The Cochrane collaboration has weighed in that hormone therapy is not expected to be favorable for cognition. I do use it as part of the Bredesen protocol, and I understand that any intervention on its own is often shown to be useless, but all of them together have helped a good number of people, but I am intrigued enough to look up the most recent research. In particular for apoE4, where some evidence would make one concerned that it has opposite effects (not the glucose utilization, but the final outcome in rodents and in some human studies).
So if you have recent articles, please point them out, but so far, it's a negative on the following, specifically for estradiol (I didn't find any studies of BiEst):
Cochrane Database Syst Rev. 2017
Long-term hormone therapy for perimenopausal and postmenopausal women.
Marjoribanks J, et al.
PLoS Med. 2015 Jun; 12(6): e1001833.
Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS–Cognitive and Affective Study
Carey E. Gleason et al.
Neurology. 2016 Aug 16;87(7):699-708.
Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis.
Henderson VW et al.
Neurobiol Aging. 2008 Dec; 29(12): 1783–1794.
The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol
Brown CM et al (this one doesn't really say how it would work out clinically).
Hormone Replacement Therapy E4 Women
Re: Hormone Replacement Therapy E4 Women
Thanks for posting this. It's a bit concerning, but I'm guessing all the studies used synthetic hormones. All we have to do is consider all the ways our apoe4 misshapen proteins screw things up to surmise that the non-bioidentical hormones wouldn't behave naturally either. I'd like to see some good studies using bioidentical hormones and cognition outcomes.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
Re: Hormone Replacement Therapy E4 Women
Type matters with regards to using bio-identical versus CEE. A 2014 study looking at women for high risk of dementia found, “Our results suggest that CEE does not confer the same benefits as 17β-E either in terms of metabolism or cognition. In fact, we previously reported that at baseline women taking 17β-E performed 3 standard deviations higher in verbal memory than women taking CEE, and their verbal memory performance positively correlated with metabolism in Wernicke's area…” This study also confirmed prior findings that HT increases blood flow and brain metabolism. The median level of estrogen in their HT group was 36 pg/mL so you don't need to go that high.
Prospective Randomized Trial to Assess Effects of Continuing Hormone Therapy on Cerebral Function in Postmenopausal Women at Risk for Dementia (2014)
http://journals.plos.org/plosone/articl ... ne.0089095
Prospective Randomized Trial to Assess Effects of Continuing Hormone Therapy on Cerebral Function in Postmenopausal Women at Risk for Dementia (2014)
http://journals.plos.org/plosone/articl ... ne.0089095
Re: Hormone Replacement Therapy E4 Women
No, I was very careful in my reviews. These are using bioidentical estradiol. The KEEPS study is transdermal.
There are certainly no studies of BiEst, which is in large part estriol, which really interferes with its ability to stimulate the estradiol receptor in the brain.
The brain makes its own estradiol, we should figure out what goes on after menopause. I think it works really, really well for some people, and should be tried in most cases.
The levels will be important too. Susanj's study is interesting but I really would like endpoint studies - it's been frustrating that the basic science and biomarkers and imaging all look better but the women overall aren't. Does that mean some get worse, and balance out the ones we know get better (for having observed it)?
There are certainly no studies of BiEst, which is in large part estriol, which really interferes with its ability to stimulate the estradiol receptor in the brain.
The brain makes its own estradiol, we should figure out what goes on after menopause. I think it works really, really well for some people, and should be tried in most cases.
The levels will be important too. Susanj's study is interesting but I really would like endpoint studies - it's been frustrating that the basic science and biomarkers and imaging all look better but the women overall aren't. Does that mean some get worse, and balance out the ones we know get better (for having observed it)?
Re: Hormone Replacement Therapy E4 Women
Thank you for posting! Need to make this decision by Monday at least for the short term as I am seeing the naturopathic doc. I was leaning toward transdermal estradiol. I am not having any symptoms and am 5 years post menopause (that happened at age 47). That and the fact that migraines stopped after menopause , combined with seeing all of this research, makes me lean away from messing with it.
I have also read much of what is posted in favor. Confusing!
I now have the ketoflex diet under control and have begun testing, enrolled in Recode, added omega 3's and a few other supplements. Unsure of next steps, but maybe more testing!
I have also read much of what is posted in favor. Confusing!
I now have the ketoflex diet under control and have begun testing, enrolled in Recode, added omega 3's and a few other supplements. Unsure of next steps, but maybe more testing!
Re: Hormone Replacement Therapy E4 Women
Isn't detecting PET scan changes in high-risk women (E4, FH or major depression) a good endpoint? For me, the study points towards benefits with estradiol and as low a dose of progesterone as you can use. But certainly, we need more studies using these scans as this one did have technical problems on their scan follow-ups.
Re: Hormone Replacement Therapy E4 Women
I’m flying home today after two day symposium in CA and just happened to run into Dr. Bredesen’s hormone replacement expert, Dr. Ann Hathaway, yesterday and asked her opinion of the Cochrane report. She scoffed and noted (as Circ has already mentioned,) the majority of studies are not using bHRT. She cautions against making conclusions without teasing out the difference between synthetic and bHRT. I’m not sure if you’ve seen it yet, myrtoache, but you may want to take the time to check out a Power Point that she’s previously shared with us examining the evidence re HRT and Cognition in which she carefully teases out that detail plus many other nuances.
