How and When to Consider Estradiol for Cognitive Decline

In this 21-minute interview, IFM’s Dan Lukaczer speaks with Ann Hathaway, MD. Dr. Hathaway has been successfully treating women and men using a Functional Medicine approach since 1995. Dr. Hathaway is a specialist in the use of bioidentical hormone replacement for menopausal women.

For some women with cognitive decline, estradiol treatment may offer therapeutic options. Dr. Hathaway describes her approach, the lab tests that guide her treatment, and other considerations, including breast cancer.


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Dan Lukaczer, ND: Well, hello, I’m Dan Lukaczer. I’m the director of medical education at The Institute for Functional Medicine, and I am sitting here with Ann Hathaway, who is a board certified family physician and is also an IFM certified practitioner. And we’re going to talk a bit about cognitive decline in women and specifically hormone replacement therapy in women and how Dr. Hathaway assesses and treats those women. So, Ann, thanks for joining us.

Ann Hathaway, MD: Thank you, it’s a pleasure to be here.

DL: I want to start off with just you talking a little bit about your initial workup of how you assess a woman that comes in with, you’ve determined cognitive decline—how do you determine that she has cognitive decline? Do you do some testing on that and then is there some follow-up laboratory testing after you’ve talked about hormone replacement therapy and talked about some of the benefits that you think that would accrue from that? How do you kind of start that process?

AH: Well, I’ve been working with the Bredesen protocol for almost two years now. Now, the Bredesen protocol, you’re familiar with it, but maybe not all the listeners are, but the Bredesen protocol is a very complex assessment of someone based on a lot of different biomarkers. One of those biomarkers is their estradiol level.

So, in a post-menopausal woman, you would want to assess multiple hormones, including:

  • Estradiol
  • Estrone
  • Progesterone
  • DHEA
  • Pregnenolone

In the context of doing the entire Bredesen protocol, that involves diet, sleep, exercise, stress, stress reduction, and a large number of biomarkers.

We’re looking at methylation markers, we’re looking at vitamin and nutrient level, of course looking at vitamin D. All those things are important. One important marker that we found in post-menopausal women, in terms of their risk of developing Alzheimer’s disease, is their estradiol level.

For example, I have seen a 72-year-old woman who came in to my office with cognitive impairment. Her husband noticed that she wasn’t able to put on a conference that she had put on every year for many years. And she asked him for help. In the process of her asking him for help, he realized, “Wow, you are impaired.” Through a process, they end up coming to see me, and what I find out in the process of interviewing her is that at age 72, she was taken off her estradiol patch that she’d been on since menopause. Three months later, she had this cognitive impairment that was quite full-blown. Over the process of evaluating her for many things and correcting many biomarkers, we also corrected her estradiol level back from about a 2 up to about a 38. With that, she was able to regain her ability to put on this conference, to organize her mind, to organize the material for the conference, to follow a schedule, to remember people’s names—all the things she was having a tremendous amount of trouble with. So that’s an example of the kind of person who we would really think about strongly that estrogen is an important factor in her cognitive function.

Now, we corrected many things. If you are familiar with Dr. Bredesen’s protocol, you know he talks about there are 36 holes in the roof when you are looking at a brain with cognitive impairment. But there is significant research that strongly suggests, without going into the details, that if you started women on estradiol at the time of menopause and continue it, continue it on into their 60s, 70s, even 80s—we don’t know for sure because there’s no research that answers that question—that we would prevent at least 30-40% of Alzheimer’s disease in women.

DL: So that raises some interesting questions. You obviously, as you pointed out, are fixing a number of holes in the roof, and so, using systems biology, a Functional Medicine approach, and hormone balancing/replacement as but one. So with focusing down on that specific area, then, you’re looking at particular hormonal levels in the blood. Are you looking at serum markers?

AH: Yes.

DL: Estradiol specifically. And then I’m curious, and I think the listeners will be curious, is you alluded to, well, how long do you keep them on, that you do that indefinitely and follow up? And as another part to that question, what if a woman is perimenopausal and has some cognitive decline that you’ve measured in some way? Are you doing that same kind of—it’s a little bit harder because you don’t know where the estradiol levels are, but can you speak to both of those, to the two bigger questions?

