Jay Feldman 0:05
Your thyroid is affected by everything in your environment, from how many carbs and calories you eat to the types of fat you eat. And this information is vital if you trying to reverse hypothyroidism, we're going to be going over all this information and more in today's episode of the energy balance podcast, a podcast where we dig into the physiology behind the bioenergetic view of health and teach you everything you need to know to maximize your cellular energy. Today's episode is part 2 of our hypothyroidism series, where we'll be going over and discussing the factors that affect thyroid hormone production, conversion, transport and uptake, as well as how high TSH levels can cause damage to the thyroid gland, high carb diets versus low carb diets for thyroid health, why restricting calories is not the way to go if you're struggling with hypothyroidism, the effects of PUFA or polyunsaturated fats and endotoxin on thyroid hormone activity and the problems with both deficiencies and excesses of iron, iodine and vitamin A for thyroid health. As always. If you'd like to take a look at the show notes, where we'll link to the studies and articles and anything else that we reference throughout the episode, head over to Jay Feldman wellness.com/podcast, and with that, let's get started.

All right, so let's start digging into all of the factors that affect thyroid hormone production, thyroid hormone conversion, thyroid hormone transport, thyroid hormone uptake, basically all of the aspects of our environment that we want to be tuned into, and things that we want to adjust in our diet and otherwise that are going to affect our thyroid state, and that can drive a hypothyroid state or euthyroid state or hyperthyroid state. Potentially, this is there's a lot to dig into here, and I think it's particularly important. I think this is kind of the the meat in terms of the thyroid physiology, that's extremely important to discuss because, yeah, this is where we're going to get all of our recommendations from, as far as what we actually want to do with diet and lifestyle supplements for thyroid issues. So there's a handful of different factors that are going to be important here. The biggest and most central one, which we have already alluded to when talking about the broader context of thyroid hormones and hypothyroidism, is energy availability. And the kind of other flip side of that is stress, physiological stress. And what we're basically going to find, and we'll dig it through the details, is that any situation with low energy availability and increased physiological stress, and this can be states of caloric restriction, where we're dieting or just trying to restrict calories so we can live forever again. We've talked about that. Yeah, that too, whether we're trying intermittent fasting or other long term fasts, if we're doing excessive amounts of exercise, if we are dealing with any sorts of other issues that could be inhibiting our energy production or driving stress, this could be environmental toxins, which we'll discuss. Could be a lack of nutrients. It can be a lack of sleep. It could be, yeah, I mean the presence of excessive amounts of certain nutrients, the presence of heavy metals, all these factors that drive a low energy, high stress state are going to at different points, basically cause low thyroid activity. And so we'll kind of talk through each of these and what parts of the thyroid system they impact and how that translates to our thyroid health. So when it comes to the general physiological stress state, there's a couple things that will happen. One is it'll actually directly inhibit the thyroid hormone production at the thyroid gland. Another is that it's going to reduce the conversion of t4 to t3 via activity on the d1 and potentially d2 diodense enzymes, depending on the tissue. And then the other piece is that it'll tend to increase reverse t3 production via the activity of diode nice three. So we'll talk about different factors involved in physiological stress, the main ones being the stress hormones, and then kind of secondary ones being the inflammatory cytokines and how they affect the conversion of thyroid hormones and production. But again, the basics, which we just described, is that anything is going to drive the state is going to lead to reduced thyroid hormone conversion and reduced thyroid hormone production. That includes sleep deprivation or or not good sleep. Low carb diets, low fat diets, which we've talked about, how those can cause increased stress as well. I'll link back to that episode and research there, alcohol, low calorie diets, caloric restriction, excessive exercise, all of that is going to drive these, these issues. Yeah. At the very basic Well, I guess, to start with the stress hormones and the cytokines, the stress hormones we have, the glucocorticoids, the the we have glucagon and we have epinephrine. And for the most part, the glucocorticoids are going to be most responsible for reducing the thyroid hormone production at the thyroid gland, and they do this, as we mentioned earlier, in a couple ways. The first thing they do is they reduce the production of TRH from the hypothalamus, and so that's the one that tells the pituitary to increase TSH production. The other thing that they do is they reduce the pituitary response. So this is directly in the pituitary. They reduce the response to TRH, so this reduces TSH production as well. So in those two ways, we have reduced signals telling the thyroid to produce thyroid hormone, as we've talked about, whether you have high cortisol or you're using some sort of glucocorticoid medication, this can create a state where you have low TSH, but you're still very hypothyroid, because your body's still low in thyroid hormones. But it's not proper. It's basically inhibited the feedback signals the glucocorticoids have be by exhibiting these effects, the other thing that they'll do directly in the thyroid gland is they'll inhibit the thyroid peroxidase, as we discussed, is the primary enzyme required for thyroid hormone production, and it also inhibits one of the steps of thyroid hormone production, which involves the hydrolysis of the colloid in the follicular cells, which is one of the main steps needed for thyroid hormone production. So that would be the the main way that the glucocorticoids affect thyroid hormone production. Now the other side is the inflammatory cytokines, the interleukins, interleukin six and ou can one are pretty commonly discussed, TNF alpha, interferon gamma. These are all inflammatory cytokines, and they also have a very similar effect to the glucocorticoids, where they inhibit the pituitary response to TRH, and then they also uniquely inhibit the conversion of t4 to t3 within the thyroid gland. So this is, you know, we've talked about things that will reduce peripheral, peripheral production of t3 and we'll discuss those in more detail. But this is something that actually reduces the t3 production into thyroid gland, and so that'll lead to it, you know, producing that the very few micrograms already that it's supposed to produce won't be produced in the context of high amounts of inflammatory cytokines.