While KEEPS did utilize bHRT in one arm, the database consisted of women with an average of age 52 and the intervention only lasted 4 years. My guess is that we’d need to see a much longer intervention to see how the various interventions play out with regard to cognition. Dr. Hathaway mentioned that despite that flaw, KEEPS was helpful in that it demonstrated no increase in breast cancer or CAD using bHRT.
Re. E4, I think the most compelling evidence still comes from this old chestnut:
Accelerated Cell Aging in Female APOE-ε4 Carriers: Implications for Hormone Therapy Use
http://journals.plos.org/plosone/articl ... ne.0054713
Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery
http://journals.plos.org/plosone/articl ... ne.0185926
While KEEPS did utilize bHRT in one arm, the database consisted of women with an average of age 52 and the intervention only lasted 4 years. My guess is that we’d need to see a much longer intervention to see how the various interventions play out with regard to cognition. Dr. Hathaway mentioned that despite that flaw, KEEPS was helpful in that it demonstrated no increase in breast cancer or CAD using bHRT.
Re. E4, I think the most compelling evidence still comes from this old chestnut:
Accelerated Cell Aging in Female APOE-ε4 Carriers: Implications for Hormone Therapy Use
http://journals.plos.org/plosone/articl ... ne.0054713
Additionally, this very recent study beautifully demonstrates the reduction in cerebral glucose utilization (early symptom of Alzheimer’s) that accompanies menopause. You’ll recall that E4 carriers already show a deficit in this area as early as age 20.Abstract
Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-ε4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N = 63, Mean age = 57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N = 32) remained on their HT regimen and half (N = 31) went off HT for approximately two years (Mean = 1.93 years). Participants included 24 APOE-ε4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR = 6.26, 95% CI = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-ε4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-ε4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.
Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery
http://journals.plos.org/plosone/articl ... ne.0185926
Abstract
After advanced age, female sex is the major risk factor for Alzheimer’s disease (AD). The biological mechanisms underlying the increased AD risk in women remain largely undetermined. Preclinical studies identified the perimenopause to menopause transition, a neuroendocrine transition state unique to the female, as a sex-specific risk factor for AD. In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency which is sustained thereafter. This study bridges basic to clinical science to characterize brain bioenergetics in a cohort of forty-three, 40–60 year-old clinically and cognitively normal women at different endocrine transition stages including premenopause (controls, CNT, n = 15), perimenopause (PERI, n = 14) and postmenopause (MENO, n = 14). All participants received clinical, laboratory and neuropsychological examinations, 18F-fluoro-deoxyglucose (FDG)-Positron Emission Tomography (PET) FDG-PET scans to estimate CMRglc, and platelet mitochondrial cytochrome oxidase (COX) activity measures. Statistical parametric mapping and multiple regression models were used to examine clinical, CMRglc and COX data across groups. As expected, the MENO group was older than PERI and controls. Groups were otherwise comparable for clinical measures and distribution of APOE4 genotype. Both MENO and PERI groups exhibited reduced CMRglc in AD-vulnerable regions which was correlated with decline in mitochondrial COX activity compared to CNT (p’s<0.001). A gradient in biomarker abnormalities was most pronounced in MENO, intermediate in PERI, and lowest in CNT (p<0.001). Biomarkers correlated with immediate and delayed memory scores (Pearson’s 0.26≤r≤0.32, p≤0.05). These findings validate earlier preclinical findings and indicate emergence of bioenergetic deficits in perimenopausal and postmenopausal women, suggesting that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.
Re: Hormone Replacement Therapy E4 Women
How amazing that you happen to run in to Ann Hathaway today!
Another fact on the positive side from the KEEPS study:
"The KEEPS trial included 662 women with an average age of 52.6 years. It found that neither type of hormone benefited cognitive function [6], though in women who carried the APOE4 gene, bioidentical hormones were associated with lower levels of beta-amyloid plaques (i.e., a hallmark of Alzheimer's) in the brain compared with synthetic hormones or placebo"
Sorry if this was already mentioned.
Another fact on the positive side from the KEEPS study:
"The KEEPS trial included 662 women with an average age of 52.6 years. It found that neither type of hormone benefited cognitive function [6], though in women who carried the APOE4 gene, bioidentical hormones were associated with lower levels of beta-amyloid plaques (i.e., a hallmark of Alzheimer's) in the brain compared with synthetic hormones or placebo"
Sorry if this was already mentioned.
Re: Hormone Replacement Therapy E4 Women
I only had time to look at the Cochrane study, but I think I will dismiss their findings for now, ( I don't think they used bioidentical estrogen / progesterone) look at where they got most of their data from:
We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well-conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women.
We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well-conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women.
Re: Hormone Replacement Therapy E4 Women
Lulu, you're developing a sharp eye for detail. That is a terrific skill.
mrc cfnc fmchc
IFM/Bredesen Reversing Cognitive Decline training 2017
E2/E2
What is, is. What is, can be changed.
IFM/Bredesen Reversing Cognitive Decline training 2017
E2/E2
What is, is. What is, can be changed.