Skip to main content
Log in

Regulation of testicular descent

  • Review Article
  • Published:
Pediatric Surgery International Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 13 May 2015

Abstract

Testicular descent occurs in two morphologically distinct phases, each under different hormonal control from the testis itself. The first phase occurs between 8 and 15 weeks when insulin-like hormone 3 (Insl3) from the Leydig cells stimulates the gubernaculum to swell, thereby anchoring the testis near the future inguinal canal as the foetus grows. Testosterone causes regression of the cranial suspensory ligament to augment the transabdominal phase. The second, or inguinoscrotal phase, occurs between 25 and 35 weeks, when the gubernaculum bulges out of the external ring and migrates to the scrotum, all under control of testosterone. However, androgen acts mostly indirectly via the genitofemoral nerve (GFN), which produces calcitonin gene-related peptide (CGRP) to control the direction of migration. In animal models the androgen receptors are in the inguinoscrotal fat pad, which probably produces a neurotrophin to masculinise the GFN sensory fibres that regulate gubernacular migration. There is little direct evidence that this same process occurs in humans, but CGRP can regulate closure of the processus vaginalis in inguinal hernia, confirming that the GFN probably mediates human testicular descent by a similar mechanism as seen in rodent models. Despite increased understanding about normal testicular descent, the common causes of cryptorchidism remain elusive.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hutson J (1985) A biphasic model for the hormonal control of testicular descent. Lancet 2(8452):419–420

    Article  CAS  PubMed  Google Scholar 

  2. Hutson JM et al (2014) The power and perils of animal models with urogenital anomalies: handle with care. J Pediatr Urol 10(4):699–705

    Article  CAS  PubMed  Google Scholar 

  3. Lee MM, Donahoe PK (1993) Mullerian inhibiting substance: a gonadal hormone with multiple functions. Endocr Rev 14(2):152–164

    CAS  PubMed  Google Scholar 

  4. Lane AH, Donahoe PK (1998) New insights into mullerian inhibiting substance and its mechanism of action. J Endocrinol 158(1):1–6

    Article  CAS  PubMed  Google Scholar 

  5. Heyns CF (1990) Exstrophy of the testis. J Urol 144:724–725

    CAS  PubMed  Google Scholar 

  6. Backhouse KM (1964) The gubernaculum testis hunteri: testicular descent and maldescent. Ann Royal Colleg Surg Engl 35:15–33

    CAS  Google Scholar 

  7. Nef S, Parada LF (1999) Cryptorchidism in mice mutant for Insl3. Nat Genet 22(3):295–299

    Article  CAS  PubMed  Google Scholar 

  8. Zimmermann S et al (1999) Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 13(5):681–691

    Article  CAS  PubMed  Google Scholar 

  9. Ivell R, Hartung S, Anand-Ivell R (2005) Insulin-like factor 3: where are we now? Ann N Y Acad Sci 1041(1):486–496

    Article  CAS  PubMed  Google Scholar 

  10. Kubota Y et al (2001) Leydig insulin-like hormone, gubernacular development and testicular descent. J Urol 165(5):1673–1675

    Article  CAS  PubMed  Google Scholar 

  11. Adham IM et al (2002) The overexpression of the insl3 in female mice causes descent of the ovaries. Mol Endocrinol 16(2):244–252

    Article  CAS  PubMed  Google Scholar 

  12. Chen N et al (2011) Gone with the Wnt: the canonical Wnt signaling axis is present and androgen dependent in the rodent gubernaculum. J Pediatr Surg 46(12):2363–2369

    Article  PubMed  Google Scholar 

  13. Kaftanovskaya EM et al (2011) Suppression of insulin-like3 receptor reveals the role of beta-catenin and Notch signaling in gubernaculum development. Mol Endocrinol 25(1):170–183

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Bay K et al (2011) Testicular descent: INSL3, testosterone, genes and the intrauterine milieu. Nat Rev Urol 8(4):187–196

    Article  CAS  PubMed  Google Scholar 

  15. Virtanen HE, Toppari J (2008) Epidemiology and pathogenesis of cryptorchidism. Hum Reprod Update 14(1):49–58

    Article  CAS  PubMed  Google Scholar 

  16. Ferlin A et al (2007) Hormonal and genetic control of testicular descent. Reprod Biomed Online 15(6):659–665

    Article  CAS  PubMed  Google Scholar 

  17. Virtanen HE, Toppari J (2014) Embryology and physiology of testicular development and descent. Pediatric Endocrinol Rev PER 11(Suppl 2):206–213

    Google Scholar 

  18. Hutson JM, Baker ML (1994) A hypothesis to explain abnormal gonadal descent in persistent mullerian duct syndrome. Pediatr Surg Int 9:542–543

    Google Scholar 

  19. Hutson JM, Chow CW, Ng W-D (1987) Persistent mullerian duct syndrome with transverse testicular ectopia. Pediatr Surg Int 2:191–194

    Google Scholar 

  20. Imbeaud S et al (1995) Testicular degeneration in three patients with the persistent mullerian duct syndrome. Eur J Pediatr 154(3):187–190

