Introduction

You may think the Women’s Health Study has sounded the death knell for estrogen replacement therapy, but actually, the idea is showing new signs of life. A second-generation approach with better compounds may warrant continued investment, and yet, how does one pull that off in the face of a seemingly definitive trial failure? Sam Gandy led a panel discussion featuring Phyllis Wise, Dominique Toran-Allerand, Kristine Yaffe, Rena Li, John Breitner, and Peter Zandi on the dilemmas and opportunities of hormone replacement in the treatment of age-related dementia.

Sam Gandy, with John Breitner, Rena Li, Dominique Toran-Allerand, Phyllis Wise, Kristine Yaffe, and Peter Zandi, led this live discussion on 9 March 2006. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:
Participants: Gabrielle Strobel (Alzheimer Research Forum), Mark Smith (Case Western Reserve University), Sam Gandy (Farber Institute, Philadelphia), John Breitner (Seattle VA and University of Washington, Seattle), Phyllis Wise (University of Washington), Dominique Toran-Allerand (Columbia University), Jon Nilsen (University of Southern California), Craig Atwood (Department of Medicine, University of Wisconsin, Madison), Chris Gregory (Voyager Pharmaceutical Corporation), Lucie Arbuthnot (Preventing Alzheimer's Disease writer/speaker), Austin Yang (University of Southern California), Larry Tusick (Voyager Pharmaceutical Corporation), Mark Reger (Madigan Army Medical Center, University of Washington), Rena Li (Sun Health Research Institute, Arizona), Tzu-wei Wu (University of Southern California), Seth Shaw (Investor and consultant), Mary McAsey (Southern Illinois University School of Medicine, Springfield), Steve Hamm (Voyager Pharmaceutical Corporation), Robbie Brinton (University of Southern California), Eric Werdin (Voyager Pharmaceutical Corporation), Masha Kononova (Voyager Pharmaceutical Corporation), Carol Giamario (Voyager Pharmaceutical Corporation), Jimmy Barbee (Voyager Pharmaceutical Corporation), Steve Fiander (Voyager Pharmaceutical Corporation), Robert Struble (SIU School of Medicine AD Center), Peter Zandi (Johns Hopkins Bloomberg School of Public Health), Alix Bennett (Forest Research Institute), Liqin Zhao (University of Southern California), Brian Reynolds (Voyager Pharmaceutical Corporation), Nancy Emerson Lombardo (Boston University School of Medicine), Tim Richardson (Medicinal Chemist, Eli Lilly).

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 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.

Background

Background Text

The story of hormone replacement therapy (HRT) in Alzheimer disease treatment is a long and frustrating one. Many epidemiological studies indicate that HRT cuts the risk of developing the disease by half (e.g., Tang et al., 1996, for a meta-analysis see Yaffe et al., 1998). Together with experimental studies suggesting a biological rationale for estrogen’s effects on the aging brain, that epidemiological data led to treatment trials. However, beginning HRT at age 65 proved not to prevent dementia (Shumaker et al., 2004), and treatment of established dementia does not slow its progression (Mulnard et al., 2000). The recently uncovered cardiovascular risks of HRT (Anderson et al., 2004), further added to a constellation of setbacks that has relegated HRT to the "back burner" in much of the Alzheimer universe. Today, newer approaches ranging from vaccines to secretase inhibitors and neuroprotectives are receiving most of the attention.

Even so, one could argue that it is premature to dismiss estrogen replacement just yet. What follows is a snapshot of some of the recent research that should keep the field engaged. For one thing, consider this nagging issue: The epidemiological data (e.g., Zandi et al., 2002) strongly suggests that HRT has its greatest protective benefit when initiated at the time of menopause, not 15 yrs later, which is the only HRT/Alzheimer's protection paradigm to have been tested so far. Hence, estrogen deficiency may join the growing group of health factors that, when present in midlife, increase the risk for dementia later on (e.g., Kivipelto et al., 2005).

