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Testicular descent: INSL3, testosterone, genes and the intrauterine milieu

Nature Reviews Urology volume 8, pages 187–196 (2011)Cite this article

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Abstract

Complete testicular descent is a sign of, and a prerequisite for, normal testicular function in adult life. The process of testis descent is dependent on gubernacular growth and reorganization, which is regulated by the Leydig cell hormones insulin-like peptide 3 (INSL3) and testosterone. Investigation of the role of INSL3 and its receptor, relaxin-family peptide receptor 2 (RXFP2), has contributed substantially to our understanding of the hormonal control of testicular descent. Cryptorchidism is a common congenital malformation, which is seen in 2–9% of newborn boys, and confers an increased risk of infertility and testicular cancer in adulthood. Although some cases of isolated cryptorchidism in humans can be ascribed to known genetic defects, such as mutations in INSL3 or RXFP2, the cause of cryptorchidism remains unknown in most patients. Several animal and human studies are currently underway to test the hypothesis that in utero factors, including environmental and maternal lifestyle factors, may be involved in the etiology of cryptorchidism. Overall, the etiology of isolated cryptorchidism seems to be complex and multifactorial, involving both genetic and nongenetic components.

Key Points

  • The process of testicular descent occurs during fetal development and should be completed before birth in humans

  • Undescended testes, or cryptorchidism, confers an increased risk of testicular cancer and infertility in adult life

  • Testosterone and insulin-like peptide 3 produced by the Leydig cells both have a pivotal role in testicular descent

  • Testicular descent relies primarily on hormone-dependent development and reorganization of the ligament gubernaculum

  • The intrauterine environment is often involved in the pathogenesis of isolated cryptorchidism, whereas known genetic factors are responsible for only a small proportion of cases

  • The etiology of cryptorchidism is incompletely understood, and is regarded as both complex and multifactorial

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Figure 1: INSL3 levels in human males through fetal life to adulthood.
Figure 2: Schematic illustration of the stages of cryptorchidism, according to the system proposed by Scorer.64
Figure 3: Histological images of testicular biopsies.

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Acknowledgements

C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.

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  1. University Department of Growth and Reproduction, Rigshospitalet, Blegdamsvej 9, Copenhagen, DK-2100, Denmark

    Katrine Bay, Katharina M. Main & Niels E. Skakkebæk

  2. Departments of Physiology and Pediatrics, University of Turku, Kiinamyllynkatu 10, Turku, FI-20520, Finland

    Jorma Toppari

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All authors researched data for the article, made substantial contributions to discussions of content and reviewed and edited the article before submission. K. Bay and J. Toppari wrote the manuscript.

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Bay, K., Main, K., Toppari, J. et al. Testicular descent: INSL3, testosterone, genes and the intrauterine milieu. Nat Rev Urol 8, 187–196 (2011). https://doi.org/10.1038/nrurol.2011.23

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