AH: Absolutely. There are a number of women, probably the majority of women who have some kind of difficulty at perimenopause or what we call the menopausal transition, right? Sleep difficulties, mood changes, of course the hot flashes and night sweats, all of those things. And some of those women definitely have issues that are cognitive in nature. I’ve seen several very high-functioning women, women who function as CEOs, or run a big law firm, or that kind of thing, and they are extremely talented and good at what they do. And they go through menopause, they’re in the menopausal transition, and boom, they can’t delegate, they can’t prioritize, they are completely dysfunctional. Now this is a minority, but it is very interesting when you see that kind of a person.

And yeah, if we correct their estradiol from somewhere below 10 to back up to 40 or 50, they are back on. I’ve seen that repeatedly. I’ve been working with bioidentical hormones for over 20 years now, and so over the years, I’ve seen quite a few women in that position, even though it’s a minority. Yes, absolutely, they are astounded at how much that drop in estrogen impacts their ability to function.

DL: And how about the long term use of estradiol in their 60s, 70s, or 80s? Once you put somebody on, a woman on, that kind of therapy, are you leaving her on that therapy and continuing to monitor her estradiol levels in that case?

AH: Absolutely. I mean always, and importantly, we have to assess the woman in terms of all of her risk factors, and you always have to do a risk/benefit analysis for each woman at each stage of life. And that is quite a complex process to go through, all of it. But of course, the elephant in the room is always breast cancer, right? But it is important to know that at age 60, a woman’s risk of breast cancer, her lifetime risk of breast cancer is 9.3% going forward. Her risk of Alzheimer’s disease at age 65 is 17.2%.

So you can’t, one of my big issues here is that what is generally understood by most physicians and the general public is that estrogen increases breast cancer risk. And I think actually that’s a big black box question mark. Does it or does it not? There are only very few double-blind placebo control studies that look at that. And both of them, without going into the details, suggest that estrogen either doesn’t increase the risk, or decreases the risk.

Once you add in the usual synthetic progestin to the mix, Medroxy-Provera, of course everything changes. Because Medroxy-Provera has multiple deleterious effects on the breast. Medroxyprogesterone has been shown over and over again to increase breast cancer risk. If you take that out of the equation, everything changes. So anyway, both at the time of menopause, at 60, at 70, at 80, I would reevaluate a woman for her risk to benefit ratio and I would continue her on estrogen, all things being equal. In particular, of course if they are an ApoE4 carrier, it’s more important. If they have a family history of Alzheimer’s disease, it’s more important. If they have a history of major depression. Because all those things—ApoE4 carrier, Alzheimer’s disease in a first-degree family member, or a history of major depression—they are at an increased risk for Alzheimer’s disease. And you have to put that into balance with whatever the possible breast cancer risk is. In most cases, when you have someone with obvious cognitive decline, you’re going to err on the side of keeping them on the estrogen, in my opinion.

Bioidentical progesterone, there’s not a lot of good studies, but bioidentical progesterone has not been shown, in the one study where they used it, the KEEPS Study (Kronos Early Estrogen Prevention Study), to increase breast cancer risk when it’s used with either low dose Premarin or transdermal estradiol. It’s important—I haven’t said this yet—it’s very important to say that I only and always use transdermal estradiol. Oral estradiol is a bad idea for multiple reasons. It increases C-reactive protein, it increases fibrinogen, it increases PAI-1, so it increases the tendency toward coagulation problems. Transdermal estradiol has been shown multiple times to be superior for cognitive results, and it also has no effect on C-reactive protein, fibrinogen, or other coagulation markers.

DL: Are you using that natural progesterone along with estradiol in women with intact uteruses and that sort of thing and so are you using both of those? And, therefore, are you measuring both of those?

AH: Absolutely. Yeah. If a woman has a uterus, you have to give her progesterone to protect her uterine lining from endometrial overgrowth, which can then become endometrial cancer. That is an important thing to be aware of. And you need to balance the estrogen with the progesterone. That is a sort of technical thing where you need to learn the numbers and how they work with each other. But at a certain estrogen level, okay, do you determine this woman does well cognitively at an estradiol level of 40, but not at an estradiol level of 25? So you need to have a progesterone level that matches that estradiol level of 40 and is protective of her.

DL: So you mentioned you’re balancing the risks with cognitive decline/Alzheimer’s versus the risk for breast cancer. And you mentioned some genetic tests. Obviously, the ApoE-4 as a potential marker for cognitive decline in Alzheimer’s. Are you also then doing other tests on a regular basis, looking for genetic markers for increased risk for breast cancer? Are you looking at CYP-182?

AH: Yes.

DL: Those sorts of things, do you do that regularly?

AH: Absolutely.

DL: Tell us about those specific tests that you use.