The notion that effective prevention must begin in the 40s or 50s in order to delay or prevent dementia 20 to 30 years later presents a staggering challenge for anyone seeking to prove this principle via the gold standard of randomized, placebo-controlled, prospective clinical trials. This hurdle has virtually stopped clinical HRT research dead in its tracks. How can government or industry commit to such a trial in the face of negative reports and adverse effects? The sole investment currently comes from billionaire John Sperling, founder of both the University of Phoenix Online and the Kronos Institute, who privately supports an ongoing 5-year trial of perimenopausal HRT in 720 women for Alzheimer disease prevention. Few data will emerge until this trial (known by the acronym KEEPS, for Kronos Early Estrogen Prevention Study) is complete around the year 2010.

Meanwhile, three new academic studies have associated estrogen or its derivatives with cognitive status and neuropathology. Kristine Yaffe and colleagues at the University of California, San Francisco, studied the cognitive outcome of over 5,000 women in a trial of the selective estrogen receptor modulator (SERM) raloxifene as a treatment for osteoporosis among post-menopausal women (Yaffe et al., 2005). After three years, women taking raloxifene at 120 mg/day had a reduction in risk for either mild cognitive impairment (relative risk = 0.67) or Alzheimer disease (relative risk = 0.52), suggesting that compounds other than estrogen itself may yet prove useful.

Clinical studies on sex hormone deprivation in men are also instructive in considering hormone therapies for neurodegenerative diseases. Androgen deprivation is used to treat prostate cancer because testosterone can drive tumor growth, but the effects of this therapy on cognition are poorly understood. This month in the Journal of Urology, Tomasz Beer of Oregon Health and Science University, Portland, reported a small, 1-month study of prostate cancer patients, in which men on androgen deprivation therapy scored worse on verbal memory tests than did men who also received estradiol patches or a third group who were not on androgen deprivation (J Urol 2006;175:130-135, not in PubMed yet.) And a larger clinical study also focused on cognitive function in estrogen-deficient men. Eeva Salminen and colleagues at the University of Turku, Finland, reported cognitive decline in men with prostate cancer who were undergoing hormone suppression with flutamide and leuprolide (Salminen et al., 2005).

These two studies echo, in men, the connection between cancer, estrogen, and cognition known for aging women, but beyond that, the second one is especially interesting for two reasons. First, flutamide and leuprolide have been previously implicated as potential causes for an elevation in circulating Aβ peptide (Gandy et al., 2001). Second, the North Carolina-based pharmaceutical firm Voyager is currently recruiting people with mild-to-moderate AD into a Phase III trial (known as ALADDIN, for Antigonadotropin Leuprolide in Alzheimer’s Disease Drug INvestigation), of a form of leuprolide acetate, one of the compounds implicated in causing cognitive decline in the Finnish study. Leuprolide reduces luteinizing hormone release from the pituitary gland. Richard Bowen is the founder of Voyager and, with his colleagues, bases this approach on evidence that leuprolide lowers the level of endogenous Aβ in the brains of wildtype mice (Bowen et al., 2004; for more detail, see ARF related conference story). The fact that the Alzheimer literature supports the contradictory possibilities that leuprolide is both pro-amyloidogenic and anti-amyloidogenic illustrates how far we have to go in unraveling the relationship between gonadal hormones and dementia.

A separate study sheds further light on the link between estrogen and amyloid in mice. Last month in PNAS, Rena Li and colleagues at Sun Health Research Institute in Sun City, Arizona, crossed the Novartis APP23 plaque-forming mice with another strain from which the aromatase (Ar) gene had been deleted (Yue et al., 2005.) Aromatase is responsible for converting testosterone to estrogen, so these mice are unable to synthesize any estrogen at all. The APP23 x Ar-/- mice developed cerebral amyloid pathology quite prematurely, with plaque load in the 6-month-old crossed mice dramatically exceeding that exhibited by standard APP23 mice at 12 months of age. Eventually, however, the plaque densities were identical in the wildtype and Ar-/- mice, indicating that estrogen status apparently controlled age of onset. This would be consistent with the notion that estrogen given early might delay or prevent Alzheimer's but have no effect when given late. Studies from the tissues of these mice implicated both excess generation of Aβ by BACE and impaired Aβ clearance as potential explanations for the elevation in Aβ levels in the absence of estrogen.

