Download PDF
Eur J Pediatr Surg 2016; 26(05): 390-398
DOI: 10.1055/s-0036-1592196
Review Article
Georg Thieme Verlag KG Stuttgart · New York

What Animal Models of Testicular Descent and Germ Cell Maturation Tell Us about the Mechanism in Humans

John Medwyn Hutson
1   F. Douglas Stephens Surgical Research Group, Murdoch Childrens Research Institute, Victoria, Australia
2   Department of Urology, Royal Children's Hospital, Victoria, Australia
3   Department of Paediatrics, University of Melbourne, Victoria, Australia
,
Ruili Li
1   F. Douglas Stephens Surgical Research Group, Murdoch Childrens Research Institute, Victoria, Australia
2   Department of Urology, Royal Children's Hospital, Victoria, Australia
,
Jaya Vikraman
2   Department of Urology, Royal Children's Hospital, Victoria, Australia
,
Moshe Loebenstein
4   Department of Medicine, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia
› Author Affiliations
Further Information

Publication History

26 July 2016

02 August 2016

Publication Date:
20 September 2016 (online)

    Permissions and Reprints

Abstract

Testicular descent occurs in most mammals in two main steps that have different hormonal control and anatomical processes. The evolution of testicular descent reveals the same basic processes in humans and animals, with minor differences in timing and anatomy, especially the location of the scrotum and the processus vaginalis. Animal models are useful as they reveal some embryological processes that cannot be studies easily in humans, such as the potential role of the mammary line and the role of the genitofemoral nerve. Postnatal germ cell development is very similar in animal models and humans, except for the timing of arrival of the testis into the scrotum, which is before birth in humans versus around puberty in rodents. Once all the minor differences between animal models and humans are taken into account, animal experimentation has provided amazing insights into the mechanisms of testicular descent, and recently, how the postnatal germ cell develops in normally descended and undescended testes.

