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.
Ann Clin Transl Neurol. 2022 Jun 29.
Decreased neurofilament light chain levels in estriol-treated multiple sclerosis
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.