Posted 9 March 2006

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Note: Transcript has been edited for clarity and accuracy.

Sam Gandy
Hi, everybody. I guess that we should give folks a few more minutes to sign on before we talk about anything substantial. And we're still missing a few members of the panel. But it's nice to see that the technology works so well!

Gabrielle Strobel
Hi, and welcome everyone. It looks like we'll have a large group today. That's wonderful. I am Gabrielle, the managing editor of ARF. I am nominally the moderator today but will stay in back to let our experienced leaders run the show.

Sam Gandy
Okay. Well, I'll get us started then.

Gabrielle Strobel
Given the ups and downs hormone replacement therapy (HRT) has gone through, would the panelists get this going by stating briefly their current opinion on its value and prospects?

Sam Gandy
Interestingly, the Science Times section of the New York Times featured HRT this week. Very timely for us.

Craig Atwood
Sam, what type of HRT, conjugated equine estrogens or 17β-estradiol?

Sam Gandy
Craig, I'm not sure that HRT versus estrogen replacement therapy (ERT) was broken out. I'll send you the piece from the Times. It was a lay piece and not broken down by compound.

Craig Atwood
My point being that estrogens extracted from horse urine are different from human serum estrogens. Likewise, medroxyprogesterone has different effects than progesterone.

Phyllis Wise
Exactly, there are over 30 compounds in the conjugated equine estrogen (CEE) preparation.

Sam Gandy
Craig, when epidemiology is discussed, I assume CEE (Premarin) unless stated otherwise.

Craig Atwood
Sam, okay.

Nancy Emerson Lombardo
The form of ERT in the Women's Health Initiative (WHI) studies was derived from mare's urine and goes through the liver. The results are not a true replacement of human estrogen hormones, which plant (soy)-based products applied as topical creams (which do not go to the liver) mimic better.

Phyllis Wise
Premarin is not the only preparation used in these studies. Some used ethinyl estradiol and others used yet other preparations.

Gabrielle Strobel
Also surprising in that Science Times story was that prescription rates have not plummeted as far as one would think following the WHI data. The piece also did not deal with AD but mostly cardiovascular disease. It did quote an opponent of HRT (cardiology professor) as saying that people who still study it are simply unwilling to let go of a cherished hypothesis, regardless of the data.

John Breitner
I'm fairly amazed because I sense a reversal in the common view that because a trial negates observational data, the latter are faulty. The issue of timing seems to be in everyone's mind. How did that happen?

Phyllis Wise
As basic scientists, we have followed the WHI work with great interest. We have been focusing our recent studies on deciphering the reasons for discrepancies between it and other studies. This forum should be wonderfully enlightening. (For more information on the WHI, see the NIH website.)

Gabrielle Strobel
Phyllis, can you make some explanations for those discrepancies, based on your work?

Phyllis Wise
I think that timing, dose, and formulation are critical differentiators of the response. For example, the average age of the women in WHI was 61, and they had not received prior hormone therapy (HT). CEE clearly has different effects than estradiol 17β. Medroxyprogesterone acetate binds to both the progesterone receptor and the androgen receptor.

Mark Smith
Phyllis, how representative of HRT users were the women in the WHI study? My feeling is they were not very representative.

John Breitner
Mark, I don't think we should be distracted by the ability to generalize the study population when it comes to trials. Internal validity is virtually all any trial can promise.

Dominique Toran-Allerand
I think it is far more than that the trials were started too late. The whole WHI studies were flawed because of failure to take into account the biology of estrogens and of the estrogen receptors.

Gabrielle Strobel
Dominique, very interesting; could you expand a bit for us?

Dominique Toran-Allerand
Gabrielle, comments have already been made on the differences between ovarian 17β estradiol and CEE, but equally important is the fact that in the WHI studies the hormones, CEE and Provera (medroxyprogesterone acetate), were given continuously for years without interruption. Unlike many compounds which increase the levels of their receptors, prolonged exposure to estrogens decreases the levels of the estrogen receptor so that with time, the cells become much less responsive to estrogens. Moreover, by giving estrogens and progestins concurrently instead of the physiological manner which is sequential, estrogen is unable to up-regulate the progestin receptor to enable it to respond to progesterone, as it does after ovulation (one of its important functions), and progestins are unable to down-regulate the estrogen receptor—one of progestins’ important functions—so neither hormone can act physiologically.

Gabrielle Strobel
Dominique, very interesting. So future trials should use estrogen breaks?