Mike 7:22
Yeah, and I think this, this all kind of makes sense, where you see glucagon, cortisol, adrenaline are starting to decrease thyroid hormone signaling, because you're essentially having hormones that are saying, Hey, we don't have exogenous, adequate, exogenous substrate coming in, or we need to mobilize tons of substrate for a stressful event. And so the body saying, Okay, let's let's not then drastically increase our metabolic rate when we have these increased demands that we already have to mobilize substrate to and that that kind of makes sense, right? Because you only have a limit. You have the body has a limited amount of resources, and it has a limited ability utilize those resources in in like a period of time. So basically, the body has to fine tune the regulate what it's going to do to meet its demands. It's not going to drastically up regulate the energy output by all the cells with thyroid hormone, if it's under a stressful situation and it needs to just drive the the substrate that it's liberating to specific tissues to meet that demand, or if it's chronically eliminated, limited on its the energy coming into the system. So it makes sense that these things work in that capacity. As far as the inflammatory cytokines, you may be thinking, well, this is kind of a like, Why do are the inflammatory cytokines having this effect? And it's because the inflammatory cytokines, they're directly integrated with the stress hormones. You start to see that il six, tumor necrosis factory output, etc, will raise the stress hormones, like, like the glucocorticoids. But the other thing that they do is they are also altering energy metabolism as well. So they're basically, they the they're saying, Hey, we have this inflammatory stimulus, maybe we have an infection, maybe there's a tumor, etc, and we need to, we can't just drastically upregulate metabolism and all these other areas, because we kind of have to deal with this, this situation. So again, it's a fine tuned system that's adjusting to the constant metabolic flux that the that the body, the organism's experiencing on a regular basis, and that's why they're all intertwined. And this is where you start to see that it's not just knowing the thyroid axis, but it's understanding, okay, hypothalamic pituitary axis, understanding the sympathetic nervous system, understanding what's going on with the steroids, and understanding what's going on with the immune system, and how those pieces are interacting on each other, and then what's driving these other these other pieces as well, right? It's you can measure tumor necrosis factor alpha in. You can go and say, okay, like, this person has elevated tumor necrosis factor alpha. But the question is, why? Because, unless you start to address what's going on to that extent, like, why is that being elevated? Is there a gut issue? Is there and is there low grade and. Know, toxemia, is there, me a tumor, or something along those lines, until you start to figure out this underlying issue. If you can't, like, just throwing thyroid hormones or throwing these other things at the system, aren't necessarily like, gonna and solve the problem in and of themselves. You can help to fix what's going on in the thyroid axis, but you're not gonna help to minimize these other elements that are constantly being upregulated from whatever this external stimulus is. So it's really important to get to those roots, and that's why, when we in the beginning, the way we preface this is that hypothyroidism is not the problem entirely itself. There's something driving the hypothyroidism, and the question is, can we fix these underlying factors that are driving this lower thyroid state? And also, then, it's not that you have to do either or, but you can also fix what's going on with the thyroid as well. So like, you can take a multi pronged, multi pronged approach, but it's really important that you you fix these underlying pieces as well, because you can hop on thyroid hormone. And I've seen people do this. I've seen people do this in certain spheres, like some of the bodybuilding spheres. It's like, oh my, my hormones are low. Let me just supplement all these external hormones. But it's like, I'm on low carb, and I exercise eight days a week, and I I, I like driving these like, heavy stress. And then it's like, get weird responses to these things, and it's like, you're not you can. You're on thyroid, you're supplementing thyroid and testosterone, but your glucocorticoids are elevated from all these external life factors. And then then you're wondering why things are aromatizing And why your thyroid hormone is not working how it should. It's because those other underlying pieces weren't corrected. And this is the importance of undersight, understanding the integration of these things, and understanding that the inflammatory cytokines will directly modulate thyroid so they do it directly at the hypothalamic pituitary axis, and then also directly at the thyroid gland as well. And then they are adjusting conversion peripherally. Because they're there, they could be impairing, say, it's an endotoxin driven situation. Well, now you're having impairment at the liver. Tumor necrosis factor alpha itself can drive increases in cholesterol production alone. So the May, that's where you start to see, like understanding the integration pieces becomes really important instead of understanding things, oh, TSH is elevated. So you must is, you must be able thyroid. Oh, TSH is fine. So you must be euty, right? It's like, no, there's way more to the picture. And it's really important to understand all of these pieces in an integrated manner.

