Abstract
Cryptorchidism results in impaired fertility. Reduced numbers of testicular germ cells can be shown histologically during the first years of life. The process causing germ cell loss in cryptorchid prepubertal boys is unknown, but it could be the result of a form of programmed cell death known as apoptosis. 25 adult men with a history of surgically treated cryptorchidism were studied, 15 of whom had received an unsuccessful human chorionic gonadotropin (hCG) therapy before orchidopexy. Apoptotic DNA fragmentation was assayed in testis biopsies taken during orchidopexy by end-labeling, both in extracted DNA and histochemically in situ. Only a few scattered apoptotic spermatogonias were seen by end-labeling of biopsies from patients not treated with hCG, whereas more extensive labeling of spermatogonia was seen after hCG treatment. As estimated by gel electrophoresis, the amount of low molecular weight DNA was 4.3-fold higher in the hCG-treated group when compared with the level in scrotal testis of non-hCG-treated patients (P < 0.001). About 20 yr after the biopsy, the low molecular weight DNA fragmentation correlated negatively with the testis volume (r = -0.84; P < 0.001) and positively with serum FSH levels (r = 0.73; P < 0.001). Findings in the semen analysis were similar between the groups. Apoptotic loss of spermatogonia after hCG treatment of cryptorchidism warrants reevaluation of the safety of this treatment.
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- Adrian T., Wigand R., Richter J. Gastroenteritis in infants, associated with a genome type of adenovirus 31 and with combined rotavirus and adenovirus 31 infection. Eur J Pediatr. 1987 Jan;146(1):38–40. doi: 10.1007/BF00647280. [DOI] [PubMed] [Google Scholar]
- Albescú J. Z., Bergadá C., Cullen M. Male fertility in patients treated for cryptorchidism before puberty. Fertil Steril. 1971 Dec;22(12):829–833. doi: 10.1016/s0015-0282(16)38647-2. [DOI] [PubMed] [Google Scholar]
- Bartsch G., Frick J. Therapeutic effects of luteinizing hormone releasing hormone (LH-RH) in cryptorchidism. Andrologia. 1974;6(3):197–201. doi: 10.1111/j.1439-0272.1974.tb01202.x. [DOI] [PubMed] [Google Scholar]
- Billig H., Furuta I., Hsueh A. J. Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis. Endocrinology. 1993 Nov;133(5):2204–2212. doi: 10.1210/endo.133.5.8404672. [DOI] [PubMed] [Google Scholar]
- Billig H., Furuta I., Rivier C., Tapanainen J., Parvinen M., Hsueh A. J. Apoptosis in testis germ cells: developmental changes in gonadotropin dependence and localization to selective tubule stages. Endocrinology. 1995 Jan;136(1):5–12. doi: 10.1210/endo.136.1.7828558. [DOI] [PubMed] [Google Scholar]
- Buja L. M., Eigenbrodt M. L., Eigenbrodt E. H. Apoptosis and necrosis. Basic types and mechanisms of cell death. Arch Pathol Lab Med. 1993 Dec;117(12):1208–1214. [PubMed] [Google Scholar]
- CLERMONT Y., MORGENTALER H. Quantitative study of spermatogenesis in the hypophysectomized rat. Endocrinology. 1955 Sep;57(3):369–382. doi: 10.1210/endo-57-3-369. [DOI] [PubMed] [Google Scholar]
- Cendron M., Keating M. A., Huff D. S., Koop C. E., Snyder H. M., 3rd, Duckett J. W. Cryptorchidism, orchiopexy and infertility: a critical long-term retrospective analysis. J Urol. 1989 Aug;142(2 Pt 2):559–572. doi: 10.1016/s0022-5347(17)38815-8. [DOI] [PubMed] [Google Scholar]
- Chilvers C., Dudley N. E., Gough M. H., Jackson M. B., Pike M. C. Undescended testis: the effect of treatment on subsequent risk of subfertility and malignancy. J Pediatr Surg. 1986 Aug;21(8):691–696. doi: 10.1016/s0022-3468(86)80389-x. [DOI] [PubMed] [Google Scholar]
- Cortes D., Thorup J. Histology of testicular biopsies taken at operation for bilateral maldescended testes in relation to fertility in adulthood. Br J Urol. 1991 Sep;68(3):285–291. doi: 10.1111/j.1464-410x.1991.tb15325.x. [DOI] [PubMed] [Google Scholar]