Dominique Toran-Allerand
Gabrielle, absolutely! That is the way the body is normally exposed to these hormones during the reproductive period.

Sam Gandy
I agree with Dominique's point about the cyclical nature of hormones and the absence thereof in clinical trials.

Craig Atwood
Dominique, Sam, however, there is no cycling of estrogen and progesterone during pregnancy, or during lactational amenorrhea? So is cycling that important?

Dominique Toran-Allerand
Craig, while there may be no cycling of estrogen and progesterone during pregnancy, human gestation is finite (9 months) and does not extend for years as in the WHI trials.

Craig Atwood
Dominique, but if you take a women who has five children (almost 4 years of pregnancy) and lactation amenorrhea for ~3 years each (15 years), that’s almost 20 years of no cycling. And this is the normal hunter-gatherer situation, from which we have evolved recently.

Phyllis Wise
Dominique, we have had several opportunities to talk about this, but just for the record: Down-regulation of estrogen receptor (ER) occurs when pharmacological levels of hormone treatment are used. We have shown that with our very low hormone treatments, the receptors remain. To me, this is a very important point, because if we can use low levels of estrogen and still get protection, it may be important.

Gabrielle Strobel
Phyllis, are birth control pills with the lowest doses used to date in the range you just mentioned?

Phyllis Wise
Gabrielle, contraceptive pills still use relatively high doses because you have to prevent ovulation or implantation. The whole question is whether in postmenopausal women, where it is not necessary to control fertility, you can use much lower doses and still get the protective actions. We believe you can.

Dominique Toran-Allerand
Phyllis, we have found that continuous proestrus levels of estrogen given to mice (which are really not pharmacological) do elicit down-regulation of the estrogen receptor if given for many months without interruption.

Phyllis Wise
Dominique, I agree. Proestrus levels should be considered high and could down-regulate receptors. Our paradigm has used replacement levels that are characteristic of the other days of the cycle.

Sam Gandy
The main point of the Times piece was that all fields are revisiting HRT with the notion that the clinical trials that have turned us off were all begun too late. The issue now is, do we have to redo everything and start perimenopausally? How will that impact bone, heart, vessels? Brain?

John Breitner
Not sure about "everything," Sam, because the case may be different for neurodegenerative processes.

Sam Gandy
I was referring to "multiple systems," John, sorry for the imprecision.

John Breitner
My only point, Sam, was that these systems may differ in important ways.

Sam Gandy
Yes, indeed, John. Point well taken.

Rena Li
How about the dosage of ERT?

Chris Gregory
There are several issues around ERT that remain interesting to us. In particular, we wonder whether in the ancillary WHI Memory Study (WHIMS), findings relate to the inability of estrogen to down-regulate luteinizing hormone (LH) levels when there has been time (years) between the onset of menopause and the administration of estrogen. In other words, does the prolonged absence of estrogen prior to ERT dysregulate the hypothalamus-pituitary-gonadotrophin (HPG) axis, leading to the inability of estrogen to turn off local/systemic LH production.

Mark Smith
Chris, estrogen does not regulate LH after several years postmenopause (or ovariectomy in animal models).

Phyllis Wise
Mark, my understanding is that estrogens will continue to feed back negatively even after an animal has been ovariectomized for a prolonged period of time.

Craig Atwood
Phyllis, that is correct.

Mark Smith
Phyllis, I have read in several papers otherwise...we should discuss.

Sam Gandy
I was surprised to learn this week that there is an NIH early estrogen study that has recently begun. I don’t recall the acronym. I thought that the Kronos Early Estrogen Prevention Study (KEEPS) was the only thing going. (For more information see KEEPS website and clinical trials.gov)

Jon Nilsen
Sam, are you thinking of the Early Versus Late Intervention Trial With Estradiol (ELITE) run by Howard Hodis, testing the effect of early versus late HRT on the cardiovascular system? (For more information see clinical trials.gov.)

Sam Gandy
ELITE is the one; yes, thanks.

Sam Gandy
Is there a cognitive component to ELITE, Jon?

Jon Nilsen
Sam, there is a secondary outcome measure of neurocognitive function proposed for ELITE.

Gabrielle Strobel
What will it be able to tell us? It's not in the background text. Can you enlighten us?

Sam Gandy
Phyllis, can you tell us anything about KEEPS? Will there be periodic interim analyses?

