Mobile

Quantitative Histology of Germ Cells in the Undescended Testes of Human Fetuses, Neonates and Infants

Description
Quantitative Histology of Germ Cells in the Undescended Testes of Human Fetuses, Neonates and Infants
Categories
Published
of 5
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Related Documents
Share
Transcript
  0022-5347/95/1543-1188 03.00/0 THE ouffiwa OF URomv Copyright 1995 by A~IERICAV UROLZXICAL SSO('IATIoN, INC. Vol. 154, 188-1192. September 1995 Printed in US QUANTITATIVE HISTOLOGY OF GERM CELLS IN THE UNDESCENDED TESTES OF HUMAN FETUSES, NEONATES AND INFANTS D. CORTES, J. M. THORUP AND B. L. BECK rom the Departments of Paediatric Surgery and Pathology Rigshospitalet State University Hospital Copenhagen Denmark ABSTRACT Purpose: We investigated the number of germ cells per tubular cross section and testicular weight in cryptorchid fetuses, neonates and infants, and characterized additional abnormalities. Materials and Methods: Our series comprised 35 fetuses and 58 boys with cryptorchidism, and 22 normal fetuses and 25 normal boys. Age ranged from 28 weeks of gestation to 3 years. Results: Cryptorchid fetuses had reduced germ cells per tubular cross section values and lower testicular weights. Values were reduced in cryptorchid boys without a symptomatic inguinal hernia. If a hernia was present, values were normal in the first year of life but decreased at age 1 to 3 years. Malformations or dysplasia of the kidneys, ureter or T10 to S5 vertebrae were present in 34 of the cryptorchid fetuses and 18% of the cryptorchid boys without a symptomatic inguinal hernia. Conclusions: Our study suggests a reduced number of germ cells in undescended testes from week 28 of gestation and germ cell hypoplasia as a consequence of continued postnatal unde- scended testicular position. Cryptorchidism may result from abnormal development of the caudal developmental field. KEY WORDS: estis, cryptorchisrn, spermatogonia, embryology Germ cell hypoplasia is common in the undescended testes of boys older than 3 years.1.2 In fetuses with the prune-belly syndrome or posterior urethral valves and severe urinary tract obstruction germ cells were present in all specimens at 20 to 35 weeks of gestation but in a reduced number.3 Fur- thermore, the numerical paucity of germ cells has been re- ported in fetuses with trisomy 13 or 18, or the Klinefelter syndrome at 18 to 22 weeks of ge~tation.~ n anencephalic fetuses germ cells were scarce when Leydig cells were seem- ingly absent but the presence of even a small number of Leydig cells was accompanied by a fairly normal distribution of germ cells per tubule.5 Cryptorchidism is an invariable part of the prune-belly ~yndrome.~ n cases of trisomy 13 or 18, the Klinefelter syndrome, posterior urethral valves or anencephaly, which is often associated with spina bifida? the incidence of cryptorchidism is increased.6.7 In the first year of life the mean values of germ cells per tubular cross section have been described as similar in un- descended and normally descended testes but the standard deviation of the cryptorchid group was high.2 Therefore, it has been hypothesized that the irregular distribution of germ cells per tubular cross section values may be due to a mixture of undescended testes with normal testes of a somewhat high anatomical location.2 The purpose of our study was to inves- tigate the number of germ cells in undescended testes in male individuals ranging in age from 28 weeks of gestation to 3 years in relation to normal controls. The lower age limit was chosen according to the results of a previous autopsy study of 178 fetuses and neonates." In that series 75 of the subjects at 28 weeks of gestation had descended testes and until term the incidence increased only 5% PATIENTS AND METHODS The cryptorchidism study group comprised 35 subjects who were stillborn or died within the first 3 days of life in whom the testes were intra-abdominal or intra-canalicular. The normal controls consisted of 16 subjects with scrotal testes who were stillborn or died within the first 3 days of life. Accepted for publication March 24 1995. Supported by a grant from the Alfred Benzon Foundation. Furthermore, 6 stillborns from a previous report of normal testes were included.9 Excluded from the control group were twins, and those with abnormalities revealed