Hormone Replacement Therapy E4 Women

[Stavia]

"Seed rotation": I'm not sure of the validity of this - the dose of each co-factor would be tiny, I can't see how it could make a significant impact.
Not to say that nuts and seeds are not useful for general nutrition in terms of omegas and co-factors and etc.
Has anyone got any scientific studies that support this as a valid option, or is it anecdotal?
I see it is the opinion of a nutritionist and blogger
https://www.hormonesbalance.com/about/

[Orangeblossom]

I am starting to wonder if HRT is a good thing or not for E4s. I would like to take it for osteoporosis risk though. have a look at this paper, not sure if any of this has been discussed in the past but it is concerning, any thoughts? I know there are issues with the WHI study but the other one, was a bit concerning to me. Has anything since then come out to change this view?

Apolipoprotein E, Gender, and Alzheimer’s Disease: An Overlooked, but Potent and Promising Interaction (2014)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282773/

"There is a wide literature exploring the relationship between estrogen and cognitive decline (Henderson, 2009). The results, however, are mixed. The Women’s Health Initiative Memory famously determined that hormone replacement therapy (HRT), at least when initiated post-menopause, is associated with increased, not decreased, rates of dementia (Coker et al., 2010). However, the study did not explicitly examine the interaction’s relationship with hormone replacement therapy, and the studies that have examined that interaction complicate the picture. Yaffe et al. for instance found that estrogen use is associated with less cognitive decline in APOE4 negative healthy older women than in women who are APOE4 carriers (Yaffe, Haan, Byers, Tangen, & Kuller, 2000). Subsequently, Kang et al, in a large and longitudinal study of 16,514 nurses, showed similarly that the fastest rates of cognitive decline were registered by APOE4 carriers who were HRT users (Kang & Grodstein, 2012). These studies together suggest that the jury is still out on the relationship between HRT and cognitive decline, that this relationship may be more subtle than initially suggested, and that the interaction of APOE4 and AD may be crucial to understanding it."

However when I looked into the latter study, I noticed that

"The large majority (74%) of current hormone users used estrogen alone. Of those currently using estrogen, 71% was oral conjugated estrogen, 7% oral estradiol, 5% oral piperazine estrone sulfate, 4% transdermal estrogen, and the remaining 12% various other estrogens."

I think that means they were mainly using Premarin, or horse equine, and that may have affected things https://en.wikipedia.org/wiki/Conjugated_estrogens

Apologies if this has been discussed in the past. Just wanted to check it out, as found it a bit concerning. Have there been other studies since showing any benefit to E4s from other oestrogens I wonder.

This one about the telomeres was fascinating and more positive. https://www.alzforum.org/news/research- ... tive-cells

[slacker]

I am starting to wonder if HRT is a good thing or not for E4s.

It's very hard to tell if a particular paper has been discussed here previously! Stavia's hormone replacement section of the primer has an excellent summary, and also points the reader to other threads, a video, and power point presentation. It's a lot to digest, and also incredibly thorough.

In general, many meta-analyses (reviews that combine the results of many studies to get larger sample sizes) on hormone replacement do not differentiate between types of estrogen or progesterone. The majority of meds used for hormone replacement are not bioidentical (at least in the US). And most of the estradiol used is oral, which has been shown to have greater risks than topical estradiol. So these meta analyses are not all that helpful. You have to read the fine print.

If and when to start bHRT is a tough call, and must be made on an individual basis, including a discussion with a knowledgeable medical provider.

[SusanJ]

The type of hormonal preparation does matter 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.

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

[Orangeblossom]

As time goes on and people use less Premarin and more of the other types maybe we will get more of an idea. I've got a few years to go yet to needing it. I suppose with regard to what to do now the other types look a better bet, and in low amounts, as people are doing on here. And yes monitoring for how you feel on it and with the guidance of a doctor is best.

[Orangeblossom]

The type of hormonal preparation does matter 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.

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

Useful study. From reading that it seems definitely to be a good idea- but the right kind, and starting at the menopause. I noticed it also said

"Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins (with either 17βE or CEE)."

But we need them don't we to prevent womb cancer (I think) wonder if any way round that. Could it be about synthetic ones or a certain type perhaps. Is it possible to just take small amounts of estradiol without progesterone long term I wonder? I notice with the NHS guide here https://www.gwh.nhs.uk/media/163808/wil ... e_2014.pdf it says about low amounts and oestrogen only in the over 60s...

Think when the time comes I'm going to take that study and share with the GPs and try and stay on it then..

[Orangeblossom]

This is interesting. I read oestrogen can up-regulate and increase levels of APOE, and then I saw this paper.

http://bmjopen.bmj.com/content/3/9/e003200

Oestrogen receptor polymorphisms are an associated risk factor for mild cognitive impairment and Alzheimer disease in women APOE ɛ4 carriers: a case–control study

"The less represented alleles of SNPs studied are associated with MCIa and AD in APOE*E4 carriers. In particular, the genetic profile created with the less represented alleles of ESR1 and ESR2 SNPs are associated with an increased risk for MCIa and AD in women APOEɛ4 allele carriers."

