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Current understanding of hypospadias: relevance of animal models

Nature Reviews Urology volume 12, pages 271–280 (2015)Cite this article

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Key Points

  • Hypospadias occurs in approximately 1:200–1:300 newborn males, and is the second most common congenital abnormality in boys

  • For the overwhelming majority of patients with hypospadias the aetiology remains unknown

  • Relevant animal models of hypospadias are needed to improve our understanding of this congenital anomaly

  • Normal and hypospadic development of the mouse, rat and human penis and prepuce involves similar epithelial fusion events and disruption of urethra-associated erectile bodies, leading to similar penile and preputial defects

  • The ultimate goal of hypospadias research is to prevent or reduce the incidence of hypospadias in humans by defining the underlying environmental causes and genetic susceptibilities

Abstract

Hypospadias is a congenital abnormality of the penile urethra with an incidence of approximately 1:200–1:300 male births, which has doubled over the past three decades. The aetiology of the overwhelming majority of hypospadias remains unknown but appears to be a combination of genetic susceptibility and prenatal exposure to endocrine disruptors. Reliable animal models of hypospadias are required for better understanding of the mechanisms of normal penile urethral formation and hence hypospadias. Mice and/or rats are generally used for experimental modelling of hypospadias, however these do not fully reflect the human condition. To use these models successfully, researchers must understand the similarities and differences between mouse, rat and human penile anatomy as well as the normal morphogenetic mechanisms of penile development in these species. Despite some important differences, numerous features of animal and human hypospadias are shared: the prevalence of distal penile malformations; disruption of the urethral meatus; disruption of urethra-associated erectile bodies; and a common mechanism of impaired epithelial fusion events. Rat and mouse models of hypospadias are crucial to our understanding of hypospadias to ultimately reduce its incidence through better preventive strategies.

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Figure 1: Examples of human hypospadias.
Figure 2: Penile anatomy and development.
Figure 3: Mid-sagittal haematoxylin–eosin stained sections of the adult mouse penis.
Figure 4: Gross anatomy and histology of the mouse and rat penis.
Figure 5: Scanning electron micrographs of penises from mice with postnatal diethylstilbestrol exposure.
Figure 6: Human penile urethral development.
Figure 7: Transverse sections through the genital tubercles of 18-day embryonic mice.
Figure 8: Sections through an 18-day embryonic mouse genital tubercle.
Figure 9: Development of the distal adult mouse urethra.

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Change history

  • 29 April 2015

    In the version of this article initially published online, the legend of Figure 5h contained a labelling error (f instead of h). The error has been corrected for the print, HTML and PDF versions of the article.

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Acknowledgements

This work was supported by NSF Grant IOS-0920793 and NIH grant RO1 DK0581050.

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Authors and Affiliations

  1. Department of Urology, University of California, San Francisco, 400 Parnassus Avenue, A610, San Francisco, 94143, CA, USA

    Gerald R. Cunha, Adriane Sinclair & Laurence S. Baskin

  2. Department of Anatomy & Developmental Biology, Monash University, Clayton Campus, Building 76, Level 3, Wellington Road, Clayton, 3800, VIC, Australia

    Gail Risbridger

  3. Urology Department, Royal Children's Hospital, Parkville, Melbourne, 3052, VIC, Australia

    John Hutson

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Contributions

All authors researched data for the article and provided a substantial contribution to discussions of content. G.R.C., AS., G.R., J.H. and L.S.B. all contributed equally to writing the article, and to reviewing and/or editing the manuscript before submission.

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Correspondence to Gerald R. Cunha.

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Supplementary information

Supplementary Table 1

Anatomical and developmental characteristics of the human and mouse penis (DOCX 26 kb)

Supplementary Table 2

Findings from experimental studies of murine hypospadias (DOCX 26 kb)

Supplementary Table 3

Similarities and differences between human and mouse penis and urethral hypospadias (DOCX 26 kb)

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Cunha, G., Sinclair, A., Risbridger, G. et al. Current understanding of hypospadias: relevance of animal models. Nat Rev Urol 12, 271–280 (2015). https://doi.org/10.1038/nrurol.2015.57

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