Hormone Replacement Therapy E4 Women

[Julie G]

I am "peri-menopausal" now almost 3 months since my last cycle and starting to have hot flashes. Is this bad for my brain? I don't think hot flashes are due to lack of estrogen per se, it is believed that they are due to some complex interactions in the hypothalamus, probably having to do with excess FSH and other responses to the low serum estrogen that make the hypothalamus extra sensitive to tiny changes in body temperature. But the brain is not starved for estrogen, because it makes its own estrogen, right? Does anyone know what happens to brain estrogen in menopause?

My understanding is that estrogen helps to play a role in delivering fuel to the brain and an abrupt drop, that can sometimes happen during perimenopause, is what causes the problem. This sets off a cascade of other pathology that can affect our genotype more aggressively. We know that E4 carriers (in a dose dependent fashion) already deal with decreased utilization of cerebral glucose starting in our third decade. Any degree of insulin resistance, that also tends to strike around this same time, also exacerbates this neural fuel shortage. When we add perimenopause to the mix, many E4 women are hit hard. FWIW, I suffered horribly from hot flashes (20+ per day) seemingly overnight when I was transitioning to menopause. BHRT was a lifesaver for me. You might find this paper helpful.

From a mechanistic perspective, estrogen dysregulation during perimenopause significantly affects brain bioenergetics [4]. The brain is dependent upon glucose as the principal metabolic fuel to generate ATP–a system that is partially regulated by estrogen. During perimenopause, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters, inducing a hypometabolic state which is accompanied by deposition of amyloid-beta (Aβ, a hallmark of AD pathology), decreased mitochondrial function, and decline in synaptic plasticity [6–8].

[karelena]

I think a big part of the problem in human subject research is that our OR or RR is so high being E4s. It really hard to make a dent in the risk for such high risk groups. So many studies show "no benefit for carriers of E4", but there could be a benefit that is small, but not statistically significant because the risk is so high to begin with. For each one change we make there may not be any evidence that shows benefit.

[KatieS]

In the early days of this lengthy thread, there was a small French study analyzing the decreased mortality with HRT correlated to the estrogen receptor SNPs. Turns out my 101 y/o, 3/4, Met/Val mom hit the jackpot, correlating with 0.6 mortality using HRT, marking over five decades of estrogen. Dr. Greicius who authored the APOE and AD review article, declared "that she must have a protective SNP" having undergone cognitive testing for hours and MRI. I had decreased mortality, but a three-fold risk of breast cancer, having twoof the three of the estrogen protective receptor SNPs. I suspect there exists subsets when estrogen is highly protective, but I have not found updated evidence of these estrogen receptors influence on mortality. Meanwhile we have to note our female relatives for some guidance.

[Julie G]

I think a big part of the problem in human subject research is that our OR or RR is so high being E4s. It really hard to make a dent in the risk for such high risk groups. So many studies show "no benefit for carriers of E4", but there could be a benefit that is small, but not statistically significant because the risk is so high to begin with. For each one change we make there may not be any evidence that shows benefit.

AGREE and a good reason to push for all E4 data datasets and/or sub-analysis of currently published evidence.

[hairyfairy]

I briefly tried HRT a few years ago in the hope of bringing my cholesterol levels down. It had the opposite effect. I had unpleasant side effect with statins, so Iv`e run out of options.

[Hboroughs]

In the early days of this lengthy thread, there was a small French study analyzing the decreased mortality with HRT correlated to the estrogen receptor SNPs. Turns out my 101 y/o, 3/4, Met/Val mom hit the jackpot, correlating with 0.6 mortality using HRT, marking over five decades of estrogen. Dr. Greicius who authored the APOE and AD review article, declared "that she must have a protective SNP" having undergone cognitive testing for hours and MRI. I had decreased mortality, but a three-fold risk of breast cancer, having twoof the three of the estrogen protective receptor SNPs. I suspect there exists subsets when estrogen is highly protective, but I have not found updated evidence of these estrogen receptors influence on mortality. Meanwhile we have to note our female relatives for some guidance.

Hi KatieS - do you have any more detail on the specific SNPs? Would love to investigate that more. Thank you!

[BrianR]

I briefly tried HRT a few years ago in the hope of bringing my cholesterol levels down. It had the opposite effect. I had unpleasant side effect with statins, so Iv`e run out of options.

Ezetimibe might help (possibly along with very low dose of a different type of statin).

[KatieS]

In the early days of this lengthy thread, there was a small French study analyzing the decreased mortality with HRT correlated to the estrogen receptor SNPs. Turns out my 101 y/o, 3/4, Met/Val mom hit the jackpot, correlating with 0.6 mortality using HRT, marking over five decades of estrogen. Dr. Greicius who authored the APOE and AD review article, declared "that she must have a protective SNP" having undergone cognitive testing for hours and MRI. I had decreased mortality, but a three-fold risk of breast cancer, having twoof the three of the estrogen protective receptor SNPs. I suspect there exists subsets when estrogen is highly protective, but I have not found updated evidence of these estrogen receptors influence on mortality. Meanwhile we have to note our female relatives for some guidance.

Hi KatieS - do you have any more detail on the specific SNPs? Would love to investigate that more. Thank you!

The study was in a previous 2014 (page 16 of this thread) post by Silverlining: viewtopic.php?t=119&start=150 T.

[circular]

Forgive me for not reading this gargantuthread for the info, but does anyone happen to know when is the best time to measure testosterone in postmenopausal women? I need to do fasting labs, and I usually use a compounded cream once a day after my morning shower, so I can use it right after my shower and before the test and get it going up (how long before it registers high, who knows?), or I can skip it and get it at its low but never know how high it's going.

[floramaria]

Forgive me for not reading this gargantuthread for the info, but does anyone happen to know when is the best time to measure testosterone in postmenopausal women? I need to do fasting labs, and I usually use a compounded cream once a day after my morning shower, so I can use it right after my shower and before the test and get it going up (how long before it registers high, who knows?), or I can skip it and get it at its low but never know how high it's going.

Hi circ, This is just a guess on my part, extrapolating from information that I hope I am remembering correctly. ( How is that for a disclaimer? ) anyway, FWIW I believe that when I heard Ann Hathaway speak she recommended testing E2 for women with the patch at mid-point of patch life, when E2 would be highest. My guess would be you’d want to test your testosterone at post application level rather than skipping it before the test.