Phyllis Wise
Sam, golly, my understanding is that the trial will use CEE compared to estradiol in patch form supplemented with progesterone, and that endpoints will be measured at annual intervals. But do not quote me on this. I would be happy to contact Mitch Harman if you would like.

Gabrielle Strobel
Phyllis, in KEEPS, what are the endpoints? Just clinical (dementia diagnosis, cognitive performance, etc.), or is there also blood and CSF work on biomarkers, Aβ/tau levels, brain imaging?

Phyllis Wise
Gabrielle, the major endpoints are cardiovascular, but some cognitive endpoints will be measured. Again, I feel a bit uncomfortable going into too much more detail until I consult with Mitch about the final design that they decided to use. There was a lot of discussion about how much could be done with the funds and the relatively small group of women.

Gabrielle Strobel
Thanks, Phyllis. There is much excitement about biomarkers in AD research these days. It would be wonderful if they could be included, but I see that money is an issue, as always.

Craig Atwood
Sam, how old are the ELITE participants?

Sam Gandy
Craig, no age is stated. Just "completed menopause" as the entry criterion.

Craig Atwood
Sam, it would be better if they had started a little earlier.

Rena Li
Our preliminary data from animal studies support early treatment rather than late.

Phyllis Wise
Rena, great confirmation of the principle that time of treatment is critical.

Craig Atwood
Rena, great.

Chris Gregory
Rena, reduced estrogen in AD brains compared to normal brains with similar serum estrogen levels (your PNAS paper) correlated nicely with our gonadotrophin-based mechanistic hypothesis of AD.

Phyllis Wise
Rena, we too have completed a preliminary study that shows that when mice are ovariectomized and then not treated for a long period, subsequent estradiol does not protect against stroke injury. With some luck, we will submit this in a couple of months. Daniel et al. (2006) show that immediate replacement in middle-aged rats improves memory but not after a long period of deprivation.

Rena Li
Phyllis, our data show that late treatment does not improve AD pathology in animal models.

Mark Smith
Rena, mechanistically, why do you think that is?

Rena Li
Because late estrogen treatment does not activate clearance of Aβ.

Sam Gandy
Rena, how did your animals parse out with respect to gender? Did males and females show the same thing?

John Breitner
But who the heck can follow immediately postmenopausal women for 30 years to observe incidence of dementia and AD? It seems to me this is one area where there is an urgent need for surrogate indicators—all caveats notwithstanding.

Peter Zandi
John, right. I wonder how a 5-year trial, assuming this is the distance, can show anything relevant, early versus late.

Craig Atwood
John, Mark Sagar has a study here in Wisconsin—the Wisconsin Registry for Alzheimer’s Prevention (WRAP) —that is doing just that. The study has recruited over 600 individuals, who must have a parent with confirmed AD. Not sure how many are on hormone replacement.

John Breitner
I know, Craig, but I'll be dead by the time the results are out.

Craig Atwood
John, I'm sorry to hear that.

Mark Smith
John, not if you take a few nonsteroidal anti-inflammatories (NSAIDS).

Nancy Emerson Lombardo
John and Mark, brain healthy nutrition and exercise will help you stay alive with no AD a lot longer than NSAIDs.

Craig Atwood
John, better still, take leuprolide. Steve Austad showed that leuprolide increased longevity in rats by 18 percent with 6 months of treatment.

Mark Smith
Craig, but a high price for John to pay?

Craig Atwood
Mark, yes, but what cost life?

Sam Gandy
John, is 30 years the real minimum number of years to have enough power to see an effect, based on the average age at onset of menopause and AD?

John Breitner
Sam, as usual, it all comes down to money and resources. The younger the cohort, the more subjects you need to achieve the number of incident cases, which is what drives power.

Gabrielle Strobel
John and Peter, this brings up a bullet point question listed in the background text: What sorts of shorter, cheaper trials can address this time factor (mid-life treatment versus late-life diagnosis)? That would be worth brainstorming about, it seems. Everyone, can animal models be employed to address this question?

John Breitner
Gabrielle, animal models are clearly a contender, but the problem is we don't know how true to life the animal models are. Most of our models focus squarely on the Aβ hypothesis. Robbie Brinton's work suggests there may be a timing interplay between Aβ and estrogen treatment, but I think I'm more intrigued with the biomarkers idea. If only we could get biomarkers for AD, such as the CD4 counts and viral load we have for HIV disease! But that would probably require that we know a lot more about root causes.