at autopsy and with evidence of maternal diabetes. The study group also comprised histological material from the undescended testes of 34 cryptorchid boys and 24 boys who underwent surgery for cryptorchidism and a symptom- atic inguinal hernia that had not been incarcerated. The normal controls included the testes of 11 boys who had died suddenly and unexpectedly, or from meningitis or pneumonia less than 6 days in duration. No other disease was known and autopsy revealed no abnormalities. Furthermore, the control material included 3 testicular biopsies obtained from the scrotal testes of boys who underwent contralateral inguinal herniotomy. A total of 11 cases was included from previously published normal material.9 All fetuses had undergone autopsy, including careful ex- amination of the kidneys and the urinary tract. In 31 of the cryptorchid fetuses an x-ray of the spine had been done. In cryptorchid boys with additional symptoms further inves- tigations were performed to confirm the diagnosis and, there- fore, excretory urography or ultrasonography of the kidneys, ureters and bladder was done in 19% and an x-ray of the spine in 17%. In 10 cases a normal 46,XY karyotype was proved and the remaining cases presented with a normal 46,XY phenotype. The testes were fixed in Stieves or Cleland's fluid. Sections (4 pm.) were made for light microscopic examination, and stained with iron hematoxylin and eosin. In blinded fashion the number of germ cells per tubular cross section was meas- ured from at least 100 tubular cross sections, as previously de~cribed.~ n 29 cryptorchid and 15 normal fetuses the pairs of testes and epididymides had been weighed, and body weight was also documented. The weight of 6 pairs of autopsy testes from previously published normal material was not included because only the testes had been weighed. ' From 18 normal and 17 cryptorchid individuals the pairs of testes were analyzed. In these cases the mean of the germ cells per tubular cross section values from the right. and left estes was used in the figures, medians. ranges and st;ttistical analyses. IXY  GERM CELL HISTOLOGY IN CRYPTORCHIDISM 1189 E4 E m -3 - E m - s2 1 5 4 3 5 2 1 0 . *. + ++e + +;. +* + ++ . . Y :t x m m . m 0 r. 0 0,5 1 1,5 2 2.5 3 Age (years) FIG. 1. Number of germ cells per tubular cross section (S/T) ac- cording to age in years of 35 cryptorchid fetuses and 34 torchid boys without symptomatic inguinal hernia +), 24 cryptoxd boys with symptomatic nguinal hernia *), nd 22 normal fetuses and 25 normal boys (0) with 0 at x-axis broken line) indicating 40 weeks of gestation of fetuses and time of birth of boys. For statistical analyses the Mann-Whitney and Spearman rank ests were used. RESULTS The number of germ cells per tubular cross section was statistically lower in the cryptorchid than normal fetuses (fig. 1 and table 1 . The cryptorchid fetuses also had lower weights of pairs of testes and epididymides compared to normal (Mann-Whitney test, p <0.001, fig. 2). In contrast, the body weight of these cryptorchid fetuses was not lower than nor- mal (Mann-Whitney test, p >0.1, fig. 3). The germ cells per tubular cross section values decreased with increased age of the cryptorchid fetuses (Spearman rank test, p (0.05, fig. 1 but this relationship was not demonstrated in the normal fetuses (Spearman rank test, p >0.2). The 22 fetuses with intra-abdominal testes did not have lower germ cells per tubular cross section values, weight of pairs of testes and epididymides, and age of gestation than the 13 fetuses with intra-canalicular testes (Mann-Whitney test, p >0.6, 0.3 and >0.8, respectively). The weight of pairs of testes and epididymides, and the body weight increased with increasing age in both groups of fetuses (Spearman rank test, cryp- torchid p <0.01 and <0.001, normal p (0.01 and <0.001, respectively, figs. 2 and 3). The group of zero to 1-year-old cryptorchid patients had germ cells per tubular cross section values that were not statistically lower than normal (fig. 1 and table 1 . n con- trast, the subgroup of cryptorchid boys zero to 1 year old without a symptomatic inguinal hernia had decreased values compared to normal (Mann-Whitney test, p <0.01), whereas the subgroup of patients zero to 1 year old with such a hernia had values that were not statistically different from normal 28 30 32 34 36 38 40 Age (weeks of gestatlon) FIG. 2. Wei ht of testes and epididymides in 29 cryptorchid +) and 15 normaf fetuses (0) mrdmg to weeke of pestahon. 