AH: This is a complicated set of data, and usually when I talk about this, there is a big diagram up on the screen that shows the metabolites for all of your estrogens. But yes, I look at the estrogen metabolites in all my patients. Estradiol and estrone both are metabolized down the 2-hydroxy pathway, the 4-hydroxy pathway, and the 16-hydroxy pathway. We favor the 2-hydroxy pathway. Two-hydroxy can turn into 2-methoxy, and 2-methoxy estradiol is an anti-inflammatory and an anti-proliferative compound. So we very much favor metabolism across that pathway.

And you can enhance that pathway by the 1A1 enzyme, which turns the estradiol into 2-hydroxy. So that can be enhanced by cruciferous vegetables, by diindolylmethane, indole-3-carbinol, which are supplements that include the active ingredient in the cruciferous vegetables. Adequate iodine and adequate selenium also improve that pathway. And the lignans from flaxseed also improve that pathway.

Then to get from 2-hydroxy to 2-methoxy, it’s a methylation enzyme. B-12 methyl folate, and all the things that we know that enhance methylation, will enhance the metabolism of the 2-hydroxy estradiol to 2-methoxy estradiol. We want to avoid the pathway from estradiol, estrone down the 1B1 pathway, because that turns into 4-hydroxy estradiol or estrone. The 4-hydroxy estrogens are able to be metabolized into a 3,4-quinone. A 3,4-quinone is our real bad guy here, because a 3,4-quinone is a planar molecule shaped like a hydrocarbon, and it can diffuse directly into the nucleus of the cell—and in this case we’re concerned with breast cells—and break your DNA. It binds, it makes what we call DNA adducts, breaks the DNA—pieces of DNA fall out, and over time, if you are producing a lot of 3,4-quinones and breaking a lot of DNA, eventually your risk for breast cancer goes up.

So, we can avoid or we can decrease the 1B1 metabolism by avoiding xenoestrogens and other toxins, phthalates, bisphenol A, some of the well-known toxins we’re exposed to. Of course, bisphenol A is on every receipt that you’re handed in the bank or the grocery store. It’s in many canned products, the inside lining of a can. Phthalates of course are in plastics, so every plastic bag that your food is wrapped in, or that you touch, you are exposed to a little tiny bit of phthalates. Organochlorines and other toxins are also metabolized by the cytochrome-p450 1B1 enzyme. When you decrease your exposure to xenoestrogens, eat organic foods, avoid plastics, avoid bisphenol A, you decrease your breast cancer risk.

DL: So you’re doing, in terms of the testing, you’re doing tests for phenotype as opposed to the genotypic tests. Are you doing the 1B1 test and using that as part of your assessment or are you mostly doing the two, four, and sixteen serum or urine?

AH: I used to do the genetic tests, but I stopped doing that because I think actually measuring the markers is more pertinent. What level of 4-hydroxy and 4-methoxy are they making? That’s a good question.

DL: So are there certain women that you are very reluctant—from a genotypic standpoint, they’re BRACA1 or BRACA2, or I don’t know, there are other gene markers that put a woman at a higher risk. Are you more reluctant? Or again, are you weighing the risks and benefits and then continuing to follow up with these serum marker etcetera?

AH: Well, I will say that I have only had three known BRACA patients, BRACA 1 or 2 positive patients in my practice over the years, and in one case, she very much wants to be on estrogen replacement. She is aware of significant benefits from that, and we do follow her very closely, but I do have her on a low dose of bioidentical estrogen and progesterone with a very thorough informed consent, of course. She understands the risk and benefits. She is a very compliant patient; she is very careful about her diet and her supplements. There is even a question in my mind, does estrogen increase the risk of breast cancer with BRACA-1 or is it a different mechanism?

Because what people may not realize is that estradiol has multiple antioxidant properties. We have estradiol receptors in our mitochondria. It upregulates mitochondria. We produce less reactive oxygen species with estradiol present. Estradiol binds to intracellular receptors that activate antioxidant species being produced in the cell. The same reasons why estradiol is protective in the brain, there may be protective activities in the breast, especially if you metabolize your estrogens correctly. And that is something that we, as individuals, and we as the physicians advising them, have a tremendous ability to impact the health of the breast on estradiol by the kinds of things we talked about when we’re talking about the metabolic pathways.

DL: Well, I want to thank you, Ann, for giving us a larger, systems-based Functional Medicine approach to not only cognitive decline in an older woman, but really specifically diving down to what you do in terms of hormone replacement therapy.

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