Estriol

[Tekla]

Not a recommendation but rather just sharing info on what I'm taking....

I've been taking 8 mg oral Estriol daily since last October. My PCP added medroxyprogesterone 2.5 mg, which I take from day 15 to 25 of each monthly cycle (day one being the day I start my period). She says this will help prevent tissue buildup in my uterus.

My Estriol is obtained from a local compounding pharmacy. My insurance pays about half.

The basis behind the 8 mg dose, which is fairly high, is to approximate third trimester pregnancy levels.

I started it about the same time as Copaxone and Cymbalta. Something in the cocktail has made me feel much better. I'm hoping my next MRI in late September will look much improved.

[Shayk]

Tekla--welcome and thanks for letting us know what you're taking. I hope all is going well for you.

Somehow I missed your post until now. I'm curious, have you considered bio-identical progesterone instead of the MPA?

Lab research suggests MPA doesn't have the neuroprotective properties of progesterone, plus some info I recently discovered indicates that the choice of "progestin" may influence the risk of breast cancer. Unequal risks for breast cancer associated with different hormone replacement therapies

the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone or dydrogesterone.

Now, on another topic, here's some more info about a potential link between a facet of the MS disease process and estrogen. First, I have no idea what it really is, but "abnormally phosphorylated tau" has been associated with neuronal and axonal loss in people with MS per this abstract

The pathological correlate of clinical disability and progression in multiple sclerosis is neuronal and axonal loss; however, the underlying mechanisms are unknown.

Abnormal phosphorylation of tau is a common feature of some neurodegenerative disorders

We investigated the presence of tau hyperphosphorylation and its relationship with neuronal and axonal loss.......in brain samples from patients with secondary progressive multiple sclerosis.

Significantly, analysis of secondary progressive multiple sclerosis brain tissue also revealed abnormally phosphorylated tau and the formation of insoluble tau.

Together, these observations provide the first evidence implicating abnormal tau in the neurodegenerative phase of tissue injury in experimental and human demyelinating disease.

Now, I recall reading about that tau stuff and wondering if hormones might impact it. Guess what--maybe estrogen does. Per this abstract (not an easy read, not MS research)

E2 inhibits tau hyperphosphorylation

E2 in this case refers to estradiol. So, as I understand it, they found "tau hyperphosphorylation" linked to neurodegeneration and neuronal and axonal loss in people with SPMS. Now there's some research suggesting estradiol might inhibit it.

Sharon

[Tekla]

Shayk, the choice of Provera (medroxyprogesterone) was made by my primary care doctor, to prevent endometrial hyperplasia.

I have corresponded periodically via email with Rhonda Voskuhl, the neurologist leading the clinical trials of Estriol that are currently underway at seven medical centers in the US. She said that the progesterone which I am taking is "fine" - so I'll stick with it.

In addition to the initial positive results of the first Estriol trial, Phase II preliminary trial results showed that estriol treatment decreases matrix metalloproteinase (MMP). MMP "plays a critical role in the migration of inflammatory cells into the CNS. Elevated levels of MMP-9 have been described in serum and cerebrospinal fluid of multiple sclerosis patients, and they predict the occurrence of new active lesions on brain MRIs."

My MRI results from 9/29/08, after one year on Copaxone & Estriol, showed no enhancing lesions, no increase in existing lesion size, and only "possibly" one small new lesion. Not as exciting as the trial results, but I've had MS for about 17 years now. Symptomatic relief in the past year has been dramatic.

http://autoimmunedisease.suite101.com/a ... _sclerosis
http://www.jimmunol.org/cgi/content/full/171/11/6267

[Shayk]

Tekla

Great to hear from you and learn that your symptoms have improved so much. Wonderful news.

Shayk, the choice of Provera (medroxyprogesterone) was made by my primary care doctor, to prevent endometrial hyperplasia.

Got it. Undoubtedly Provera (MPA) is the standard and most widely prescribed form of progesterone in the US to prevent endometrial hyperplasia in women who are taking estrogen. As far as I know bio-identical progesterone does that as well. It's just that I've also been interested in the potential of progesterone (not just estriol) to help manage MS too and from what I've been able to cobble together (I have no medical or scientific background), progesterone wins hands down over MPA in that category on multiple fronts.

I certainly have high regard and respect for Dr. Voskuhl. Per the link you posted (thanks for that updated info) Dr. Voskuhl stated:

In addition, estriol reduces the ability of immune cells to attack the brain, and it makes the brain more resistant to damage. Dr. Voskuhl calls this a two-pronged approach in which there’s an anti-inflammatory prong that reduces attacks on the brain and a neuroprotective plug that helps the brain heal in case of an attack.

