Enhancing Brain Health With HRT

Ann Hathaway, MD

BHRT in almost all women, postmenopausal women, has a tremendously positive effect on cognition. It has a tremendous impact on many things, including cardiovascular health and bone health. Bone health is the one thing that is not controversial. It’s a very important thing. Because when you have osteoporosis, the drugs that they can give you to help are short-lived. You can only take this drug for a year or that drug for two years. In my opinion, you can take estradiol indefinitely. A 2017 report by a group of scientists, researchers, and clinicians who studied the literature for six to eight months, reading everything, and wrote five or six papers that came out in 2017 saying that they said all the benefits of estrogen, including benefits in some Alzheimer’s patients, and we can look at three studies that show cognitive benefits in Alzheimer’s patients.

These are studies by Astana and Wharton, where they took out women with Alzheimer’s, and small studies put them on estrogen. Half on estrogen, half not on estrogen. It’s important the estrogen they use; they use Transdermal Estradiol. If you use oral estrogen, it’s conjugated equine estrogen, but even with oral estradiol, you’re going to have some positives but also many negatives. That’s one of the reasons why the literature is so confusing. But anyway, in the Wharton and Astana study, the largest one, had 43 patients. In three months, they showed absolute, very significant cognitive improvement in the women on the Transdermal Estradiol and not in the women who were put on the placebo. This was a randomized, controlled trial. I believe that the trial needs follow-up.  The other important piece that people don’t know that most gynecologists don’t know is the huge amount of medical literature by neurologists, many of them women neuroscientists who have been studying the brain and estrogen for 40 years. There’s a 40-year treasure trove of research on how estradiol affects the brain.

You mentioned that the neurons have estrogen receptors. They have estrogen receptors on the membrane in the cell body, in the nucleus, in the mitochondria, in the neuronal support cells, the microglia, the astrocytes, etc.; they all have estrogen receptors that are more highly concentrated in the areas of the brain that are affected by Alzheimer’s disease, the hippocampus, the posterior cingulate gyrus, the hypothalamus, and the whole temporal lobe in general. In all of these areas, there’s this belief among most gynecologists now that it’s okay to give hormones at the time of menopause and for five or ten years after that. But after that, you get some negative impacts. The data is based on oral estrogen and medroxyprogesterone. I don’t think it’s valid data. The 2017 North American Menopause Society Group that met said the data do not support discontinuation at ten years after menopause, but the data do support continuation if you’re using transdermal estradiol. Of course, we don’t ever want to use medroxyprogesterone. That’s the hormone that was used in the huge Women’s Health Initiative study that was reported in 2002. The result of that was that everyone believed that estrogen and progesterone increased the risk of breast cancer. A careful study of that original paper and what they say in that paper shows that with conjugated equine estrogen and medroxyprogesterone, the increase in breast cancer almost reached statistical significance the way the confidence interval, the 95% confidence interval.

Here, I’m getting technical. I’m not a statistician, but I do know that when the 95% confidence interval crosses one, that’s not statistically significant. If you look at the paper, that is what happened, and some stories about this are hearsay. I can’t report on those myself. But when challenged on that, what people have told me who was in the room is that they were told we had to kick the statistical police out of the room when we were writing this paper, which is because the reason why I say that is so important is because this dramatically changed the hormone replacement. How much hormone replacement was done? My generation, women who were turning 50 or 52 around that time, completely missed it. They had the chance to get hormones, but now they’re too old to get hormones. Now you can’t start hormones supposedly in women who are over ten years out from menopause. Even though some research suggests otherwise, I have to say, that I do start women on hormones with a careful evaluation of all their risk factors.

