Stem Cell Transplant to Generate Testosterone for Hypogonadism?

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, say Japanese researchers.

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.

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).

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.

The research was recently published in Endocrinology.

The team says they “successfully generated functional testosterone-producing Leydig-like cells,” but acknowledge that “several issues” remain.

Chief 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.

The researchers note, however, that as the testis is “an immune-privileged site,” transplanting cells there is a “rational strategy to overcome immune rejection,” although conversely, “raises some concerns about tumorigenesis.”

They therefore suggest “encapsulating” the cells in a “semipermeable device — similar to approaches being trialed for pancreatic islet transplantation in type 1 diabetes — and then transplanting them into either the subcutaneous or peritoneal space” of the testis.

Very Interesting Concept…a Good Start

Once such issues are “resolved”, the hope is the Leydig-like cells could be used for “cell transplantation therapy for late-onset hypogonadism.”

Wael S. Almajed, MD, who was not involved in the study, described it as a “very interesting concept” and a “good start” to generating Leydig-like cells, but agreed with the researchers that there are “a lot of things to work on.”

He highlighted the relatively short lifespan of testosterone generated by the cells and the fact that the hormone didn’t seem to “spike” in response to stimulation by luteinizing hormone. This is contrary to what normally happens in the body, whereby testosterone levels fluctuate throughout the day, under the control of the hormone. 

“Generally speaking, it would be better to have the normal circadian rhythm of testosterone secretion, and that would be an advantage compared to injection or medications for testosterone replacement therapy,” Almajed, from the Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, told Medscape Medical News.

Manesh Kumar Panner Selvam, PhD, also from Tulane University School of Medicine, added that there needs to be “more data on the bioavailability of the testosterone secretion by these cells and to see the effect on the testes.”

He emphasized to Medscape Medical News that further studies, including in animal models, are needed before this approach could even be considered for the management of hypogonadism.

Promising Alternative to Conventional Testosterone Replacement?

Late-onset hypogonadism is characterized by fatigue, reduced libido, erectile dysfunction, depression, anemia, and decreased muscle mass and bone density, which the Japanese researchers say 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.”

There have been several attempts to generate and transplant Leydig cells as a means of offering a more durable and effective testosterone replacement therapy. However, prior attempts at cell induction from iPSCs have been complex and yielded limited testosterone production.

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.

Researchers next exposed LNCaP prostate cancer cell lines to testosterone produced by the induced Leydig-like cells, which increased the proliferation of LNCaP cells to the same extent as commercially available synthetic testosterone, indicating that the hormone produced by the induced Leydig-like cells was functional.

“Since our experimental system regulates the expression of NR5A1 in a doxycycline-dependent manner, NR5A1-induced pluripotent stem cells can be maintained and expanded and cryopreserved in the absence of doxycycline, and differentiation can be started promptly at any time by adding doxycycline,” the Japanese scientists observe.

Testosterone production, measured from day 21 to 49, revealed that peak levels varied up to day 35 and then gradually decreased.

“Based on these results, Leydig-like cells induced by our protocol seem able to continue to produce testosterone for at least 4 weeks, although the testosterone levels at days 42 and 49 were significantly lower than those at day 21,” the team says.

“This is therefore the first report showing testosterone production for a long time after the completion of the differentiation processes,” they observe.

However, they add, “our current technology cannot determine whether the amount of testosterone secretion by individual cells decreased over time or whether the number of cells decreased.”

Nevertheless, “Leydig cell transplantation is expected to be a promising alternative to conventional testosterone replacement therapy for late-onset hypogonadism,” they conclude.

The study was supported by a grant from the Japan Agency for Medical Research and Development, JSPS KAKENHI, and Research Assistance Funds from Shinryokukai General Incorporated Association and Akira Sakagami Fund for Research and Education, Kobe University Graduate School of Medicine.

The authors have reported no relevant financial relationships.

Endocrinology. 2021;162:bqab202. Full text

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