This Is MS Multiple Sclerosis Knowledge & Support Community

Unfortuantely, or really fortunately, I started taking estriol and LDN at the same time. I used to know when I was going to start my period by my MS symptoms. Now, I never know unless I keep a calender. There no longer seems to be a relationship between ovulation and MS symptoms, which now makes more sense. Thanks so much for the info. Alot to think about, and I will have to go back and reread all the info I once new about this subject, which is when I was at my worst with MS.

Hi Cathy,

Maybe we should put a poll up on the site and ask women taking LDN to answer?

Felly

I think that is a great idea. It would be interesting to know how many women had or have premenstral symptoms, as the Docs seem to believe this doesn't exist, at least 99% of the ones I have seen. Then to find out if those on LDN noticed relief. I have to say that I am so happy that my neuro was willing to prescribe LDN without hesitation. And that for the most part (having trouble now becasue of the heat and a UTI, I think) I feel better than I have in years.

I think the survey idea is a great one Felly. The connection you make with LDN is also fascinating.

And I think you have a great point Cathy about progesterone working for some women and perhaps not others. That is totally consistent with what I've been reading and why I've locked onto hormone testing. It seems clear to me that one could do more harm than good if not careful with all of this.

Stay well everyone.

Sharon

At Felly's request, I've created a new poll on the front page regarding MS symptoms during menstruation before and after taking LDN...

just another estrogen-related study...


Estrogen receptor alpha signaling in inflammatory leukocytes is dispensable for 17beta-estradiol-mediated inhibition of experimental autoimmune encephalomyelitis.

Garidou L, Laffont S, Douin-Echinard V, Coureau C, Krust A, Chambon P, Guery JC.

Institut National de la Sante et de la Recherche Medicale Unite 563, Centre de Physiopathologie de Toulouse Purpan, Institut Claude de Preval, Hopital Purpan, Toulouse, France.

Estrogen treatment has been shown to exert a protective effect on experimental autoimmune encephalomyelitis (EAE), and is under clinical trial for multiple sclerosis. Although it is commonly assumed that estrogens exert their effect by modulating immune functions, we show in this study that 17beta-estradiol (E2) treatment can inhibit mouse EAE without affecting autoantigen-specific T cell responsiveness and type 1 cytokine production. Using mutant mice in which estrogen receptor alpha (ERalpha) has been unambiguously inactivated, we found that ERalpha was responsible for the E2-mediated inhibition of EAE. We next generated irradiation bone marrow chimeras in which ERalpha expression was selectively impaired in inflammatory T lymphocytes or was limited to the radiosensitive hemopoietic compartment. Our data show that the protective effect of E2 on clinical EAE and CNS inflammation was not dependent on ERalpha signaling in inflammatory T cells. Likewise, EAE development was not prevented by E2 treatment in chimeric mice that selectively expressed ERalpha in the systemic immune compartment. In conclusion, our data demonstrate that the beneficial effect of E2 on this autoimmune disease does not involve ERalpha signaling in blood-derived inflammatory cells, and indicate that ERalpha expressed in other tissues, such as CNS-resident microglia or endothelial cells, mediates this effect.

PMID: 15294957 [PubMed - in process]

Arron, even if it is “just another article on estrogen” , I for one really appreciate it.

Since there’s also that great front-page story on estrogen I thought I’d add a few more tidbits from the evolving and what I think is promising research in this area.

Scientists in China are also examining the affect of estrogen on the immune response on dendritic cells in rats with EAE. The abstracts I’ve read basically conclude estrogen can affect the differentiation, maturation and function of dendritic cells, which may also help explain its protection against EAE and the remission of MS patients in pregnancy.

Researchers in Toronto published an article in March that may also be relevant (or not). Essentially, the abstract states that the presence of an estrogen receptor (ER) in myelin has not been reported although a nuclear form has been detected in oligodendrocytes. That abstract concludes:

The discovery of the ER in the oligodendrocyte plasma membrane and within the myelin sheath indicates a potential role for estrogen in myelin maintenance or functions.

