilateral cryptorchidism survived and developed normally. In this group there was only a 60 per cent pregnancy rate; no pregnancy occurred in either female rat mated with 3 male rats and 2 other male rats could impregnate only 1 of the 2 female rats. All of the rats that underwent unilateral orchiectomy survived and were normal. Their pregnancy rate of 94 per cent was significantly better than the group with unilateral cryptorchidism (p <0.02). A retrospective
215
FERTILITY IN CRYPTORCHIDISM
Fertility results Procedure
No. Rats
No. Female Rats Pregnant/Total
10
17/20 (85)
(%)
Sham operation (controls) Bilat. mechanical cryptorchidism Unilat. mechanical cryptorchidism Unilat. orchiectomy Sesame oil alone (controls) Estradiol-full dose Estradiol-full dose, short course Estradiol-half dose
10
Mean Litter Size
Mean Fetal Wt. (gm.)
12.9
3.39
0/20
10
12/20 (60)
12.6
2.1
9 9
17/18 (94) 17/18 (94)
12.2 12.6
2.4 1.3
9
5
0/18 0/10
5
0/10
For statistical comparisons only data from pregnant female rats were considered.
comparison of the unilateral cryptorchidism group with controls revealed no statistically significant difference (p <0.08). In all groups male rats that fathered offspring had virtually identical litter sizes (12.9 versus 12.6 versus 12.2). However, there were statistically significant differences in mean fetal weight between controls and rats with unilateral cryptorchidism (p <0.025), and between controls and rats with unilateral orchiectomy (p <0.05). Endocrinological cryptorchidism. The control group (treated with sesame oil only) showed testicular descent in 100 per cent and a pregnancy rate of 94 per cent; only 1 female rat failed to become pregnant (see table). All rats treated with 17,6-estradiol had bilateral cryptorchidism and none showed fertility (p <0.001 versus controls). One of the male rats in the 30-day full dose group died at the age of 21 days during injection. All other rats did well without any further complications. DISCUSSION
Evaluation of infertility data requires standard criteria. The most widely used method is semen analysis, where a level of more than 20 X 106 sperm per ml. has been accepted as sufficient for fertility. 3 However, other factors are relevant, including morphology, motility and the presence of antisperm antibodies. Unfortunately, these factors seldom are evaluated in patients followed after treatment for cryptorchidism. A more appropriate end-point is the ability to impregnate a female subject, which by necessity takes into consideration the aforementioned factors as well as all others. Unfortunately, proof of paternity is complex and expensive, requiring lengthy followup and HLA typing of parents and children. Aside from considerations of defining fertility human studies of cryptorchidism are hampered by the difficulty of physical examination, the heterogeneity of the disease and its treatment, and the lengthy followup necessary. Even the best examiner can confuse retractile, incompletely descended and ectopic testes. Obviously, the ramifications of each diagnosis are different. Similarly, the group with true cryptorchidism includes patients with unilateral and bilateral undescended testes, as well as those whose testes descend spontaneously after birth. Furthermore, in each group the cause may be different, including mechanical, endocrinological and inherent testicular abnormalities, among others. Finally, treatment, whether hormonal and/or surgical, and the age at treatment vary considerably. Consequently, the validity of conclusions of any study of fertility reached 20 to 30 years after the diagnosis of cryptorchidism and including widely disparate patients must be questioned. For all of the aforementioned reasons it remains even to date nearly impossible to counsel parents accurately about the chances for fertility in their newborns with cryptorchidism. Therefore, an animal model was developed in which the
cause, treatment and mating could be controlled and fertility monitored. Sprague-Dawley rats were chosen because of their availability and short life-span, and they are relatively inexpensive. Furthermore, later phases of sexual differentiation including penile growth and testicular descent, occur after birth and have been studied extensively. 2 • 4 Consequently, it is possible hormonally and mechanically to prevent testicular descent in newborn rats and, thereby, simulate cryptorchidism in the human fetus. Male rats are highly fertile and female rats have multiple pregnancies. Thus, it appears that mating studies involving rats can detect subtle changes in fertility. 