Jay Feldman 12:30
Yeah, absolutely. And I don't think we clarified specifically what the inflammatory cytokines are, but just in case anybody is not familiar with those, basically, these are signals that signal inflammation. That's why they're called inflammatory cytokines. They're just chemical messengers, essentially that are signaling that state. So it's another way of saying that inflammation and distress, including in all the contexts that you were talking about Mike, is going to inhibit the thyroid hormone production by inhibiting the signaling and also the actual production within the gland. And then, as you mentioned, as well, these things do affect conversion as well. So the in the case of the production and the stress hormones, it's mostly cortisol that's going to have that effect. But when it comes to conversion, all of the stress hormones, the glucocorticoids, mostly cortisol, epinephrine and glucagon will all inhibit the conversion of t4 to t3 and increase the conversion of t4 to reverse t3 and so this is that situation where they inhibit the deiodinase one and stimulate diode and Ace three, which is what we discussed earlier, in terms of the regulation and the inflammatory cytokines have that exact same effect. Again, pulling out the larger context, I think, I think we're making the point. But it's not like these things are random. There's this. The predominating view in biology is that it's all based around this randomness. But these things are all extremely cohesive responses. It's not just random that they happen to inhibit d1 and stimulate d3 or happen to decrease thyroid hormone activity. So of course, all happens to be problematic for a thyroid. It is directly due to the fact that it is a response to our environment, and we are adapting to like these are the ways that we adapt to our environment, in this case, in terms of the thyroid.

Mike 14:18
Yeah, and just to Well, a couple things, the it's not like these things are kind of, as you're saying. It's not like these are just a series of facts, like glucagon does this? Adrenaline does that? It's like there's a coordinated picture and response in context to understand these things. And that was, I think that was one of the largest values that pushed us with like Ray's work, because it provided that context to understand these things in terms of energy metabolism. Now the second piece I want to mention is, but Jay glucagon isn't a stress hormone...

Jay Feldman 14:52
Yes, yeah, and except, if you look at all of its effects...

Mike 14:56
Yeah I was gonna say, except all the, go ahead. Finish. Finish.

Jay Feldman 14:59
Let's. Yeah, except if you look at all of its effects, it is, you know, it does everything a stress hormone does. So looks like a stress hormone and quacks like you're referring to a couple episodes we did in a discussion based on some some comments from Robb Wolf, where we did talk about the elevation of glucagon on a low carb diet. We will be talking about low carb diets and their effects on thyroid hormone production and conversion. But yeah, that is we talked in more detail about glucagon as a stress hormone in those episodes. So I'll link to those.