Researchers in Argentina reported in February on the interaction between sex steroids and the neuroimmune system in acute EAE Wistar rats. (I think I’ve figured out that means surgically castrated rats, or, if not, these rats were surgically castrated per the abstract.) Anyway, that abstract concluded:

These results indicate that sex hormone levels regulate cell mediated immunity and the specificity of anti-myelin basic protein antibodies related to the induction and development of acute EAE.

Now, out of the lab and on to real people with MS. Voskuhl from UCLA who did the small clinical trial with estriol (a form of estrogen) and found it reduced brain lesions in women with RRMS, reported at the American Academy of Neurology meeting in April that further analyses of the MRIs taken before, during and after treatment in the trial slowed the rate of accumulation of “ black holes” during treatment, suggesting that estriol may also offer neuroprotection in addition to impacting immune activity.


Take care everyone…I'm going to try and find my articles about the risks of hormone replacement therapy (HRT) and post references for anyone who might be interested. As you know, I personally think the risks have not been presented very well in the US...that's why they yanked me off HRT to start with.

BTW--I am happy to report I got the results of my hormone testing. I started a new script this week for HRT that includes 8 mg of estriol and 300 mg progesterone, since I didn't have ANY of that.)

Sharon

link to article http://www.nutrapharma.com/investor/pr/10_14_04.htm

gallom,

If you will note, we addressed nutra-pharma in another thread in quite a bit of detail. You might want to review that.

Deb

I’ve come across some more information on hormones and MS. This is the abstract (emphasis added) of an extensive (and highly scientific) review article focused primarily on estrogen. Most of this information has already been posted. What may be new is the information about fluasterone, an analogue of DHEA.

Neuroimmunoprotective effects of estrogen and derivatives in experimental autoimmune encephalomyelitis: Therapeutic implications for multiple sclerosis. J Neurosci Res. 2004-Oct 28 PMID 15515048

Offner H.

Department of Neurology, Oregon Health and Science University, and Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon.

The extensive literature and the work from our laboratory illustrate the large number of complex processes affected by estrogen that might contribute to the striking ability of 17beta-estradiol (E2) and its derivatives to inhibit clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in mice. These effects require sustained exposure to relatively low doses of exogenous hormone and offer better protection when initiated prior to induction of EAE. However, oral ethinyl estradiol (EE) and fluasterone, which lacks estrogenic side effects, could partially reverse clinical EAE when given after the onset of disease. The three main areas discussed in this review include E2-mediated inhibition of encephalitogenic T cells, inhibition of cell migration into central nervous system tissue, and neuroprotective effects that promote axon and myelin survival. E2 effects on EAE were mediated through Esr1 (alpha receptor for E2) but not Esr2 (beta receptor for E2), as were its antiinflammatory and neuroprotective effects. A novel finding is that E2 up-regulated the expression of Foxp3 and CTLA-4 that contribute to the activity of CD4(+)CD25(+) Treg cells. The protective effects of E2 in EAE suggest its use as therapy for MS, although the risk of cardiovascular disease may complicate treatment in postmenopausal women. This risk could be minimized by using subpregnancy levels of exogenous E2 that produced synergistic effects when used in combination another immunoregulatory therapy. Alternatively, one might envision using EE or fluasterone metabolites alone or in combination therapies in both male and female MS patients.

For women concerned about the risks of oral contraceptives (EE, ethinyl estradiol, is the basis of many birth control pills) and cardiovascular disease, there’s some good news. An article on the topic, from Medscape, entitled New WHI Analysis: Oral Contraceptives May Reduce CVD Risk, can be accessed at http://www.medscape.com/viewarticle/491753. I think you have to register, but it’s free.

