Dr Rhonda Voskuhl Explains How Understanding Sex Differences Can Lead to MS Treatments

Research has shown that females are more susceptible to developing multiple sclerosis (MS) than males, but males have worse disease progression, and studying those sex differences can help lead to new treatments, said Rhonda Voskuhl, MD, Jack H. Skirball chair of MS research, director of the MS program, and professor of neurology at the University of California, Los Angeles (UCLA).

Transcript

How has studying sex differences advanced care in multiple sclerosis?

So with respect to the sex differences, what we’ve shown is that it appears testosterone is protective in males, and that’s probably why they’re less susceptible. They do tend to have lower levels.

And we’ve done a trial where we gave men with MS who have low testosterone levels, we brought them into a high/normal level—a low/normal range to a high/normal range—using AndroGel, and we’ve found that it slowed brain atrophy, it slowed corticol atrophy. And so, we wanted to do a trial—this is one of those things that could be safe and cheap and so forth—but we wanted to do another trial with men with MS, treat them with testosterone and then look more specifically to see does this help fatigue, it could help fatigue, it could help cognitive function, it could help their motor strength and walking. So, we want to do another trial and sort through that.

Of course, then the question will be: then why do men do worse? Well, we don’t think it’s because of the testosterone, because we think testosterone is protective. So, then you get into sex chromosome effects, and that’s XX versus XY gene effects. And so, we have a unique model to study sex chromosome effects that are independent of sex hormone effects. Because, usually, if you have XX, you have estrogen; if you have XY, you have testosterone. So, it’s hard to study sex chromosomes alone, because we know the hormones play a role.

So, we just have a mass model that’s now being used widely through these [National Institutes of Health] grants, and through other diseases even, to study sex chromosome effects. And what we’ve found is it appears that the XY genotype is worse for neurodegeneration, which makes sense about why males would be worse, particularly when the testosterone is low, because it’s protective. So, see, now you’ve got this genetic susceptibility, not to disease, but to do worse on progression, and when they have really high testosterone levels when they’re 20 years old, they do ok. But when testosterone levels start to drop, when they’re 40 or so, then that can be why the disabilities are particularly bad.

Now, the flip side of the sex chromosomes story is that we found that when we looked at XX versus XY and we looked at the immune phase of the disease—basically, this is like susceptibility and relapses, immune activation, their C4T cell responses to be specific—we looked at XX versus XY gene effects and we found that the XXX is much worse than the XY. And we did this is both the MS model and the lupus model. Systemic lupus erythematosus is 9 to 1 female over male. And so the same thing was happening in both, that XX makes a more robust, more disease promoting disease response than XY. And this is probably why females are worse than males for susceptibility to all these autoimmune diseases.

So, what we’re doing now, we’re figuring out, well what is the X gene. We know XX is worse than XY, but what are the genes on X that are making the immune response so much more robust, and if we figure that out, we will block that gene in females. So, it can lead to new treatments if you understand sex differences.