- De Rooij D. G., Lok D. Regulation of the density of spermatogonia in the seminiferous epithelium of the Chinese hamster: II. Differentiating spermatogonia. Anat Rec. 1987 Feb;217(2):131–136. doi: 10.1002/ar.1092170204. [DOI] [PubMed] [Google Scholar]
- Dunkel L., Perheentupa J., Apter D. Kinetics of the steroidogenic response to single versus repeated doses of human chorionic gonadotropin in boys in prepuberty and early puberty. Pediatr Res. 1985 Jan;19(1):1–4. doi: 10.1203/00006450-198501000-00001. [DOI] [PubMed] [Google Scholar]
- Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grasso M., Buonaguidi A., Lania C., Bergamaschi F., Castelli M., Rigatti P. Postpubertal cryptorchidism: review and evaluation of the fertility. Eur Urol. 1991;20(2):126–128. doi: 10.1159/000471680. [DOI] [PubMed] [Google Scholar]
- Gross-Bellard M., Oudet P., Chambon P. Isolation of high-molecular-weight DNA from mammalian cells. Eur J Biochem. 1973 Jul 2;36(1):32–38. doi: 10.1111/j.1432-1033.1973.tb02881.x. [DOI] [PubMed] [Google Scholar]
- Hadziselimović F., Girard J., Herzog B., Stalder G. Hormonal treatment of cryptorchidism. Horm Res. 1982;16(3):188–192. doi: 10.1159/000179501. [DOI] [PubMed] [Google Scholar]
- Happ J., Kollmann F., Krawehl C., Neubauer M., Beyer J. Intranasal GnRH therapy of maldescended testes. Horm Metab Res. 1975 Sep;7(5):440–441. doi: 10.1055/s-0028-1095673. [DOI] [PubMed] [Google Scholar]
- Hedinger E. Histopathology of undescended testes. Eur J Pediatr. 1982 Dec;139(4):266–271. doi: 10.1007/BF00442177. [DOI] [PubMed] [Google Scholar]
- Heiskanen P., Billig H., Toppari J., Kaleva M., Arsalo A., Rapola J., Dunkel L. Apoptotic cell death in the normal and cryptorchid human testis: the effect of human chorionic gonadotropin on testicular cell survival. Pediatr Res. 1996 Aug;40(2):351–356. doi: 10.1203/00006450-199608000-00026. [DOI] [PubMed] [Google Scholar]
- Hikim A. P., Wang C., Leung A., Swerdloff R. S. Involvement of apoptosis in the induction of germ cell degeneration in adult rats after gonadotropin-releasing hormone antagonist treatment. Endocrinology. 1995 Jun;136(6):2770–2775. doi: 10.1210/endo.136.6.7750502. [DOI] [PubMed] [Google Scholar]
- Hjertkvist M., Läckgren G., Plöen L., Bergh A. Does HCG treatment induce inflammation-like changes in undescended testes in boys? J Pediatr Surg. 1993 Feb;28(2):254–258. doi: 10.1016/s0022-3468(05)80288-x. [DOI] [PubMed] [Google Scholar]
- Huckins C. The morphology and kinetics of spermatogonial degeneration in normal adult rats: an analysis using a simplified classification of the germinal epithelium. Anat Rec. 1978 Apr;190(4):905–926. doi: 10.1002/ar.1091900410. [DOI] [PubMed] [Google Scholar]
- Huff D. S., Hadziselimovic F., Snyder H. M., 3rd, Duckett J. W., Keating M. A. Postnatal testicular maldevelopment in unilateral cryptorchidism. J Urol. 1989 Aug;142(2 Pt 2):546–572. doi: 10.1016/s0022-5347(17)38811-0. [DOI] [PubMed] [Google Scholar]
- Kato T., Sano M., Mizutani N. Inhibitory effect of intravenous lysine infusion on urea cycle metabolism. Eur J Pediatr. 1987 Jan;146(1):56–58. doi: 10.1007/BF00647285. [DOI] [PubMed] [Google Scholar]
- Kerr J. B., Sharpe R. M. Focal disruption of spermatogenesis in the testis of adult rats after a single administration of human chorionic gonadotrophin. Cell Tissue Res. 1989 Jul;257(1):163–169. doi: 10.1007/BF00221647. [DOI] [PubMed] [Google Scholar]
- Lipshultz L. I., Caminos-Torres R., Greenspan C. S., Snyder P. J. Testicular function after orchiopexy for unilaterally undescended testis. N Engl J Med. 1976 Jul 1;295(1):15–18. doi: 10.1056/NEJM197607012950104. [DOI] [PubMed] [Google Scholar]
- Luck W., Nau H. Nicotine and cotinine concentrations in the milk of smoking mothers: influence of cigarette consumption and diurnal variation. Eur J Pediatr. 1987 Jan;146(1):21–26. doi: 10.1007/BF00647276. [DOI] [PubMed] [Google Scholar]