 It has to be done on an individual basis. You have to be careful. I do start women who are more than ten years out from menopause on bioidentical topical estrogen in real progesterone. I see benefits in cognition. Now I’m doing the reversal of cognitive decline programs. Women are getting the full spectrum of benefits from that program, which is, as we all know, many interventions are being done. But sometimes you can see that once you get that estradiol up to over 60 or 70, that serum level. There’s a change in cognition. They notice a difference in many cases, not all certainly. But in many cases, they notice a significant benefit. I’m fortunate in that when the 2002 paper came out, I already knew that it was based on the wrong hormones because I’d been studying hormone replacement since around the early nineties. I already knew what women needed to be on and what I needed. So I’m here, in part because I started hormone therapy immediately at the time of menopause. That is the optimal time to start, no doubt about it. That is when you want to initiate hormone therapy. That is the optimal and most beneficial time. We continue to see cardiovascular benefits, bone benefits, brain benefits, and muscle benefits. Women on estrogen say they feel and look younger. Those are also important things. That’s the bulk of what I want to tell people about why estrogen and progesterone should be considered for most women, no matter what their age.

Dale Bredesen, MD

That’s very helpful to know. You’ve already said the optimal time is at menopause. What’s the optimal dose that you start with? I assume, as you said, you want to get up there above 80, somewhere in there, in terms of the serum level. What’s the typical way to get it started?

Ann Hathaway, MD

If you start a little lower with a prescription than what you want to attain, except if the woman is right at perimenopause or menopause, then you can go ahead and get her on a full dose, whatever dose she needs. The thing to understand is that the same dose is going to make a difference in the results for different women. In some women, if you give them 0.3 milligrams of topical estradiol a day, they’ll get a good serum level immediately, up to 50 or so in other women. You’ll need to go up to a milligram, but somewhere in that range is going to give you a good level. Estradiol is an extremely potent molecule. Tiny amounts of estrogen have a powerful effect on the body, unlike progesterone, which requires you to give a thousandfold amount of progesterone to get a significant effect. Progesterone turns into many other things. It has a big metabolic pathway that turns into a pathway that turns into testosterone. in some women, and it goes down the chain to aldosterone and cortisol, etc., That would be a starting dose. somewhere between points three and If you’re using the patch, the patch has five different doses, starting with points zero to five up to 2.1. In an older woman, I would start with the lower dose because if she’s been on no estrogen for many years, you don’t find a shocker system. After all, that might lead to feelings of breast tenderness, etc. I start low and let them build up gradually to the goal level of, hopefully, 80. If you have osteoporosis, you can reverse it. I see a 12% increase in bone mineral density over four or five years in many women. No medication can improve bone density. Bone density is very important. If you’re over 70 and you have a fall, your risk of death is profoundly elevated because that fracture results in immobilization. When you’re elderly, immobilization is tragically dangerous.

Dale Bredesen, MD

Very good point. What about any postmenopausal bleeding? Do you see people bleeding with people who are going back on? That’s what scares people.

Ann Hathaway, MD

I checked women’s history. If they’ve had a history of fibroids, heavy bleeding, or anything like that, you want to check on them and have them have a pelvic exam and a pelvic sonogram to see. Because if you’re looking at uterine fibroids, which project into the inside of the uterus, the chance that when you give estrogen, you’re going to get bleeding is much higher. You do run into that problem. Some women are prone to developing polyps on the inside of their uterus when you give them estrogen. Those will also bleed. So you need to be very careful to keep it in some of those women. If you give a high enough dose of progesterone, that will balance it out and they will not have bleeding. But yes, bleeding is a problem. You do need to worry about bleeding because, over time, if there’s too much estrogen for the level of progesterone, this imbalance in the lining of the uterus called the endometrium will grow. If it grows excessively, that hyperplasia can turn into dysplasia. Dysplasia can turn into a form of uterine cancer or endometrial cancer. You need to watch for that, and you need to be conscientious about that. When women have to bleed and there’s no good explanation for it, they need to have a full evaluation.

Dale Bredesen, MD

Very helpful. then you already indicated you would continue this for the life of the person who has, at least for the person who has cognitive decline and for someone presumably that you’re treating, bone density issues, cardiovascular issues, things like that. What do you do about it? So you’ve talked a little bit about where you want the estradiol to be. Where do you want the progesterone levels to be?