Keywords

testicular descent - undescended testis - germ cell - gonocytes
 

  • References

  • 1 Hutson JM. Development of the urogenital system. In: Standring S, ed. Grays Anatomy. 40th ed. Edinburgh, Scotland: Churchill Livingstone Elsevier; 2008: 1305-1325
    Google Scholar
  • 2 Hutson JM, Thorup JM, Beasley SW. Descent of the Testis. 2nd ed. Switzerland: Springer; 2016
    CrossrefGoogle Scholar
  • 3 Hutson JM. A biphasic model for the hormonal control of testicular descent. Lancet 1985; 2 (8452) 419-421
    PubMedGoogle Scholar
  • 4 Hutson JM. Testicular feminization: a model for testicular descent in mice and men. J Pediatr Surg 1986; 21 (3) 195-198
    CrossrefPubMedGoogle Scholar
  • 5 Nef S, Parada LF. Cryptorchidism in mice mutant for Insl3. Nat Genet 1999; 22 (3) 295-299
    CrossrefPubMedGoogle Scholar
  • 6 Zimmermann S, Steding G, Emmen JM , et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 1999; 13 (5) 681-691
    CrossrefPubMedGoogle Scholar
  • 7 Bay K, Andersson AM. Human testicular insulin-like factor 3: in relation to development, reproductive hormones and andrological disorders. Int J Androl 2011; 34 (2) 97-109
    CrossrefPubMedGoogle Scholar
  • 8 Hutson JM, Southwell BR, Li R , et al. The regulation of testicular descent and the effects of cryptorchidism. Endocr Rev 2013; 34 (5) 725-752
    CrossrefPubMedGoogle Scholar
  • 9 Bedford JM. Anatomical evidence for the epididymis as the prime mover in the evolution of the scrotum. Am J Anat 1978; 152 (4) 483-507
    CrossrefPubMedGoogle Scholar
  • 10 Williams MPL, Hutson JM. The phylogeny of testicular descent. Pediatr Surg Int 1991; 6 (3) 162-166
    PubMedGoogle Scholar
  • 11 Steinberger A. Effects of temperature on the biochemistry of the testis. Adv Exp Med Biol 1991; 286 (286) 33-47
    PubMedGoogle Scholar
  • 12 Setchell BP. The Parkes lecture. Heat and the testis. J Reprod Fertil 1998; 114 (2) 179-194
    CrossrefPubMedGoogle Scholar
  • 13 Miller RA. The inguinal canal of primates. Am J Anat 1947; 80 (1) 117-142
    CrossrefPubMedGoogle Scholar
  • 14 Engle ET. Experimentally induced descent of the testis in the macacus monkey by hormones from the anterior pituitary and pregnancy urine. Endocrinology 1932; 16 (5) 513-520
    CrossrefPubMedGoogle Scholar
  • 15 Deming CL. The evaluation of hormonal therapy in cryptorchidism. J Urol 1952; 68 (1) 354-357
    PubMedGoogle Scholar
  • 16 Bartsch G, Frick J. Therapeutic effects of luteinizing hormone releasing hormone (LH-RH) in cryptorchidism. Andrologia 1974; 6 (3) 197-201
    PubMedGoogle Scholar
  • 17 Rajfer J, Handelsman DJ, Swerdloff RS , et al. Hormonal therapy of cryptorchidism. A randomized, double-blind study comparing human chorionic gonadotropin and gonadotropin-releasing hormone. N Engl J Med 1986; 314 (8) 466-470
    CrossrefPubMedGoogle Scholar
  • 18 Thorsson AV, Christiansen P, Ritzén M. Efficacy and safety of hormonal treatment of cryptorchidism: current state of the art. Acta Paediatr 2007; 96 (5) 628-630
    CrossrefPubMedGoogle Scholar
  • 19 Coveney D, Shaw G, Hutson JM, Renfree MB. Effect of an anti-androgen on testicular descent and inguinal closure in a marsupial, the tammar wallaby (Macropus eugenii). Reproduction 2002; 124 (6) 865-874
    CrossrefPubMedGoogle Scholar
  • 20 Renfree MB, , O WS, Short RV, Shaw G. Sexual differentiation of the urogenital system of the fetal and neonatal tammar wallaby, Macropus eugenii . Anat Embryol (Berl) 1996; 194 (2) 111-134
    PubMedGoogle Scholar
  • 21 Nation T, Balic A, Buraundi S , et al. The antiandrogen flutamide perturbs inguinoscrotal testicular descent in the rat and suggests a link with mammary development. J Pediatr Surg 2009; 44 (12) 2330-2334
    CrossrefPubMedGoogle Scholar
  • 22 Krajnc-Franken MA, van Disseldorp AJ, Koenders JE, Mosselman S, van Duin M, Gossen JA. Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol 2004; 24 (2) 687-696
    CrossrefPubMedGoogle Scholar
  • 23 Tickle C. Patterning systems—from one end of the limb to the other. Dev Cell 2003; 4 (4) 449-458
    CrossrefPubMedGoogle Scholar
  • 24 Buraundi S, Balic A, Farmer PJ, Southwell BR, Hutson JM. Gubernacular development in the mouse is similar to the rat and suggests that the processus vaginalis is derived from the urogenital ridge and is different from the parietal peritoneum. J Pediatr Surg 2011; 46 (9) 1804-1812
    CrossrefPubMedGoogle Scholar
  • 25 Lopez-Marambio FA, Hutson JM. The relationship between the testis and tunica vaginalis changes with age. J Pediatr Surg 2015; 50 (12) 2075-2077
    CrossrefPubMedGoogle Scholar
  • 26 Miller A, Hong MK, Hutson JM. The broad ligament: a review of its anatomy and development in different species and hormonal environments. Clin Anat 2004; 17 (3) 244-251
    CrossrefPubMedGoogle Scholar
  • 27 Hutson JM, Albano FR, Paxton G , et al. In vitro fusion of human inguinal hernia with associated epithelial transformation. Cells Tissues Organs 2000; 166 (3) 249-258
    CrossrefPubMedGoogle Scholar
  • 28 Welsh M, Saunders PT, Fisken M , et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 2008; 118 (4) 1479-1490
    CrossrefPubMedGoogle Scholar
  • 29 Tomiyama H, Hutson JM, Truong A, Agoulnik AI. Transabdominal testicular descent is disrupted in mice with deletion of insulinlike factor 3 receptor. J Pediatr Surg 2003; 38 (12) 1793-1798