    CAS  PubMed  Google Scholar 

  21. Huynh J et al (2007) Signalling molecules: clues from development of the limb bud for cryptorchidism? Pediatr Surg Int 23(7):617–624

    Article  PubMed  Google Scholar 

  22. Wolpert L (1999) Vertebrate limb development and malformations. Pediatr Res 46(3):247–254

    Article  CAS  PubMed  Google Scholar 

  23. Dudley AT, Ros MA, Tabin CJ (2002) A re-examination of proximodistal patterning during vertebrate limb development. Nature 418(6897):539–544

    Article  CAS  PubMed  Google Scholar 

  24. Nation T et al (2009) The antiandrogen flutamide perturbs inguinoscrotal testicular descent in the rat and suggests a link with mammary development. J Pediatr Surg 44(12):2330–2334

    Article  PubMed  Google Scholar 

  25. Su S et al (2012) Regression of the mammary branch of the genitofemoral nerve may be necessary for testicular descent in rats. J Urol 188(4 Suppl):1443–1448

    Article  PubMed  Google Scholar 

  26. Coveney D et al (2002) The development of the gubernaculum and inguinal closure in the marsupial Macropus eugenii. J Anat 201:239–256

    Article  PubMed Central  PubMed  Google Scholar 

  27. Nightingale SS, Western P, Hutson JM (2008) The migrating gubernaculum grows like a “limb bud”. J Pediatr Surg 43(2):387–390

    Article  PubMed  Google Scholar 

  28. Krajnc-Franken MA et al (2004) Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol 24(2):687–696

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Na AF et al (2007) Cell membrane and mitotic markers show that the neonatal rat gubernaculum grows in a similar way to an embryonic limb bud. J Pediatr Surg 42(9):1566–1573

    Article  PubMed  Google Scholar 

  30. Churchill JA et al (2011) Gubernaculum as icebreaker: do matrix metalloproteinases in rodent gubernaculum and inguinal fat pad permit testicular descent? J Pediatr Surg 46(12):2353–2357

    Article  PubMed  Google Scholar 

  31. Das S, Singer A (1990) Controversies of perinatal torsion of the spermatic cord: a review, survery and recommendations. J Urol 143:231–233

    CAS  PubMed  Google Scholar 

  32. Welsh M et al (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 118(4):1479–1490

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Nation TR et al (2011) The effect of flutamide on expression of androgen and estrogen receptors in the gubernaculum and surrounding structures during testicular descent. J Pediatr Surg 46(12):2358–2362

    Article  PubMed  Google Scholar 

  34. Lewis LG (1948) Cryptorchism. J Urol 60:345–356

    CAS  PubMed  Google Scholar 

  35. Beasley SW, Hutson JM (1987) Effect of division of genitofemoral nerve on testicular descent in the rat. ANZ J Surg 57:49–51

    Article  CAS  Google Scholar 

  36. Schwindt B et al (1999) Localization of calcitonin gene-related peptide within the genitofemoral nerve in immature rats. J Pediatr Surg 34(6):986–991

    Article  CAS  PubMed  Google Scholar 

  37. Yamanaka J, Metcalfe SA, Hutson JM (1992) Demonstration of calcitonin gene-related peptide receptors in the gubernaculum by computerized densitometry. J Pediatr Surg 27:876–878

    Article  CAS  PubMed  Google Scholar 

  38. Yamanaka J et al (1993) Testicular descent. II. Ontogeny and response to denervation of calcitonin gene-related peptide receptors in neonatal rat gubernaculum. Endocrinology 132(1):280–284

    CAS  PubMed  Google Scholar 

  39. Hrabovszky Z, Hutson JM (1999) Capsaicin restores gubernacular contractility in TS rats. J Pediatr Surg 34(12):1769–1772

    Article  CAS  PubMed  Google Scholar 

  40. Park W-H, Hutson JM (1991) The gubernaculum shows rhythmic contractility and active movement during testicular descent. J Pediatr Surg 26(5):615–617

    Article  CAS  PubMed  Google Scholar 

  41. Momose Y, Griffiths AL, Hutson JM (1992) Testicular descent III. The neonatal gubernaculum shows rhythmic contraction in organ culture in response to calcitonin gene-related peptide. Endocrinology 131:2881–2884

    CAS  PubMed  Google Scholar 

  42. Terada M et al (1994) Ontogeny of Gubernacular Contraction and Effect of Calcitonin Gene-Related Peptide in the Mouse. J Pediatr Surg 29(5):609–611

    Article  CAS  PubMed  Google Scholar 

  43. Yong EXZ 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 Surg 43(8):1533–1539

    Article  PubMed  Google Scholar 

  44. Shenker NS et al (2006) A new role for androgen in testicular descent: permitting gubernacular cell proliferation in response to the neuropeptide, calcitonin gene-related peptide. J Pediatr Surg 41(2):407–412

    Article  PubMed  Google Scholar 

  45. Ng YH et al (2009) Growth of the rat gubernaculum in vitro and localisation of its growth centre. J Pediatr Surg 44(2):422–426

    Article  PubMed  Google Scholar 

  46. Terada M et al (1994) Calcitonin gene-related peptide receptors in the gubernaculum of normal rat and 2 models of cryptorchidism. J Urol 152(2 Pt 2):759–762