Furthermore, the molecular biology of estrogen signal transduction continues to surprise. Dominique Toran-Allerand at Columbia University in New York, and Eric Prossnitz at the University of New Mexico have reported advances in characterizing membrane-bound estrogen receptors (ERs; Toran-Allerand et al., 2002, Revankar et al., 2005). Toran-Allerand’s new pathway begins with a non-ERα, non-ERβ protein, dubbed “ER-X”, that is located at the plasma membrane and coupled to MAPK/ERK where it signals through the neuroprotective phosphatidylinositol 3-kinase-Akt pathway. The molecule described by Revankar et al. is quite different: Unexpectedly, their molecule turned out to be an orphan G-protein-coupled receptor localized to the endoplasmic reticulum and playing a role in controlling calcium flux. More recently, Toran-Allerand et al. (2005) have identified the ligand of ER-X as the 17α isomer of estradiol. They hypothesize that it is synthesized not in the gonads but locally in the brain, where they believe it functions independently of the classical hormone/receptor endocrine system. This is a controversial finding. Scientists generally believe the brain does not synthesize estrogen, and 17α-estradiol is held by conventional wisdom to lack neuroactivity and neuroprotective properties. Indeed, this compound is routinely applied to signaling experiments as a competitive inhibitor of signaling across a typical estrogen receptor in order to establish that the signal under study indeed utilizes the standard estrogen receptor, so, heretofore, 17α has served as a negative control.

The continuing discovery of estrogenic pathways suggests that we may still be at the “tip of the iceberg” in elucidating estrogen physiology. Clearly, if we are to understand the pleiotropic actions of estrogens in the brain, in bone, and in other tissues, we must develop a comprehensive knowledge base of all of estrogen’s receptors, as well as their signaling pathways and downstream effectors.

Midlife lifestyle factors, including estrogen, are gaining more and more attention (see the "Maintain Your Brain" campaign by the Alzheimer’s Association). We must develop strategies for evaluating these factors rigorously so that we can strengthen their scientific underpinning and justify the inclusion of lifestyle factor management in practice parameters developed by the major professional associations (see related ARF Live Discussion). As other SERMs are developed, the industrial sector will perform more studies such as that of Yaffe et al., in which cognitive decline is either a primary or secondary endpoint. KEEPS may well be a watershed study, either reinvigorating the notion that HRT might prevent AD or else excluding a role for HRT once and for all.

I suggest the following questions for discussion:

• How can midlife risk factors, including estrogen decline, be tested short of financing large prospective trials?
• What sorts of less-expensive pilot trials could give useful information?
• Do we know enough about brain-specific estrogen signaling to devise more specific SERMs?
• What targets other than the gonadal hormones themselves are attractive?
• While KEEPS is ongoing, what animal and cell-based studies could provide the necessary research base for next-generation therapies?
• Which resources could be mined to obtain comprehensive data about human estrogen ligands, receptors, and pathways?
• Should the AD field shrug off the discouraging findings of the Women’s Health Study results and keep investigating estrogen pathways? Early cytokine and NMDA receptor antagonist trials failed, yet these molecules still hold promise. Or better to cut losses and focus on new approaches altogether?

References:
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O'Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12. Abstract

Bowen RL, Verdile G, Liu T, Parlow AF, Perry G, Smith MA, Martins RN, Atwood CS. Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition. J Biol Chem. 2004 May 7;279(19):20539-45. Abstract

Gandy S, Almeida OP, Fonte J, Lim D, Waterrus A, Spry N, Flicker L, Martins RN. Chemical andropause and amyloid-beta peptide. JAMA. 2001 May 2;285(17):2195-6. Abstract

Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005 Oct;62(10):1556-60. Abstract

Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thal LJ. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. 2000 Feb 23;283(8):1007-15. Erratum in: JAMA 2000 Nov 22-29;284(20):2597. Abstract

Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005 Mar 11;307(5715):1625-30. Abstract

Salminen EK, Portin RI, Koskinen AI, Helenius HY, Nurmi MJ. Estradiol and cognition during androgen deprivation in men with prostate carcinoma. Cancer. 2005 Apr 1;103(7):1381-7. Abstract

Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH; Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2947-58. Abstract

Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet. 1996 Aug 17;348(9025):429-32. Abstract

