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). 

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    19 Comments

  • Bonny   Feb 14, 2014 10:33 AM
    This is exciting information. How would this approach work for someone with a history or estrogen receptive breast cancer?
  • Jennifer Knight   Feb 14, 2014 10:33 AM
    Have you considered what you would do for women whom are estrogen sensitive (where estrogen supplementation causes migraines)?
  • Dean Taylor   Feb 14, 2014 10:46 AM
    I'm low in Testosterone so my Doc put me on a 1% injection every 3 weeks, seems to help my fatigue, but sex drive is done. Seem's she doe's want to go more because of the other problems, heart attacks or prostate problems.
  • Dawn Pocobello   Feb 14, 2014 1:08 PM
    Thank you for posting this very exciting news! I was diagnosed in 1992 and in 1997, I had a hysterectomy which caused me to go into early menopause a few years later. Since menopause started, I have had several and more severe exacerbations and often wondered how estrogen would effect the course of my MS. Please keep us posted on your progress!!
  • Christine Thomas   Feb 14, 2014 2:36 PM
    I found that after sex my MS felt better, my mind felt more alert and walking was easier. It has been some time now without a physical relationship, and I have suffered more depression, and MS symptoms are far worse.
    It seems very difficult to establish a close and physical relationship which I believe is so important for people with MS.
  • Avatar
    Marcus  Feb 14, 2014 4:05 PM
    I am very interested in the repair in people with MS. I have primary progressive MS (PPMS) and I would like to know more about the clinical trials.
  • pete wood   Feb 14, 2014 4:43 PM
    people with ms are looking for help please find the answer we need to put this to bed for me it has been 20 years
  • Tina   Feb 14, 2014 6:14 PM
    I would be very interested in joining these trials in New Mexico. Could I please get some information on this?
  • Darek   Feb 14, 2014 6:56 PM
    I am 42, still moving too. I would love to have a sex life. LIKE sands in an hour glass, I feel like time is running a little to fast. I want to join a clinical study with testosterone. I have mentioned to the family doc. and the ms doc., that I thought I might be low with the T level. I suspected. Never was given the results. I wish there was someone to talk to about this. I would like it if I could get some help here.
  • Kristin Foushee   Feb 14, 2014 7:21 PM
    Dawn Pocobello, I had a partial hysterectomy that caused my MS to be diagnosed. I'm very fatigued, very low sex drive, pain in my bones as if in a device crushing pressure, brain feels like someone shaking it causing the off balance feeling, or such bad pressure building in my head. But not like a migraine as if blood vessels are clamped off causing pressure to build.