Since you're in contact with her periodically, do you happen to know what that "neuroprotective plug" is that Dr. Voskuhl is referring to that helps heal the brain in case of an attack? I'm really curious since estrogen (and progesterone) both impact glutamate excitotoxicity and BDNF levels and both have been implicated in neurodegeneration in MS. I'm just wondering if Dr. Voskuhl is referring to either one or both of those or something else being the "neuroprotective plug"?

And, sort of on topic, there was some additional info from the World Congress on Treatment and Research in MS that was held in Montreal in September.

(Just have to make an editorial comment that the search words "estrogen" and "progesterone" produce no results for abstracts at this conference despite the fact this abstract has both in the title. )

ID# P162 Location: 220C Time of Presentation:
Sep 18 3:30 PM - 3:30 PM
Presentation Category: Experimental Disease Models

Estrogen and progesterone prevent demyelination and affect oligodendrocyte function in the cuprizone modelA. C. Braun1; A. Norkute1; S. Johann1; S. Komoly2; P. Acs2; C. Beyer1; M. Kipp1
1. Neuroanatomy, RWTH Aachen, Aachen, Germany.
2. University of Pecs, Neurology, Pecs, Hungary.

Sex hormones are thought to affect and delay progression of multiple sclerosis (MS) during pregnancy.

Both steroid hormones are regarded as neuroprotective factors in the brain.

Only the influence of estrogen supplementation on disease progression has so far been tested in clinical trials.

In this study, we focused on the underlying mechanisms of protective hormonal effects.

Adult male mice were fed with cuprizone for a defined time interval to induce demyelination of the corpus callosum. Animals were exposed to estrogen and progesterone by subcutaneous injection.

A combined treatment with both hormones nearly completely counteracted the process of demyelination. Furthermore, premature and mature oligodendrocyte markers were significantly increased.

These data support the concept that sex steroids can protect the brain from demyelination during MS.

So, I'm still sticking with estriol and progesterone. I've been diagnosed over 5 years now and so far, so good I think. My neuro only does MRIs if clinically indicated to consider any change in treatment and so far I've only had my diagnostic MRI, so can't report anything on that front.

Take care and definitely keep us posted. Thanks!

Sharon

[Tekla]

Tekla

Great to hear from you and learn that your symptoms have improved so much. Wonderful news.

Undoubtedly Provera (MPA) is the standard and most widely prescribed form of progesterone in the US to prevent endometrial hyperplasia in women who are taking estrogen. As far as I know bio-identical progesterone does that as well. It's just that I've also been interested in the potential of progesterone (not just estriol) to help manage MS too and from what I've been able to cobble together (I have no medical or scientific background), progesterone wins hands down over MPA in that category on multiple fronts.

I certainly have high regard and respect for Dr. Voskuhl. Per the link you posted (thanks for that updated info) Dr. Voskuhl stated:

In addition, estriol reduces the ability of immune cells to attack the brain, and it makes the brain more resistant to damage. Dr. Voskuhl calls this a two-pronged approach in which there’s an anti-inflammatory prong that reduces attacks on the brain and a neuroprotective plug that helps the brain heal in case of an attack.

Since you're in contact with her periodically, do you happen to know what that "neuroprotective plug" is that Dr. Voskuhl is referring to that helps heal the brain in case of an attack? I'm really curious since estrogen (and progesterone) both impact glutamate excitotoxicity and BDNF levels and both have been implicated in neurodegeneration in MS. I'm just wondering if Dr. Voskuhl is referring to either one or both of those or something else being the "neuroprotective plug"?

So, I'm still sticking with estriol and progesterone. I've been diagnosed over 5 years now and so far, so good I think. My neuro only does MRIs if clinically indicated to consider any change in treatment and so far I've only had my diagnostic MRI, so can't report anything on that front.

Dr. Voskuhl is speaking specifically of estriol when she refers to the "neuroprotective plug", and taken in context I believe she is referring to the "other prong" of the two-pronged approach. She just said "plug".

"In the 1990s, Dr. Rhonda Voskuhl, the Director of UCLA’s MS Program, discovered that the hormone estriol, which rises in pregnancy, suppressed symptoms in MS. As a treatment estriol holds an advantage because it can be taken orally. In addition, estriol reduces the ability of immune cells to attack the brain, and it makes the brain more resistant to damage. Dr. Voskuhl calls this a two-pronged approach in which there’s an anti-inflammatory prong that reduces attacks on the brain and a neuroprotective plug that helps the brain heal in case of an attack."

Very interesting information on the estrogen/progesterone combination being more effective than either on its own. Thanks for sharing. I have no doubt that hormones play a significant role in immune modulation.