    CrossrefPubMedGoogle Scholar
  • 30 Ivell R, Hartung S, Anand-Ivell R. Insulin-like factor 3: where are we now?. Ann N Y Acad Sci 2005; 1041 (1) 486-496
    CrossrefPubMedGoogle Scholar
  • 31 Virtanen HE, Toppari J. Epidemiology and pathogenesis of cryptorchidism. Hum Reprod Update 2008; 14 (1) 49-58
    CrossrefPubMedGoogle Scholar
  • 32 Husmann DA, McPhaul MJ. Reversal of flutamide-induced cryptorchidism by prenatal time-specific androgens. Endocrinology 1992; 131 (4) 1711-1715
    CrossrefPubMedGoogle Scholar
  • 33 Hutson JM, Hasthorpe S, Heyns CF. Anatomical and functional aspects of testicular descent and cryptorchidism. Endocr Rev 1997; 18 (2) 259-280
    CrossrefPubMedGoogle Scholar
  • 34 Nation TR, Buraundi S, Balic A , et al. The effect of flutamide on expression of androgen and estrogen receptors in the gubernaculum and surrounding structures during testicular descent. J Pediatr Surg 2011; 46 (12) 2358-2362
    CrossrefPubMedGoogle Scholar
  • 35 Lewis LG. Cryptorchism. J Urol 1948; 60 (2) 345-356
    PubMedGoogle Scholar
  • 36 Beasley SW, Hutson JM. Effect of division of genitofemoral nerve on testicular descent in the rat. Aust N Z J Surg 1987; 57 (1) 49-51
    CrossrefPubMedGoogle Scholar
  • 37 Schwindt B, Farmer PJ, Watts LM, Hrabovszky Z, Hutson JM. Localization of calcitonin gene-related peptide within the genitofemoral nerve in immature rats. J Pediatr Surg 1999; 34 (6) 986-991
    CrossrefPubMedGoogle Scholar
  • 38 Park W-H, Hutson JM. The gubernaculum shows rhythmic contractility and active movement during testicular descent. J Pediatr Surg 1991; 26 (5) 615-617
    CrossrefPubMedGoogle Scholar
  • 39 Cousinery MC, Li R, Vannitamby A, Vikraman J, Southwell BR, Hutson JM. Neurotrophin signaling in a genitofemoral nerve target organ during testicular descent in mice. J Pediatr Surg 2016; 51 (8) 1321-1326
    CrossrefPubMedGoogle Scholar
  • 40 Churchill JA, Buraundi S, Farmer PJ , et al. Gubernaculum as icebreaker: do matrix metalloproteinases in rodent gubernaculum and inguinal fat pad permit testicular descent?. J Pediatr Surg 2011; 46 (12) 2353-2357
    CrossrefPubMedGoogle Scholar
  • 41 Heyns CF. The gubernaculum during testicular descent in the human fetus. J Anat 1987; 153 (153) 93-112
    PubMedGoogle Scholar
  • 42 Das S, Singer A. Controversies of perinatal torsion of the spermatic cord: a review, survey and recommendations. J Urol 1990; 143 (2) 231-233
    PubMedGoogle Scholar
  • 43 Hutson JM, Baskin LS, Risbridger G, Cunha GR. The power and perils of animal models with urogenital anomalies: handle with care. J Pediatr Urol 2014; 10 (4) 699-705
    CrossrefPubMedGoogle Scholar
  • 44 Husmann DA, Levy JB. Current concepts in the pathophysiology of testicular undescent. Urology 1995; 46 (2) 267-276
    CrossrefPubMedGoogle Scholar
  • 45 Nightingale SS, Western P, Hutson JM. The migrating gubernaculum grows like a “limb bud”. J Pediatr Surg 2008; 43 (2) 387-390
    CrossrefPubMedGoogle Scholar
  • 46 Nagraj S, Seah GJ, Farmer PJ , et al. The development and anatomy of the gubernaculum in Hoxa11 knockout mice. J Pediatr Surg 2011; 46 (2) 387-392
    CrossrefPubMedGoogle Scholar
  • 47 Park W-H, Hutson JM. A new inbred rat strain (TS) with suprainguinal ectopic testes: a model for human cryptorchidism. Pediatr Surg Int 1991; 6 (3) 172-175
    PubMedGoogle Scholar
  • 48 Goh DW, Momose Y, Middlesworth W, Hutson JM. The relationship among calcitonin generelated peptide, androgens and gubernacular development in 3 animal models of cryptorchidism. J Urol 1993; 150 (2 Pt 2): 574-576
    PubMedGoogle Scholar
  • 49 Terada M, Hutson JM, Farmer PJ, Goh DW. The role of the genitofemoral nerve and calcitonin generelated peptide in congenitally cryptorchid mutant TS rats. J Urol 1995; 154 (2 Pt 2): 734-737
    CrossrefPubMedGoogle Scholar
  • 50 Hadziselimovic F, Zivkovic D, Bica DTG, Emmons LR. The importance of mini-puberty for fertility in cryptorchidism. J Urol 2005; 174 (4 Pt 2): 1536-1539 , discussion 1538–1539
    CrossrefPubMedGoogle Scholar
  • 51 Hutson JM, Li R, Southwell BR, Petersen BL, Thorup J, Cortes D. Germ cell development in the postnatal testis: the key to prevent malignancy in cryptorchidism?. Front Endocrinol (Lausanne) 2012; 3: 176
    PubMedGoogle Scholar
  • 52 Ong C, Hasthorpe S, Hutson JM. Germ cell development in the descended and cryptorchid testis and the effects of hormonal manipulation. Pediatr Surg Int 2005; 21 (4) 240-254
    CrossrefPubMedGoogle Scholar
  • 53 Li R, Thorup J, Sun C, Cortes D, Southwell B, Hutson J. Immunofluorescent analysis of testicular biopsies with germ cell and Sertoli cell markers shows significant MVH negative germ cell depletion with older age at orchiopexy. J Urol 2014; 191 (2) 458-464
    CrossrefPubMedGoogle Scholar
  • 54 Giwercman A, Müller J, Skakkebaek NE. Carcinoma in situ of the testis: possible origin, clinical significance, and diagnostic methods. Recent Results Cancer Res 1991; 123 (123) 21-36
    PubMedGoogle Scholar
  • 55 Su S, Szarek M, Vooght A, Hutson J, Li R. Gonocyte transformation to spermatogonial stem cells occurs earlier in patients with undervirilisation syndromes. J Pediatr Surg 2014; 49 (2) 323-327
    CrossrefPubMedGoogle Scholar