Testicular descent to the scrotum involves complex anatomical rearrangements and hormonal regulation. The gubernaculum remains the key structure, undergoing the `swelling reaction' in the transabdominal phase, and actively migrating out of the abdominal wall to the scrotum in the inguinoscrotal phase. Insulin-like hormone 3 (Insl3) is the primary regulator of the first phase, possibly augmented by Müllerian inhibiting substance/anitmüllerian hormone (MIS/AMH), and regression of the cranial suspensory ligament by testosterone. The inguinoscrotal phase is controlled by androgens acting both directly on the gubernaculum and indirectly via the genitofemoral nerve, and release of calcitonin gene-related peptide from its sensory fibres. Outgrowth of the gubernaculum and elongation to the scrotum has many similarities to an embryonic limb bud.
Cryptorchidism occurs because of both failure of migration congenitally, and failure of elongation of the spermatic cord postnatally. Germ cell development postnatally is disturbed in congenital cryptorchidism, but our current understanding of germ cell biology suggests that early orchidopexy, around 6 months of age, should provide a significant improvement in prognosis compared with a previous generation. Hormone treatment is not currently recommended. Acquired cryptorchid testes may need orchidopexy once they no longer reach the scrotum, although this remains controversial.
Adham, I.M. and Agoulnik, A.I. (2004) Insulin-like 3 signalling in testicular descent . Int J Androl27: 257-265.
2.
Agoulnik, A.I. (2007) Relaxin and related peptides in male reproduction . Adv Exp Med Biol612: 49-64.
3.
Anderson, L.E. and Seybold, V.S. (2004) Calcitonin gene-related peptide regulates gene transcription in primary afferent neurons. J Neurochem91: 1417-1429.
4.
Attah, A.A. and Hutson, J.M. (1993) The role of intra-abdominal pressure in cryptorchidism . J Urol150: 994-996.
5.
Backhouse, K.M. (1982) Embryology of testicular descent and maldescent . Urol Clin North Am9: 315-325.
6.
Barteczko, K.J. and Jacob, M.I. (2000) The testicular descent in human. Origin, development and fate of the gubernaculum hunteri, processus vaginalis peritonei, and gonadal ligaments. Adv Anat Embryol Cell Biol156: III-X, 1-98.
7.
Barthold, J.S., Mccahan, S.M., Singh, A.V., Knudsen, T.B., Si, X., Campion, L. et al. (2008) Altered expression of muscle- and cytoskeleton- related genes in a rat strain with inherited cryptorchidism. J Androl29: 352-366.
8.
Beasley, S.W. and Hutson, J.M. (1987) Effect of division of genitofemoral nerve on testicular descent in the rat. Aust N Z J Surg57: 49-51.
9.
Clarnette, T.D., Rowe, D., Hasthorpe, S. and Hutson, J.M. (1997) Incomplete disappearance of the processus vaginalis as a cause of ascending testis. J Urol157: 1889-1891.
10.
Clarnette, T.D., Sugita, Y. and Hutson, J.M. (1997) Genital anomalies in human and animal models reveal the mechanisms and hormones governing testicular descent. Br J Urol79: 99-112.
11.
Cortes, D., Thorup, J. and BI, P. (2003) The spermatogonia may be harmed when the mother smoke at least 10 cigarettes per day during pregnancy - a pilot study including cryptorchid boys. Horm Res60: 1-175.
12.
Cortes, D., Thorup, J. and Visfeldt, J. (2000) Hormonal treatment may harm the germ cells in 1 to 3-year-old boys with cryptorchidism. J Urol163: 1290-1292.
13.
Ferlin, A., Zuccarello, D., Garolla, A., Selice, R. and Foresta, C. (2007) Hormonal and genetic control of testicular descent . Reprod Biomed Online15: 659-665.
14.
Fisher, J., Macpherson, S., Marchetti, N. and Sharpe, R. (2003) Human `testicular dysgenesis syndrome': a possible model using in-utero exposure of the rat to dibutyl phthalate. Hum Reprod18: 1383-1394.
15.
Foresta, C., Zuccarello, D., Garolla, A. and Ferlin, A. (2008) Role of hormones, genes, and environment in human cryptorchidism. Endocr Rev29: 560-580.
16.
Franke, F.E., Pauls, K., Rey, R., Marks, A., Bergmann, M. and Steger, K. (2004) Differentiation markers of sertoli cells and germ cells in fetal and early postnatal human testis. Anat Embryol (Berl) 209: 169-177.
17.