Now, even though I don’t have a scientific background, the extensive review article by Offner also contains some really interesting tidbits:

Because of the increased susceptibility of females to autoimmune diseases, some have assumed that female sex hormones, including estrogen, actively facilitate the disease process. In contrast to this view, our studies clearly demonstrate an important regulatory role of estrogen in EAE. Both estrogen and testosterone had inhibitory effects on immunity, and it may be that the enhanced susceptibility to autoimmune disease in females vs. males is due simply to less potent natural inhibition by estrogen than by testosterone.

Also, the abstract referenced fluasterone (a synthetic analogue) of DHEA, yet another hormone. Here’s what the article says in part about that:

DHEA is one of the three principal adrenal steroids, a precurosor of both androgens and estrogens, including 17b-estradiol, which is the focus of this review. Along with its active metabolites, DHEA has been described as a natural “antiglucocorticoid”, “immune stimulatory”, and “anti-inflammatory agent, attenuating many of the undesirable effects of glucocorticoid (GC) hormones…….

DHEA and its synthetic analogue fluasterone are steroidal compounds that attenuate disease in several mouse models of EAE with an efficiency similar to that reported for IFN-b. However, benefit in the rodent is observed only at high doses of fluasterone, which may not be readily achievable in man. Other metabolites might be more potent in limiting EAE than the parent compound and would therefore require lower doses to provide therapeutic benefit, a distinct advantage for possible MS trials. This would drive the development of more practical therapeutic strategies, (i.e., tansmucosal (buccal), transdermal, or s.c. administration ) to ameliorate MS in man. Because the steroid-like compounds are nontoxic, are inexpensive to produce, and are as good as or better than IFN-b in limiting EAE, similar or greater efficacy in man, at more readily achievable doses, would provide real clinical as well as economic benefit to patients with MS.

Researchers at Vanderbilt University (including Sriram) found that DHEA suppressed EAE in mice. http://www.mult-sclerosis.org/news/Jan2 ... lOfMS.html and
a very small “non-traditional” study of DHEA found low levels in people with MS. http://www.itmonline.org/arts/dhea.htm

And, remember, even though DHEA is available over the counter in the US, just like any hormone, it should only be taken under the supervision of a physician.

Lastly guys, I haven’t forgotten about you. I’m hoping to post more about testosterone soon.

Here’s to healthy and balanced hormone levels for everyone.

Sharon

Hi, Sharon!

You know, we've (you and I, I mean) touched upon that before (i.e. the hormone interaction, etc.) I also find that avenue of interest, although I've not become nearly as familiar with it as you have.

It's really interesting what they are finding in that area, isn't it? And something else I found intriguing with your last post there was the quick reference to adrenals. I found earlier "somewhere" a similar connection.

It's such a complex process! (Physiologically, I mean.)

I still can't help thinking that there are some or even MANY treatments or combination of treatments that aren't nearly so risky safety-wise that could/should very well be extremely helpful for MS! (Which I believe is similar to what you may be leaning toward, also, if I understand your very informative posts and comments correctly.)

DHEA......darn. I know I read about DHEA in the recent past (although I'm not even sure it was in relationship to MS, though), but it was a "good" thing. I don't know why I'm mentioning it though if I can't remember what the heck I'm even trying to say! I guess just that when I saw "DHEA", I stopped and thought "wait a second.......this is really interesting". It rang a bell.

Thanks for keeping us updated in this area! And thanks for following it! If you might recall, over the years, I've ended up with what I laughingly refer to as my "cocktail formula" of certain vitamins, etc. etc. that appear to work well for me (not a cure, of course, but certainly have appeared to assist in keeping me as healthy as can be expected). And if you know me, now I'm going to go run and look at all my supplements and see what's in 'em! LOL I doubt if that's one of them, though.

Oh....yea......I found some mention recently about progesterone and MS, too. (Maybe I posted somewhere or another.) Anyway, I only mention that because it appears more and more likely that hormones play some sort of role, doesn't it?

Thanks again!