Toran-Allerand CD, Guan X, MacLusky NJ, Horvath TL, Diano S, Singh M, Connolly ES Jr, Nethrapalli IS, Tinnikov AA. ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J Neurosci. 2002 Oct 1;22(19):8391-401. Abstract

Toran-Allerand CD, Tinnikov AA, Singh RJ, Nethrapalli IS. 17alpha-estradiol: A brain active estrogen? Endocrinology. 2005. Sep;146(9):3843-50, doi:10.1210/en.2004-1616. Abstract

Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA. 1998 Mar 4;279(9):688-95. Abstract

Yaffe K, Krueger K, Cummings SR, Blackwell T, Henderson VW, Sarkar S, Ensrud K, Grady D. Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry. 2005 Apr;162(4):683-90. Abstract

Yue X, Lu M, Lancaster T, Cao P, Honda S-I, Staufenbiel M, Shen Y, Li R. Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's animal model. Proc Natl Acad Sci U S A. 2005 Dec 27 ; 102(52):19198-203. Abstract

Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JC; Cache County Memory Study Investigators. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002 Nov 6;288(17):2123-9. Abstract

Comments

1. • Eef Hogervorst
     Loughborough University
   • Posted: 03 Feb 2006

   On the basis of our own clinical trial, and the literature reviews and meta-analyses that we have carried out, I think that estrogens, both estradiol and conjugated equine estrogens, may improve cognition, but only for a limited period of 2-3 months, after which effects plateau and then may even reverse (after >1 year). Effects seem to be strongest in women with menopausal symptoms and on verbal memory functions.

   However, several studies (which held up in the rigorous Cochrane meta-analyses that I did in collaboration with Kristine Yaffe and Felicia Huppert) have also found effects in women with dementia, effects which again could not be maintained for longer than 2-3 months. This indicates that the "window of opportunity theory" may not necessarily be true. It may well be that the short-lived effects of estrogens are due to treatment regimen effects. Dr. Farook Al Azzawi and I would like to collaborate with other clinical centers to set up a controlled trial to test our alternative regimens in a long-term treatment trial (2 years).

   See also:

   Hogervorst, E. The short-lived effect of HRT on cognition function (2006) In N Rasgon. Estrogen's effects on brain function. What's next?

   References:

   Hogervorst E, Yaffe K, Richards M, Huppert FA. Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Database Syst Rev. 2009;(1):CD003799. PubMed.

   Hogervorst E, Yaffe K, Richards M, Huppert F. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev. 2002;(3):CD003122. PubMed.

   Hogervorst E, Smith AD. The interaction of serum folate and estradiol levels in Alzheimer's disease. Neuro Endocrinol Lett. 2002 Apr;23(2):155-60. PubMed.

   Hogervorst E, Bandelow S, Moffat SD. Increasing testosterone levels and effects on cognitive functions in elderly men and women: a review. Curr Drug Targets CNS Neurol Disord. 2005 Oct;4(5):531-40. PubMed.

   Hogervorst E, De Jager C, Budge M, Smith AD. Serum levels of estradiol and testosterone and performance in different cognitive domains in healthy elderly men and women. Psychoneuroendocrinology. 2004 Apr;29(3):405-21. PubMed.

   Hogervorst E, Williams J, Combrinck M, David Smith A. Measuring serum oestradiol in women with Alzheimer's disease: the importance of the sensitivity of the assay method. Eur J Endocrinol. 2003 Jan;148(1):67-72. PubMed.

   Hogervorst E, Lehmann DJ, Warden DR, McBroom J, Smith AD. Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer's disease in men. Int J Geriatr Psychiatry. 2002 Oct;17(10):938-40. PubMed.

   Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience. 2000;101(3):485-512. PubMed.

