Optimizing Hormones for APOE4 Brain Health: Vitamin D, HRT, Testosterone & Thyroid

[0:00]There is a window where hormones can protect your brain from Alzheimer's disease. If you miss it, those exact same hormones might do the opposite. Here's the part that no one tells you when your estrogen and testosterone starts dropping, the right replacement can stabilize your brain.

[0:22]But if you wait 15 years after menopause, and if your blood vessels have already changed, the same hormones could raise your risk of dementia. Timing is more or less everything, and almost no tells you this. I am Dr. Kevin Tran and an ApoE4/4 carrier And that's why I sat down again with Dr. Grant Fraser to go through the hormones that quietly run your brain one at a time.

[0:47]In this episode, we're covering why vitamin D is actually a hormone and why the recommended dose isn't close to enough. The truth about that keeps women from even asking. And the one vary number your doctor is probably reading wrong. If you want to protect your brain, watch this one to the end.

[1:09]Let's get into it. So let's move on to hormones now. Let's start with vitamin D. So a lot of people don't know that vitamin D because it has vitamin D in its name is actually a hormone. So tell us more about it so I think your big things with vitamin D is that there there is a sweet spot you know, whether it be, you know, 40 to 60 or 50 to 70 you know, probably, you know, 40 to 70 looks good we know that for you know, somebody who's had a heart attack that they decrease their rate of having another heart attack if they have optimal vitamin D measured and and it's important to do a serum level.

[1:42]The amount that you take, the so the US RDA is 800 international units per day. my average patient in order to get a therapeutic level is taking somewhere around 5,000 international units per day. So it is something where you need to measure level because some people don't need a supplement to have an optimal level.

[2:02]Some people require, you know, 10,000 units per day to get an optimal level. But it is something where we're looking at modest degree on brain health, you know, significant issue on bone health, osteoporosis, and vascular health with this. And I think it's an important thing to look at.

[2:20]It's important also to make sure that you have adequate magnesium, so reasonable to measure on your labs and RBC magnesium as part of this, and also to take vitamin K2, typically MK7 for vascular health, so that you're less likely to deposit Calcium that will be absorbed with vitamin D being optimal and get that into your blood vessels is certainly the theory.

[2:44]So usually 200 micrograms of the K2MK7. If you've got weakness in your bones, then the evidence is to also have the MK4 in much much larger doses, it's much less potent. but it is something where it's reasonable to have those things together. Okay, makes sense. I mean vitamin D definitely you have to test as you mentioned, right?

[3:06]You don't want it too high, you don't want it too low, and it changes a lot with even like your natural way of producing it if you're under the sun or not. so in men, estradiol comes from testosterone. In women, a substantial amount of estradiol comes from testosterone.

[3:22]Women have much more testosterone in their system than estradiol. The units are different, but if you take a look at the absolute amount, it's more testosterone as far as actual uh quantity. and this is something Where having a normal level and keeping that normal for life is probably a quite sensible thing and it's certainly something where for brain health, it does stabilize mitochondrial function, reduces neuroinflammation, supports cholinergic signaling, improves cerebral blood flow, improves synaptic plasticity, improves glucose metabolism, and supports mitochondria.

[4:01]The challenging area with this is this whole discussion around, hey, I'm now you know 15 years post-menopausal and have not normalized my hormones because my doctors told me no, you don't need that, and you know, whatever, or you're scared, you know, it's gonna cause breast cancer, which it doesn't and you know, you look back at the old you know, form of Premarin and Provera, which is different than what we use now and that's probably the bigger conversation here, is that in general, unless you have a specific contraindication to being on hormone replacement therapy It's a very sensible thing to to start and to actually start on some supplementation, initially a progesterone, and then later estrogen as that drops as your perimenopause,

[4:44]because it impacts your sleep and your function, which is an important part of your health. Your sleep's not good and the rest of your health's not good. yeah, so there's really an art to doing this as woman head into the ten years before menopause, of normalizing those things.