Fu, P., Layfield, S., Ferraro, T., Tomiyama, H., Hutson, J., Otvos Jr L. et al. (2004) Synthesis, conformation, receptor binding and biological activities of monobiotinylated human insulin-like peptide 3 . J Pept Res63: 91-98.
18.
Goodman, E.C. and Iversen, L.L. (1986) Calcitonin gene-related peptide: novel neuropeptide . Life Sci38: 2169-2178.
19.
Hack, W.W., Sijstermans, K., Van Dijk, J., Van Der Voort-Doedens, L.M., De Kok, M.E. and Hobbelt-Stoker, M.J. (2007) Prevalence of acquired undescended testis in 6-year, 9-year and 13-year-old dutch schoolboys. Arch Dis Child92: 17-20.
20.
Hadziselimovic, F., Herzog, B., Firard, J. and Stalder, G. (1984) Cryptorchidism - histology, fertility and treatment . Prog Reprod Biol Med10: 1-15.
21.
Hadziselimovic, F., Zivkovic, D., Bica, D.T. and Emmons, L.R. (2005) The importance of mini-puberty for fertility in cryptorchidism. J Urol174: 1536-1539; discussion 1538-1539.
22.
Harnaen, E.J., Na, A.F., Shenker, N.S., Sourial, M., Farmer, P.J., Southwell, B.R. et al. (2007) The anatomy of the cremaster muscle during inguinoscrotal testicular descent in the rat. J Pediatr Surg42: 1982-1987.
23.
Hasthorpe, S., Tainton, K., Peart, M., Roeszler, K.N., Bell, K.M., Lusby, P.E. et al. (2007) G2/M checkpoint gene expression in developing germ cells. Mol Reprod Dev74: 531-538.
24.
Heyns, C.F. and Hutson, J.M. (1995) Historical review of theories on testicular descent . J Urol153: 754-767.
25.
Hrabovszky, Z., Di Pilla, N., Yap, T., Farmer, P.J., Hutson, J.M. and Carlin, J.B. (2002) Role of the gubernacular bulb in cremaster muscle development of the rat. Anat Rec267: 159-165.
26.
Huff, D.S., Fenig, D.M., Canning, D.A., Carr, M.G., Zderic, S.A. and Snyder 3rd, H.M. (2001) Abnormal germ cell development in cryptorchidism. Horm Res55: 11-17.
27.
Hutson, J.M. (1985) A biphasic model for the hormonal control of testicular descent. Lancet2: 419-421.
28.
Hutson, J.M., Albano, F.R., Paxton, G., Sugita, Y., Connor, R., Clarnette, T.D. et al. (2000) In vitro fusion of human inguinal hernia with associated epithelial transformation. Cells Tissues Organs166: 249-258.
29.
Hutson, J.M. and Beasley, S.W. (1987) The mechanisms of testicular descent. Aust Paediatr J23: 215-216.
30.
Hutson, J.M. and Hasthorpe, S. (2005) Testicular descent and cryptorchidism: the state of the art in 2004. J Pediatr Surg40: 297-302.
31.
Kollin, C., Hesser, U., Ritzen, E.M. and Karpe, B. (2006) Testicular growth from birth to two years of age, and the effect of orchidopexy at age nine months: a randomized, controlled study. Acta Paediatr95: 318-324.
32.
Kolon, T.F., Patel, R.P. and Huff, D.S. (2004) Cryptorchidism: diagnosis, treatment, and long-term prognosis. Urol Clin North Am31: 469-480; viii-ix.
33.
Lam, S.K., Clarnette, T.D. and Hutson, J.M. (1998) Does the gubernaculum migrate during inguinoscrotal testicular descent in the rat? Anat Rec250: 159-163.
34.
Lewis, L. (1948) Cryptorchidism. Journal of Urology60: 345-356.
35.
Maclaughlin, D.T. and Donahoe, P.K. (2004) Sex determination and differentiation. N Engl J Med350: 367-378.
36.
Miller, A., Hong, M.K. and Hutson, J.M. (2004) The broad ligament: a review of its anatomy and development in different species and hormonal environments. Clin Anat17: 244-251.
37.
Na, A.F., Harnaen, E.J., Farmer, P.J., Sourial, M., Southwell, B.R. and Hutson, J.M. (2007) Cell membrane and mitotic markers show that the neonatal rat gubernaculum grows in a similar way to an embryonic limb bud . J Pediatr Surg42: 1566-1573.
38.
Nef, S. and Parada, L.F. (1999) Cryptorchidism in mice mutant for Insl3. Nat Genet22: 295-299.
39.