    Please if anyone has same problems please email me. My neurologist doesn't listen to my problems and only focuses on one thing. I really want to know if something else is going on. And I'm only 37 single mom with fatigue and low to no sex drive.
    Please help with any information from your own experiences or advice from your own doctors.
    Thank you, Kristin
  • msjadair  Feb 15, 2014 11:53 PM
    I had my first MS attack when Iwas 23 and 3 months pregnant. Second bad attack was about two months after my second child was born in 1982. Haven't had significant problems since. Thank God. I am now 58 years old and haven't taken anything since 1982. (Prednisone) my neurologist that I went to recently put me on Avonex. Bad side effects. Felt better before it! About to quit with any more MS meds. Frustrated!
  • Eva Marsh   Feb 16, 2014 2:22 PM
    In 1967 I was immobile from neck down, diagnosed, told that healing was impossible and I would never recover. I DID recover and return to work in Pharmacology research lab with medical library. I found research proving that myelin repairs with movement and I have never looked back. At 70, I have recovered from all symptoms, and am fully mobile. I have watched as this work (Bunge et al 1961) was ignored, and the study of ms complicated to the extreme. When a problem remains unsolved for a long time, we must re-examine the basic beliefs. I'm still waiting ...
  • Lyns   Feb 17, 2014 10:59 PM
    I really appreciate hearing about the work you are doing. I'm 57 and my husband died 4 years ago, so its been rather difficult with our sons as they seem to forget their Mom has had MS for 37 years and well before I had them! My deceased spouse and I waited until I was 30 years old to have children as we were going to college and establishing our careers. Since I was 30, I decided to read some books as way back then they were saying that women in their 30's may be considered high risk even thought I was extremely healthy. In my reading,it said to take my temperature and how a stair step increase could indicate potential low progesterone production in my body. Well, I became pregnant right away and brought my temperature charts to my OBGYN and she just tossed my charts and told me this was nonsense. I ended up going in to Labor but didn't realize what was happening to me; but I ended up losing my twins. My OB GYN said to me that my theory was just stupid and that miscarriages were common and I became pregnant again and had another miscarriage. It was really hard on me and I asked my GP about whom he felt would be the best Doc for me and fortunately he referred me to a Wonderful OB GYN whom tested both my spouse and me and sure enough he said to me that my progesterone was low and he prescribed Natural Progesterone for me and I was able to have my two sons.I felt great during the pregnancy of both sons and had endless energy after they were born too. I was in an exasperation when I conceived my 2nd son and had an appointment scheduled for a methipredisolone infusion on a Monday with my Neurologist and when I went in to see him for this infusion which I had never had before, I remember going in to his office and telling him I was taking my temperature and I was worried about receiving this treatment as my temperature had just gone up the day before and he said, "Well if you are by any chance pregnant, we will have to abort your child." I was so scared and had him call my OBGYN and they were arguing back and forth on the phone as my OBGYN was telling the Doc whom was supposed to specialize in my MS, that he should not give me the treatment and that he would do a test and start me on the progesterone right away and this would take care of my MS attack, He was right as the progesterone immediately halted my attack & I was in fact pregnant and had my second healthy son. My OBGYN, whom I still continue to see 23 years later kept saying he believed that 75% of misscarriages were due to hormonal imbalances and he still maintains that progesteone is great for me. He would give it to me on and off for a number of years dispite my Nuerologist's feelings about it, but I swear it made me feel great and even my skin and hair looked great too. I went throught menopause with absolutely nothing that any of my friends complained about and my OBGYN during that time seemed to feel hat I should not receive any of the nasty hormones that are usually given to women & I have done just great. I just like to eat well and exercise to control my MS and the only thing I have ever done was take the 4-AP well before it was finally approved by the FDA as Ampyra and continue to take the freshly compounded 4-AP instead of the Pharma kind as I used it only to combat the heat, so it really surprised me that they were suddenly advertising this as the "Walking Drug" & charging a ton of money for it as my price has never changed during the 22 years I've been using it at the 15 mg level of only $60/month! What are your thoughts or has anyone else had this experience? My Mom & my older brother also have MS, so I did a lot of reading and I take the B-12 sublingual under my tongue to repair my myelin and I keep my levels of Vit D-3 between 60-75 & my Doctors I think look at me as, "Well, this woman is doing just fine, but she is too in to this stuff and won't touch fluoride, insists on the preservative free flu shots because she doesn't want any mercury in her body & is really going a bit overboard, but Oh well, if it's working, lets let her do her own thing!" I've also had Raynaud's since I was 17 which was just very manageable until this past year as it suddenly turned in to this non-stop cold icy feeling & then unbearable nerve pain, so they have done every test, can't find anything wrong and have me taking gabapentin. I keep telling them that I do have sjogren's too & I think this caused my Raynaud's & maybe to turn in to this suddenly horrible pain. My BP is extremely low, so they really can't give me any of the meds for this except for the gabapentin, I am thinking of asking them if progesterone might help. This has been going on for a good 1 1/2 years now but is really hard to even go outside bcause I live in Wisconsin and this harsh winter is really tough on me. Is there any research going on and what are your thoughts about me asking for progesterone again? If anyone else has had this experience or any of my others, please feel free to e-mail me. Thanks.
  • sharon alvord   Feb 18, 2014 11:12 AM
    I have a question. I am a woman who has always had too much testosterone. I had MS in the 80's. It was discovered only in 2005 I had SIADH. My MS was severe for years but disappeared and I was undiagnosed in 2005. I went thru menopause the entire begining to post menopause late. I was 57. It happened in 6 months. Since I have the MS back with a vengence. Even seizures. I have had 4+ strokes in the past year. I know the testoserone I had in more than abundance is now low plus the estrogen I never really had is also now gone. I had CADH. What hormone would be given to me? I'm curious. I know my health turned for the worse with the addition of menopause. Any answers or observations to my relapse would be helpful. I was rediagnosed in late 2013 again. Had 2 lesions for 30 years. Now 15 in brain and some huge ones in the brain stem. A hemangioma at t1 also. Its intermingled with the ms lesion.
  • willielollar  Mar 5, 2014 5:35 AM
    Thank you so much for what you do ! I am in need of any info for people like me who have "probable Ms"I am basically R&R, for 8 yrs but told my MRI shows no active lesions. So I have no definitive diagnosis.
  • Avatar
    count_olaf  Mar 6, 2014 2:52 PM
    Thank you for your work and please please please dont stop now :D
  • Rebecca Wright   Aug 2, 2016 2:29 PM
    Hi Rhonda,

    Very interested in this article, Have you found any benefit temperature intolerences/ imbalances experienced by some people (women) with MS?
  • Heidi McGee   Aug 9, 2016 10:10 PM
    I am getting a hysterectomy tomorrow, uter,tubes and overies. I have RRMS and i really don't like the way a feel already. Trying to reverse some thickening of the uterus and irregular cell in the last four months with Provera. It helped some but he is affraid i could get cancer in the future. He is giving me a month of estrodiol. My bones and brain and just feel like i am in a continual relapse. It could be because of this hormone shift while trying to reverse the situation. I know i need the estrogen. What is the dose you give your patients. I see Dr. Waubant at UCSF. I had asked about it in the past but I still had my overies and still had periods , but tomarrow that will change and I know I got to get a handle on it. I FEEL TERRIABLE! Please help me with this.I have not contacted my doctor inUCSF because I know you specialize in this . Thank you for your time. Heidi McGee
  • John gore   Jul 1, 2017 2:31 AM
    Interesting for the future