5 •6 In our model the difference in fertility between the sham operated control rats and those with bilateral mechanically induced cryptorchidism was striking (85 and O per cent pregnancy rates, respectively) but the difference in the impregnation rate attained by the rats with unilateral mechanical cryptorchidism compared to controls was not statistically significant. Interestingly, newborns undergoing unilateral orchiectomy had a paternity rate significantly higher than the rats with unilateral cryptorchidism. Although preliminary, these data suggest an inhibitory effect of the cryptorchid testis on the function of the contralateral normal testis. Another interesting finding was the smaller fetal size in the unilateral cryptorchidism and orchiectomy groups, which implies that it took longer for the male rats to impregnate the female animals in those groups and suggests that not only a grossly abnormal testis but also an absent testis have some effect on fertility in the rat. To delineate better the reasons for the differences seen morphological, histological, endocrinological and immunologi~ cal studies are underway. Interestingly, Kogan and associates were unable to demonstrate any differences in similar studies although the ability to impregnate a female rat was not inves~ tigated. 1• 7 Many clinicians would suggest that hormonal problems are far more common than mechanical problems in children with cryptorchidism. Therefore, we also developed a model of endocrinological cryptorchidism. Initial dosages were based on other studies 2 and were highly effective in preventing testicular descent but these rats were smaller than controls and drank 2 to 3 times more water, suggesting that the estradiol had significant pituitary or hypothalamic effects, interfering with the production of growth and antidiuretic hormones. Later in the study lower dosages were used that obviated these problems but were equally effective in preventing testicular descent. Since these rats were observed to attempt intercourse, it is unlikely that their infertility resulted from female imprinting of their brains. It certainly is possible that the estradiol, in ways as yet unclear, causes infertility independent of preventing testicular descent. On the surface this is a weakness in the model· however, it is not dissimilar to the human experience. There i~ increasing evidence that humans with cryptorchidism may be hypogonadotropic and that this, in turn, may limit spermatogenesis. 8 Since the purpose of the model is to mimic the human experience, the use of estradiol seems appropriate. Further studies are underway in an effort to decrease the estradiol used and to create unilateral endocrinological cryptorchidism. This animal model is the first in which several causes of cryptorchidism can be studied and fertility can be compared with the use of pregnancy as an end-point. Most exciting is that this model is the first to allow prospective evaluation of hormonal and surgical treatment, as well as the effects of early versus late treatment. Although it is unwise to extrapolate directly from rats to humans, it is hoped that this model will provide insight into the cause and treatment of infertility owing to cryptorchidism in man. REFERENCES 1. Kogan, S. J.: Fertility in cryptorchidism. In: Cryptorchidism: Man-
agement and Implications. Edited by F. Hadziselimovic. New York: Springer-Verlag, chapt. 6, pp. 71-82, 1983.
216
JUENEMANN, KOGAN AND ABOZEID
2. Rajfer, J. and Walsh, P. C.: Hormonal regulation of testicular descent: experimental and clinical observations. J. Urol., 118: 985, 1977. 3. Freund, M.: Standards for the rating of human sperm morphology: a cooperative study. Int. J. Fertil., 11: 97, 1966. 4. Hadziselimovic, F.: Embryology of testicular descent and maldescent. In: Cryptorchidism: Management and Implications. New York: Springer-Verlag, chapt. 3, pp. 11-34, 1983. 5. Nagler, H. M. and de Vere White, R.: Long-term effects of testicular torsion on reproductive capacity in the adult male rat. Surg. Forum, 33: 619, 1982. 6. Cosentino, M. J., Rabinowitz, R., Valvo, J. R. and Cockett, A. T.
K.: The effect of prepubertal spermatic cord torsion on subsequent fertility in rats. J. Androl., 5: 93, 1984. 7. Kogan, S. J., Vatandaslar, F., Gondos, B., Bennett, B., Nehlsen, S., Sun, E., Fleckman, A., Smey, P. and Levitt, S.: Experimental unilateral cryptorchidism: is there a contralateral effect on the descended testis? Read at annual meeting of American Academy of Pediatrics, San Francisco, California, p. 51, October 22-27, 1983. 8. Hadziselimovic, F., Thommen, L., Girard, J. and Herzog, B.: The significance of postnatal gonadotropin surge for testicular development in normal and cryptorchid testes. J. Urol., 136: 274, 1986.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1986 by The Williams & Wilkins Co.