[4:58]And we do a menstrual cycle map where you get a urine every two days and you'll map out and see how everything's going, and usually it's a progesterone defect early on during luteal phase, and you supplement that. I mean, that's a there's quite a bit of detail to it, but it's something where it's not just menopause that you're starting to supplement because the estradiol decline is actually late, and and we do measure, you know, kind of look look at you know, lab test of FSH going up is kind of the indication that your menopause, but also estradiol dropping to an abnormal level.

[5:31]But we like to not let that happen and actually kind of as the defect gets worse that we are adjusting and supplementing so that everything remains normal. But our women that have been you know greater than 10 years, 15 years, 20 years postmenopause, it ends up being a real challenge because there's kind of the question as to whether Your brain now has less neuroplasticity, that you're that you know, you've you've now got an issue where the vascular response is likely to be more dysfunctional, you have more endothelial dysfunction that's happened, and then you suddenly give the hormones.

[6:07]Are you going to cause harm? And it's possible that you're going to cause harm. There's some data indicating that this is something where it's likely to increase your rate of dementia. Along with that. That's assuming that you've got the endothelial dysfunction, that you've got mitochondrial impairment, that you've got inflammation.

[6:27]So the question becomes, is there a way to measure in a woman and go, you know, do you have this endothelial dysfunction? Do you have this mitochondrial dysfunction? You know, other things that you know, and if you don't, we can probably supplement you, but if you don't, if if you do, then we might cause harm.

[6:42]And I think that's a real challenge as far as how how you approach that And I think in general it's an individualized decision on that. If I have somebody who, you know, my assessment is that their functions really good, their vascular stuff's really good, I've image, they don't have any white matter changes in their brain, you know, they do a pre-mas and they score an eighty you know, I think that you know, their high sensitivity CRP is low you know CT coronary angiogram, no vascular disease, you know, these things where you go like their endothelial function's probably pretty good and their brains working pretty good.

[7:18]I'm probably more likely to go, I think it would be reasonable to do HRT, somebody who's got, you know, more changes where you go like look, you're looking a little more like you are having some significant aging. we might cause harm, but I don't have any science behind that.

[7:34]But that's kind of my gestalt. But this is an individualized discussion with women. And just briefly, Estradiol should be done topically, whether you're using Bi Est cream or most of my patients just on the commercial FDA-approved patches, doses 0.025 milligrams per day, up to 0.1 milligram per day.

[7:53]Monitored levels, we tend to target 40 to 70 on the estradiol. Progesterone, in my opinion, is it should be given to everybody. It's not just because you have a uterus that or don't have a uterus that you need that. It's it's kind of a silly thing to think.

[8:07]That the only function of progesterone is to diminish the rate of uterine cancer if you have a uterus. It's like no, you've receptors on your brain. It's powerful. GABA agonist makes a big difference as far as normalizing sleep and mood. So it's something where it can be game-changing for a lot of women with sleep disturbance, which is very typical with perimenopause and menopause.

[8:27]So it is something where everybody gets progesterone. And that's just going to be oral FDA-approved micronized progesterone. And then the FDA approved patches most of my patients. And then I think we had the discussion also on testosterone. So with men on estradiol, it's actually important One of the downsides of men getting low testosterone is that they don't make as much estrogen because it's it comes from the testosterone.

[8:53]So our goal with our men is to kind of in the mid-20s is where I like most men. You know, if you if they bump that up really high and get into above the mid-30s, you start getting Gynecomastia you know, growing breasts, you start getting you know, excess fat in areas that would be typical of where a woman would deposit them around the hips and thighs and so forth.

[9:15]So there's a sweet spot there. But if you're really low, I find that men actually have like mood disturbance, but you also have excess osteoporosis too, cause it's protecting you from the same things that it does with women. So for both genders it is something that we're wanting to make make sure that we have an optimal level.

[9:33]And interestingly the male level you're saying twenty five and the woman you're saying optimal is forty to seventy. It's surprisingly not that much different. but that that's where our goals are with this and we can I'm not sure if you want to talk around talk about testosterone supplementation and men and I guess we can do men and women.

[9:50]Yes do that yes, so Dr. Susan Davis is an interesting doctor. She's in Australia, and Australia is the only country in the world that has a compound of testosterone commercially available that's made specifically for women. So and she's been the one who's driven a lot of the research and she she's got some great podcasts some of the best ones are with Simon Hill on his podcast called The Proof.