Sam Gandy
John, Pittsburgh compound B (PIB). (See ARF related news story on the use of PIB to measure Aβ plaques in the brain.)

John Breitner
Sam, yes! Possibly PIB. It's amazing also how little we know about the longitudinal trace of some of the lower-tech biomarkers in preclinical phases of AD.

Sam Gandy
Gabrielle, there are some interesting strategies to try to cut the cost of long trials by using phone screening.

Gabrielle Strobel
Pray, expand, Sam! Is testing people for inclusion/exclusion criteria a major cost factor?

Sam Gandy
Basically, versions of the various cognitive instruments are being adapted for use by phone, so that clinic visit expense is eliminated.

Gabrielle Strobel
John, very interesting. I am just putting finishing touches on a meeting report on an academic/biotech/pharma workshop on biomarkers for AD. Tony Wyss-Coray's talk on his proteomic fingerprinting test of a composite of 12 inflammation-related markers was a highlight. Small subject numbers, but it predicted with 97 percent accuracy (see ARF related news story).

Sam Gandy
John, can't some assumptions be made in order to guesstimate a plausible prediction regarding duration and reasonable cohort sizes, etc.?

John Breitner
Yes, Sam, but the results are likely to be disheartening. Especially in the present funding environment, I think animal models or especially surrogate indicators are the way to go.

Sam Gandy
John, but the FDA will want humans before giving its blessing, no?

John Breitner
Sam, almost certainly yes.

Chris Gregory
John, as imaging and biomarker analysis and genomics (proteomics and metabolomics) continue to be increasingly applied to AD research, there will hopefully be an enhanced ability to identify patients likely to progress and thus shorten the length of those trials and decrease the number of patients necessary for the trial.

Rena Li
Monitoring hormone levels is important. I know NIH is calling for small business grants to develop small medical devices for that purpose.

Robert Struble
I think, before we focus, we should emphasize Dr. Toran-Allerand's earlier statement (and it is showing up again and again). We need to understand the biology of the nervous system as it relates to hormone therapy. As we have seen, clinical intervention studies not based on good science can cause major problems.

Gabrielle Strobel
All, what would be some good biomarkers to develop to track the effect of estrogen?

John Breitner
Gabrielle, we know almost nothing about which putative AD biomarkers are sensitive to change in preclinical stages of AD pathogenesis.

Sam Gandy
All, does the complexity of hormones, coupled with the chronic nature of Alzheimer's, equate to a hopelessly complex situation?

Craig Atwood
Do high estrogen levels during pregnancy lead to high progesterone receptor (PR) levels? Or does the high progesterone suppress PR level?

Sam Gandy
What feasible model for Alzheimer's would everyone agree would be the best preclinical surrogate for human disease? Transgenic monkeys?

Mark Smith
Sam, Down syndrome (DS).

Gabrielle Strobel
Sam, is that a feasible model?

Sam Gandy
Mark, there are no cognitive norms for DS, and every DS person is slightly different. I can’t see any enthusiasm for DS.

Mark Smith
Sam, but it is the best model.

Gabrielle Strobel
Mark, can you imagine the ethical/informed consent/regulatory issues with experimenting on DS patients with compounds shown to increase the risk of cardiovascular disease?

Mark Smith
Gabrielle, complex, I agree, but no more so than testing drugs in AD patients.

Mark Smith
Has anyone looked at HRT in Down syndrome?

Sam Gandy
Nicole Schupf.

John Breitner
Sam, what does Nicole find?

Sam Gandy
Age at onset of dementia in DS correlates with menopause (see Schupf et al., 2003).

Nancy Emerson Lombardo
Mark et al., I also think Down's could be the way to go. One could select a narrowed population with particular criteria. Is there any indication the Down's research community is open to estrogen therapy? One of the leading Down's/AD researchers is here in Boston...Frances Lai (spelling?). She is leading a multinational trial, I think, with vitamin E. It is not strong enough in my opinion for a single nutritional substance to do much. I have been in touch with her about possible nutritional interventions.

John Breitner
Nancy, Down's study would be very interesting, but probably would not pass muster for clinical use because of the generalizability issue.

Nancy Emerson Lombardo
John, good point, though it might give us a quicker understanding of mechanisms that could be applied to the more usual population, and by then we might have the biomarkers to measure changes in the brain presymptomatic to AD.

John Breitner
Nancy, yes.

Gabrielle Strobel
All, has funding for estrogen-brain research dropped further in the wake of the WHI disappointment?