Deb

P.S. And...I will say, I've always claimed now and again that my hormones MUST be out of whack. At least during some of the worst times.

Thanks Deb. I personally think hormones may have a role in the expression and possible progression of MS, but just for the record, while I am taking alpha lipoic acid and ALCAR, I’m not taking DHEA.

Ok guys, here’s more information on testosterone.

First, this from a very general WebMD segment, emphasis added, http://my.webmd.com/content/araticle/57/66103.htm Multiple Sclerosis, What Causes It? (According to the web site this information is reviewed by doctors at the Mellen Center for Multiple Sclerosis Research at The Cleveland Clinic)

Are There Other Potential Factors That Cause MS

There is growing evidence suggesting that hormones, including sex hormones, can affect and be affected by the immune system. For example, both estrogen and progesterone, two important female sex hormones, may suppress some immune activity. Testosterone, the primary male hormone, may also act as an immune response suppressor. During pregnancy, estrogen and progesterone levels are very high, which may help explain why pregnant women with MS usually have less disease activity. The higher levels of testosterone in men may partially account for the fact that women with MS outnumber men with MS by 2-3 to 1.

Near the beginning of this thread, reference was made to an article, Dysregulation of the hypothalamic-pituitary-gonadal axis in EAE and MS, by Foster, (and others with the Oregon research group) PMID 12864974.

The abstract concluded: Gender differences in the sensitivity of the hypothalamic-pituitary-gonadal (HPG) axis to inflammation may be an important factor regulating the duration and severity of central nervous system (CNS) autoimmunity.

From the text of that article (emphasis added):

Sexual dysfunction is quite common in MS and is generally attributed to autonomic dysfunction resulting from spinal cord damage……..The results of this study are the first to demonstrate that serum testosterone levels are reduced in male mice with passive EAE and in some men with MS. The significance of this finding is twofold. First, the reduction in serum testosterone levels may play a role in the high frequency of sexual dysfunction that occurs in MS. Second, because testosterone is known to suppress inflammatory immune responses, a reduction in serum testosterone levels may act to increase the severity or prolong the duration of disease attacks.

Sort of restating the same thing in different words, the last paragraph of this article states:

The decrease in circulating testosterone levels in men with MS may have significant implications for disease progression. Inflammatory mediators secreted during a demyelinating episode may disrupt the hypothalamic-pituitary-gonadal axis resulting in low serum testosterone levels. Because testosterone is immunomodulatory, reduction in testosterone levels during an MS exacerbation might increase the severity and/or duration of the attack. The increased sensitivity of the male HPG axis to inflammatory cytokines may provide a partial explanation for the increased incidence of progressive MS in men. Further study of the importance of testosterone and the HPG axis in disease severity in males with MS is warranted.

A general education piece on men and hormones http://www.aeron.com/new_page_24.htm
offers the following tidbits (among many others)

“Studies are now showing that the sex steroid hormones, mainly testosterone, but also DHEA, androstenedione and even estradiol, have an impact on a man’s bone, heart, and sexual health thoughout his lifetime……Men….lose approximately 1% of their testosterone and 2.5% of their DHEA per year beginning at age 30.”

If the above link doesn’t happen to take you directly to the article, you can also access it by going to www.aeron.com scroll down to hormonal updates and you’ll see Hormonal Update Volume 1 Number 8, Men Have Hormones, Too. I regret this source is from a commercial lab, (btw this is not an endorsement of that lab, I’ve never used it and certainly don’t have any financial interest in it) I offer it only as a site that contains an introduction to information on the topic.

All in all it seems to me that it’s starting to look like testosterone may be a factor in the MS puzzle too. Unfortunately, I’m not aware that the Phase I study of testosterone for MS at UCLA has been completed.

May everyone be as healthy as possible. (BTW ladies, there’s also been some research that testosterone improves sex for some women. Women have testosterone too and it also declines as we age.)

