It is now well accepted that MS goes into a period of dormancy during pregnancy. This of course is a protective effect so that the female body doesn’t reject the foetus that is growing within (the foetus is a foreign entity as it’s whole genetic makeup does not come from the mother alone). Increasingly it has become apparent this effect is mediated via the oestrogen hormone, a female sex hormone; in particular estriol a minor oestrogen.
Using estriol as an add-on treatment to Glatiramer acetate (aka Copaxone), the group in UCLA demonstrate that serum (blood) neurofilament light chain levels reduce at 12 months versus those on placebo (i.e. dummy treatment) plus Glatiramer acetate (GA) – see figure 1 below. Adequate circulating estriol levels are achieved at 6 months and maintained at 12 months.
They also found through modelling that changes in log-transformed NfL (you do this when your data isn’t normally distributed which happens in all biomarker analyses) against change in T2 lesion volume (i.e. the volume of MS lesions), neurofilament light chain levels tended to decrease when there was reduction in T2 volume with estriol treatment, but not with placebo where it remained static (see Figure 1b above). Interestingly, they found no relationship with gadolinium enhancing lesions, which is probably because everyone was also on GA.
It is therefore always difficult to interpret this type of research. There isn’t an arm with no treatment (this would be unethical with so many good drugs available) and as such you cannot expressly separate out the effect of estriol versus glatiramer acetate. The lack of modulation of serum neurofilament light chain levels unwittingly also suggests that glatiramer acetate overtime has little cumulative impact on serum neurofilament levels!
Secondly, the authors conclude that estriol has a neuroprotective (i.e. protects axons) versus anti-inflammatory effect based on a latency of 12 months to achieve an effect on serum neurofilament light chain levels. I would argue that this is not the case, but the opposite. Their study group achieved adequate serum estriol levels only at 6 months and therefore if there is going to be an effect on serum neurofilament levels it would be seen after this i.e. 12 months as far as this study is concerned. This taken together with the effect on T2 lesion volume, the primary biological effect of estriol is anti-inflammatory based on this study.
Last but not least, it is a shame that we do not have access to the raw data. I find the interpretation of percentiles notoriously difficult. The reason why statisticians like to use them is that they’re straightforward to calculate regardless of the shape of distribution of the original readouts. However, percentiles are rather uniform in their distribution and far from the original shape of the raw data. If you take the example below (What Percentile Means), by definition 1% of the students who sat the exam are can be found at each percentile. Therefore you cannot assess the mean score or the variance in the values – it would inaccurate. This also means that differences between the raw data at the extremes of scores is much greater than revealed by simply eyeballing the difference between the corresponding percentile ranks. Whilst, for those percentile close together in the middle of the distribution the difference in the raw data is much less.
What Percentile Means
Percentiles should not be confused with percentages. The latter is used to express fractions of a whole, while percentiles are the values below which a certain percentage of the data in a data set is found. In practical terms, there is a significant difference between the two. For example, a student taking a difficult exam might earn a score of 75 percent. This means that he correctly answered every three out of four questions. A student who scores in the 75th percentile, however, has obtained a different result. This percentile means that the student earned a higher score than 75 percent of the other students who took the exam. In other words, the percentage score reflects how well the student did on the exam itself; the percentile score reflects how well he did in comparison to other students (source: http://www.thoughtco.com)
From a clinical perspective this is an interesting study and adds value to the pregnancy and MS data. The authors rightfully caution against unopposed and long-term oestrogen treatment.
Abstract
Ann Clin Transl Neurol. 2022 Jun 29.
Decreased neurofilament light chain levels in estriol-treated multiple sclerosis
Rhonda Voskuhl , Jens Kuhle , Prabha Siddarth , Noriko Itoh , Kevin Patel , Allan MacKenzie-Graham
Estrogens have neuroprotective actions depending on estrogen type, dose, and timing in both preclinical models and in women during health and disease. Serum neurofilament light chain is a putative biomarker of neurodegeneration in multiple sclerosis, aging, and other neurodegenerative diseases. Here, oral treatment with an estrogen unique to pregnancy (estriol) using an 8 mg dose to induce a mid-pregnancy blood estriol level reduced serum neurofilament light chain in nonpregnant MS women at mean age of 37 years. This is consistent with estriol-mediated protection from neuro-axonal injury and supports the use of serum neurofilament light chain as a biomarker in MS.
Silly question, I’m sure, but I can’t help asking it. The subjects were all women. Could estriol be given to men, and if so might it produce similar results?