Craig Atwood
Sam, Gabrielle, a big yes.

Sam Gandy
Gabrielle, I can read you my pink [rejection] sheets….

Craig Atwood
It is surprising to me that in Europe, 17β-estradiol is used for HRT rather than CEEs, and most studies from Europe suggest that this form of HRT is beneficial on a number of levels. Any comments?

Sam Gandy
I agree with your sentiment, Craig.

Liqin Zhao
Yes, Craig, we believe the formulation of estrogen therapy is another very crucial factor affecting study outcomes.

Nancy Emerson Lombardo
Estradiol is what we should be using in the U.S. as well...my point that Premarin and similar mare urine-based compounds aren't human.

John Breitner
All, longitudinal biomarker data could at least guide us as to which HRT formulations to test in long-term human trials.

Liqin Zhao
From our previous in vitro studies we have found that only select estrogen components contained within the complex formulation of CEE are effective at the levels they attain in plasma.

Sam Gandy
And now there's Ellis Levin's endoplasmic reticulum estrogen receptor (ERER) as well (see Revankar et al., 2005 and Pietras et al., 2005).

Gabrielle Strobel
Sam, where does that fit in? What hypothesis does it suggest? I can't picture it....

Sam Gandy
The ERER plays a role in calcium homeostasis, which certainly could dovetail with conventional models of neurodegeneration.

Chris Gregory
Phyllis, are the brain estrogen levels (versus serum levels) more important for protective effects? Dr. Li's paper seemed to address this issue.

Phyllis Wise
Chris, Dominique's data would suggest that brain estrogen levels are important and there may be different estradiol isomers in the brain than in plasma.

Rena Li
The brain does make estrogen itself and has brain-specific aromatase (see Sasano et al., 1998).

Dominique Toran-Allerand
Regarding brain versus serum estrogen levels, we have found by mass spectrometry that the level of endogenous 17β-estradiol levels in the neocortex, hippocampus, and cerebellum are very, very low, but the levels of 17α estradiol, which does not circulate and which appears to be made in the brain, are astronomical and likely to be very important.

Gabrielle Strobel
Rena, does this brain-specific estrogen production change after menopause? Are the ovaries and the brain production coupled?

Rena Li
Gabrielle, that is not clear.

Phyllis Wise
Rena, I think that we should keep in mind that aromatase knockout mice will have higher-than-normal levels of androgens (since they cannot be converted to estradiol) and that androgens themselves may have influence. In stroke models, most investigators have found that androgens exacerbate. Christian Pike has shown that, in vitro, androgens may protect against β amyloid injury (see Pike, 2001 and Ramsden et al., 2003 for in vivo effects of androgen on amyloid-β in rodent brain).

Rena Li
Phyllis, that is true in our animals. Male animals do not develop the same degree of pathology as female aromatase knockouts.

Chris Gregory
Rena, Dominique, aren't we talking about "autocrine" estrogen signaling in the brain?

Rena Li
Chris, we really don't know. We're working on it.

Chris Gregory
Rena, have you considered that brain estrogen levels may influence brain gonadotrophin levels (e.g., LH)? We would like to have a discussion with you about this topic.

Rena Li
Chris, good point and should be further pursued, but we haven't done it yet. Let's discuss details later.

Chris Gregory
Rena, I will give you a call early next week to discuss this autocrine signaling idea.

Craig Atwood
A lot of talk about the sex steroids, but there is a Phase III trial ongoing for leuprolide acetate. Since leuprolide suppresses sex steroid production, and the Phase II results look very encouraging, i.e., no cognitive loss over 48 weeks, any thoughts/comments on other hormones that might be involved, or other mechanisms. Chris, do you wish to discuss?

Sam Gandy
Craig, I gather that those men get supplemental testosterone.

Gabrielle Strobel
Craig and Chris, good point. Can you enlighten me about the discrepant findings of leuprolide effect between your/Voyager studies and work by Sam and the Finnish study by Salminen (see Salminen et al., 2005)?

Craig Atwood
In the women’s Phase II, women did not get estrogen add-back. In a second Phase II (men only), the men are being supplemented with testosterone. This is ongoing. Results will be available mid-year, I believe.

Chris Gregory
Craig, Sam, the males in Voyager's Phase II studies are receiving supplemental testosterone (T) to maintain their T levels. We think that this is a key distinction with the Finnish study.

Mark Smith
Lupron was given based on the gonadotrophin hypothesis. Leuprolide acetate also works very, very well in Tg2576 mice (see Casadesus et al., 2006).

