Testosterone Triggers Protein That Protects Against Multiple Sclerosis

A so-called “guardian molecule” that is induced by testosterone was found to reverse an immune response in female mice models of multiple sclerosis (MS), according to a new study published by the Proceeding of the National Academy of Sciences.

Women have been shown to be much more likely to develop MS compared with men due to testosterone; however, specifically how the hormone protected against the condition was unknown, the researchers noted.

In the study, the authors discovered that the testosterone-induced molecule protected mice against MS. When female mice with MS were treated with the molecule, the symptoms were eliminated, which suggests a potential new treatment approach, according to the authors.

“This suggests a mechanism for the reduced incidence of multiple sclerosis and other autoimmune diseases in males compared to females,” said lead study author Melissa Brown, PhD. “These findings could lead to an entirely new kind of therapy for MS, which we greatly need.”

Women are up to 4 times more likely to develop MS compared with men. The findings of this study suggest that women may also be able to benefit from testosterone’s protective effects.

“This is why it’s vital to study sex differences in research,” Dr Brown said.

The researchers discovered that testosterone causes mast cells to produce cytokine IL-33 in male mice, which then triggers a cascade of chemicals that inhibit Th17 immune cells from attacking the myelin, according to the study.

In mice models, females produced more of the Th17 cells compared with males, which is similar to humans. This finding was significant because immune cells destroy myelin and contribute to disease progression.

However, the damage was reversed among females treated with IL-33, according to the study.

“Because testosterone levels are seven-to-eight times lower in adult women compared to men, we speculate there are insufficient levels in females to activate this protective pathway,” Dr Brown said. “But we showed we can activate the pathway with the guardian molecule, IL-33.”

In addition to sex disparities that are associated with disease risk, gender also seems to play a role in the age of onset and subtype of MS. Women typically develop MS at a younger age and are diagnosed with relapsing-remitting disease, while men typically develop the condition later in life and generally do not improve. The authors noted that later development of MS in men correlates with a reduction in testosterone production.

The study noted there are a handful of clinical trials including men with MS that have demonstrated testosterone therapy can partially reverse myelin damage, thus alleviating symptoms. Currently, testosterone therapy is not viable due to undesirable adverse events, according to the authors.

“Our findings have identified new and more specific cellular and molecular targets for immune intervention that we hope will lead to better therapies that leave most of the immune system intact,” Dr Brown said. “This testosterone-driven protective pathway should also be studied in other female-biased autoimmune diseases.”