I am going to bring the progesterone vs. progestin conversation up with my PCP and explore that further. Wouldn't want to be missing out on the maximum benefit!

Glad that it's working for you, too.

[DIM]

I have bought some Emerita bio-intedical progesterone creams for my wife and when I give her DHEA (increases estrogen levels) she uses also the progesterone cream as both hormones work much better than progesterone or estriol alone or at least this is what I believe from what have read!
But, who knows?

[Tekla]

I have bought some Emerita bio-intedical progesterone creams for my wife and when I give her DHEA (increases estrogen levels) she uses also the progesterone cream as both hormones work much better than progesterone or estriol alone or at least this is what I believe from what have read!
But, who knows?

Thinking just from a logical standpoint, the placenta produces both estriol and progesterone during pregnancy. In the estriol clinical trials they give the patients progesterone. I think it is important to take both to maintain balance.

Concerning progestin vs. progesterone, Dr. Voskuhl's response to me was "no evidence that a progesterone is more neuroprotective. Go with what the gyn wants you to use to protect your uterus from "unopposed" estrogens".

Not the first time an MD has cited "no evidence" because there is only anecdotal data (LDN is a good example); but what I'm taking is working for me.

Again, all I take is 2.5 mg of Provera, 10 days/month.

[Shayk]

Tekla

Thanks for sharing Dr. Voskuhl's perspectives--on estriol being "the neuroprotective plug" and

Concerning progestin vs. progesterone, Dr. Voskuhl's response to me was "no evidence that a progesterone is more neuroprotective. Go with what the gyn wants you to use to protect your uterus from "unopposed" estrogens".

As a layperson, I respectfully disagree with Dr. Voskuhl's perspective on the evidence concerning progestin vs. progesterone and neuroprotection. And, I think there are researchers who would disagree with her as well. Perhaps the difference is in what one considers "evidence" as you suggest, but I definitely think there's research beyond "anecdotal" statements.

Certainly I think we'd all love to have a lot more research/evidence than seems to exist, but there is some pre-clinical and clinical research on the topic. Here's a sample:

Progesterone-Induced Neuroprotection

Here, we review the data from various laboratories including our own that support the protective role of progesterone and describe the multiplicity of mechanisms by which progesterone elicits these protective effects.

Finally, we contrast the neurobiology of progesterone with that of the clinically used progestin, medroxyprogesterone acetate (MPA), and suggest that the "natural" progesterone may be the better choice when considering which progestin to use for future therapeutic/ palliative purposes in CNS-related disorders.

I think MS is a CNS-related disorder.

Progestins and neuroprotection: are all progestins created equal?

And though additional research is certainly needed to explore the neurobiology of progesterone and its related progestins more completely, we provide evidence that, at least with respect to the brain, not all progestins are created equal.

Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective

The ovarian hormone progesterone is neuroprotective in different experimental models of neurodegeneration.

In conclusion, our findings indicate that progesterone is neuroprotective against kainic acid excitotoxicity in vivo while the synthetic progestin MPA is not and suggest that progesterone metabolism to its reduced derivatives DHP and THP is necessary for the neuroprotective effect of the hormone.

Medroxyprogesterone acetate exacerbates glutamate excitotoxicity

We previously demonstrated that progesterone functions as a neuroprotective agent whereas medroxyprogesterone acetate (MPA; Provera) does not.

Moreover, MPA antagonized the neuroprotective and neurotrophic outcomes induced by 17beta-estradiol (E2).

Results of these analyses indicated that both crystalline MPA and a pharmaceutical formulation (Depo-Provera) lacked neuroprotective efficacy, indicating that the effects were not dependent upon MPA formulation.

Likewise, MPA in the prevention and treatment paradigms were equally ineffective at promoting neuronal survival, indicating that timing of MPA administration was not a factor.

Further, the detrimental effects of MPA were not due to the presence of the acetate group, as medroxyprogesterone was as ineffective as MPA in promoting neuronal survival.

Moreover, MPA pretreatment exacerbated neuron death induced by glutamate excitotoxicity as indicated by a 40% increase in neuron death

Collectively these results predict that the progestin formulation of hormone therapy will affect the vulnerability of the central nervous system to degenerative insults.

And, last but not least, slides 11 and 12 in the following link highlight some of the neuroprotective properties of progesterone, not MPA. Progesterone has had at least two successful clinical trials in traumatic brain injury. I'm not aware that MPA has had any.

Hormonal Therapy of MS by Patricia K. Coyle, Professor and Acting Chair of Neurology, Director, MS Comprehensive Care Center, SUNY at Stony Brook, New York

Now, I totally agree with you that it is important to take both to maintain balance as well. I'm all for people having their hormone levels tested and "balanced" accordingly. Since what you're taking is working for you, you've got every reason to stick with it. Undoubtedly the "evidence" is slim on the topic of progestins vs. progesterone and neuroprotection, but there is research.