Chris Gregory
Mark, could you comment on the effects you see with leuprolide in Tg2576s?

Mary McAsey
Craig, in the women's Phase II study, was there an increase in depression rates in women on lupron?

Craig Atwood
Mary, not that I'm aware of. Chris?

Chris Gregory
Mary, there were no negative effects on depression in the women's study

Craig Atwood
Obviously if leuprolide suppresses sex steroids, and cognition is not declining, do we need to look elsewhere for an etiological agent that drives the disease? I should mention that those taking leuprolide were also taking acetylcholinesterase inhibitors.

Chris Gregory
Craig, as you know, leuprolide appears to maintain cognition and lower amyloid levels.

Craig Atwood
So if leuprolide lowers amyloid and maintains cognition, maybe I should go for a beer!

Phyllis Wise
Craig and Mary, were estradiol levels measured in these studies.

Craig Atwood
Yes, but as you know, leuprolide suppresses estrogen to castrate levels.

Gabrielle Strobel
Eef Hogervorst posted a comment suggesting the estrogen effect in aging women lasts 2-3 months. Any thoughts?

Sam Gandy
That sounds like a mood or attention effect.

Phyllis Wise
Gabrielle, what estrogen effects were being measured?

Mary McAsey
Gabrielle, what do you mean by "estrogen effect"?

Gabrielle Strobel
Mary, Dr. Hogervorst posted a comment on the background page to this discussion. She writes that her own trial and literature reviews show that estradiol and conjugated equine estrogens improve cognition for 2 to 3 months, not longer.

Rena Li
Anybody know about phytoestrogen trials? Are there any?

Craig Atwood
Carey Gleason at UW-Madison has some interesting phytoestrogen trials happening. Contact me if you want her details.

Sam Gandy
We have 10 minutes left and I think that all we have done is identify the problems. Anyone have any serious hope that anything truly positive will come out of all this in our lifetimes?

Mark Smith
Sam, for transgenic mice the prospects have never been better.

Sam Gandy
Oh, to be a mouse....

Nancy Emerson Lombardo
Sam, now would you really want to be a mouse? Think of all that you would be missing living in a cage or the field or my kitchen cabinets.

Sam Gandy
You mean like writing grants? Yes, I would miss that—not.

Nancy Emerson Lombardo
Sam, in the broader sense of finding out what we can do in our forties, fifties, and sixties to reduce the risk of AD and understand its true (complicated) etiology—yes, yes, yes. But it won't be just estrogen or just insulin...or just any one factor is my guess.

John Breitner
Comment for all, there are more or less two lines of chat here. One on pathophysiology and modeling, the other on development of interventions for humans and the problems faced here. I think we need to pursue both. The lab scientists can tell us more about which interventions could be used, and when, while those involved in clinical trials and human studies should be thinking about how most effectively and efficiently to test these interventions. Very good conversation!

Robert Struble
We seem to be losing focus on the important question of protecting from dementia and focusing on mechanisms. The key question is whether there is a pattern/method/whatever to use 17β-estradiol (E2) as a "neuroprotective" agent. If we find it is neuroprotective, then let's find out why. The mechanism is irrelevant at the moment when women (and men) are aging. Rodent studies show that after ovariectomization, E2 improves performance or protects from stroke, but long-term or delayed treatment loses efficacy. Why? What can we do to improve protection and can that be translated to clinical trials?

Mark Smith
Robert, you hit the nail on the head.

Sam Gandy
I guess that we can all hope that KEEPS or ELITE raises enthusiasm for continuing to hammer away.

Sam Gandy
Does anyone know when we can expect to hear updates from KEEPS or ELITE?

Phyllis Wise
Sam, I would be happy to contact Mitch and find out.

Sam Gandy
Phyllis, thanks. I would love to know. I am asked that all the time and have no idea.

Sam Gandy
I will find out about ELITE, since I now know who is the principal investigator.

Robbie Brinton
The ELITE trial is being conducted by Howard Hodis here at University of Southern California. It will be quite a while before data from ELITE trial will be available; recruitment is still in process but remarkably, the recruitment process is going well.

Gabrielle Strobel
Hi, Robbie, good to have you. All the more reason for everyone to stay and chat some more.

Sam Gandy
Robbie, how long is quite a while regarding ELITE? Five years? More?