Also, is there something about Copaxone that gave the team a reason for choosing it over other MS drugs for the first study of this kind? I imagine that given the ethical considerations you mention, the next step in determining estriol’s ability to lower NFL readings might be to pair it with other DMTs in similar studies.
Thanks for calling attention to this interesting work.
Oestrogen at these doses shouldn’t be given to men as it would lead to an imbalance with the male hormone testosterone. Although men do produce oestrogen the quantity is small.
This is a supplementary study to the main study published in the Lancet Neurology; unfortunately the reason for picking GA isn’t given. If you go with highly active DMTs that already lower neurofilament light chain levels significantly you’re probably unlikely to see any added effect on NfL with add on estriol. if you want to demonstrate an effect in such instances you’ll need to do CSF analysis where the quantities of NfL can be in the thousands rather than below 100 as in the blood.
because GA is the only safe DMT during pregnancy?
Its all about testing.. maybe if you show more agents are shown to be IRTS then you can have pregnancy with having to drug yourself.
Prescribing MS patients glatiramer acetate in the present day is unethical. I wish there was someone who could discipline these negligent creeps, but sadly they are just going to get away with effectively destroying the brains of 111 people.
When I was first diagnosed I remember reading about estriol research and MS. This paper is 20 years old (same lead researcher)::
https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwjBkanbvOH4AhUIiVwKHVg4AgMQFnoECDwQAQ&url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F12325070%2F&usg=AOvVaw29EMu8D8iOffCap4oI7Krc
Staggering that 20 years later nothing has really changed ie estriol isn’t being prescribed (as far as I know) to women with MS. I also recall that testosterone was considered to be neuroprotective (possible reason why more woman than men get MS). Again, this research seems to have hit a brick wall.
NDG – I wish you the best of luck with the Sizomus trial. I think more of these small scale, shortish timescale studies are the way forward to test ways of reducing inflammation within the CNS. The studies on hormones (estriol and testosterone) have been allowed to drift along for years without any definitive answer ie should these hormones be given to MSers?
Good pick up Eve. We have previously referenced this paper when talking about the effects of hormones on MS. Unfortunately, without big institutional or pharma backing (i.e. substantial sums of money) it’s hard to do the Phase 3 multi-centre studies that are needed for drug licensing. The investigator in question did a Phase 2 study in 2016. I do not know what their ongoing plans are.
Thanks Re-SIZOMUS. We’re fortunate that Takeda is funding the work and hopefully gives us the results to move this forward to a Phase 3 study in MS. It is still a Phase 1/2 study as the drug is licensed in multiple myeloma but not MS.
Thanks again NDG. It seems the question that needs to be answered is whether there is, or ever will be, enough evidence to incorporate oestrogen into treatment protocols for women newly diagnosed with MS. Otherwise this line of inquiry is confirming what’s already fairly well established.
P
From the outside it doesn’t seem right that smart, committed people spend years on work that has little prospect of ending with a new product to sell and therefore will not attract funds in the seven-digit range.
Any thoughts on how estradiol would do instead of estriol? Many post-menopausal women use that anyway.
Likely should switch from estradiol to a 3rd gen Selective estrogen receptor modulator (SERM) like bazedoxifene that can eliminate the cancer risk while still providing benefits to osteoporosis and menopause symptoms, along with possible neuroprotective benefits. Estradiol is stronger than estriol and poses greater risk of cancer promotion for ER+ tumors. Estriol and estradiol are also different expression patterns during/before pregnancy, with estriol more prominent during pregnancy, and estradiol more long term reproductive year expression. Estriol has a single additional hydroxyl group (OH) vs estradiol marking its different binding characteristics to ER receptors.
Considering the comment by RA, a discussion of a paper by Voskuhl would be good
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976208/pdf/zpq14813.pdf
which goes into the difference in mouse models for ERalpha vs ERbeta activation for anti inflammatory vs. neuroprotection, and how current menopause medications and SERMs would fit into this ERalpha vs ERbeta paradigm
But as a man, I am not sure if the benefit of reduced brain inflammation outweighs the risk of gyno
Thank you for highlighting this work. Hope it leads to effective treatments. As a woman who was diagnosed with MS in the second trimester of pregnancy, I felt doubly betrayed by my body. One because my immune system attacked itself and, second, because MS wasn’t supposed to do that during pregnancy. Don’t forget us outliers. Emergency Room Docs need to know it happens in order to treat promptly. Maybe investigating outliers like me will help further illuminate the role of pregnancy on MS.