5 I a 0 c4 a 0 3 t3 a E E2 3 E Sl 5 0 + 4 + +t IIIJI,I,IIIII 28 30 32 34 38 38 40 Age (weeks of gestation) FIG. 3. Body weight of 29 cryptoxhid +) and 15 normal fetuses (0) ccording to weeks of gestation. (table 2). There were decreased germ cells per tub& ross section values in the 1 o 3-yeardd cryptorchid patients, in- luding the subgroups without Mann-Whitney test, p <0.00005) and with a hernia fig. 1, and tables 1 nd 2). Germ cell hypoplasia, that is a germ cells per tubular cross section value below the lowest normal value for age, was present in 23% of cqptorchid fetuses, and 22% of the zero to 1-year-old and 92% of the 1 to 3-year-old cryptorchid boys without a symptomatic inguinal hernia. However, 8 of the zero to 1-year-old and 75 of the 1 o 3-yeardd cryptorchid boys with a hernia had germ cell hypoplasia (fig. 1 . The youngest patient with the pattern of Sertoli cells only was 2 years old. TABLE . Number of germ cells per tubular cross section of undescended compnred to that of normal testes Undeaeended Testes Normal Testes Mann-Whitney Test Median age (wks. gestation) 32.6 (28-40) 33.4 2e-40) >0.7 Median No. germ celldtubular cross section 1.58 (0.774.683 2.70 (1.31-4.543 <0.001 Median No. erm celldtubular cross section 1.03 (0.07-4.61) 1.58 (0.6W.61) 0.101 Median age (yrs.) 2.20 (1.6&2.99) 1.73 (1.02-2.99) CO.06 Total No. 35 22 Median age yrs.) 0.17 (0.02-0.99) 0.18 (0.01-0.71) 20.3 Total No. 21 16 Median No. germ celldtubular emas section 0.16 0.00-0.89) 0.68 (0.38-1.11) <O.ooOo6 Total No. 37 9 values in parentheses are range.  1190 GERM CELL HISTOLOGY IN CRYPTORCHIDISM TABLE . Number of germ cells per tubular cross sertlon in undescended testes from boys with a syriiptoniatic inguinal hernia cornpared to -~ ~ -~_ hat of normal testes ~ ~ Hernia Normal Mann-Whitney Test Median age (yrs.1 0.19 t0.03-0.99) 0.18 0.01-0.71) :.0.2 Median age tyrs. 2.35 11.50-2-99) 1.73 [1.02-2.991 ,0.1 No. pts. 12 9 Median No. germ cellsitubular cross section 1.89 0.52-4.61) 1.58 0.69-3.61) >O.R No. pts. 12 16 Median No. germ cells/tubular cross section 0.22 0.01-0.881 0.68 0.38-1.111 <0.005 Values in parentheses are range. Additional diagnoses were made in 43 of cryptorchid fetuses, 44 of cryptorchid boys without a symptomatic in- guinal hernia and 21% of patients with a hernia (table 3). Malformations and/or dysplasia of the kidneys, ureters and T10 to S5 of the spine was present in 34 of the cryptorchid fetuses and 18% of he cryptorchid boys without a symptom- atic inguinal hernia but only 4 of the cryptorchid patients with a hernia. The 12 cryptorchid fetuses with these malfor- mations or dysplasia did not differ from the other cryptorchid fetuses in regard to germ cells per tubular cross section values, weight of pairs of testes and epididymides, body weight and age of gestation (Mann-Whitney test, p >0.3, >0.4, 0.6 and >0.5, respectively). The values of the 7 cryp- torchid boys with these malformations or dysplasia also had a pattern equivalent to the values of the remainder of the cryptorchid patients (fig. 4). n no case was intratubular germ cell neoplasia demonstrated. DISCUSSION Our study suggests that the number of germ cells per tubular cross section is reduced in intra-abdominal and intra- canalicular testes in fetuses older than 28 weeks of gestation. Furthermore, the total number of germ cells may be mark- edly reduced in cryptorchid fetuses because our study also proved reduced testicular weight in cryptorchid fetuses and it has been demonstrated that the number of germ cells per tubular cross section correlates with the numerical density of spermatogonia and gonocytes.9 A reduced number of germ cells have previously been reported in fetuses with the prune- belly syndrome, which is always associated with cryptorchid- ism, and posterior urethral valves? trisomy 13 or 18: the Klinefelter syndrome4 or anencephaly,s which may be asso- ciated with cryptorchidism. The cryptorchid fetuses in our series had reduced testicular weight without a corresponding decrease in body weight. This pattern has also been noted in cases of anencephaly.s.7 This condition was induced ex- perimentally in newborn cynomolgus monkeys in which the pituitary-testicular axis was suppressed from the time of mid- gestation with a long-acting luteinizing hormone-releasing hormone analogue,lO and in lambs that were made bilaterally cryptorchid at birth. These data from the literature are not in conflict with our observation of a reduced number of germ cells in cryptorchid fetuses. Generally, a numerical paucity of fetal germ cells can re- sult from impaired colonization of the gonadal ridge, reduced cellular proliferation or increased cellular 10~s.