Robbie Brinton
Sam, I would guess that the ELITE trial is 5 years (funding cycle), but I'll check with Howard. There are multiple endpoints including a supplement for cognition which is being conducted by Victor Henderson.

Sam Gandy
There is a bit of a circular problem in that the basic science funding is suffering because of the state of the clinical trial data.

Rena Li
To all, start ERT studies at younger ages. Still asking about dosage.

Phyllis Wise
Sam, absolutely. I think that a great deal more basic science research should be steered to looking at the importance of timing, preparation, and dose. Once we figure out the mechanisms of action that are involved in protective pathways, we should be able to design better selective estrogen receptor modulators (SERMS). Although it would be ideal to measure risk of AD, that may be prohibitively expensive. If we can use other endpoints that appear earlier and are good indicators (vascular plaque, diameter as in the KEEPS study), we may be able to design better clinical studies.

Rena Li
I think dosage is relevant because each individual will have a different level of estrogen due to absorption rate variability. Therefore, monitoring estrogen level in the ERT user might be very important.

Nancy Emerson Lombardo
Sam and panel, thanks for a great and informative chat.

Robbie Brinton
Dear all, our mechanistic analyses indicate that convergence of E2 action onto the mitochondria is a critical factor in regulating calcium homeostasis. Our current studies are determining the impact of E2 and progestins on mitochondrial calcium buffering capability prior to, versus following, exposure to disruptions in calcium homeostasis. The data thus far are quite interesting.

Robbie Brinton
A question to the community, determining the key biomarkers for prevention remains unanswered in my mind. Ideas?

Sam Gandy
Robbie, my answer is PIB but Mark, Craig, et al. will vomit.

Chris Gregory
Voyager looks forward to collaborating with some of the distinguished panel members. Thanks for inviting us to participate.

Craig Atwood
Thanks, Sam, for a stimulating dialogue.

Robbie Brinton
Sam, what is PIB?

Sam Gandy
The Pittsburgh B plaque burden PET imaging compound.

Chris Gregory
FYI, we think PIB might be a great tool.

Craig Atwood
PIB, great for imaging, gotta go.

Robbie Brinton
Sam, thanks!

Sam Gandy
Serial PIB scans every year after menopause -/+ ERT?

Chris Gregory
Sam, agreed, that could be a very interesting study, using PIB scans every year after menopause (-/+ ERT = +/- LH).

Nancy Emerson Lombardo
Sam, what is the going price per scan to use PIB as a biomarker in a clinical trial?

Sam Gandy
Nancy, I don't know. Outrageous, I am told, but I don’t know the figure. I gather that General Electric (GE) has the rights and has priced it out of everyone's reach. But that is gossip. I don’t know that on authority.

Sam Gandy
Chris, can we do control, ERT, and leupron arms? (Would Voyager support it?)

Chris Gregory
Sam, we'd be happy to have those conversations with you.

Sam Gandy
Chris, I look forward to it. I think that it might actually be a good experiment.

Dominique Toran-Allerand
I think we need to look more at the non-ovarian 17α-estradiol endogenous to the brain, as a potential therapeutic tool for menopause.

Sam Gandy
Dominique, are those available for clinical trials or only basic science?

Dominique Toran-Allerand
Unfortunately, I think only for basic science now.

Jon Nilsen
Sam and Dominique, 17α has been used in Phase I clinical trials (see Dykens et al., 2005).

Dominique Toran-Allerand
Jon, what dosage and how was it administered? I think it needs to be given transdermally, not orally since it does not circulate.

Jon Nilsen
Dominique, I don't know the dosage, but it was administered as sodium sulfate conjugate orally.

Robbie Brinton
Since we are talking clinical trials here, is there a mechanism in the ET community for clinical trials of PhytoSERMs?

Jimmy Barbee
In the long run, the cost of the diagnostic tools verses the cost of long-term care is definitely money well spent. Eventually, prevention is the goal of each of us.

Sam Gandy
Jimmy, I think that everyone would agree with your sentiment, except perhaps the government, which operates on 4-year cycles.

Nancy Emerson Lombardo
Jimmy, I agree, but funding limits at NIH and elsewhere don't seem to take that idea into account, especially when we are cutting costs at home to pay for things abroad.

Sam Gandy
Fiscal year 2007 is predicted to be the worst NIH budget on record, per Congressional staffers.

Mark Smith
Sam, surely you have $$$$.

Robbie Brinton
All, with news of the worst funding year, I am getting back to work. Thank you all for your thoughts and community!