Mike 15:33
Yeah, yeah. And something I want to point out here is that there's a couple things. So the first thing is, you may not see such a massive effect of glucagon compared to something like the glucocorticoids, and I think that's and again, I might this is kind of like me theorizing and putting into my own context here, but the glucagon like that's a norm. It's, it's a normal hormone that you're gonna up regulate between meals. It's kind of like a short term signal of what's going on with energy, whereas the glucocorticoids are a much stronger response in terms of long term energy balance, in terms of like towards the depletion side, and then also inflammatory signaling. So glucagon, I think it like, it ties into those different perspectives, and it's kind of bridging the gap from like that longer term stress to just like this, shorter term adjustments in energy, energy balance. But so like, I kind of see them as like a like a tiered response, and this why you don't see this massive effect from glucagon, like you do with glucocorticoids. But there's still definitely effect, definitively, in effect from glucagon in terms of signaling, lower thyroid hormone function, et cetera. The second piece that I did want to mention is just, it's a little bit tangential, but the sympathetic nervous system and thyroid kind of go hand in hand with each other to some extent. But the way that they go hand in hand with each other is that the thyroid hormone makes the cells much more sensitive to sympathetic nervous system innervation. Do you actually need less sympathetic nervous nervous system intervention? You need less adrenaline and noradrenaline to have an actual effect on the on on the target cell if you have adequate thyroid hormone function, whereas in states of hypothyroidism, what you see is this drastic upregulation of the sympathetic nervous system and then the gluco the catecholamines, like noradrenaline and adrenaline. So because a lot there's kind of in the research, can be like a little bit if you're first going through it, you can be like, a little bit confused. I know for me it was like, a little confusing at first to see this interaction, and then when you there's some interesting studies that start to put this into perspective. And basically you're showing that thyroid hormone allows you to get by, essentially, with less of the catecholamines so and on the flip side, something that I think this plays in part, with people's responses to it, maybe initially, is that if you're coming off low carb, if you're coming off keto, carnivore, anything like that, intermittent fasting or like, low calorie dieting, and you have lower thyroid function, and then you try to just implement t3 or like, or NDT or active thyroid hormone, and you get a really bad response initially. I don't think that's because thyroid is just bad for you. I think it's a combination of having lower thyroid hormone function and then driving a high sympathetic nervous system, high Catecholaminergic state, which these things are known to do, and then trying to put thyroid hormone on top of that. And it's like now the cells are going to be more responsive to this higher resting tone of sympathetic innervation, and that's what causes the people get severe anxiety. They can get palpitations, things along those lines and that, I think that's kind of what's driving that situation for people. And again, this speaks to addressing all of the other situations, the underlying context around nutrient dense diet, having carbohydrates in your diet, not having a 20 hour fasting window, and trying to get your 2000 or 3000 calories a day into a four hour window, etc, fixing those things, and then, you know, kind of seeing where the chips fall, and then bring thyroid hormone. Now it doesn't mean that that it may not be helpful to use maybe earlier, but it's just something to keep in mind is that you may respond better once your ducks are in a row. Then if you kind of just, like, try to just throw it on board, because you hear Dr Pete or Georgie or Danny or whoever talk about how strong thyroid hormone is, like, Oh, I'm gonna just take, you know, sign a mail from pharmacy at El Nino whatnot. It's like, yeah, I just, I put that out there, because I have had quite a few people who have had a bad experience at first, and then we kind of work through things, and then eventually they're like, oh, now I'm, you know, I tolerate it much better, like, feel really good with it, etc. So it's kind of a just some perspective to add there.

Jay Feldman 19:57
Yeah, yeah, keeping that context in mind, of course. Which? Research is the general suggestion. But people can, you know, take those things and just get excited about the substance, which is understandable. So to kind of go backward, I want to talk through a couple things you mentioned. One was the situation where thyroid hormone increases sensitivity to stress hormones, essentially. And as you were saying that might, you know, it might sound like that's a negative thing, but in reality, what that means, and what you're getting is that means that we get by on less stress hormones. Anytime we have stress, we don't need as much glucagon, adrenaline or cortisol. And that's so important because it is the presence of those messengers, those signals, that downregulates our metabolism and our function in every single way. And it's very parallel to, for example, TSH. Like very high TSH levels come at a cost as well, which we'll talk about. And so anytime that we are increasing the stress signals, which we talked about in terms of hormesis, but now talking about terms of thyroid and in terms of the increased sensitivity here, anytime we're increasing those stress signals, and the amount of them, the worse off we are. And so it's better to be able to have the same effect, which with much less of those stress hormones. That'd be a very good thing. So that's part one, and it does dovetail directly into what you were saying with glucagon, which is that glucagon is like the lower version. It's the lower version of the stress hormones relative to epinephrine and cortisol. And so it's not going to have as dramatic of effects as something like cortisol, of course, and it's going to be the first one released. It's like the first layer of that stress system, and then it just gets deeper and deeper. And so just because it's not as strong as cortisol doesn't mean it's not a stress hormone or anything like that. But yeah, you were just kind of making some clarifications there. Yeah, yeah. The last thing I want to mention when it comes to stress is another byproduct of physiological stress that affects thyroid hormone activity through another mechanism, and so that is the level of free fatty acids. So anytime we increase stress and increase the production of glucagon, adrenaline and cortisol, one of the main things they do is they shift us toward a fat burning state, the one that we're told is is supposed to be ideal. But again, we've discussed many times why that's not the case. One of the reasons it's not ideal is because it causes a state of high free fatty acids. And one of the things that those free fatty acids do is they actually displace or inhibit the binding of thyroid hormone to the thyroid binding globulin, so this prevents it from being delivered to the tissues that it would need to to have its effect. Now, interestingly, this is something that has been found to happen if the free fatty acids are polyunsaturated, but the more saturated they are, the less of an effect this has. So if you have very saturated free fatty acids. It's actually not going to inhibit this effect anywhere near as much, or inhibit the binding anywhere near as much, but the more unsaturated it is, the more of an impact it'll have here. So again, we already don't want to be in that stress state. We talked about the stress hormone. So even if you're only liberating saturated fats, it's better. It's still not great. But if you're especially liberating less saturated fats, that's also going to inhibit thyroid activity even further.

Mike 23:08
Yep, yeah, I don't necessarily have anything directly to add to that one. I think it's pretty, pretty clear overall. I mean, you we could go into a tangent about the effect of poof on cellular structure and membranes, but I don't know if we've already done videos on that, so you just link to it.

