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Molecular mechanisms of cellular dysfunction in testes from men with non-obstructive azoospermia

Nature Reviews Urology volume 21, pages 67–90 (2024)Cite this article

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Abstract

Male factor infertility affects 50% of infertile couples worldwide; the most severe form, non-obstructive azoospermia (NOA), affects 10–15% of infertile males. Treatment for individuals with NOA is limited to microsurgical sperm extraction paired with in vitro fertilization intracytoplasmic sperm injection. Unfortunately, spermatozoa are only retrieved in ~50% of patients, resulting in live birth rates of 21–46%. Regenerative therapies could provide a solution; however, understanding the cell-type-specific mechanisms of cellular dysfunction is a fundamental necessity to develop precision medicine strategies that could overcome these abnormalities and promote regeneration of spermatogenesis. A number of mechanisms of cellular dysfunction have been elucidated in NOA testicular cells. These mechanisms include abnormalities in both somatic cells and germ cells in NOA testes, such as somatic cell immaturity, aberrant growth factor signalling, increased inflammation, increased apoptosis and abnormal extracellular matrix regulation. Future cell-type-specific investigations in identifying modulators of cellular transcription and translation will be key to understanding upstream dysregulation, and these studies will require development of in vitro models to functionally interrogate spermatogenic niche dysfunction in both somatic and germ cells.

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Fig. 1: NOA phenotypes and intratesticular heterogeneity observed during microTESE.
Fig. 2: Five states of human spermatogonial stem cells.
Fig. 3: Interplay between testicular cell abnormalities associated with NOA.
Fig. 4: Proposed personalized and precision medicine workflow for restoring sperm production using IVS.

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Acknowledgements

The authors thank the American Urologic Association Rising Star Award, Michael Smith Health Research Foundation Health Professional Investigator and Vancouver Coastal Health Research Institute for support related to R.F.’s work in this field.

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  1. These authors contributed equally: Arina Piechka, Sydney Sparanese.

Authors and Affiliations

  1. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada

    Arina Piechka, Sydney Sparanese, Luke Witherspoon, Faraz Hach & Ryan Flannigan

  2. Vancouver Prostate Centre, Vancouver, British Columbia, Canada

    Arina Piechka, Faraz Hach & Ryan Flannigan

  3. Division of Urology, Department of Surgery, University of Ottawa, Ontario, Canada

    Luke Witherspoon

  4. Department of Urology, Weill Cornell Medicine, New York, NY, USA

    Ryan Flannigan

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A.P., S.S. and R.F. researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

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Piechka, A., Sparanese, S., Witherspoon, L. et al. Molecular mechanisms of cellular dysfunction in testes from men with non-obstructive azoospermia. Nat Rev Urol 21, 67–90 (2024). https://doi.org/10.1038/s41585-023-00837-9

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