Ann Hathaway, MD

I want to say that the same amount of estrogen with the same amount of progesterone can give different results in different women. You have to measure most gynecologists who treat post-menopausal hormones, they never measure hormones. I always measure periods. It’s instructive, and it’s helpful to know. By the way, I want to mention the benefits of progesterone, calmness, and sleep. In most women, sleep onset is improved, deep sleep can be improved, and the duration of sleep can be improved. Many women love their progesterone for that reason. You have to match the progesterone level to the estrogen level. The medical literature is very unhelpful in this regard because, again, gynecologists don’t measure it. They typically give X doses of estrogen and progesterone, but they do not know what the blood levels are or what the serum levels are. Over the years, I’ve come up with my safe evaluation because you want that if your estrogen is around 30, it’s a good rule that if your estradiol is 30, you want your progesterone to be at least two. If you’re 40, you want your progesterone to be at least three. You can just go up like that because at each level, and that’s a crude measurement, it could be an 80 and estradiol, six or seven, which is probably going to be fine.

The nerve protection and then 100, which is where I keep my estradiol, are what Felice Gersh and O’Keefe recommend in their paper on cardiovascular benefit; they say to keep the level at 100 or at least at 50 to get the cardiovascular benefit. It’s a very good paper that reviews a lot of what I’m reviewing here in terms of the right hormones versus the wrong hormones. But that’s where they recommend keeping the estradiol level in women who tolerate that. If you run into bleeding, breast tenderness, or other issues, you might have to drop back a bit. By the way, for breast tenderness, we treat with iodine; there’s an iodine deficiency. Iodine works extremely well. I’ll drop the estrogen back for a little bit, build up the iodine level, then gradually go back up on the estrogen. There are three different ways that I prescribe progesterone. It can be given orally. That’s the most common because it’s easiest, and there is orally available commercially available progesterone trade name Prometrium, but they’re generics. The problem with it is that it’s only in doses of 100 and 200. Those work for many women, one of those two doses. But some women, need a different dose, a little bit lower or quite a bit higher sometimes.

Then you can use an oral compounded progesterone. There’s a small group of women who have a bad reaction to oral progesterone. It’s complicated to explain why, but it has to do with the fact that progesterone in the brain transforms into an Allopregnanolone, and that binds to the GABA receptor. That’s why most women get calmness and improved sleep because GABA is a calming neurotransmitter. But in some women, there is some difference in their GABA receptor, some genetic alteration, or some certain alteration, and they get a lower mood or irritability. A patient called me and said that she wanted to strangle her husband. I have no reason. He’s a nice guy. I’m just crabby. That is often the progesterone problem. I switch them either to a transdermal or vaginal suppository. Vaginal suppositories work the best for that reaction to progesterone because you get much less Allopregnanolone in the brain. I don’t know for sure. But there’s a vast literature on this in the Scandinavian Medical Literature. Most of the time, if you switch to bad, in those women it’s about eight percent in my practice book. Call me and say I hate this progesterone. You can get a benefit from using one of those other two deliveries.

Dale Bredesen, MD

Some claims say, Well, it’s the estradiol that seems to help Alzheimer’s, and the progesterone doesn’t seem to enhance the effect; in fact, it may mitigate the effect to some extent. The question is, do you cycle these or do you keep them together at all times? How do you approach this?

Ann Hathaway, MD

Some women are three weeks on, and one week off. Some people believe that, because before menopause, The way that our cycle works, the way that a female cycle works, is that you only make progesterone for the second half of the cycle. Some people theorize, and it may be true that you get better progesterone receptor sensitivity and a better response to progesterone if you cycle it on half the month and off half the month. that works for some women. The problem you run into is that some women will have spotting or bleeding every time they go off. That’s a classic progesterone withdrawal in post-menopausal women, they do not want to have bleeding. They feel they’re done with that, and they want to be done with that. That’s the problem. It’s a little better. You have a lot less likelihood of that if you do three weeks of progesterone and one week off. We do that sometimes. However many women want to be on progesterone every night because of the sleep benefits. That’s a reason why in many of my patients, maybe 75%, even 70, 75%, they’re on it continuously and they do well.