Jay Feldman 23:24
Yeah, yeah, definitely, definitely. So there are, like, kind of the next piece here, the flip side of the stress side is the lack of energy side. And we talked about this earlier in terms of the uptake of thyroid hormones being dependent on energy. And so this is, of course, a situation where a lack of energy is going to inhibit the cell's ability to take up thyroid hormone, which, of course, is basically a hypothyroid state. And so there's a quote from this paper titled thyroid hormone transport into cellular tissue, and it describes this pretty clearly. So they state, since the transport of thyroid hormones into the cell is largely energy dependent. Any Condition associated with reduced production of the cellular energy. IE, mitochondrial dysfunction could also be associated with reduced transport of thyroid hormone into the cell. Furthermore, the transporter for t4 is much more energy dependent. It requires more energy than the transporter for t3 even slight reductions in cellular energy, ie, mitochondrial function, can result in dramatic declines in the cellular uptake of t4 while the uptake of t3 appears to be much less affected. So the most important point here is just saying that anything that disrupts energy production can inhibit the uptake of thyroid hormones. The reason why he's making this distinction between t4 or t3 or at least, why He's emphasizing it is because this is it comes back to how we want to treat the state where, if somebody's in the state, using t3 is much more helpful than using t4 or at least, using a combination is much more helpful than using only t4 so we'll talk about that later. But that's why he's emphasizing that. Then the last quote here from that type. States reduced t4 and t3 transport into the cells in peripheral tissues is seen in a or with a wide range of common conditions, including insulin resistance, diabetes, depression, bipolar disorder, hyperlipidemia, chronic fatigue syndrome, fibromyalgia, neurodegenerative diseases, migraines, stress, anxiety, chronic dieting and aging, and so to see that in all of these states there's reversed there's reduced uptake of the thyroid hormones into the cell, is just some very clear evidence that of the of a couple things, one, the fact that a lack of energy drives those other states, and mitochondrial dysfunction drives those other states. Two is that those is that that is going to actually cause a hypothyroid state, that lack of energy, and that. Three is that there's a direct connection between hypothyroidism or low metabolism and all of these other chronic health issues.

Mike 25:55
Yeah, and I think the key piece here is that it's kind of like this weird cyclical situation, right? So if you have this dysfunction going on that's impairing energy production of the cells, then you're further less able to uptake that thyroid hormone, and so then that, then that's even lower energy production itself. Again, this isn't, this isn't, I don't think this is necessarily like because the body's trying to self sabotage itself. But say, for example, let's take, let's take diabetes, or let's take, like a metabolic dysfunction, if you have a significant metabolic dysfunction and the cell is basically stuck in this high amount of fatty acid oxidation, even incomplete fatty acid oxidation, and lowered ATP levels. The thought if the cell, the the cell may not be able to then handle a push on that metabolic state, particularly because if it's running this high amount of fatty acid oxidation, it could be driving this large volume of ROS so it's basically could be, like a protective mechanism of the cell to kind of be like, Look, I can't, I can't handle this, you know, this situation anymore. It's kind of like you have a kid at gym class. You make him do 100 push ups. He kind of pooped. And it's like, all right, gym teacher comes in and whips him to do 50 more push ups with teeth. It's like, kind of, that's what it is, I would assume, to throw t3 on some of these cells that are like struggling to that extent. You can kind of maybe push them over the edge to an extent, and so they're kind of down regulating their ability to respond to the hormone, and then up regulating the conversion of that t3 into reverse t3 and being like, All right, we need to chill out. I need to go take a break and get some water. And need to, like, sleep the night, slow and not do push ups. So that's kind of, that's kind of the way I see some of these, some of these things. And again, this isn't just like, what's with all of these syndromes, insulin resistance, diabetes, depression, bipolar, et cetera. We've talked about numerous elements where some of these things are driven by stress hormones, or possibly driven, for example, diabetes being driven by like, endotoxemia, insulin resistance, being driven by low grade endotoxemia. Those up regulating those cytokines and that affecting the energy metabolism of the cell. And then, like, all the hormonal axis across the board. So it's kind of, again, it's not just this random energy dysfunction at the cell and then thyroid then the cell just doesn't respond to thyroid hormone. It's this coordinated, coordinated responses to things going on in the environment. And why environment? I mean, not only external things, but also internal things going on in the system. That same study that you as an example that you discussed, Jane, think that was the whole Tor study they they talk about in that study that after they did, like, cycles of dieting, and I think this was in rats, the weight weight loss occurred at half the rate, and then weight gain occurred at three times the rate, and that was a function of the uptake of the cell. So essentially the organism was exposed to this drastic caloric restriction or and basically energy restriction. It upregulated all of these, these hormones, corticoids, catecholamines, glucagon, etc, maybe growth hormone. And essentially it put the cells in like a bit of an energy depleted state, and then now they're not responding to thyroid hormone as well. And now the the system is prone toward, because the metabolic rate is lower, toward storing more weight. And so it's like, again, these, it's a multitude of responses are going on. You have the external element of lowered energy intake by basically going on these on a harsh diet, and then subsequently, you have the internal hormonal responses that are driving these changes in the metabolic state of the cells. And then there's subsequent responses to things like thyroid hormone, which can again, like that becomes like a delicate balance to reverse, but just the overall picture of how there's like a coordinated response metabolically to what's going on on an energetic level.