[10:17]There's he did a series with her which is worth listening to if you're a woman and interested in HRT, just kind of going through the details of why HRT is sensible, but also why testosterone is sensible I'm not gonna go through all the stuff. It's like, you know, it's a four I think it's like four hours of videos, but it's really, really good science and really clever physician who's an endocrinologist going through this.

[10:40]It was it was a lot of what I learned was from her with those series. I think that in general It's an optional item. It's something where women have a level of testosterone normally. I tend to target, you know, somewhere in the free testosterone, you know four to eight level you know, probably on the lower side of that in general, is going to be reasonable.

[11:02]I do see a lot of my women who are pre-menopausal have as low as two So maybe something where I'm targeting a little bit higher than what's needed. I've not had, you know, issues with people, you know, growing facial hair and getting you know husky voices and this type of stuff with targeting this doses for women tend to be in the four to ten milligrams per day topically.

[11:24]I tend to just do it as a topical cream. Where with men typically our doses are going to be, you know, fifty to a hundred milligrams per day. So, you know, big difference in dosing if we're doing topical testosterone, which I've tended to favor just for for ease.

[11:40]You know, you can do injectable. you know, women oftentimes you're gonna do like, you know, five milligrams a week injectable you know, men oftentimes you're going to split it up and probably the most typical doses in the, you know, thirty to forty milligrams twice weekly or you know double that weekly if you're going to do the injectable testosterone cypionate but you know our goals with men are going to be to tend to be in the you know fifty percent tile or higher.

[12:09]And I think that's something as far as you know well-being, lean body mass, osteoporosis and a lot of men who are low, they go, you know, if I supplement, I you know, am I gonna get roid rage? Is this and no, if you have low testosterone, you're likely to actually be moody and unstable And when we put you back into a normal level, you're actually gonna be much more stable.

[12:29]This kind of roid rage is you know is yes, if you end up suddenly taking a thousand milligrams of testosterone injectable each week. Yep, and that's what our weightlifters do they'll take huge amounts of growth hormone, you know, ten times the physiological level, they'll do ten times the physiologic level of testosterone.

[12:47]And yeah, absolutely but normalizing testosterone is actually helpful from a mood standpoint and I think with men, you know, our normal levels for free testosterone are typically kind of eight to twenty depending upon or twenty-two depending upon the assay. I tend to like to see people in the, you know, fifty percentile or higher.

[13:09]and you know, I get a lot of men that are coming in with you know level of you know, four where it's abnormally low And then the issue is sorting out. Do you have an issue where you have primary testicular failure, which is the minority? Or do you have a situation where your brain is not telling your testicles to make enough testosterone?

[13:28]And that's the most common situation. And that's where we don't use testosterone directly in most of my men. You end up doing things to bump up the effects of luteinizing hormone, or actually to make you produce more luteinizing hormone, whether it be in Clomiphene, Clomiphene gonadorelin Or if you end up doing injectable HCG, which is the pregnancy hormone, which interestingly to your testicle looks exactly like LH So you can inject that and it will stimulate your testicle to make more testosterone.

[13:58]But testosterone for men is a last option because you enter something which is irreversible or you get testicular atrophy and so forth. And if you can make your testicles make more testosterone, which most people can, that's a much better route because if you stop stop doing it, you just go back to how you were.

[14:16]But if you end up do doing a testosterone supplementation, you stop doing it, you end up being worse off because your testicles now are able to make even less than what they were able to before. so and the other thing is testosterone is a controlled substance and that ends up being something where if I have somebody fifty and I'm strong them on this, you know, who says that they're going to find a doctor ten years from now who's going to go, Yeah I'm happy prescribing this controlled substance and thinks that is reasonable for you.

[14:42]So it's much better to do the things to stimulate production. But with you know, with women it's gonna be direct supplementation. And I think these things are beneficial as far as, you know, brain health and function, beneficial as far as you know osteoporosis lean muscle mass, insulin sensitivity, all these things, as long as it's in a physiologic level, because people look this up and you go, you know, you bump your testosterone way up.