Dominique Toran-Allerand
Sam, must go now. Thank you for inviting me.

Rena Li
Thank you, Sam and all.

Jimmy Barbee
The Alzheimer Disease Neuroimaging Initiative (ADNI) biomarkers arm may provide much insight into the prevention arena as will the imaging side.

Mark Smith
Last question, Sam: What is a good argument against the Voyager Phase II results?

Sam Gandy
Mark, I simply want to see a definitive trial. I agree that the data are encouraging, but the sample size (“n”) is small.

Mark Smith
Hear, hear! True, but epidemiology is 1.5 million!

Sam Gandy
Trials with small n’s (like experiments with same) are often misleading. I say the exact same thing about statins. And HRT, for that matter.

Mark Smith
One and a half million is bigger than most of my experimental n’s.

Sam Gandy
Epidemiology is not the gold standard, Mark. Epidemiology can be misleading, too. HRT is based on epidemiology.

Sam Gandy
Sufficiently powered, randomized, double-blind, placebo controlled trials are required.

Nancy Emerson Lombardo
Agreed, but as John Breitner indicated, by the time all the clinical trials and prevention trials are funded and completed, the baby boom generation will all be dead or demented. So what do we do in the meantime? We keep plugging along and doing the best we can to prove with gold standard random controlled trials, but in the meantime we have a public health crisis that needs addressing, which the Alzheimer’s Association and now the CDC are making a start with. I think we scientists need to have this on our minds as well.

Mark Smith
Definitely, it's being done.

Chris Gregory
Sam, we agree about the controlled clinical trials and that is what we are working on right now.

Sam Gandy
Yes, I know about Voyager's trials, but strictly speaking, "working on" is simply not "there." I'm not disagreeing or criticizing. I'm just withholding judgment until the data are in.

Mark Smith
Fair enough. What data does HRT have that leuprolide has to have to make it more promising?

Sam Gandy
Mark, I never said that clinical ERT had better epidemiology than leupron (though I must admit I have not seen the leupron epidemiology data).

Mark Smith
What has HRT shown that leuprolide hasn't to make HRT more promising?

Sam Gandy
Nothing.

Mark Smith
Great!

Sam Gandy
HRT is in worse shape.

Mark Smith
I agree.

Sam Gandy
The clinical trials are a bust, at least perhaps because they were done too late. If a perimenopausal HRT trial is ever done and is negative, I give up.

Mark Smith
Then, as a treatment, HRT is a bust?

Sam Gandy
Absolutely. It's prevention or nothing for HRT at this point.

Chris Gregory
Sam, as we have discussed, we are not mechanistically far apart from the discussions raised in today's forum. The well-powered trials will provide the answer, but like everyone else doing AD studies, these trials are long (at least 12 months now and in some cases 18 months). Not an excuse, just the reality that we all have to deal with.

Nancy Emerson Lombardo
Sam, but be sure the perimenopausal trials are done with the right human-like ERT and properly administered, per this discussion! If premarin were used only, then I still wouldn't necessarily believe the results.

Sam Gandy
Nancy, I agree that the issues of cycling, preparation, progestins, etc., are all issues that must be accounted for and optimized.

Sam Gandy
It makes more sense to me to "prevent" the acute hormone withdrawal than to allow the body to re-equilibrate for 20 years and then try to go in and get anywhere.

Mark Smith
But as John said, prevention is very expensive and fraught with its own problems (as John can equally attest!).

Sam Gandy
Mark, that's why these phone instruments are being developed, to cut the cost of prevention trials. Just because it's hard doesn’t mean we shouldn’t try....

Nancy Emerson Lombardo
Sam, I totally agree. By the way probably the correct administration of a phytoestrogen or phytoHRT would be transdermally; that would also prevent the heart problems according to the HRT specialists I follow. They predicted the WHI MS trial would fail and that premarin creates heart/stroke problems.

Sam Gandy
Phytoestrogens are another variable in the queue as far as I am aware.

Mark Smith
Sam, lets do beer in Madrid to discuss further. Adios.

Sam Gandy
I'll have espresso, but sure (alcohol gives me migraines).

Mark Smith
Okay, my treat.

Nancy Emerson Lombardo
Yes, beer and red Spanish wine in Madrid. Here we come...I know an Irish guy that owns a great pub in Madrid that I am eager to check out.

Sam Gandy
Okay, now I think that we are really winding down. Thank you all very much. I am taking off now, too.