~ mpaired germ cell colonization of the gonadal ridge may occur in the Klinefelter syndrome in which a high number of extrago- nadal teratomas have been noted.4 Reduced germ cell prolif- eration may be important. In chromosome disorders a rela- TABLE . Additional diagnoses in individuals with undescended testes 35 34 24 Boys Fetuses Bovs With Hernia Bilat. renal agenesis:' With lumbar myelomeningocele.x scrota1 agenesis, imperforate anus Unilat renal agenesis * With lumbar spina bifida,* esophageal atresia, cleft lip and palate, cardiac malformation, 46,XY With lumbar myelomeningocele' With prune-belly syndrome With imperforate anus. cardiovascular malformation, malformation of base of skull, pituitary gland agenesis, With thoracolumhosacral vertebral malformations and dysplasia." urethral atresia, imperforate anus, cardiovascular Bilat. renal dysplasia:* microstomia malformation Horseshoe kidney.* cardiac malformation: Unilat. duplex kidney," imperforate anus, esophageal atresta. unilat. hypoplasia of face and skull Severe degree of hydronephrosis and megaureter' Thoracolumbar vertebral malformations and dysplasia,* imperforate anus, overed bladder exstrophy epispadias, pulmo- Lumhar vertebral malformations and dysplasia.^ imperforate anus. duodenal membrane, syndactyly, hypospadias, 46 XY Lumbar myelomeningocele- and hydrocephalus Bladder exstrophy. Crohn's disease. Hypospadias. With thoracolumbar vertebral malformations and dysplasia.' esophageal and duodenal atresia, bilat. radial aplasia nary trunk stenosis, 46.W With hemi-scrotum. 46,XY With Beckwith-Wicdemann syndrome. omphalocele. 46 XY With unilat. diaphragmatic hernia With corpus cnllosum ayenc4s. polydactyly. 46 m With Hirschsprung's disease, growth hormime deficiency. 46.XY With priivtd 46.XY lJnilat. diaphragmtic hernia Cardiovascular malfnrmatinns and dysplasias: Kallmann syndrnme. 46.XY Neurofihrinnatisis with tumor 1 rhiasmo n11ic.s~. etrolcmticular fibrosis. 46.XY 1 1 2 1 1 1 1 1 1 1 I 1 1 1 1 1 1 1 1 1 1 1 2 1  GERM CELL HISTOLOGY IN CRYPTORCHIDISM 1191 0 0,s 1 13 2 2,5 3 Age (years) FIG. 4. Number of germ cells per tubular transverse section (S/T) according to age of 12 fetuses and 7 bo s with association of cryp- torchidism, and malformations and dyspfasia of kidneys, ureters and T10 o S5 part of spine (A), nd 23 fetuses and 51 boys without this association +). tionship was demonstrated between the rate of germ cell reduction and severity with marked germ cell reduction in trisomies 13 and 18, and moderate germ cell reduction in the Klinefelter syndrome.4 These cases had no Leydig cell abnor- malities.4 In anencephalic fetuses germ cell reduction related to the extent of Leydig cell depletion.6 In contrast, Leydig cell hyperplasia was demonstrated in fetuses with the prune- belly syndrome and germ cell depletion but the total number of Leydig cells was unknown since testicular weight was not considered.3 Based on patients with the androgen insensivity syndrome who had a normal number of germ cells until they were 5 years old it has been hypothesized that fetal germ cell proliferation may occur without the normal function of an- drogen receptors.12 Increased germ cell loss during gestation is a possible cause of numerical germ cell paucity. Between 16 and 20 weeks of gestation germ cell degeneration is com- mon in normal human testes7 and in the 49 syn- drome it appears to increase excessively.4 In our group of zero to 1-year-old patients the germ cells per tubular cross section values in the subgroup with a symp- tomatic inguinal hernia did not differ from the values of normal testes, whereas the subgroup without a hernia had reduced values. To our knowledge this distinction has not previously been made in studies of undescended testes and it may explain the great range of values demonstrated in some studies.2.' In 1 study testicular biopsies were obtained