Sex hormones & MS: An interview with Dr. Rhonda Voskuhl

Following our December webcast, Promising MS Research to Repair, Protect and Restore the Nervous System, we sat down with Dr. Rhonda Voskuhl, MS Program Director at the University of California, Los Angeles, to discuss the work her lab is doing in the area of neuroprotection.

Dr. Voskuhl, would you please explain what neuroprotection is and how that is different from the therapies we have available now?

The therapies we have now were all designed based on our understanding of the immune attack that occurs during MS, where immune cells go in and attack the brain and spinal cord.  Currently, mechanisms involved in that immune attack were all targeted for therapies, which include all the disease modifying therapies on the market today. They were all designed to stop or slow down this immune attack. They have been successful in that they reduce relapses by half or more, but the problem is that they don’t halt permanent disability accumulation.

Neuroprotection would be distinct from that in the sense that it would be new therapies designed to target not primarily the immune system but rather cells in the brain and spinal cord, namely neurons, oligodendrocytes, and astrocytes (important cells in the brain) to build up their resistance or protection from a given immune attack. This would protect the immune cells from cell death or cell damage.

What would the difference be between these two approaches to treatment in term of results people with MS may see?

They would be quite different. The anti-inflammatories reduce relapses and have a modest effect on permanent disability progression. On the other hand, the neuroprotective therapies may have minimal effect on relapses but would likely have a great impact on permanent disability accumulation – and they may even cause some reversal or improvement in disability.

Are you doing work in this area?

Yes. We’ve studied several mechanisms involved in neurodegeneration (nerve destruction) as well as cells related to that process. We’ve also looked at treatments that could be neuroprotective, and have focused a lot on sex hormones. These have had a pretty profound effect on nervous system cells in other neurological disease models. Estrogen (in females) and Testosterone (in males) can be very neuroprotective and directly affect brain cells.

We currently have extensive translational sex hormone research going on both at the pre-clinical and clinical levels. We’ve completed several pre-clinical studies as well as two clinical trials, and we have two additional ongoing trials, with another trial planned.

Several months ago we discussed your research related to Estrogen, but we’d love to hear more about the research exploring sex hormones in men.

These two areas may possibly merge into a common theme in the sense that testosterone is naturally converted to estrogen in the brain. Therefore, if you treat women with estrogen and men with testosterone, you could end up in the same place – binding to estrogen receptors in brain cells to cause protective effects.

Specifically related to testosterone in men, we’ve done extensive pre-clinical work in the MS model – giving testosterone to male mice with the disease – and have seen much improvement, including neuroprotective mechanisms. We also conducted a pilot clinical trial of testosterone treatment in men with MS. In this small study, we gave testosterone to men with MS to increase their blood levels to the high normal range, and we found a 67 percent reduction in the brain atrophy rate as well as an improvement in their cognitive testing. We are now hoping to follow that study up with a larger study we just submitted to the NIH to request funding through a large infrastructure called NeuroNEXT.

With up to 25 sites across the US, this would be a much larger study of 110 men with MS. We will give participants a dose of testosterone – boosting them from low or low-normal ranges into a high-normal range. The reason we’re staying in this range is that a lot is known about the safety of giving men testosterone in this range. The treatment is a gel that participants rub on their skin once a day.

In addition to being much larger than our pilot study, this study will be placebo controlled. The primary outcome will be brain MRIs of gray matter atrophy (shrinkage) in areas of the brain known to be involved in disability and cognitive deterioration. A secondary outcome will be specific cognitive tests related to MS. We will be looking for improvements in these outcomes that are very important for disability and cognition in men with MS.

One other notable fact is that testosterone may have several other positive side-effects in men with MS – it’s known to improve muscle mass and muscle strength, improve bone density, decrease fatigue, and improve cognition in older men going through andropause. In addition to exploring and documenting these potential beneficial effects, this trial will provide valuable information about safety of testosterone supplementation for men with MS. While we have a good understanding of safety information for the general public, this study will allow us to identify any potential issues specific to the MS population.

Are you seeing similar results related to cognition in women with estrogen supplementation?

We have an ongoing trial of Estriol, the safest of the estrogens, which is present during pregnancy. We are still enrolling participants in this trial with sites at UCLA, Colorado, New Mexico and University of Pennsylvania. This study is very similar to the study of testosterone in men – however it will have cognition as the primary outcome.

We also have another study that will finish this spring exploring estrogen’s potential treatment effect on relapses in women with MS. Preclinical data has shown that, in addition to being neuroprotective, Estriol is also anti-inflammatory. With estrogen, you’re getting this two-pronged approach of neuroprotection and reduced inflammation, so it can theoretically affect relapses as well. On the other hand, testosterone appears to be only modestly anti-inflammatory, but appears to be more dramatically neuroprotective.

What makes you most excited about this area of research?

This is a new way of doing things. By that, I mean that so much work has gone into taking things from the bench to the bedside. I’m not against that, but there’s a risk in choosing and targeting one molecule – or even one mechanism – in diseases such as MS that are complex. These diseases often have many molecules and many mechanisms involved in their pathogenesis – if you block one, then other mechanisms will kick in, and the disease will march right on.

The hormone therapy research we’re conducting is different. This is a story that isn’t bench to bedside. This is a story of bedside to bench to bedside. We know that pregnancy is good for MS, and that estrogen is high during pregnancy. We also know that men don’t get MS very often, and when they do it is often later in life when their testosterone has begun to drop. We’re taking something that we know is clinically significant and relevant to people with MS, then trying to figure that out, ultimately taking that back to the bedside in the form of clinical trials.

It’s a different approach that is starting with the patients and saying, “What phenomena are going on here that we don’t understand? Can we figure it out? And can we capitalize on it?” I think it will involve many molecules and many mechanisms, because it’s a dramatic clinical effect that we’re trying to figure out. And I think that’s why treatments using the bedside to bench to bedside approach will work – they’ll work through many mechanisms rather than one.
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Rhonda

Rhonda Voskuhl, M.D.

Dr. Rhonda Voskuhl, UCLA MS Program Director, is a widely recognized expert in the study of the immunology of MS, working both with MS patients' blood immune cells as well as with the mouse model of MS, experimental autoimmune encephalomyelitis (EAE).