FERTILITY IN CRYPTORCHIDISM: AN EXPERIMENTAL MODEL KLAUS-PETER JUENEMANN, BARRY A. KOGAN*
AND
MOHAMED H. ABOZEID
From the Department of Urology, University of California School of Medicine, San Francisco, California
ABSTRACT
Because the long-term efficacy of treatment for cryptorchidism is difficult to evaluate in humans, we developed an animal model to study the effects of cryptorchidism on fertility. Sprague-Dawley rats were treated within the first few days of life to create either mechanical or endocrinological cryptorchidism. The ability to father offspring was used as a measure of fertility. Significant differences in fertility between rats with bilateral cryptorchidism and controls were observed, regardless of whether the cause was mechanical or endocrinological. Rats with unilateral cryptorchidism were significantly less fertile than those that underwent unilateral orchiectomy. Further development of this model will permit prospective evaluation of different treatment modalities in cryptorchidism. Although cryptorchidism has been recognized for thousands of years considerable investigation has failed to date to elucidate the mechanism of infertility in patients with cryptorchidism.1 Furthermore, there is no clear-cut evidence that current treatment modalities improve fertility. Since human studies of this condition are fraught with difficulties an animal model was developed to gain more insight into this problem. MATERIALS AND METHODS
We separated 67 newborn Sprague-Dawley rats into 2 major groups according to the cause of cryptorchidism-mechanical or endocrinological. Each group was split into subgroups, including control series, to elucidate the effects of different types of cryptorchidism on fertility. Mechanical cryptorchidism. Mechanical cryptorchidism was simulated by suturing the testis of newborn rats in its intraabdominal position. The 2 to 5-day-old rats were anesthetized with 0.075 to 0.39 mg. sodium pentobarbital (according to age on the day of operation) administered intraperitoneally. The animal was placed in a supine position and a transverse incision of about 1 cm. was made in the lower abdomen just above the base of the penis. Through this approach the as yet undescended testicle was identified on either side and sutured in its intra-abdominal position with 6-zero polyester fiber. Skin closure was performed with 8-zero polyglycolic acid. Four subgroups were formed with 10 rats in each group (except for group 4, which had 9 rats): 1) controls-only sham operations were performed (that is the testicles were exposed but left untouched), 2) bilateral mechanical cryptorchidismboth testes were sutured in their intra-abdominal positions, 3) unilateral mechanical cryptorchidism-only the right testis was sutured and 4) unilateral orchiectomy-the right testis was removed. Endocrinological cryptorchidism. The second major group consisted of rats with hormonally induced cryptorchidism to simulate the effect of endocrinological abnormality on testicular maturation and descent. The technique used was that of Rajfer and Walsh, that is daily subcutaneous injections of 17{3estradiol in sesame oil for 30 days, beginning 2 days after birth. 2 Four subgroups were formed: 1) controls-9 male rats were injected for 30 days with sesame oil alone, starting 2 days after Supported in part by grants from the Committee on Research of the Academic Senate and from the Research Evaluation and Allocation Committee, University of California, San Francisco, California, and by an award from B. Braun Stiftung, Melsungen, Federal Republic of Germany. * Requests for reprints: Department of Urology, U-518, University of California, San Francisco, California 94143. 214
birth with 0.1 ml. for 10 days, then 0.2 ml. for days 11 through 20 and 0.3 ml. for days 21 through 30, 2) full dose 17(3estradiol-9 rats were injected for 30 days with estradiol, starting with 0.01 mg. in 0.1 ml. sesame oil for 10 days, then 0.02 mg. in 0.2 ml. for the next 10 days and 0.03 mg. in 0.3 ml. sesame oil for days 21 through 30 (in 3 rats injection was continued for 30 more days, increasing the dosage of 17(3estradiol and sesame oil every 10 days by 0.01 mg. and 0.1 ml., respectively, until a dosage of 0.06 mg. in 0;6 ml. was reached on days 51 through 60), 3) full dose 17(3-estradiol, short course-5 rats were injected with 0.01 mg. estradiol in 0.1 ml. oil for 7 days only and 4) half dose 17(3-estradiol-5 rats were injected with half of the amount of estradiol (0.005 to 0.015 mg.) for 30 days, according to the schedule for group 2. When the rats were mature (64 to 66 days old), each male rat was mated with 2 female rats that previously had produced at least 1 litter. After 24 days the female rats were sacrificed and the number of all fetuses as well as the mean weight were determined. Differences among groups in the number of female rats impregnated were analyzed with a chi-square technique, while differences in litter size and mean weight were analyzed with a 1-sided t test. RESULTS
