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  • Review Article
  • Published:

Possible fetal determinants of male infertility

Nature Reviews Endocrinology volume 10, pages 553–562 (2014)Cite this article

Subjects

This article has been updated

Key Points

  • The fetal environment, which includes placental function, maternal metabolism and lifestyle factors (including maternal smoking), influences testicular development and function later in life

  • Endocrine disruption during fetal development might have important consequences for fertility

  • Testicular dysgenesis can result in impaired germ cell differentiation, cryptorchidism, hypospadias and a short anogenital distance at birth and later in life

  • Long-term consequences of testicular dysgenesis include male infertility, reduced levels of testosterone and testicular cancer

Abstract

Although common reproductive problems, such as male infertility and testicular cancer, present in adult life, strong evidence exists that these reproductive disorders might have a fetal origin. The evidence is derived not only from large epidemiological studies that show birth-cohort effects with regard to testicular cancer, levels of testosterone and semen quality, but also from histopathological observations. Many infertile men have histological signs of testicular dysgenesis, including Sertoli-cell-only tubules, immature undifferentiated Sertoli cells, microliths and Leydig cell nodules. The most severe gonadal symptoms occur in patients with disorders of sexual development (DSDs) who have genetic mutations, in whom even sex reversal of individuals with a 46,XY DSD can occur. However, patients with severe DSDs might represent only a small proportion of DSD cases, with milder forms of testicular dysgenesis potentially induced by exposure to environmental and lifestyle factors. Interestingly, maternal smoking during pregnancy has a stronger effect on spermatogenesis than a man's own smoking. Other lifestyle factors such as alcohol consumption and obesity might also have a role. However, increasing indirect evidence exists that exposure to ubiquitous endocrine disrupting chemicals, present at measurable concentrations in individuals, might affect development of human fetal testis. If confirmed, health policies to prevent male reproductive problems should not only target adult men, but also pregnant women and their children.

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Figure 1: Sperm quality and neoplastic cells in ejaculate.
Figure 2: Testicular dysgenesis syndrome.
Figure 3: Histological features of severe oligozoospermia or azoospermia.
Figure 4: Measurement of anogenital distance in boys.
Figure 5: Relationship between levels of testosterone and fertility status.

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Change history

  • 28 July 2014

    In the original version of this article published online the legend to Figure 3 was incorrect. 'CIS marker phospholipase A2-activating protein' should be 'CIS marker placental-like alkaline phosphatase'. This error has now been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors acknowledge the Kirsten and Freddy Johansen Foundation for supporting the start of the International Research and Research Training Centre in Male Reproduction and Child Health (EDMaRC).

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Authors and Affiliations

  1. Department of Growth and Reproduction and International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, Faculty of Medical and Health Sciences, University of Copenhagen, Blegdamsvej 9, Copenhagen, DK-2100, Denmark

    Anders Juul, Kristian Almstrup, Anna-Maria Andersson, Tina K. Jensen, Niels Jørgensen, Katharina M. Main, Ewa Rajpert-De Meyts, Jorma Toppari & Niels E. Skakkebæk

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  1. Anders Juul
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Contributions

A.J., K.A., A.-M.A., T.K.J., N.J., K.M.M., E.R.-D.M., J.T. and N.E.S. researched the data for the article, provided substantial contribution to discussions of the content and wrote the article. A.J., K.A., A.-M.A., N.J., K.M.M., E.R.-D.M., J.T. and N.E.S. reviewed and edited the manuscript before submission.

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Correspondence to Anders Juul.

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Juul, A., Almstrup, K., Andersson, AM. et al. Possible fetal determinants of male infertility. Nat Rev Endocrinol 10, 553–562 (2014). https://doi.org/10.1038/nrendo.2014.97

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