"...an interaction with ApoE. Estradiol increased ApoE levels and neurite outgrowth.."

Ok, so presumably these polymorphisms meant less oestrogen expression and that linked in with APOE4 to mean more cognitive impairment. Which would tie in with the idea that increasing oestrogen might help...I think! (not sure on what the polymorphisms mean).

Just checked mine (ESR) and I see I have the first and second variants mentioned on ESR1 and the other one on ESR2 Not a good combination with the E4 then. https://www.snpedia.com/index.php/rs9340799

I wonder if those of us with these variants HRT / oestrogen might help us even more, and might be especially important. Best to think of what we can do I guess. But if it is about the receptor gene, would it still work though? It seems maybe not ....

https://www.ncbi.nlm.nih.gov/pubmed/194 ... t=Abstract

"Sequence variants in the estrogen receptor alpha gene (ESR1) and beta gene (ESR2) may alter the effects of estrogen."

[Orangeblossom]

Ok so had a look at oestrogen receptors here https://en.wikipedia.org/wiki/Estrogen_receptor
Seems people with these variants might possibly need more of it if they have less receptors for it?

Also a section on AD here about it- wonder what the 17βE2 treatment is?

https://en.wikipedia.org/wiki/Estrogen_receptor_beta

Alzheimer's Disease[edit]
Genetic variation in ERβ is both sex and age dependent and ERβ polymorphism can lead to accelerated brain aging, cognitive impairment, and development of AD pathology. Similar to CVD, post-menopausal women have an increased risk of developing Alzheimer’s disease (AD) due to a loss of estrogen, which affects proper aging of the hippocampus, neural survival and regeneration, and amyloid metabolism. ERβ mRNA is highly expressed in hippocampal formation, an area of the brain that is associated with memory. This expression contributes to increased neuronal survival and helps protect against neurodegenerative diseases such as AD. The pathology of AD is also associated with accumulation of amyloid beta peptide (Aβ). While a proper concentration of Aβ in the brain is important for healthy functioning, too much can lead to cognitive impairment. Thus, ERβ helps control Aβ levels by maintaining the protein it is derived from, β-amyloid precursor protein. ERβ helps by up-regulating insulin-degrading enzyme (IDE), which leads to β-amyloid degradation when accumulation levels begin to rise. However, in AD, lack of ERβ causes a decrease in this degradation and an increase in plaque build-up[19].

ERβ also plays a role in regulating APOE, a risk factor for AD that redistributes lipids across cells. APOE expression in the hippocampus is specifically regulated by 17βE2, affecting learning and memory in individuals afflicted with AD. Thus, estrogen therapy via an ERβ-targeted approach can be used as a prevention method for AD either before or at the onset of menopause. Interactions between ERα and ERβ can lead to antagonistic actions in the brain, so an ERβ-targeted approach can increase therapeutic neural responses independently of ERα. Therapeutically, ERβ can be used in both men and women in order to regulate plaque formation in the brain[20].

Synaptic Strength and Plasticity[edit]
ERβ levels can dictate both synaptic strength and neuroplasticity through neural structure modifications. Variations in endogenous estrogen levels cause changes in dendritic architecture in the hippocampus, which affects neural signaling and plasticity. Specifically, lower estrogen levels lead to decreased dendritic spines and improper signaling, inhibiting plasticity of the brain. However, treatment of 17βE2 can reverse this affect, giving it the ability to modify hippocampal structure. As a result of the relationship between dendritic architecture and long-term potentiation (LTP), ERβ can enhance LTP and lead to an increase in synaptic strength. Furthermore, 17βE2 promotes neurogenesis in developing hippocampal neurons and neurons in the subventricular zone and dentate gyrus of the adult human brain. Specifically, ERβ increases the proliferation of progenitor cells to create new neurons and can be increased later in life through 17βE2 treatment[21][22].

[slacker]

Also a section on AD here about it- wonder what the 17βE2 treatment is?

Estradiol is 17 beta E2.

[Stavia]

Orangeblossom, the current best summary is Anne Hathaway's lecture to us at our San Diego meetup last year. Its on our apoe4.info channel on youtube. Her slides are attached to the HRT section of the primer.
Youre asking all the right questions that we have discussed as a group and with Anne. To get up to speed with the current science and where we are as a group, you'll need to read/watch this first.
If you look at Announcements and Events/Stavia's report on San Diego meetup, youll see my notes on her lecture. I think Ive linked the slides there too.

So... the bottom line is that the current best neuroprotective HRT is 17 beta oestradiol transdermally plus cycled micronised progesterone either orally or transdermally or even vaginally, in a dose sufficient to maintain endometrial protection if there is a uterus.
Because many many reasons.
The most compelling for me is the APP cleavage.
The WHI was deeply flawed.

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