DIM--There's an interesting note on DHEA on slide 13 in that link that I think reinforces your statement. But I'm with you, who knows?

Take care both

Sharon

[Tekla]

Thanks, Sharon - very interesting material. I hadn't considered progesterone as having a role besides "estrogen opposition" before this conversation.

Are there any oral formulations of progesterone?

It can be frustrating dealing with doctors who don't think outside the box. I've found this to usually be the case, especially in MS treatment.

[Shayk]

Tekla

Yes, there are oral formulations of progesterone. The brand name in the US is Prometrium and progesterone can also be compounded in capsules (and cream).

It can definitely be difficult to deal with doctors who don't think outside the box. It actually took me about a year to find one. I think frustrating is an understatement.

All the best if you do decide to switch.

Sharon

[Fighter]

Hello, I am seriously considering asking my Doctor about trying biogenetic hormone replacement therapy. Thank you for the wealth of information. Can you please tell me the following
1. Did your neurologist prescribe the hormone therapy for you?
2. Is your insurance covering the treatment?

Thank you

[Shayk]

Hi Fighter

Always a pleasure to welcome "fighters".

1. No, my neuro would not and does not prescribe the hormones for me. My ob/gyn does. My neuro indicated early on he would be willing to work with my ob/gyn. It actually took me quite some time to find an ob/gyn who would work with me, but eventually I did.

2. Insurance (an Anthem product) does pay for the progesterone and up until this past spring when the FDA issued a letter about bioidentical hormones, they had also paid for the estriol. A rough guess is that the estriol costs about $20.00 per month.

Feel free to pm me as well if you have more questions.

I hope you'll let us know what you decide. Thanks!

Sharon

[Fighter]

Thanks for the information. I am going to speak to my neurologist about them. I think that it is the way I want to go.
Andrea

[Shayk]

Hi all

There was a bit more news on the hormone front at the
World Congress on Treatment and Research in MS. 2008 data --only 16 years after some initial data in 1992.

Menstrual cycle and menopause in patients with multiple sclerosis. How do these affect the symptoms of disease?
M. Avila1; G. A. Suarez1; D. Brandt1; J. Ramirez1; G. J. Hutton1; V. M. Rivera1
1. Baylor College of Medicine-MMMS Clinic, Houston, TX, USA.

To document clinical changes in MS symptoms during the menstrual cycle, menopause and pregnancy.

A total of 100 patients will be evaluated. At the present time 71 patient have been included (94% relapsing-remitting MS, 6% secondary progressive MS) mean age of 41, 66% Caucasians, 17% Hispanic, 12% African American and 5% other ethnic background.

42% complained of worsening of symptoms while menstruating,

and 21% worsening prior to the menstrual period.

Twenty-eight patients had at least one pregnancy after their MS diagnosis; of these 57% reported improvement of symptoms during pregnancy, 19% had a relapse in a 12-month period after delivery and one patient had a relapse during pregnancy.

In our menopausal group of patients (n=13), 77% had worsening after menopause and 46% had increase in their number of clinical relapses after menopause.

Female hormones play an important role in MS. This may have therapeutic implications in the future.

A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle 1992 initial data

11 premenopausal and 19 postmenopausal women

Eighty-two per cent of menopausal women reported an increase in severity premenstrually.

Of the postmenopausal women 54% reported a worsening of symptoms with the menopause,

and 75% of those who had tried hormone replacement therapy reported an improvement.

The results of this pilot study indicate the need for further research to clarify the effects of the menopause and hormone replacement therapy upon multiple sclerosis.

From my perspective this clarification is proceeding at a ridiculously slow pace.

Take care everyone

Sharon

[3dognight]

Hi:
OK, so I saw my neuro last week and asked about the Estriol trial and he told me that he doesn't keep up on the new trials. Well that gave me a warm fuzzy feeling... not. It seems to me that as my menopause symptoms have gotten worse, so have my MS symptoms. I told him I was seeing my PCP the next day for my yearly exam and could I pursue that with her and he said he saw no problem with it. She seemed quite excited when I showed her some of the information I had on the trial but didn't feel qualified to do that level of hormone prescribing as she is an internal medicine dr. She's referred me to an OB/GYN who I see on Monday. (Hey when you tell them your insurance is changing at the end of the month, they really seem to try to work you in.)

My questions are: with the FDA position on bio identical hormones, is it still possible to get Estriol from a compounding pharmacy. And for those of you who do take it, how long before/if you notice any improvements?

Thanks,
Peggy