at surgery to correct a concomitant inguinal hernia14 and in another biopsy was done at the time of combined herniorrha- phy/orchiopexy.13 In both series the number of germ cells per tubular cross section was not decreased in the first V3 or 914 months of life but a defective transformation of gono- cytes into spermatogonia was demonstrated at about age 4 months, and there was a corresponding prolonged persis- tence of gonocytes.13.14 It is possible that undescended testes with a symptomatic inguinal hernia may be interpreted as normal testes that are mechanically inhibited in scrotal de- Scensus because of the hernia. In our series germ cells per tubular cross section values of cryptorchid boys without a symptomatic inguinal hernia were at the same level as in a previously published study of undescended testes.' All of the 1 o 3-year-old cryptorchid patients had reduced germ cells per tubular cross section values. Severe germ cell hypoplasia (value of 0.01) was observed in the undescended testis of a 1.5-year-old boy with a symptomatic inguinal her- nia. Therefore, germ cell hypoplasia may result from a post- natal suprascrotal testicular position, according to experi- mental cryptorchidism.11 However, this study suggests that a low number of germ cells in cryptorchid patients may not only be caused by a high postnatal position of the testes, corresponding to the observation of a reduced number of germ cells per tubular cross section in the contralateral testis of patients with unilateral cryptorchidism.1.2 The pattern of Sertoli cells only was not proved until age 2 years in our series, which is in accordance with earlier stud- ies.1.2 The pattern of Sertoli cells only is a bad prognostic factor for fertility potential.16.l6 After age 1 year germ cell hypoplasia was predominant even in cryptorchid boys with a symptomatic inguinal hernia. Therefore, the recommenda- tion to treat undescended testes before age 1 year seems logical.6.14 It remains to be proved that early operation im- proves fertility potential and, since the fetal undescended testes in our series had a reduced number of germ cells, it is illogical o presume that surgical treatment alone will restore normal germ cell physiology. Stimulation of the gem cells in undescended testes has been proposed,17.1S and it is possible that improvement will result from hormonal treatment in addition to surgical placement of the testis in the scrotum. Based on clinical and animal studies stimulation with lutein- izing hormone-releasing hormone, and subsequently with exogenous miillerian inhibiting substance has been suggest- ed.*S In normal male individuals from 28 weeks of gestation to 3 years old a peak in the total number of germ cells at about age 100 days was demonstrated.12 The timing of this peak correlated well with the normal postnatal surge in luteinizing and follicle-stimulating hormones, and testoster- one secretion.12 High levels of miillenan inhibiting substance have been reported in the first 4 to 12 months of life simul taneously with the transformation from gonocytes to sper- matogonia. 18 Malformations and dysplasia of the kidneys, ureters and T10 to S5 of the spine were the dominant additional abnor- malities noted in 34% of cryptorchid fetuses and 18% of cryptorchid boys without a symptomatic inguinal hernia. An association between cryptorchidism and renal, ureteral and T10 to 55 vertebral malformations, and dysplasia has been demonstrated in boys with imperforate anus.19 The unde- scended testes of our patients with this association did not differ from the rest of the undescended testes, which corre- sponds to a previous study 19 It is also in accordance with these previous findings that cryptorchidism was ipsilateral to the renal and ureteral malformations, and dysplasia in 93 of the patients. Therefore, our series strengthens the hypothesis that investigation of the association of cryp- torchidism and renal, ureteral and T10 to 55 vertebral mal- formations, and dysplasia may help to clarify cryptorchidism in general.19 It is important that relatively few patients un- derwent imaging of the spine and urological system, which may be a selection factor that should be considered. Testidar biopsy during surgery for undescended testes in boys with abnormal sex chromosomes, andlor abnormal and ambiguous external genitalia has been recommended to ex- amine for intratubular germ cell neoplasia, also called carci- noma in situ.20 Our study proved no case of intratubular germ cell neoplasia. CONCLUSIONS Our study suggests a reduced number of germ cells in undescended testes from week 28 of gestation, and germ cell hypoplasia as a consequence of a continued postnatal unde- scended position of the testes. In some cases cryptorchidism may be interpreted as a result of abnormal development in the caudal developmental field. Tue Tjur, nstitute of Mathematical Statistics, University of Copenhagen assisted with the statistical analysis.  