Sharon

Even though this information is not directly related to MS, I thought I’d post it anyway because it made “headlines”, is stress and perhaps hormone (cortisol) related. Some of us even think there could be some association between MS and stress.

These are some quotes from a Washington Post story (11/29), titled: Study is First to Confirm that Stress Speeds Aging (emphasis added):

Scientists have identified the first direct link between stress and aging, a finding that could explain why intense, long-term emotional strain can make people get sick…

Chronic stress appears to hasten the shriveling of the tips of the bundles of genes inside cells, which shortens their life span and speeds the body’s deterioration….

If the findings are confirmed, they could provide the first explanation on a cellular level for the well-documented association between psychological stress and increased risk of physical disease….

The researchers examined structures inside cells called telomeres. Telomeres are the caps at the ends of chromosomes—the molecules that carry genes. Every time a cell divides, telomeres get shorter. In the natural aging process, the telomeres eventually get so short that cells can no longer divide, and they then die....

The researchers found that chronic stress appears to accelerate this process....

The researchers studied telomeres and telomerase in white blood cells taken from blood samples. Prematurely aged white blood cells alone could make people more prone to illness because white blood cells are a key part of the immune system. But the findings probably hold true for other types of cells as well……

It is unclear exactly how stress might affect telomeres and telomerase levels, but it could be that chronically elevated levels of stress hormones such as cortisol damage the telomeres and other genes in the body and lower telomerase levels, inhibiting the cells’ ability to respond.

An internet quote from lead author Elissa Epel of UC San Francisco:

Chronic stress appears to have the potential to shorten the life of cells, at least immune cells.

The study appeared in the 11/29/04 issue of Proceedings of the National Academy of Sciences.

So folks, looks like another reason people who associate stress with their MS symptoms might want to consider incorporating stress management and stress reduction techniques in their “regimens.”

I sure hope everyone's relaxed.

Sharon

Hi all and happy 2005! Hormones are still with us in the New Year.

I've come across additional information on progesterone that I thought I'd post since it seems to be hopeful for neuroprotection and myelin repair. Unfortunately, it's all mice and rats again.

Steroid effects on glial cells: detrimental or protective for spinal cord function concludes "In terms of beneficial or detrimental consequences, these PROG effects may be supportive of neuronal recuperation, as shown for several neuronal functional parameters that were normalized by PROG treatment of spinal cord injured animals. Thus, PROG effects on glial cells go in parallel with morphological and biochemical evidence of survival of damaged motoneurons." (PROG is progesterone abbreviated.)

Progesterone treatment reduces NADPH-diaphorase/nitric oxide synthase in Wobbler mouse motoneuron disease concludes "In summary, PROG treatment during the early symptomatic stage of the disease caused a significant reduction of NADPHD-active motoneurons and astrocytes and also reduced vacuolated degenerating cells, suggesting that blockade of NO synthesis and oxidative damage may contribute to steroid neuroprotection."

Progesterone up-regulates neuronal brain-derived neurotrophic factor expression in the injured spinal cordconcludes "Our findings suggest that PROG enhancement of endogenous neuronal BDNF could provide a trophic environment within the lesioned spinal cord and might be part of the PROG activated-pathways to provide neuroprotection."

Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination states "Although there are only a few studies addressing the biological significance of PROG synthesis in the brain, the autocrine/paracrine actions of locally synthesized PROG are likely to play an important role in the viability of neurons and in the formation of myelin sheaths...... Local synthesis of PROG in the brain and the neuroprotective and promyelinating effects of this neurosteroid offer interesting therapeutic possibilities for the prevention and treatment of neurodegenerative diseases, for accelerating regenerative processes and for preserving cognitive functions during aging."

If MS is a neurodegenerative disease as some think, progesterone is looking promising.

Take care everyone

--sharon(who had no progesterone when she had her hormones tested )

sharon, you will most definitely want to take a look at the new hormone study on the front page