    CAS  PubMed  Google Scholar 

  47. Terada M et al (1995) The role of the genitofemoral nerve and CGRP in congenitally cryptorchid mutant TS rats. J Urol 154:734–737

    Article  CAS  PubMed  Google Scholar 

  48. Nation T et al (2011) Androgen and estrogen receptor expression in the spinal segments of the genitofemoral nerve during testicular descent. J Pediatr Surg 46(8):1539–1543

    Article  PubMed  Google Scholar 

  49. Sengelaub DR et al (1989) Hormonal control of neuron number in sexually dimorphic spinal nuclei of the rat: III. differential effects of the androgen dihydrotestosterone. J Comp Neurol 280(4):637–644

    Article  CAS  PubMed  Google Scholar 

  50. Popper P, Micevych PE (1990) Steroid regulation of calcitonin gene-related peptide mRNA expression in motoneurons of the spinal nucleus of the bulbocavernosus. Brain Res Mol Brain Res 8(2):159–166

    Article  CAS  PubMed  Google Scholar 

  51. Yang LY, Verhovshek T, Sengelaub DR (2004) Brain-derived neurotrophic factor and androgen interact in the maintenance of dendritic morphology in a sexually dimorphic rat spinal nucleus. Endocrinology 145(1):161–168

    Article  CAS  PubMed  Google Scholar 

  52. Forger NG et al (1998) Ciliary neurotrophic factor receptor alpha in spinal motoneurons is regulated by gonadal hormones. J Neurosci 18(21):8720–8729

    CAS  PubMed  Google Scholar 

  53. Bartoletti A et al (2002) Heterozygous knock-out mice for brain-derived neurotrophic factor show a pathway-specific impairment of long-term potentiation but normal critical period for monocular deprivation. J Neurosci 22(23):10072–10077

    CAS  PubMed  Google Scholar 

  54. DeChiara TM et al (1995) Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell 83(2):313–322

    Article  CAS  PubMed  Google Scholar 

  55. Liu Y et al (2012) Sexually dimorphic BDNF signaling directs sensory innervation of the mammary gland. Science 338(6112):1357–1360

    Article  CAS  PubMed  Google Scholar 

  56. Husmann DA (2009) Testicular descent: a hypothesis and review of current controversies. Pediatr Endocrinol Rev 6(4):491–495

    PubMed  Google Scholar 

  57. Clarnette TD, Hutson JM (1996) The genitofemoral nerve may link testicular inguinoscrotal descent with congenital inguinal hernia. Aust NZ J Surg 66(9):612–617

    Article  CAS  Google Scholar 

  58. Buraundi S et al (2011) 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 46(9):1804–1812

    Article  PubMed  Google Scholar 

  59. Clarnette TD, Hutson JM, Beasley SW (1996) Factors affecting the development of the processus vaginalis in the rat. J Urol 156(4):1463–1466

    Article  CAS  PubMed  Google Scholar 

  60. Clarnette TD, Lam SKL, Hutson JM (1998) Ventriculo-Peritoneal shunts in children reveal the natural history of closure of the processus vaginalis. J Pediatr Surg 33:413–416

    Article  CAS  PubMed  Google Scholar 

  61. Hadziselimovic F et al (2007) Infertility in cryptorchidism is linked to the stage of germ cell development at orchidopexy. Horm Res 68(1):46–52

    Article  CAS  PubMed  Google Scholar 

  62. Sugita Y et al (1999) Calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibres and receptors in the human processus vaginalis. Hernia 3:113–116

    Article  Google Scholar 

  63. Hutson JM et al (2000) In vitro fusion of human inguinal hernia with associated epithelial transformation. Cells Tissues Organs 166(3):249–258

    Article  CAS  PubMed  Google Scholar 

  64. Cook BJ, Hasthorpe S, Hutson JM (2000) Fusion of childhood inguinal hernia induced by HGF and CGRP via an epithelial transition. J Pediatr Surg 35(1):77–81

    Article  CAS  PubMed  Google Scholar 

  65. Hutson JM, Temelcos C (2005) Could inguinal hernia be treated medically? Med Hypotheses 64(1):37–40

    Article  PubMed  Google Scholar 

  66. Hrabovszky Z, Hutson JM (2002) Androgen imprinting of the brain in animal models and humans with intersex disorders: review and recommendations. J Urol 168:2142–2148

    Article  CAS  PubMed  Google Scholar 

  67. Clarnette TD et al (1997) Incomplete disappearance of the processus vaginalis as a cause of ascending testis. J Urol 157:1889–1891

    Article  CAS  PubMed  Google Scholar 

  68. Kollin C, Ritzen EM (2014) Cryptorchidism: a clinical perspective. Pediatric Endocrinol Rev PER 11(Suppl 2):240–250

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John M. Hutson.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hutson, J.M., Li, R., Southwell, B.R. et al. Regulation of testicular descent. Pediatr Surg Int 31, 317–325 (2015). https://doi.org/10.1007/s00383-015-3673-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00383-015-3673-4

Keywords

Navigation