Mechanical cryptorchidism. The control rats (sham operation) had normal testes that descended after they were approximately 21 days old. One control rat died during examination at the age of 58 days. The rats that were operated on had intraabdominal unilateral or bilateral cryptorchidism without any further complications. Those rats undergoing unilateral orchiectomy were otherwise normal. The results of fertility proved by the ability to father offspring are shown in the table. After mating with control rats, 85 per cent of the female rats became pregnant within 24 days (in 3 cases 1 of the female rats had just delivered on day 24). One of the 10 control rats failed in paternity, while a second produced pregnancy in 1 of 2 female rats only. Bilateral cryptorchidism prevented paternity in all cases. Compared to controls, this difference was statistically significant (p <0.001). All of the rats with unilateral cryptorchidism survived and developed normally. In this group there was only a 60 per cent pregnancy rate; no pregnancy occurred in either female rat mated with 3 male rats and 2 other male rats could impregnate only 1 of the 2 female rats. All of the rats that underwent unilateral orchiectomy survived and were normal. Their pregnancy rate of 94 per cent was significantly better than the group with unilateral cryptorchidism (p <0.02). A retrospective
215
FERTILITY IN CRYPTORCHIDISM
Fertility results Procedure
No. Rats
No. Female Rats Pregnant/Total
10
17/20 (85)
(%)
Sham operation (controls) Bilat. mechanical cryptorchidism Unilat. mechanical cryptorchidism Unilat. orchiectomy Sesame oil alone (controls) Estradiol-full dose Estradiol-full dose, short course Estradiol-half dose
10
Mean Litter Size
Mean Fetal Wt. (gm.)
12.9
3.39
0/20
10
12/20 (60)
12.6
2.1
9 9
17/18 (94) 17/18 (94)
12.2 12.6
2.4 1.3
9
5
0/18 0/10
5
0/10
For statistical comparisons only data from pregnant female rats were considered.
comparison of the unilateral cryptorchidism group with controls revealed no statistically significant difference (p <0.08). In all groups male rats that fathered offspring had virtually identical litter sizes (12.9 versus 12.6 versus 12.2). However, there were statistically significant differences in mean fetal weight between controls and rats with unilateral cryptorchidism (p <0.025), and between controls and rats with unilateral orchiectomy (p <0.05). Endocrinological cryptorchidism. The control group (treated with sesame oil only) showed testicular descent in 100 per cent and a pregnancy rate of 94 per cent; only 1 female rat failed to become pregnant (see table). All rats treated with 17,6-estradiol had bilateral cryptorchidism and none showed fertility (p <0.001 versus controls). One of the male rats in the 30-day full dose group died at the age of 21 days during injection. All other rats did well without any further complications. DISCUSSION
Evaluation of infertility data requires standard criteria. The most widely used method is semen analysis, where a level of more than 20 X 106 sperm per ml. has been accepted as sufficient for fertility. 3 However, other factors are relevant, including morphology, motility and the presence of antisperm antibodies. Unfortunately, these factors seldom are evaluated in patients followed after treatment for cryptorchidism. A more appropriate end-point is the ability to impregnate a female subject, which by necessity takes into consideration the aforementioned factors as well as all others. Unfortunately, proof of paternity is complex and expensive, requiring lengthy followup and HLA typing of parents and children. Aside from considerations of defining fertility human studies of cryptorchidism are hampered by the difficulty of physical examination, the heterogeneity of the disease and its treatment, and the lengthy followup necessary. Even the best examiner can confuse retractile, incompletely descended and ectopic testes. Obviously, the ramifications of each diagnosis are different. Similarly, the group with true cryptorchidism includes patients with unilateral and bilateral undescended testes, as well as those whose testes descend spontaneously after birth. Furthermore, in each group the cause may be different, including mechanical, endocrinological and inherent testicular abnormalities, among others. Finally, treatment, whether hormonal and/or surgical, and the age at treatment vary considerably. Consequently, the validity of conclusions of any study of fertility reached 20 to 30 years after the diagnosis of cryptorchidism and including widely disparate patients must be questioned. For all of the aforementioned reasons it remains even to date nearly impossible to counsel parents accurately about the chances for fertility in their newborns with cryptorchidism. Therefore, an animal model was developed in which the