[15:06]Yeah, it worsens a bunch of things, but having it in a physiologic level is important and it's important also to not measure You have to measure your total testosterone, but that's not what you look at as what the free is, because I have patients that have a have a total testosterone of eleven but that's not what you look at as what the free is, because I have patients that have a have a total testosterone of eleven hundred and are low on their free testosterone.

[15:26]And you go, How can that be? Well, there's sex hormone binding globulin and that gets higher as people get older and it binds up all that. So you can have a high level, because my testosterone's like 220, which is low. But my free testosterone is like twenty where I'm at the kind of upper limit of normal with that low total testosterone, but that's because I have very little sex hormone binding globulin.

[15:47]So it's important to look at the the free, not the not the total. And I see so many primary care doctors who aren't specialists, have any training in hormone replacement. You know, somebody goes, I want my testosterone measured, they just measure the testosterone then you have no idea do you have a active amount that's normal or not So you've got to have a free testosterone to understand whether you're low or normal total testosterone is absolutely useless in isolation because you have no idea how much sex hormone binding globulin you have.

[16:18]Does your free testosterone percentage changes over time? other than long age changes or like would you recheck it often? Yeah, I think that it's something where for men who have a normal level, I'm going to check them yearly. it's not gonna be a quarterly test it's unlikely that's going to rapidly change for men who we are supplementing or doing something to stimulate production of testosterone early on, I'm going to probably check every six weeks until I get it normal and adjust whatever we're doing.

[16:51]And then once we have it stable, probably do it at three months and then probably just yearly at the point that we're saying look we've got some good stability with what we're doing But it is something, it's just like thyroid hormone where you know when you're adjusting things you know kind of checking every four to six weeks and just adjusting things rather than letting it run longer than that.

[17:10]You don't gain anything by doing, you know, by saying, I'll check it in three months or six months. If you need an adjustment, it's evident within four to six weeks. Okay, very interesting Yeah, I have many friends that are around my age that are also like toying with the idea of going like a bit supra physiological testosterone.

[17:28]So it's I know it's a a very hot topic these days in the longevity space. Is it's a good way to age yourself prematurely, is one of the things because you definitely it's interesting these weightlifters doing what they do. You know, part of the protocol when you start into growth hormone and testosterone is that you're your starting salvo is a 100 milligram 100 hundred units of Lantus insulin every day.

[17:53]because that's probably still not gonna control your blood sugar when you're doing 18 units of growth hormone plus you're doing, you know, a thousand milligrams of testosterone every week is like your blood sugar's through the roof, your IGF-1s through the roof, you are rapidly heading into, you know, either getting a cancer or aging very quickly combination.

[18:14]But the fact that your standard protocol with these guys is straight off the thing they know they're gonna need at least a hundred units of long acting insulin per day. It is just shows how unhealthy it is. yeah, fascinating topic, this one. So let's move on to the last hormone for today thyroid Yes.

[18:31]Thyroid is a great one because the current targets in the US are are incorrect by my estimation and the the happy spot for TSH is 0.5 to 1.5 our most of the labs are zero it’s going to be 4.5 or less is where they will flag as abnormal.

[18:56]I think in Europe the approach has been to flag at 2.5 is where where they're saying if it's above that it's abnormal. So in general, I will tend to use 2.5 as a trigger if somebody's over 2.5 on their TSH is a trigger to say we should consider starting some thyroid hormone in order to normalize things.

[19:19]And depending upon how abnormal they are, the dosing will change. Usually we start at a low dose and monitor every four to six weeks until we have a TSH that's at target I usually measure the free T3 and free T4 Most people get supplementation of just thyroxine which is T4 The main reason why that's been chosen rather than T3 is that has a long half-life and it's very stable It's kind of seven or eight days half-life So it's ends up being a very stable source of the thyroxine where with the T3, which is cytomel you'll end up having, you know, it's a much shorter acting.

[19:55]So some people, if you're giving a significant dose, are going to get, you know, palpitations, even atrial fibrillation, if you're giving big doses of it so but a lot of times some people do better on desiccated thyroid like NP thyroid or armor thyroid where you have a mix of T3 and T4 in a physiologic manner.