Ng Y.H., Farmer P.J., Sourial M., Southwell B.R., Hutson J.M. (2009) Growth of the rat gubernaculum in vitro and localisation of its growth centre. J Pediatr Surg44: 422-426.
40.
Nightingale, S.S., Western, P. and Hutson, J.M. (2008) The migrating gubernaculum grows like a ``limb bud''. J Pediatr Surg43: 387-390.
41.
Nistal, M. and R.P. (1984) Infertility in adult males with rectactile testes. Fertility and Sterility41: 395-403.
42.
Pham, S.B., Hong, M.K., Teague, J.A. and Hutson, J.M. (2005) Is the testis intraperitoneal? Pediatr Surg Int21: 231-239.
43.
Rabinowitz, R. and Hulbert Jr W.C. (1997) Late presentation of cryptorchidism: the etiology of testicular re-ascent. J Urol157: 1892-1894.
44.
Renfree, M.B. and Short, R.V. (1988) Sex determination in marsupials: evidence for a marsupialeutherian dichotomy. Philos Trans R Soc Lond B Biol Sci322: 41-53.
45.
Ritzen, E.M., Bergh, A., Bjerknes, R., Christiansen, P., Cortes, D., Haugen, S.E. et al. (2007) Nordic consensus on treatment of undescended testes. Acta Paediatr96: 638-643.
46.
Rosenfeld, M.G., Mermod, J.J., Amara, S.G., Swanson, L.W., Sawchenko, P.E., Rivier, J. et al. (1983) Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific rna processing. Nature304: 129-135.
47.
Satokata, I., Benson, G. and Maas, R. (1995) Sexually dimorphic sterility phenotypes in hoxa10-deficient mice. Nature374: 460-463.
48.
Schwindt, B., Farmer, P.J., Watts, L.M., Hrabovszky, Z. and Hutson, J.M. (1999) Localization of calcitonin gene-related peptide within the genitofemoral nerve in immature rats. J Pediatr Surg34: 986-991.
49.
Scott, D.J., Fu, P., Shen, P.J., Gundlach, A., Layfield, S., Riesewijk, A. et al. (2005) Characterization of the rat Insl3 receptor . Ann N Y Acad Sci1041: 13-16.
50.
Shenker, N.S. and Hutson, J.M.Challenging Orthodoxy: A New Theory of the Origin of Cremaster. Clinical Anatomy (in press).
51.
Shono, T., Ramm-Anderson, S. and Hutson, J.M. (1994) Transabdominal testicular descent is really ovarian ascent. J Urol152: 781-784.
52.
Smith, J.A., Hutson, J.M., Beasley, S.W. and Reddihough, D.S. (1989) The relationship between cerebral palsy and cryptorchidism. J Pediatr Surg24: 1303-1305.
53.
Thorsson, A.V., Christiansen, P. and Ritzen, M. (2007) Efficacy and safety of hormonal treatment of cryptorchidism: current state of the art. Acta Paediatr96: 628-630.
54.
Thorup, J., Haugen, S., Kollin, C., Lindahl, S., Lackgren, G., Nordenskjold, A. et al. (2007) Surgical treatment of undescended testes . Acta Paediatr96: 631-637.
55.
Tickle, C. (2003) Patterning systems--from one end of the limb to the other. Dev Cell4: 449-458.
56.
Tong, S.Y., Hutson, J.M. and Watts, L.M. (1996) Does testosterone diffuse down the wolffian duct during sexual differentiation? J Urol155: 2057-2059.
57.
Van der Schoot, P. and Elger, W. (1993) Perinatal development of gubernacular cones in rats and rabbits: effect of exposure to anti-androgens. Anat Rec236: 399-407.
58.
Virtanen, H.E. and Toppari, J. (2008) Epidemiology and pathogenesis of cryptorchidism . Hum Reprod Update14: 49-58.
59.
Yong, E.X., Huynh, J., Farmer, P., Ong, S.Y., Sourial, M., Donath, S. et al. (2008) Calcitonin gene-related peptide stimulates mitosis in the tip of the rat gubernaculum in vitro and provides the chemotactic signals to control gubernacular migration during testicular descent. J Pediatr Surg43: 1533-1539.
60.
Zhou, B., Hutson, J., Hasthorpe, S. and Baker, M.Normal pre-pubertal development of spermatogonia in immature testicular feminized (Tfm/Y) mice with complete androgen resistance. J Pediatr Surg (in press).
61.
Zimmermann, S., Steding, G., Emmen, J.M., Brinkmann, A.O., Nayernia, K., Holstein, A.F. et al. (1999) Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol13: 681-691.