cause, treatment and mating could be controlled and fertility monitored. Sprague-Dawley rats were chosen because of their availability and short life-span, and they are relatively inexpensive. Furthermore, later phases of sexual differentiation including penile growth and testicular descent, occur after birth and have been studied extensively. 2 • 4 Consequently, it is possible hormonally and mechanically to prevent testicular descent in newborn rats and, thereby, simulate cryptorchidism in the human fetus. Male rats are highly fertile and female rats have multiple pregnancies. Thus, it appears that mating studies involving rats can detect subtle changes in fertility. 5 •6 In our model the difference in fertility between the sham operated control rats and those with bilateral mechanically induced cryptorchidism was striking (85 and O per cent pregnancy rates, respectively) but the difference in the impregnation rate attained by the rats with unilateral mechanical cryptorchidism compared to controls was not statistically significant. Interestingly, newborns undergoing unilateral orchiectomy had a paternity rate significantly higher than the rats with unilateral cryptorchidism. Although preliminary, these data suggest an inhibitory effect of the cryptorchid testis on the function of the contralateral normal testis. Another interesting finding was the smaller fetal size in the unilateral cryptorchidism and orchiectomy groups, which implies that it took longer for the male rats to impregnate the female animals in those groups and suggests that not only a grossly abnormal testis but also an absent testis have some effect on fertility in the rat. To delineate better the reasons for the differences seen morphological, histological, endocrinological and immunologi~ cal studies are underway. Interestingly, Kogan and associates were unable to demonstrate any differences in similar studies although the ability to impregnate a female rat was not inves~ tigated. 1• 7 Many clinicians would suggest that hormonal problems are far more common than mechanical problems in children with cryptorchidism. Therefore, we also developed a model of endocrinological cryptorchidism. Initial dosages were based on other studies 2 and were highly effective in preventing testicular descent but these rats were smaller than controls and drank 2 to 3 times more water, suggesting that the estradiol had significant pituitary or hypothalamic effects, interfering with the production of growth and antidiuretic hormones. Later in the study lower dosages were used that obviated these problems but were equally effective in preventing testicular descent. Since these rats were observed to attempt intercourse, it is unlikely that their infertility resulted from female imprinting of their brains. It certainly is possible that the estradiol, in ways as yet unclear, causes infertility independent of preventing testicular descent. On the surface this is a weakness in the model· however, it is not dissimilar to the human experience. There i~ increasing evidence that humans with cryptorchidism may be hypogonadotropic and that this, in turn, may limit spermatogenesis. 8 Since the purpose of the model is to mimic the human experience, the use of estradiol seems appropriate. Further studies are underway in an effort to decrease the estradiol used and to create unilateral endocrinological cryptorchidism. This animal model is the first in which several causes of cryptorchidism can be studied and fertility can be compared with the use of pregnancy as an end-point. Most exciting is that this model is the first to allow prospective evaluation of hormonal and surgical treatment, as well as the effects of early versus late treatment. Although it is unwise to extrapolate directly from rats to humans, it is hoped that this model will provide insight into the cause and treatment of infertility owing to cryptorchidism in man. REFERENCES 1. Kogan, S. J.: Fertility in cryptorchidism. In: Cryptorchidism: Man-
agement and Implications. Edited by F. Hadziselimovic. New York: Springer-Verlag, chapt. 6, pp. 71-82, 1983.
216
JUENEMANN, KOGAN AND ABOZEID
2. Rajfer, J. and Walsh, P. C.: Hormonal regulation of testicular descent: experimental and clinical observations. J. Urol., 118: 985, 1977. 3. Freund, M.: Standards for the rating of human sperm morphology: a cooperative study. Int. J. Fertil., 11: 97, 1966. 4. Hadziselimovic, F.: Embryology of testicular descent and maldescent. In: Cryptorchidism: Management and Implications. New York: Springer-Verlag, chapt. 3, pp. 11-34, 1983. 5. Nagler, H. M. and de Vere White, R.: Long-term effects of testicular torsion on reproductive capacity in the adult male rat. Surg. Forum, 33: 619, 1982. 6. Cosentino, M. J., Rabinowitz, R., Valvo, J. R. and Cockett, A. T.
K.: The effect of prepubertal spermatic cord torsion on subsequent fertility in rats. J. Androl., 5: 93, 1984. 7. Kogan, S. J., Vatandaslar, F., Gondos, B., Bennett, B., Nehlsen, S., Sun, E., Fleckman, A., Smey, P. and Levitt, S.: Experimental unilateral cryptorchidism: is there a contralateral effect on the descended testis? Read at annual meeting of American Academy of Pediatrics, San Francisco, California, p. 51, October 22-27, 1983. 8. Hadziselimovic, F., Thommen, L., Girard, J. and Herzog, B.: The significance of postnatal gonadotropin surge for testicular development in normal and cryptorchid testes. J. Urol., 136: 274, 1986.