- Madhwa Raj H. G., Dym M. The effects of selective withdrawal of FSH or LH on spermatogenesis in the immature rat. Biol Reprod. 1976 May;14(4):489–494. doi: 10.1093/biolreprod/14.4.489. [DOI] [PubMed] [Google Scholar]
- Majno G., Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995 Jan;146(1):3–15. [PMC free article] [PubMed] [Google Scholar]
- Martin D. C. Malignancy in the cryptorchid testis. Urol Clin North Am. 1982 Oct;9(3):371–376. [PubMed] [Google Scholar]
- OAKBERG E. F. A description of spermiogenesis in the mouse and its use in analysis of the cycle of the seminiferous epithelium and germ cell renewal. Am J Anat. 1956 Nov;99(3):391–413. doi: 10.1002/aja.1000990303. [DOI] [PubMed] [Google Scholar]
- Okuyama A., Nonomura N., Nakamura M., Namiki M., Fujioka H., Kiyohara H., Matsumoto K., Sonoda T. Surgical management of undescended testis: retrospective study of potential fertility in 274 cases. J Urol. 1989 Sep;142(3):749–751. doi: 10.1016/s0022-5347(17)38876-6. [DOI] [PubMed] [Google Scholar]
- Puri P., O'Donnell B. Semen analysis of patients who had orchidopexy at or after seven years of age. Lancet. 1988 Nov 5;2(8619):1051–1052. doi: 10.1016/s0140-6736(88)90067-0. [DOI] [PubMed] [Google Scholar]
- Pyörälä S., Huttunen N. P., Uhari M. A review and meta-analysis of hormonal treatment of cryptorchidism. J Clin Endocrinol Metab. 1995 Sep;80(9):2795–2799. doi: 10.1210/jcem.80.9.7673426. [DOI] [PubMed] [Google Scholar]
- Russell L. D., Alger L. E., Nequin L. G. Hormonal control of pubertal spermatogenesis. Endocrinology. 1987 Apr;120(4):1615–1632. doi: 10.1210/endo-120-4-1615. [DOI] [PubMed] [Google Scholar]
- Schindler A. M., Diaz P., Cuendet A., Sizonenko P. C. Cryptorchidism: a morphological study of 670 biopsies. Helv Paediatr Acta. 1987 Oct;42(2-3):145–158. [PubMed] [Google Scholar]
- Schwartzman R. A., Cidlowski J. A. Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr Rev. 1993 Apr;14(2):133–151. doi: 10.1210/edrv-14-2-133. [DOI] [PubMed] [Google Scholar]
- Schwarz H. P., Aebi S., Perisic M. Success and relapse rate after treatment of cryptorchidism with intranasal LHRH. Acta Paediatr Scand. 1985 Mar;74(2):274–280. doi: 10.1111/j.1651-2227.1985.tb10964.x. [DOI] [PubMed] [Google Scholar]
- Tapanainen J. S., Tilly J. L., Vihko K. K., Hsueh A. J. Hormonal control of apoptotic cell death in the testis: gonadotropins and androgens as testicular cell survival factors. Mol Endocrinol. 1993 May;7(5):643–650. doi: 10.1210/mend.7.5.8316250. [DOI] [PubMed] [Google Scholar]
- Taskinen S., Taavitsainen M., Wikström S. Measurement of testicular volume: comparison of 3 different methods. J Urol. 1996 Mar;155(3):930–933. [PubMed] [Google Scholar]
- Teebi A. S., Al-Awadi S. A., Farag T. I., Naguib K. K., el-Khalifa M. Y. Phenylketonuria in Kuwait and Arab countries. Eur J Pediatr. 1987 Jan;146(1):59–60. doi: 10.1007/BF00647286. [DOI] [PubMed] [Google Scholar]
- Tilly J. L., Hsueh A. J. Microscale autoradiographic method for the qualitative and quantitative analysis of apoptotic DNA fragmentation. J Cell Physiol. 1993 Mar;154(3):519–526. doi: 10.1002/jcp.1041540310. [DOI] [PubMed] [Google Scholar]
- Troiano L., Fustini M. F., Lovato E., Frasoldati A., Malorni W., Capri M., Grassilli E., Marrama P., Franceschi C. Apoptosis and spermatogenesis: evidence from an in vivo model of testosterone withdrawal in the adult rat. Biochem Biophys Res Commun. 1994 Aug 15;202(3):1315–1321. doi: 10.1006/bbrc.1994.2074. [DOI] [PubMed] [Google Scholar]
- Wessel A., Simon C., Regensburger D. Bacterial and fungal infections after cardiac surgery in children. Eur J Pediatr. 1987 Jan;146(1):31–33. doi: 10.1007/BF00647278. [DOI] [PubMed] [Google Scholar]
- de Muinck Keizer-Schrama S. M. Hormonal treatment of cryptorchidism. Horm Res. 1988;30(4-5):178–186. doi: 10.1159/000181057. [DOI] [PubMed] [Google Scholar]