Testosterone Production for Hypogonadism by Stem Cell Transplantation?

Hypogonadism refers to a condition in which little or no hormone is produced by the testes or ovaries. There are many possible etiologies for this condition, and it depends if where onset before or after puberty, this last one is called late-onset hypogonadism (LOH).

The primary source of testosterone in males is Leydig cells in the testes, and it is thought the age-related decline in testosterone production in males is due to a decrease in number of these cells, and possibly, dysfunction.

What are the symptoms? 

Late-onset hypogonadism is characterized by fatigue, reduced libido, erectile dysfunction, depression, anemia, and decreased muscle mass and bone density, which leads to “poor quality of life.”

The current standard treatment is testosterone replacement therapy. Although testosterone is available in injectable, oral, and ointment forms, its effectiveness is limited and there are “various adverse effects.”

Is there an alternative for Testosterone treatment?

The aim of treating late-onset hypogonadism (LOH) with transplanted testicular cells may have taken a step closer to reality with the successful generation of hormone-producing cells using a simple protocol.

To try to generate Leydig cells in vitro, Takaki Ishida, MD, from Kobe University, Japan, and colleagues used a two-step protocol employing clones of human induced pluripotent stem cells (iPSCs). 

Ishida and colleagues generated Leydig cells by exposing male-derived iPSCs to doxycycline to force the over-expression of the nuclear receptor subfamily 5 group A member 1 (NR5A1) gene, which is involved in sexual differentiation and plays an important role in the development of the gonads and adrenal glands. These iPSC-generated Leydig cells produce the male hormone testosterone. Morphologically, the induced cells also had a similar appearance to Leydig cells in human testes.

After 21 days, the researchers were able to generate cells that had many of the characteristics of Leydig cells and secreted testosterone for at least 4 weeks after differentiation, although concentrations of testosterone produced tailed-off over time. Although the testosterone levels at days 42 and 49 were significantly lower than those at day 21.

Successfully generated functional testosterone-producing Leydig-like cells, but acknowledge that “several issues” remain. An example among these is the potential for immune rejection and tumorigenicity, in addition to which “no report has yet described the transplantation of human iPSC-derived Leydig cells” into people.

As we can see, leydig cell transplantation is expected to be a promising alternative to conventional testosterone replacement therapy for late-onset hypogonadism. Nonetheless, more data and experimental studies on animal and human models  are needed to see the risk and benefits of this potential therapy. Also , it is important to establish a safe way to do this transplantation in the future. 


Takaki Ishida, Michiyo Koyanagi-Aoi, Daisuke Yamamiya, Atsushi Onishi, Katsuya Sato, Keiichiro Uehara, Masato Fujisawa, Takashi Aoi (September 21, 2021). Differentiation of Human Induced Pluripotent Stem Cells Into Testosterone-Producing Leydig-like Cells. Endocrine Society. Retrieved from: https://academic.oup.com/endo/article-abstract/162/12/bqab202/6373541