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Advances in stem cell research for the treatment of primary hypogonadism

Abstract

In Leydig cell dysfunction, cells respond weakly to stimulation by pituitary luteinizing hormone, and, therefore, produce less testosterone, leading to primary hypogonadism. The most widely used treatment for primary hypogonadism is testosterone replacement therapy (TRT). However, TRT causes infertility and has been associated with other adverse effects, such as causing erythrocytosis and gynaecomastia, worsening obstructive sleep apnoea and increasing cardiovascular morbidity and mortality risks. Stem-cell-based therapy that re-establishes testosterone-producing cell lineages in the body has, therefore, become a promising prospect for treating primary hypogonadism. Over the past two decades, substantial advances have been made in the identification of Leydig cell sources for use in transplantation surgery, including the artificial induction of Leydig-like cells from different types of stem cells, for example, stem Leydig cells, mesenchymal stem cells, and pluripotent stem cells (PSCs). PSC-derived Leydig-like cells have already provided a powerful in vitro model to study the molecular mechanisms underlying Leydig cell differentiation and could be used to treat men with primary hypogonadism in a more specific and personalized approach.

Key points

  • Primary hypogonadism is mainly treated using testosterone replacement therapy (TRT). However, TRT has adverse effects and is unsuitable for men with hypogonadism wishing to maintain fertility.

  • Stem-cell-based therapy, in which a cell lineage can be re-established in human bodies to produce testosterone normally, would be the ideal choice for treating primary hypogonadism.

  • Stem Leydig cells, mesenchymal stromal cells, pluripotent stem cells and fibroblasts are newly discovered sources of Leydig cells.

  • Stem-cell-derived Leydig cells have many potential applications, including understanding the underlying mechanisms of primary hypogonadism, treating primary hypogonadism using transplantation therapy, and discovering drugs aimed at recovering Leydig cell function.

  • Research is needed in the applications of Leydig cells, including constructing 3D testicular organoids, promoting in vitro culture conditions of Leydig cells, and exploring the in vivo transplantation locations of Leydig cells.

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Fig. 1: The hypothalamus–pituitary–gonadal axis and pathophysiology of male hypogonadism.
Fig. 2: The development of human Leydig cells.
Fig. 3: Induction of human Leydig-like cells from different cell types.
Fig. 4: Applications of stem cell-derived, Leydig-like cells for the study and treatment of primary hypogonadism.

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L.L. and V.P. researched data for the article, made substantial contributions to the discussion of its content, wrote the article, and reviewed and edited the manuscript before submission.

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Correspondence to Vassilios Papadopoulos.

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Competing interests

V.P. is named co-inventor on patents reporting on new molecules inducing testosterone production by normal and hypofunctional Leydig cells issued and filed with U.S.P.T.O. and other international agencies. These patents were licensed by McGill University to IASO BioMed, Colorado, USA. V.P. has received stock from IASO BioMed. L.L. declares no competing interests.

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Glossary

Ductal structures

Embryos contain two sets of ductal structures, the Wolffian and Müllerian ducts, which develop into the male and female reproductive tracts, respectively.

Total testosterone

All testosterone in the blood, including free testosterone and testosterone bound to albumin and sex hormone binding globulin (SHBG).

Free testosterone

Testosterone in the blood not bound to any proteins.

Blastocyst

Mammalian preimplantation embryos consisting of an inner cell mass (giving rise to embryos) and trophectoderm (giving rise to the placenta).

Stemness

The ability of a cell to proliferate, to differentiate and to keep a balance between proliferation, regeneration and quiescence.

Myoid cells

Smooth muscle cells surrounding the seminiferous tubule.

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Li, L., Papadopoulos, V. Advances in stem cell research for the treatment of primary hypogonadism. Nat Rev Urol 18, 487–507 (2021). https://doi.org/10.1038/s41585-021-00480-2

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