   View all comments by Eef Hogervorst

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References

News Citations

1. Ocean Waves Stimulate Brain Waves: Meeting Report from Caribbean 22 Nov 2002
2. Sorrento: They’ve Just Got to Have It—Where’s That Biomarker? Part 2 23 Mar 2005
3. Translational Biomarkers in Alzheimer Disease Research, Part 1 20 Feb 2006

Webinar Citations

1. Reducing the Risk of Alzheimer Disease 23 Dec 2005
2. Not Dead Yet: Estrogen Deserves Another Chance 28 Jan 2006

Paper Citations

1. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O'Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, . Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12. PubMed.
2. Bowen RL, Verdile G, Liu T, Parlow AF, Perry G, Smith MA, Martins RN, Atwood CS. Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition. J Biol Chem. 2004 May 7;279(19):20539-45. PubMed.
4. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005 Oct;62(10):1556-60. PubMed.
5. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thal LJ. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. 2000 Feb 23;283(8):1007-15. PubMed.
6. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005 Mar 11;307(5715):1625-30. PubMed.
7. Salminen EK, Portin RI, Koskinen AI, Helenius HY, Nurmi MJ. Estradiol and cognition during androgen deprivation in men with prostate carcinoma. Cancer. 2005 Apr 1;103(7):1381-7. PubMed.
8. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH, Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2947-58. PubMed.
9. Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet. 1996 Aug 17;348(9025):429-32. PubMed.
10. Toran-Allerand CD, Guan X, Maclusky NJ, Horvath TL, Diano S, Singh M, Connolly ES, Nethrapalli IS, Tinnikov AA. ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J Neurosci. 2002 Oct 1;22(19):8391-401. PubMed.
11. Toran-Allerand CD, Tinnikov AA, Singh RJ, Nethrapalli IS. 17alpha-estradiol: a brain-active estrogen?. Endocrinology. 2005 Sep;146(9):3843-50. PubMed.
12. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA. 1998 Mar 4;279(9):688-95. PubMed.
13. Yaffe K, Krueger K, Cummings SR, Blackwell T, Henderson VW, Sarkar S, Ensrud K, Grady D. Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry. 2005 Apr;162(4):683-90. PubMed.
14. Yue X, Lu M, Lancaster T, Cao P, Honda S, Staufenbiel M, Harada N, Zhong Z, Shen Y, Li R. Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model. Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19198-203. PubMed.
15. Daniel JM, Hulst JL, Berbling JL. Estradiol replacement enhances working memory in middle-aged rats when initiated immediately after ovariectomy but not after a long-term period of ovarian hormone deprivation. Endocrinology. 2006 Jan;147(1):607-14. PubMed.
16. Schupf N, Pang D, Patel BN, Silverman W, Schubert R, Lai F, Kline JK, Stern Y, Ferin M, Tycko B, Mayeux R. Onset of dementia is associated with age at menopause in women with Down's syndrome. Ann Neurol. 2003 Oct;54(4):433-8. PubMed.
17. Pietras RJ, Levin ER, Szego CM. Estrogen receptors and cell signaling. Science. 2005 Oct 7;310(5745):51-3; author reply 51-3. PubMed.
18. Sasano H, Takashashi K, Satoh F, Nagura H, Harada N. Aromatase in the human central nervous system. Clin Endocrinol (Oxf). 1998 Mar;48(3):325-9. PubMed.
19. Pike CJ. Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons. Brain Res. 2001 Nov 16;919(1):160-5. PubMed.
20. Ramsden M, Nyborg AC, Murphy MP, Chang L, Stanczyk FZ, Golde TE, Pike CJ. Androgens modulate beta-amyloid levels in male rat brain. J Neurochem. 2003 Nov;87(4):1052-5. PubMed.
21. Casadesus G, Webber KM, Atwood CS, Pappolla MA, Perry G, Bowen RL, Smith MA. Luteinizing hormone modulates cognition and amyloid-beta deposition in Alzheimer APP transgenic mice. Biochim Biophys Acta. 2006 Apr;1762(4):447-52. PubMed.
22. Dykens JA, Moos WH, Howell N. Development of 17alpha-estradiol as a neuroprotective therapeutic agent: rationale and results from a phase I clinical study. Ann N Y Acad Sci. 2005 Jun;1052:116-35. PubMed.

Other Citations

1. KEEPS

External Citations

1. Alzheimer’s Association
2. NIH website
3. WHIMS
4. clinical trials.gov
5. clinical trials.gov
6. Wisconsin Registry for Alzheimer’s Prevention
7. Alzheimer Disease Neuroimaging Initiative

Further Reading