Jay Feldman 29:45
Yeah, yeah, absolutely. That's a really great point. And I like that study a lot, talking about the weight regain and everything. It's one we'll have to break down in a future episode. I think it's a Yeah. It's a really important one. Yeah. Yeah. So moving on from energy availability, another factor that will directly affect thyroid hormone production, and this is something that we were talking about in terms of a balance within the thyroid gland, is oxidative stress. Do you want to touch on that one?

Mike 30:16
So we kind of already touched on this one above. But essentially, in order to produce thyroid hormone, you need thyroid peroxidase. And thyroid peroxidase uses hydrogen peroxide. It uses an oxidation reaction, or peroxidation reaction, to produce thyroid hormone. So if you have a situation where you're have large amounts of oxidative stress in the body, say, and this could be driven by quite a few things, it could be driven by the excess fatty acid oxidation. It could be driven by the by like nutrient deficiency. It can be driven by the stress hormones directly. In those situations, if you're starting to increase that oxidative stress, since the thyroid hormone is using an oxidative reaction, has a large amount of oxidative stress that has to deal with, you can kind of tip that balance over to some extent, and then you can essentially lead to an excess of the oxidative stress. And then the oxidation reactions can be quite damaging to the actual cellular structures. So, and that's what you can see in in some of the states, like with uh for example, some of the autoimmune states, where you see like a larger amount of oxidative stress inside the thyroid gland, for example, in Hashimotos. And then that's that can drive damage to the thyroid gland, and you see this immune response to those damaged tissues, which we kind of talked about in the bioenergetic are the bioenergetic ideas of autoimmunity. But it's the other thing you can see is, even without an autoimmune response, if you're if you're in a an overall state of oxidative stress, if your TSH is elevated, and it's telling your thyroid produce hormone, produce hormone, and it's your thyroid gland is responding, trying to produce more hormone, is up regularly, up regulating that oxidative stress, then you can start to also see damage to the gland. And you could see like, the different problems that happen under this high stimulation of TSH over time, like cancer and things along those lines. So now it's important that, like multiple again, there's multiple elements here, like nutrient deficiencies can drive oxidative stress. As an example, copper and manganese are acquired for the for the superoxide dismutase and manganese superoxide dismutase these different enzymes, the the iron is involved in catalase and some of these different enzymes. So it's a nutrient deficiencies can drive it. The stress hormones can drive oxidative stress. The low carb, high fat diets can drive it. And then again, in the thyroid, specifically TSH, can drive that oxidative stress. So if you have a situation, say, you have somebody with Hashimotos, it may be important to have that to try to suppress that TSH, if it is drastically elevated, to take the stress off the gland, because the thyroid, as Jay, as you discussed earlier, TSH, is one of the primary stimulus to say to the thyroid into the TPO, hey, produce more hormone. Hey, make more thyroid hormone. And again, it's going to do that through this oxidative reaction. So it's really important to to look at mostly multiples of these factors with with things going on directly at the thyroid gland, because the thyroid gland is so sensitive to the oxidative stress, because it has a high oxidative burden already.

Jay Feldman 33:16
Yeah, yeah, absolutely. And we'll, we'll circle back a little bit later on and talk more specifically about the autoimmune side. But of course, this is a huge driver in that state. And as you mentioned, TSH is a main driver of oxidative stress in the thyroid. And that's a key point that I had never heard brought up until Ray Peter mentioned it. And I think it's something that's largely overlooked. There's a nice quote here from a paper titled oxidative damage to macromolecules in the thyroid, experimental evidence, and they state that thyrotropin, or TSH, the main secretory and growth stimulate stimulatory factor for the thyroid, is obviously involved in the production of hydrogen peroxide in that gland. A major meaning of that fact is that an increased production of hydrogen peroxide with subsequently enhanced formation of free radicals, especially hydroxyl radicals, takes place in any conditions accompanied by the increased blood TSH concentration. Thus TSH stimulation results in goiter formation and under certain conditions and thyroid cancer initiation via the mechanism of at least in part, oxidative stress. So yeah, this stated very clearly that the elevation of TSH itself, which is part of the adaptive response, just like the stress hormones, comes at a cost, and actually drives oxidative stress. So we this is another reason why we don't want to be in a hypothyroid state, and we'll talk about this in terms of autoimmunity a little bit later on, in terms of the damage that could be caused. One other thing that's brought up by this paper is that antioxidants don't actually resolve the issue unless there's a deficiency. So you mentioned, you know, like copper, manganese, selenium is involved as well. If there's a deficiency of those things, then restoring sufficiency is very important. But if there's not, it actually is not going to be enough to overcome for example, very high TSA. Level, and they state that here, they state that the results obtained in humans and in animal models suggest that oxidative damage in the thyroid, especially this associated with thyroid cancer, is accompanied by increased activities of antioxidative enzymes or increased production of antioxidants, what probably represents the defense mechanism. So what they're basically saying is that you already have upregulated antioxidant systems in these degenerative disease states, in terms of the thyroid, so that is obviously not sufficient to prevent that state. And this is why, if you're in that state of high oxidative stress, just up regulating those antioxidants in a larger, chronic way is not actually going to be sufficient to prevent that state. And this directly parallels with the hermesis conversation that we've had, the series that we've dug into. It very much detail where it basically, again, just highlights this idea that we do not want to be stimulating the defensive adaptive systems for some supposed benefit. Those things are there to rescue us from a less beneficial situation. They are not the solution toward improving our health. They it's again, just to be clear, we need those systems. It's really important that we have them. If we took out the antioxidant systems, we'd be way worse off. That doesn't mean we want to do things to simulate them. Doesn't mean that they are the way that we move forward in terms of health progression.

Mike 36:22
Yeah, I think it's important to so I kind of see like an element to support, right? So again, as you said, you want to make sure your nutrient sufficient, and that So, and this is where things like adequate vitamin C intake, adequate vitamin E intake, also become important. But it also like, at a certain level, it's not like you just dump in Vitamin E, and it's just like, decreases all the oxidative stress in your thyroid. So there's, like, there's multiple pieces, there's multiple elements to be sufficient in, but it's one piece the puzzle. It's not the only puzzle. And so I actually have a couple clients that I've worked with who had, um, who have Hashimotos, and they, they they're that's characterized by a degree of oxidative stress of thyroid, and we'll dig into that. And essentially some of the things, like when we when we looked at some of the testing, Selenium was actually over the reference range. So selemi selenium is something that's generally recommended for correcting things along lines with Hashimotos, and then also for dealing with oxidative stress, because involved in the glutathione enzymes, the enzymes that are produced and utilized and recycled glutathione. But in this situation, just dumping selenium, in her case, probably would have been actually more detrimental, not helpful, because she was already sufficient and to actually higher than she needed to be, and that it wasn't necessarily making that difference. So again, it's about sufficiency of these different things you want to have make sure these systems are supported so that they can help to deal with it. But another mechanism, or another piece that would have been help, that's helpful is also lowering, lowering that stimulating effect on the gland directly, which would be the TSH, which is something that that we, you know, that we worked through, that we discussed, etc, with this client specifically. And so that's what you're also seeing here with the study. Is they're talking about you basically, or alluding to bringing that TSH value down, taking the pressure off the thyroid, not needing to upregulate thyroid peroxidase and have the oxidative stress in the gland, and perhaps allowing it to, like, recover a bit.