Medroxyprogesterone was the progesterone that was used in the Women’s Health Initiative study, and that was the progesterone that was used from the late sixties until the Women’s Health Initiative study changed everything. Medroxyprogesterone was what was used to counteract the uterine effects of estradiol, which caused many women to have irritability and depression, by the way. The women who did continue on their hormone therapy in those days were generally women who would tolerate the medroxyprogesterone well, or they’d had a hysterectomy, so they didn’t need to take medroxyprogesterone, and they just took estradiol. By the way, back in those days, for women who were on estradiol alone, there were many studies showing benefits, including a decreased risk of dementia with oral estrogen. But the difference between those women was that almost all started with oral estrogen at the time of menopause. So there’s a meta-study analysis—29 studies showing cognitive benefit in women—that was published in the late 1990s.

Just after the publication, especially there were some studies on all the women’s average age, and women were 70 in the substudies on conjugated equine estrogen and medroxyprogesterone. The problem and the reason why later use of conjugated equine estrogen is so bad is that when you have no estrogen for ten or 15 years, you develop black estrogen, which protects you from the development of coronary and cerebral artery disease because of its many benefits. But if you’ve been off estrogen for many years, then you’ve developed an ordinary and cerebrovascular disease, and then you give oral estrogen, which increases clotting, increases fibrinogen, and increases inflammation by increasing C-reactive protein. Those two negatives are very bad for older women, and that’s why there’s this belief that no older woman should get any hormone replacement. That is a very unfortunate, overall generalized statement. If you give transdermal estradiol, you have no increase in inflammation, CRP is unchanged, and you get no increase in fibrinogen. Multiple studies show that. That’s why the evidence and the people, like groups like the U.S. The Preventive Health Services Task Force says, Don’t give these hormones. Do everything you can to avoid them.

Dale Bredesen, MD

You’re one of the very first patients I saw, way back in 2012. In 2013 a woman started doing pieces of the protocol, and she was getting better a little bit with each thing. then when she she got her BHRT optimized, she had a big leap. She noticed the difference, like, that was the thing that affected me the most. But then, after about a year, she came back and said, Something’s going backward again. I don’t know what’s going on. We started talking about, like, what’s happened to her. It turned out that she had been switched from transvaginal delivery of estrogen and estradiol to transdermal, and her level of transdermal was zero. The question is, do you see people where transdermal is just not getting absorbed very well?

Ann Hathaway, MD

Some patches don’t work very well. A lot of physicians like to use patches on certain people. Some women’s skin absorption varies. That’s why I say you can’t rely on X Dose is going to give you X level. Yes, I certainly do have that experience where I switch some women; we just cannot get a good level, and we switch them to a vaginal application of estradiol and right back up. I don’t need to do that, but sometimes you do. Sometimes you can just increase the amount; sometimes you have to talk about how to put it on and how long to rub it in. Various things can be amiss for someone. They put it on just very casually, and then they put a shirt over it. They exert very little.  All these little problems need to be solved constantly and continually. But, yes, doing a trans badge application, there is incredibly good absorption in that tissue. You do get a very good level that way.

Dale Bredesen, MD

The last question here, then, would be: What about testosterone in men? Have you seen that and how do you deal with it?  Have you seen improvements in cognition when you use that as part of an overall protocol?

Ann Hathaway, MD

Let me first just say that I use testosterone in women, too, even though in the United States there is no commercially available testosterone product for women. By the way, in Europe and Canada, there is a commercially available product for women. In the U.S. It’s held up for reasons that don’t make any sense. But women benefit from testosterone in terms of libido, muscle, and muscle growth, especially if you’re doing a strength workout. Yes, I have male patients who benefit tremendously from testosterone. There is commercially available testosterone for men. It’s tremendously expensive. I often use compounded for men because it’s much more reasonably priced, and there’s a certain formulation of testosterone in a compound called Athrovas that gives very good absorption in men, particularly good absorption. It’s only available from some compounding pharmacies.