1192 GERM CELL HISTOLOGY IN CRYPTORCHIDISM REFERENCES 1. Mengel, W. Hienz, H. A., Sippe, W. G., 111 and Hecker, W. C.: Studies on cryptorchidism: a comparison of histological find- ings in the germinative epithelium before and after the second year of life. J. Ped. Surg., 9 445, 1974. 2. Hedinger E.: Histopathology of undescended testes. Eur. J. Ped., 139: 266, 1982. 3. OMS, B. R., Bottles, K. and Kogan, B. A : Testicular histology in fetuses with the prune belly syndrome and posterior urethral valves. J. Urol., 139 335, 1988. 4. Coerdt, W. Rehder, H., Gausmann, I., Johannisson, R. and Gropp, A.: Quantitative histology of human fetal testes in chromosomal disease. Ped. Path., 3: 245, 1985. 5. Baker, T. G. and Scrimgeour, J. B.: Development of the gonad in normal and anencephalic human fetuses. J. Reprod. Fertil., 60: 93, 1980. 6. Hutson. J. M. and Beasley, S. W.: Descent of the Testis. London: Edward Arnold, 1992. 7. Rabinovici, J. and Jaffe, R. B.: Development and regulation of growth and differentiated function in human and subhuman primate fetal gonads. Endocr. Rev., 11: 532, 1990. 8. Heyns, C. F.: The gubernaculum during testicular descent in the human fetus. J. Anat., 153: 93, 1987. 9. Cortes. D.: Histological versus stereological methods applied at spermatogonia during normal human development. Scand. J. Urol. Nephrol., 24: 11 1990. 10. Liu, L. Cristiano, A. M., Southers, J. L., Reynolds, J. C., Bacher, J., Brown, G., Gilley, R. M., Tice, T. R., Banks, S. M., Loriaux, L. D. and Cassorla, F.: Effects of pituitary-testicular axis su- pression in utero and during the early neonatal period with a long-acting luteinizing hormone-releasing hormone analog on genital development, somatic growth, and bone density in male cynomolgus monkeys in the first 6 months of life. J. Clin. Endocr. Metab., 73: 1038, 1991. 11. Monet-Kuntz, C., Barenton, B., Locatelli, A., Fontaine, I., Perreau, C. and Hochereau-de Reviers, M. T.: Effects of exper- imental cryptorchidism and subsequent orchidopexy on semi- niferous tubule functions in the lamb. J. Androl., 8: 148, 1987. 12. Miiller, J.: Abnormal infantile germ cells and development of carcinoma-in-situ in maldeveloped testes: a stereological and densitometric study. Int. J. Androl., 10: 543, 1987. 13. Huff, D. S., Hadiiselimovic, F., Snyder, H. McC., 111 Blyth, B. and Duckett, J. W.: Early postnatal testicular maldevelopment in cryptorchidism. J. Urol., part 2, 146 624, 1991. 14. Hadiiselimovic, F., Thommen, L., Girard, J. and Herzog, B.: The significance of postnatal gonadotropin surge for testicular de- velopment in normal and cryptorchid testes. J. Urol., 136 274, 1986. 15. Hadiiselimovic, F., Hecker, E. and Herzog, B.: The value of testicular biopsy in cryptorchidism. Urol. Res., 12: 171, 1984. 16. Cortes, D. and Thorup, J.: Histology of testicular biopsies taken at operation for bilateral maldescended testes in relation to fertility in adulthood. Brit. J. Urol., 68 85, 1991. 17. Bica, D. T. G. and HadiiselimoviC, F.: Buserelin treatment of cryptorchidism: a randomized, double-blind, placebocontrolled study. J. Urol., part 2, 148: 617, 1992. 18. Zhou, B., Watts, L. M. and Hutson, J. M.: Germ cell development in neonatal mouse testes in vitro requires mullerian inhibiting substance. J. Urol., part 2, 150 613, 1993. 19. Cortes, D. Thorup, J. M., Nielsen, 0. H. and Beck, B. L.: Cryp- torchidism in boys with imperforate anus. J. Ped. Surg., 30: 1 1995. 20. Cortes, D., Tholup, J., Frisch, M., Mdler, H., Jacobsen, G. K. and Beck, B. L.: Examination for intratubular germ cell neoplasia at operation for undescended testis in boys. J. Urol., 151: 722, 1994.
Search
Similar documents
View more...
Tags
Related Search
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks