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Hi all - I just noticed that this thread has grown longer. Thanks so much Sharon for your insights and very useful info. We haven't had the chance to get the Neuro's thoughts on estriol, but we are still keen. My wife just had her first round of 3-monthly pulse steroids - only one day, but we suspect it was probably a large-ish dose.

TonyJegs - I've been reading a few of your posts with interest! You seem to be quite knowledgeable about all things MS. I never suspected that hormones and steroids were similar, and I look forward to Sharon's response to your comments. Can I ask what you would recommend someone with RRMS do? You indicated that steroids are only good for flare-ups. What about in 'normal' times? My wife can't take any of the interferons (liver enzymes) or Copaxone (allergic reaction). I assume you don't think much of these drugs anyway. And indeed, your comments about autoimmunity would indicate you don't think much of drugs like Tysabri (and immunosuppressants in general).

Most of the drugs in the MS pipeline focus on autoimmunity, but there are obviously different approaches within this class. Personally, I'm keen to see what drugs like Tovaxin and MBP8298 can do. MBP8298 seems to delay disability in SPMS, which is very exciting given the lack of drugs that achieve this goal. And Tovaxin is a bit of a mystery - but a lot of potential it seems.

There are, of course, other drugs in the pipeline which scare the crap out of me. Campath is one - the side effect profile of this sucker is interesting to say the least!

So yeah, TonyJegs, what would you recommend?

Steroids should be prohibited for use in ‘calm’ period (between relapses) or for ‘prevention’, because, when used in a long run (more than 2 weeks), they block remyelination and intensify scarification of the lesion. The same is valid for estrogens (read my post).
For RRMS the options are: proper treatment of flare-ups with proper rehabilitation after.

I’m not against immunosuppressants; I’m against their improper use. There are some forms of MS when they are favorable, but these forms are rare, about 2% of all MS.

I will post my opinion about Tysabri later, it will be negative.

Kind regards,
Tony

Thanks Sharon--- extremely helpful (and encouraging ) references!

Tony,

I will post my opinion about Tysabri later, it will be negative.

Kind regards,
Tony

I am waiting to hear your opinion on this.

Harry

connieb wrote:My neuro is actually recommending that I take estriol in addition to Copaxone-- he believes that estriol, which is apparently widely used in HRT in Europe, may actually protect against breast cancer (I'll try and get some of his references for us all later), but I am very nervous about starting on it.

Decline in Breast Cancer and HRT Use: Is There a Link?

HOUSTON, TX -- April 19, 2007 -- An extended analysis of cancer rates reinforces a strong association between use of hormone replacement therapy (HRT) and increased breast cancer incidence, according to research led by scientists at The University of Texas M. D. Anderson Cancer Center and published in the April 19th issue of the New England Journal of Medicine.

M. D. Anderson's Peter Ravdin MD, PhD, professor in the Department of Biostatistics, and Donald Berry, Ph.D., head of the Division of Quantitative Sciences, presented the first analysis of the 2002-2003 falling breast cancer rates at the December 2006 meeting of the San Antonio Breast Cancer Symposium. They have since examined breast cancer incidence in 2004.

In the published study, the investigators say that plummeting use of HRT in mid-2002, after results of the Women's Health Initiative study were announced, correlated with a steep decline in new breast cancer diagnoses that started shortly thereafter and continued through 2003. Incidence in 2004 leveled maintained the same low level of incidence, the lowest rate seen since about 1987, the researchers say.

The decline occurred primarily in women age 50-69, the researchers find, and was predominantly seen in estrogen-receptor(ER)-positive cancer - the type of tumors is fueled by estrogen, a hormone that is supplemented in HRT. Such cancers declined 14.7% in this time period, compared to a non-significant decline of 1.7% in ER-negative tumors.

"For our new data set, 2004, the drop in breast cancer incidence leveled off and remained low in that year, showing that the decreased rates seen in 2003 were also present in 2004, meaning that the decline was not a one-year wonder, a short-lived anomaly," says Ravdin, the study's lead investigator.

"This kind of study can't prove causality, but the data present a very compelling link between hormone replacement therapy and breast cancer," says Berry, the study's senior investigator.

Using data derived from National Cancer Institute cancer registries that report on 9% of the U.S. population, they found that the total decrease in breast cancer incidence was 6.7% between 2002 and 2003. They also calculated that by the end of 2002, about 20 million fewer prescriptions for HRT were written in the United States - a decrease of 38%. Interest in HRT use dropped after the 16,608-participant federal Women's Health Initiative study results were announced in July 2002 and showed that the risks of taking these agents outweighed the benefits for many post-menopausal women.

Ravdin and Berry strongly stress, however, that their study is not suggesting that all women stop their use of HRT. "This study is not saying that an individual woman will reduce her absolute risk of developing breast cancer by 15% by immediately discontinuing use of HRT," Berry says.

While it may be true that stopping use of HRT may have prevented as many as 14,000 breast cancers in 2003 compared with 2002, the percentage of decline is based on an entire population, he explains. "At best, based on this analysis, an individual woman could reduce her individual risk of developing breast cancer by one in 60, or about 1.7%, if she stopped using hormones," Berry says.

As a physician, Ravdin tells his patients to follow currently accepted guidelines for HRT use: to use the drug at the lowest dose and for the shortest time period to control hot flashes and other debilitating symptoms caused by the onset of menopause.

"The risk of developing breast cancer from use of these hormones is relatively small and for some women with postmenopausal symptoms, the benefits of HRT are well worth that risk," he says. "This is just another small piece of the puzzle to help women gauge the risks and benefits of using HRT."

The researchers also say that their study cannot answer three key questions: whether stopping the use of HRT leads to a permanent or a temporary decline in breast cancer incidence; if this effect is seen for stopping all types of HRT; and how much of a contributing role other factors may have played in the decline.

"There are several possibilities as to what effect stopping HRT has. Possibly, it slows the growth of tumors that are there but aren't big enough yet to be detected on a mammogram. Or it could be removing the hormone fuel stops the growth completely or even causes tumor regression," Berry says. "We don't know which is correct."

While Berry, an expert in statistics, adds that he was initially surprised that stopping HRT use could have such an immediate impact on breast cancer growth, Ravdin, the clinician, says he was not. "We know that if you treat ER-positive breast cancer with anti-hormone treatment, you can see shrinkage within weeks, so why wouldn't withdrawing hormones have the same kind of effect on smaller cancers that have not yet been detected?" says Ravdin. "My thought is that these tumors don't completely disappear, but they have stopped growing - hopefully, for many of them, forever."

As to the impact of other factors on breast cancer decline, the researchers say that one contributing factor could be declining use of mammography by women who have stopped using HRT. NCI data has reported a 3.2% decline in screening mammography in 2003 for women 50-65 years old, compared to 2000, Berry says, but adds, "such a change would seem insufficient to explain the decline in breast cancer incidence." A large drop in screening would have been seen in breast tumors that are both ER-positive and ER-negative, and that wasn't the case.

Finally, the researchers say that this study may lead to new insights into both the etiology of breast cancer and its prevention. "We will continue modeling incidence rates to try to understand whether what we are seeing is a slowing or a regressing of tumors, or a mix between these two things," Berry says.


SOURCE: The University of Texas M. D. Anderson Cancer Center

I hope you will find it useful, the numbers are impressive.
Also I wonder why your neuro said this about HRT in Europe? The strong negative effefect of estrogens were discussed there from mid 70-ties.

Kind regards,
Tony

Thanks Tony-- it's a very good article. I think my neuro was talking about HRT with estriol only, which is bioidentical and the weakest of estrogens, whereas these studies looked at various combined therapies with other, synthetic estrogens.

Mmm...didn't I just mention something in another thread about male neurologists and lack of progress in MS research

mjs wrote:

I never suspected that hormones and steroids were similar, and I look forward to Sharon's response to your comments.

I’m not at all certain what to say. I have no medical or scientific background. I’m quite certain I don’t really understand Tony’s points and objections to estrogen in people with MS. (or, why he thinks estrogen increases the risk of breast cancer since the estrogen only trial showed just the opposite).

I do think balancing estrogen and progesterone levels is important. I also think that neuroprotection and the prevention of neurodegeneration is important. I think estrogen, pre-clinically, exhibits neurprotective properties that might be applicable to people with MS. I definitely don’t have the impression estrogen and synthetic versions of “cortisol”, i.e., IVMP, etc. do the same things. I think the decline in hormone levels with age, including estrogen, increases the possibility for neurodegeneration in people with MS. So, with that…..some comments.

Estrogens and the Blood Brain Barrier

Based upon what I’ve read (and could understand a little), estrogens just don’t act directly after passing the blood-brain barrier as all other steroids do. Estrogens are also synthesized de novo in the CNS, as are several other hormones (progesterone, DHEA).

Glia-neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones

These findings suggest that an increase in steroidogenesis is part of an overall mechanism used by the nervous tissue to cope with neurodegenerative conditions. Neural steroidogenesis is the result of a coordinated interaction of neurons and glia.

In the central nervous system, the steroids produced by glia regulate synaptic function, affect anxiety, cognition, sleep and behavior, and exert neuroprotective and reparative roles.

To repeat, some researchers are of the opinion that some steroids, including estrogen, are produced “de novo” in the CNS to cope with neurodegeneration, provide neuroprotection and support repair.

Stable MS PM

Yes, I think most women with MS stabilize in the PM period if that means the absence of relapses. My guess would be that this is because many probably progressed from RRMS to SPMS when relapses are less frequent or cease. Personally, I don’t consider the SPMS phase of the disease to be better than the RRMS phase.

Lesions, MS and Estrogen

With regard to estrogen, lesions and scarring, I have no idea how that process occurs. But some people and researchers don’t think lesions correlate well with disability, so I have to ask how relevant is that?

And, if it is relevant, there’s some information that estrogen has a positive impact on lesions in spinal cord injuries. (There may be some similarities between SCI and MS lesions).

Estrogen attenuated markers of inflammation and decreased lesion volume in acute spinal cord injury in rats

the only currently recommended pharmacotherapy is high-dose methylprednisolone, which has limited efficacy.

Estrogen is a multi-active steroid that has shown antiinflammatory and antioxidant effects, and estrogen may modulate intracellular Ca(2+) and attenuate apoptosis

Treatment of SCI rats with estrogen reduced edema and decreased inflammation and myelin loss in the lesion and penumbral areas, suggesting its potential as a therapeutic agent.

Estrogen, Neurodegeneration and Neuroprotection

Two of the things it seems that researchers suggest may impact neurodegeneration in people with MS are mitochondrial dysfunction and glutamate toxicity. I have to resort to what Dignan once referred to as word matching, so, here’s some word matching about that as it pertains to properties of estrogen.

First, info about glutamate toxicity and estrogen.

Equine estrogens differentially prevent neuronal cell death induced by glutamate

CONCLUSIONS: Our data indicate that the neurotoxic effects of glutamate can be inhibited differentially by various equine estrogens.

estrogens may provide compounds that are useful for preventing neurodegenerative diseases in both women and men.

Now, some info about estrogen and mitochondria.

Mitochondria play a central role in estrogen-induced neuroprotection

The potent feminizing hormone, 17 beta-estradiol (E2), has shown cytoprotective activities in a host of cell and animal models of stroke, myocardial infarct and neurodegenerative diseases.

The cytoprotective and mitoprotective potencies for 14 of these analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD, PD and HD.

Is MS a chronic degenerative disorder that should be added to that list, or, to the list in the following abstract? Estrogen is being developed as a neuroprotective agent for degenerative neurological diseases.

Development of 17alpha-estradiol as a neuroprotective therapeutic agent: rationale and results from a phase I clinical study

Maintaining membrane integrity is critical to mitochondrial function, where loss of impermeability of the inner membrane initiates both necrotic and apoptotic pathways. Thus, by serving as a mitoprotectant, 17alpha-E2 forestalls cell death and could correspondingly provide therapeutic benefit in a host of degenerative diseases, including AD, PD, Friedreich's ataxia, and amyotrophic lateral sclerosis,

If you want to read more about estrogen and neuroprotection, there’s more…..

From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens

Mechanisms of neuroprotection by estrogen

Accumulating evidence from basic science studies demonstrates that estrogens exert profound protective actions against various forms of neurodegenerative diseases and injury.

recent work demonstrating that estradiol may additionally enhance the ability of the adult brain to undergo repair by influencing the production of new neurons under neuropathological conditions, as well as by promoting an anti-inflammatory response.

we increasingly appreciate that the mechanisms by which estrogens achieve these effects are diverse and complex.

Are estrogens protective or risk factors in brain injury and neurodegeneration? Reevaluation after the Women's health initiative.

work that we have done during the past 6 yr that strongly suggests that low levels of estradiol therapy exert dramatic protective actions in the adult injured brain.

Our results reveal that 17beta-estradiol slows the progression of this injury and diminishes the extent of cell death by suppressing apoptotic cell death pathways and enhancing expression of genes that optimize cell survival. Furthermore, we have found that estrogen receptors play a pivotal functional role in neuroprotection. Together, these results carry broad implications for the selective targeting of estrogen receptors in the treatment of neurodegenerative conditions resulting from disease or injury, particularly for aging, postmenopausal women.

Neuroendocrine modulation and repercussions of female reproductive aging

Furthermore, we have shown that the lack of estradiol increases the vulnerability of the brain to injury and neurodegeneration.

Estrogen, estrogen treatment and the post-reproductive woman's brain

From early embryonic life to death, estrogen is a primary regulator of brain neurogenesis and cell number, synaptogenesis and synaptolysis, multiple cognitive and autonomic functions, vascular function, immune responses and defense measures against brain lesions and dystrophy.

Estrogens, progestins, menopause and neurodegeneration: basic and clinical studies

While the mechanisms of this potent neuroprotection are currently unresolved, a mitochondrial mechanism is involved

Collectively, results of these animal and tissue culture models suggest that the loss of both estrogens and progestins at the menopause makes the brain more vulnerable to acute insults and chronic neurodegenerative diseases.

That’s way more than enough. Like I said, my interest in utilizing "estrogen" to help manage MS is for it's potential to increase neuroprotection and to prevent neurodegeneration.

I’ll post some info about why I’m not fond of other steroids (namely synthetic cortisol, methylprednisolone) to treat MS at another time. Here’s just one reason why I think it’s not exactly comparable to estrogen.

Methylprednisolone increases neuronal apoptosis during autoimmune CNS inflammation by inhibition of an endogenous neuroprotective pathway

To investigate the influence of methylprednisolone therapy on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the ON, we used a rat model of myelin oligodendrocyte glycoprotein (MOG)-induced EAE.

Methylprednisolone treatment significantly increased RGC apoptosis during MOG-EAE.

we provide evidence for negative effects of steroid treatment on neuronal survival during chronic inflammatory autoimmune disease of the CNS, which should result in a reevaluation of the current therapy regimen

I understand some people equate estrogen with methylprednisolone. Clearly, I'm not one of them. And, I do understand many people find "steroids" helpful for relapses.

Take care all...the beat definitely goes on.

Sharon

connieb wrote:I think my neuro was talking about HRT with estriol only, which is bioidentical and the weakest of estrogens, whereas these studies looked at various combined therapies with other, synthetic estrogens.

It doesn’t matter what kind of estrogen you use, the mechanism of action is the same (otherwise they will never be used at all).

Please, re-read my posts about estrogens. I tried to make it short and understandable. I usually place the core explanation in my posts, and if you get it right than it would easy to follow the subject.
When I wrote about cognitive decline in PM women using estrogens I forgot to mention that they usually experience great emotional disturbances, sometimes even OCD. The rate of epileptic seizures became greater also, opposite to usual rate decline during aging.

And remember, there is no such thing as ‘balanced HRT’, it doesn’t work either.

Kind regards,
Tony

When I wrote about cognitive decline in PM women using estrogens I forgot to mention that they usually experience great emotional disturbances,

Some refer to that as a “raging hormonal imbalance.”

Now for some news about “estrogen” and dementia from the recent AAN meeting in Boston.

Study: Hormones May Ward Off Dementia

New research suggests that hormone therapy taken soon after menopause may help protect against the mental decline of dementia,

the latest evidence suggests that timing of treatments may be key, at least for heart attacks and now for dementia

drugs do not raise the risk of heart attack for women ages 50-to-59, and they seem to survive longer with the drug.

for women who took hormones before age 65: Dementia risk was reduced by nearly half.

And, more news, a poster in the imaging section of the ACTRIMS Conference being held May 30th to June 2nd is entitled:

HRT Contributes to Neuronal Health in Postmenopausal Women with MS

Sounds like more good news to me. Take care all

Sharon