Male hypogonadism is a condition affecting almost a third of the elderly male population. The most common treatment option is testosterone replacement therapy, but the practice can have significant side effects. A new development in stem cell research suggests an alternative treatment for hypogonadism may soon become available.
With age, testosterone levels naturally decline, but male hypogonadism is a condition in which the body produces abnormally low levels of testosterone.
Such reduced levels can lead to mood disturbances, a decline in sex drive, and a decrease in muscle and bone strength.
The low testosterone levels associated with hypogonadism are sometimes due to dysfunctions in the testicles, pituitary gland, or the hypothalamus. Approximately 30 percent of older men are reportedly affected by the condition.
The common clinical approach to hypogonadism is testosterone replacement therapy. However, a significant amount of research points to the various side effects of hormone replacement therapy, including a risk of venous thromboembolism and deep vein thrombosis.
In fact, in 2014, the United States Food and Drug Administration, in collaboration with Health Canada, mandated that manufacturers add a warning of these risks on all testosterone products.
New stem cell research suggests that there may be an alternative type of treatment, which would involve transforming adult skin cells straight into testosterone-producing cells.
Testosterone is the end result of a longer process. Leydig cells – which are found in the testicles – produce androgens, and these hormones are then biosynthesized into testosterone.
Researchers led by Yadong Huang, of Jinan University, China, have examined the possibility of “creating” Leydig-like cells using direct cell reprogramming. The findings have been published in the journal Stem Cell Reports.
In stem cell research, direct cell reprogramming is said to be a quicker and safer technique to obtain the desired type of cell than regular epigenetic reprogramming.
This is why Huang and co-senior author Zhijian Su, also of Jinan University, figured that directly transforming adult skin cells into Leydig-like cells, and then transplanting them into males with hypogonadism, would be the best regenerative approach.
To test this hypothesis, the scientists used male rodents affected by hypogonadism.
They infected mouse embryonic fibroblasts – a type of cell found in connective tissue – with a vector carrying the mCherry gene. This allowed them to separate steroidogenic cells from fibroblasts.
Then, Huang and team screened 11 transcription factors that they thought might regulate Leydig cell steroidogenic gene expression.
By gradually eliminating several of the 11 transcription factors, researchers finally narrowed them down to three: Dmrt1, Gata4, and Nr5a1.
Next, the team used lentiviral vectors – a type of retrovirus that can change the expression of their target cell’s gene – to force the gene expression of these three transcriptional factors.
The result was a success. The researchers had managed to directly reprogram mouse skin cells into fully functioning, testosterone-producing Leydig cells.
Finally, the scientists transplanted these Leydig cells into the testes of testosterone-deficient rats and mice.
The cells not only survived, but they also restored normal testosterone levels in males with hypogonadism.
The success of this scientific endeavor suggests a promising alternative to androgen replacement therapy.
“In the end, we are hopeful that this research will pave the way for clinical trials testing a novel regenerative medicine approach to treat androgen deficiency in men,” says Su.
Huang also explains the significance of the study.
“Our study is the first to report a method for generating Leydig cells by means of direct cell reprogramming. This alternative source of Leydig cells will be of great significance for basic research and provides the attractive prospect of clinical application in the field of regenerative medicine.”
The authors hope that future research will focus on improving the efficiency of their approach and help to create a pure population of Leydig-like cells.
Huang and team are currently investigating in more detail the mechanisms involved in the direct reprogramming of skin cells into Leydig-like cells. They are also examining other direct cellular conversion methods that are nonviral and use small molecules.