I certainly see men who have benefits in terms of mood, and libido. A lot of times, men come for testosterone because of sexual dysfunction or wanting to improve their libido. It doesn’t prove that, but the biggest change that men report to me is an improvement in mood. I had a patient who told me he just hated his job. He was, and everything irritated him at work. He was irritated with all his coworkers, etc., and jobs were just boring him. He got on testosterone. We got his free testosterone level up to 12 or 13. He completely changed his attitude towards his work. He was engaged. He liked it again. He was finding interesting new avenues, etc., of course, his wife was thrilled because she didn’t have a crabby guy around the house all the time. We certainly see a lot of benefits for men. There are bone-strengthening benefits and muscle-strengthening benefits. The synthetics are being abused for certain muscle building. But in the doses that we use, somewhere around 50 milligrams, etc., the best delivery system, by the way, for just throwing in men is to give a subcutaneous injection.

There’s a very small and commercially available testosterone subunit. You can use a tiny needle, or a tiny syringe, and give a subcu injection twice a week. Small, very small injection. I find that that is the best; we get the best results with that. Men don’t want to give those injections, and we do use topical testosterone as well, especially for older men, older guys who don’t want to deal with it,  putting a needle into a little vial and drawing it out, etc. But both work; both are effective.

Dale Bredesen, MD

I would be remiss if I didn’t ask about people who come and say, Well, look, I’d like to go on estradiol, be on BHRT, or I’d like to go on testosterone. I have a history of hormone-sensitive cancer in the past, and I seem to be fine now, but I’m concerned about breast cancer, uterine cancer, or prostate cancer. What have you recommended to them?

Ann Hathaway, MD

Most women who’ve had breast cancer have careful follow-up.  Before I put any women on hormones, I insist that they have a mammogram or an available new technology. only here in the Bay Area now, which is a 3D sonogram by two T Health.  I’m hearing that another company’s doing 3D sonograms now that I’m looking into it, but two T Breast Health will eventually be known around the rest of the country, hopefully, and people will have that as an option. You have to be conscientious about your follow-up and taking care of breast health. I do not believe that estrogen the top of the estradiol or real progesterone, increases the risk of breast cancer. But I cannot say that with absolute certainty for every woman. We have to be conscientious. I would certainly put a woman who has post-breast cancer on hormone therapy after the appropriate treatment has been completed. She’s had a good study and is cleared by her breast oncologist. I have oncologists who I work with who are okay in certain cases within a year of treatment to restart women on hormone therapy carefully and with careful follow-up. I see that cancer depends on how complete the treatment is for prostate cancer. I would want to talk to their oncologist, their urologist, etc., to clear them for testosterone therapy after prostate cancer.

As you may know, higher testosterone levels in general correlate with a decreased risk of prostate cancer. If your PSA goes up quickly, that’s a dangerous signal, and you need to be evaluated for prostate cancer. But in general, a lower prostate, a lower testosterone level, correlates with an increased risk of prostate cancer, and a higher level, a decreased risk. Hopefully, that answers your question to some degree. It’s a long topic. I do have one BRCA-positive patient. I do want to mention this. Both her mother and her sister have had breast cancer. She’s been with me for 19 years on hormone therapy. She found out 12 years ago that she had the BRCA gene when her sister developed breast cancer premenopausal. Then her mother got tested. They’re both cancer survivors. Their mother and her sister wanted her to stay on her hormones. Now she’s been followed appropriately by a team that follows BRCA, a woman. She has an MRI alternating with a mammogram every six months, but she stays on hormone therapy. She’s cancer-free. She’s very happy with the benefits and the therapy. and I tell her at all times that it’s totally up to her whether she wants to continue or not. But it’s an interesting case.

Dale Bredesen, MD

One of the most fascinating epidemiologic articles I read was the claim that BRCA is, of course, an important risk factor for breast and uterine cancer. But if you go back to the late 1940s, the old literature, and, before BRCA was discovered, if they recover samples, they can show that these people who had BRCA mutations were not at increased risk. So, something changed. It’s not, of course; it’s the interaction of genetics with the environment. If you change the environment, the genetics don’t have the same impact on you that they did before, which I thought was fascinating. all right. This is fantastic. Thanks so much, Dr. Ann Hathaway. Thanks so much for being part of the Reverse Alzheimer’s Summit. It was great to talk with you as always, and it was great to hear your expertise as always.

Ann Hathaway, MD

I  enjoyed talking with you about this. Thank you.