[20:14]So we definitely find people that you know do well on the trade name synthroid and then you put them on generic and then you know their values go wild. We have some people that do better on Armour or NP thyroid so there's a lot of kind of trial and error with this as far as where people feel good with this.

[20:30]But typically the the TSH targets are going to be 0.5 to 1.5 is a short story on this and then as far as how we normalize it and test, you know, kind of every four to six weeks after a change And then once you have things stable, I'd say just check it at three months and then yearly with that once we have a stable dose but you know also talking about, you know, do you have Hashimoto's thyroiditis is another thing and looking at the thyroglobulin antibodies and thyroid peroxidase antibodies and so forth and seeing if you end up having autoimmune issue going on also can drive your CRP up that is something where it's fairly common where your thyroid gradually gets destroyed.

[21:18]And it can be a challenge there's all types of different approaches that people take, which is probably beyond today's scope if you have have that But it's reasonable if you're getting hypothyroid to at least once check the antibodies and see if you've basically got destruction of your thyroid going on And also I think it's target of, you know, at least getting a palpation of the thyroid make sure there's no nodules or anything that requires you know, an ultrasound to take a look at but you know, it's pretty common.

[21:46]there seems to be more common in women, both with the Hashimoto's thyroiditis and with hypothyroidism. But something worth monitoring because if you're low on your thyroid, that's a very bad thing for your brain. so I think overall it's one thing that's easy to monitor and is remarkably common.

[22:03]Would you have like any signals other than testing for those like biomarkers, but any physical symptoms? Yeah. So fascinatingly, so you know, you can have, you know, slower heart rate, So fascinatingly, so you know, you can have, you know, slower heart rate, you can end up having very low energy, you can kinda have waxy, thickened skin oftentimes even if you test your reflexes, I'll be sluggish the other fascinating thing is losing the lateral third of your eyebrows is one of the things So you look at somebody and you go like They don't have eyebrows on the lateral third.

[22:39]That's actually a physical finding which is quite common for hypothyroidism, which is interesting. Lateral thud as in it drops Okay, interesting you'll see somebody, you know, it's like, you know from here out they've got they've got a lot loss of so so I mean there's some interesting things, but a lot of times it's kinda, you know, sluggishness, depression, weight gain, because your metabolism's slower, all those types of things.

[23:05]So a lot of you know, certainly if you're taking somebody in who's having issues with depression checking a thyroid level is certainly part of the initial work up to make sure they don't have hypothyroidism. One of the best stories I had as a medical student, a third-year medical student, I had some fellow I was doing the alcohol and drug rehab at the Veterans Administration in San Diego.

[23:29]And we had this guy come in who was basically a drug manufacturer of amphetamines, and he just lost his energy. And anyway, I did his intake And as part of his intake, we measured, because he was just worn out going, I can't do this anymore. I need help, you know, and so he was hypothyroid.

[23:47]So two weeks into his one-month stay after I'd started him on thyroid hormone, he felt great enough and he realized that he actually didn't have a drug problem. He needed to get back out there, make his make his drugs his problem was actually hypothyroidism. So he was up and back making his drugs.

[24:02]So I'm not sure I benefited society by fixing his hypothyroidism, but true story. That's a very cool story. all right, I think we covered everything any last advice on all these topics, so we're good Yeah, I think these things are all complicated and can be a little bit overwhelming.

[24:24]And it's just important that you get the the right test done without over testing and make sure that whether where there's abnormalities that you address them sensibly So having somebody give you some good guidance on what to test and what our targets are, I think is helpful. And I think these this is why these sessions are helpful is that we at least give some framework to that and potentially how to respond to to that so that you know people have an understanding of you know what's going to be best practice as we understand it today and you know probably what probably what I say today there is probably gonna be a little bit different a couple of years from now

[25:00]because science keeps changing. Yeah, as long as we keep ourselves updated, it's great. Well thank you so much for your time, Grant this was really like a fascinating topic. So I'm learning a lot every time. I know you're like super busy, so thank you again for all your time on on behalf of all the members in the Phoenix community and for myself.

[25:18]Very good. It's been a pleasure. Thank you.