Estriol, Pregnancy, and MS

Take home message: Do not fear getting pregnant. Attacks decrease while pregnant but you do have a higher chance of relapse after. However in a study of 400 women, those who got pregnant after being diagnosed with MS had a time from diagnosis to wheelchair of 18  years vs 12 years for those who never got pregnant. Thus there is probably some long term protective effect of pregnancy and 6 year reduction in time of disability is fairly huge. Short version: Estriol and vit. D work together to regulate the immune system. Estriol is not a FDA-approved treatment line yet, though there are several trials. Though estriol is generally regarded as safer than other estrogens like estrodiol, it still may cause an increase risk of breast cancer similar to other hormone replacement therapies.  However some level of toxicity may be tolerable given the risks of having MS in the first place. Follow Rhonda Voskuhl’s work at UCLA for up-to-date research on estriol and MS. Detailed version: My partner on the Kilimanjaro climb was an MS researcher, Dr. Colleen Hayes. Dr. Hayes has studied many autoimmune diseases, including lupus, a but the main focus of her career has been on MS. She pointed me to some research about estriol and MS.  Apparently there is a synergy between estrogen and vit. D endocrine system that provides drastic neuroprotective effects. Without estrogen, vit. D cannot do it's work. History of estrogen and MS: Research on estrogen and MS began with observations concerning abatement of MS disease signs during pregnancy, and relapse post partum (Confavreux 1998).  The abatement of MS disease signs correlates with a 200x increase in circulating estrogen (in this case estriol produced by the placental tissue) and a nearly 3x increase in the vitamin D3 hormone, calcitriol (Elenkov 2001). Following up on that information, Voskuhl and her group investigated estriol in MS patients and found strong benefits (Sicotte 2002, Soldan 2003, and for a good review of sex hormones and MS see Gold & Voskuhl 2009). When on treatment in RRMS patients, the total enhancing lesion volume were decreased by 82% and the numbers were decreased by 82% and remained so during the course of treatment. These numbers returned to normal 3 months after treatment. When progesterone and estriol were used together the lesion volumes decreased by 88% and the number decreased by 48%. What are the mechanisms that explain beneficial effects of female hormones in MS? Estrogen and progesterone are known to have neuroprotective effects. Estrodiol and progesterone have shown to aid re-myelination, the process by which MS damage can be healed (Bruce 2009). Another mechanism relates to estrogen support of mitochondrial functions (Chen 2009, Arnold & Beyer 2009) which is essential to the well being of tissues in general. Estrogen enables mitochondria to cope with pathological processes and provide stabile local energy homeostasis and an anti-apoptotic base setting in the brain which, in turn, is a prerequisite for neuronal survival. And finally yet another mechanism relates to estrogen-mediated immunoregulation, control of the pathogenic autoimmune T lymphoyctes.  This mechanism has been convincingly demonstrated in the rodent model of MS (Offner 2004). Dr. Hayes recently published a report documenting synergy between the estrogen and vitamin D endocrine systems in rodent MS (Nashold 2009).  To summarize, in the absence of estrogen, vitamin D3 provided no benefits; when estrogen was provided to ovariectomized females, vitamin D3 benefits were restored.  We found an amplification loop.  The vitamin D3 hormone calcitriol up-regulated the estrogen receptor.  Estrogen up-regulated the vitamin D hormonereceptor.  Furthermore, the estrogen-ER pathway appears to control calcitriol biosynthesis and the calcitriol-VDR pathway appears to control estrogen synthesis.  The two systems are integrated.  For references that are relevant to this amplification loop see citations in Nashold's paper.  A few studies have now reported findings in humans similar to the data in mice (Kragt 2009; Correale 2010; Orton 2011). There are some current studies looking at the effect of estriol on cognitive and motor function being run by Dr. Voskuhl now at UCLA. From what I've heard, they are consistently having good results but those current studies won't be published for a few years yet. Here is a quote from one of the papers about weighing the benefits and negatives of hormone therapies: "While the risk/benefit ratio of estrogen treatment may be slightly of more risk than benefit in preventative medicine strategies in healthy women, in whom only minimum to no toxicity is tolerable, the risk/benefit ratio in patients with a chronic autoimmune disease is quite different, with modest toxicity tolerable."

3 thoughts on “Estriol, Pregnancy, and MS

  1. Hi Sarah, I have been umming and arrhing over what to do re. contraception for years, because I am aware of some research whose data mining indicated that females on the pill are more susceptible to getting MS than those not on the pill. However, I’ve never been completely convinced by this because of the problems in teasing out causation from mere correlation and, if my memory serves me correctly, the stats weren’t very strong. Nevertheless, my doc and I had decided to go for a low-dose progesterone-only contraception to keep additional variables out of the MS picture. HOWEVER, on reading this post you’ve given me the knowledge I needed to make my mind up. I’m now going to change to an oestrogen-based option, and as high as I can. Thank you so much for sharing the papers and, also importantly, the possible mechanisms of action, some great citations here!

    • There is a research article I read a few years ago which shows that progesterone only supplementation in the mouse model of MS had bad results. But estrogen + progesterone was beneficial. Though other research articles have shown positive benefits with progesterone only supplementation. Hormones are tricky! I think ultimately (going back to your contraceptive point) low doses of estrogen are inflammatory, but high doses are anti-inflammatory. It switches once you get to pregnancy levels. So pre-pregnancy, lower may be better. The complicated relationship of estrogen is difficult to decide what to do. I took estriol for a year and saw no benefit and maybe some decline as that was the only year since diagnosis I had new lesions. Though it of course is hard to determine cause in this single incident. Through blood testing, I found my body was converting the estriol to estradiol but not at levels quite high enough for pregnancy, so that could mean I entered a more inflammatory state. But it was all off label and experimentation from a willing doctor – perhaps the estriol formulation in the trials is tempered with something to keep it from converting to estradiol. Another component is that estrogen works in conjunction with Vit. D. Some research by Colleen Hayes at University of Wisconsin shows that if you only have vit. D but no estrogen, then the protective effects of vit. D diminish. So ultimately having healthy hormones is the best is what I take away from that. I was on birth control for 10 years prior to diagnosis and a few studies last year have shown that hormonal contraception double your risk of developing MS. I stopped once I was diagnosed to remove that from the equation so to speak. From all of this I decided to just try to keep my hormones as normal as possible rather than artificially supplement until all the data comes in since it seems that not only the absolute level but the balance between these hormones matters.

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