Jay Feldman 38:20
Yeah, yeah, absolutely. That's a great point. Great points there, great example. So I want to talk about some other factors that affect affect, thyroid hormone, conversion, production, ones that we've discussed, but I want to talk about them in a little bit more detail, in terms of things that are dictating our fuel and energy availability. This will be carbohydrates, calories, and also the feeding window and blood sugar regulation and that side of things. All right, just a quick interruption here to mention that if you're dealing with a lot of the really common symptoms of hypothyroidism, low energy and fatigue, chronic pain, weight gain, digestive symptoms, brain fog, poor sleep, hormonal imbalances or any other low energy symptoms. Then head over to Jay Feldman wellness.com/energy where you can sign up for a free energy balance mini course, where I'll go over all of the different things that you can do from a diet and lifestyle perspective to maximize your cellular energy, improve hypothyroidism and resolve these symptoms and any other chronic health conditions. So again, head over to Jay Feldman wellness.com/energy, to sign up for that free energy balance mini course. And now back to the episode. So in terms of carbohydrates, there's a couple of ways through which a low carb diet is going to reduce thyroid activity. The first that's worth mentioning. So we mentioned already that the stress hormones are going to be major drivers of a reduced t4 to t3 conversion and increased t4 to reverse t3 conversion, and also reduced thyroid hormone production at the thyroid, all of those hormones, those stress hormones, are going to be. Heavily involved in a shift toward a low carb diet, and then after that initial shift, elevations, especially in glucagon, will exist long term. And this is something we talked about in that Bravo series, so I'll refer back to those episodes, so that alone will impair t4 to t3 conversion and increase the production of reverse t3 but there are some other factors as well. So one is is low insulin. So in a low carb diet, you tend to have a much lower insulin to glucagon ratio, much lower insulin, a much higher glucagon. And the insulin itself actually has some effects on the thyroid hormone conversion, where not only does insulin directly lower the production of these stress hormones like glucagon, which is one way through which it improves t4, to two, 3t, four to t3 conversion. But also it has direct effects in increasing the diode, Ace enzyme of d1, specifically, and which helps to increase the t4, to t3 conversion. So having enough insulin, again, this is not the same as insulin resistance or diabetes, which will come, you know, I'll mention that later. Is actually that's a state of reduced thyroid hormone conversion. But in the context of good glucose metabolism, good metabolism overall, having enough insulin throughout the day actually helps to increase thyroid hormone conversion. Again, this goes directly with the larger biological context that we've talked about, where carbohydrates are a major source of really efficient energy production. I'll link back to episodes discussing that. And so we want to have signals that increase our metabolism when we have enough carbs available. Insulin acts as one of those signals, as well as decreasing the stress hormones. So that's one aspect here that's particularly important. Another aspect is just that in the research looking at high carb versus low carb diets and all sorts of different contexts, you see that in the high carb diets, you you have increased t3 and decreased reverse t3 relative to the low carb diets. Again, just exemplifying that this actually does happen in practice. And there's a great paper discussing the effects of thyroid health in a low carb diet, and this is specifically in a ketogenic diet. And again, we've talked about how the few mechanisms through which this can decrease thyroid activity, we have the increased stress hormones, the which affect the conversion and production. We also have the increased free fatty acids as well displacing the thyroid hormone from the binding protein, so that's another factor as well, and then low insulin too. So this paper is titled changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy, and they state ketogenic diet, which is high in fat and low in carbohydrates, mimics the metabolic state of starvation and is used therapeutically for pharmaco resistant epilepsy. It is known that generation of triiodothyronine or t3 from thyroxin or t4 decreases during fasting periods. In their study, they concluded that the ketogenic diet causes thyroid malfunction and l thyroxine treatment may be required. Of course, we might not agree with that last part where I don't think providing t4 thyroxine would actually be helpful in this state, but if you look at the study, what they basically found was increased incidences of hypothyroidism and reduced t3 elevated reverse t3 in these patients on the ketogenic diet. In this case, they're doing it for epilepsy. So long term ketogenic diet. Yeah, do you want to, yeah, hop in here?

Mike 43:22
Yeah, I wanted to touch on a couple things. So they're kind of like, some of them are, are, like, a little funny. So, yeah, like, there's a the idea that you don't ever need an ounce of carbohydrate, ever, because your body produces own carbohydrate. Is, it's like, yes, your body will produce its own carbohydrate through glucagon and elevated glucocorticoids, and that also comes at a cost here, and what we're seeing with the lowered insulin levels and the decreased thyroid hormone production, etc. So like, again, in this this deal goes to the conversation of like, what is optimal versus what can you get by on? So the goal is to just not get by on the on on the stress hormones and to these backup pathways that are also directly lowering metabolism. There you if you look at and you understand these relationships, what the body is saying, or, I guess we'll personify the body here, which you can, I don't know if you can personify the body, but what the body is saying here is that it's you don't have adequate exogenous energy substrate coming in, and so you have to, you will have to produce this energy substrate from other components within your diet, amino acids, glycerol backbones of fats, etc. And then it's lowering the metabolic subsequently lowering the metabolic rate in response to that. Because that's that process is a like a bit of a catabolic process, right? There's only so many amino acids and so many glycerol backbones you can harvest to produce your the glucose, versus just having taking it in exogenously. So it's the body's Interesting. All right, we're gonna have to start breaking things down. We're not going to drastically increase the rate at which we're doing this, so it starts to decrease. Reset that thyroid hormone production decrease the basically takes the foot off the gas pedal for energy metabolism. That's true. You're seeing there. And the key that's what you're seeing with the insulin increasing thyroid hormone. It's the body saying, Hey, we like. It's basically like every it's the cells are having a party, right? It's like, we got glucose, we got carbohydrate, and that's what the insulin signaling, and then with the with the glucan and whatnot, it's basically saying, all right, we're all right, back to work. Boys, we gotta. We don't have any more to the substrate. We're gonna have to produce some of this stuff, kind of like hard times mentality. And as far as the ketogenic diet, I was gonna mirror, the same thing that you said is like, I don't think in this state, providing t4 just because you have alterations in TSH is on this, like very low carb diet is actually going to solve the problem. The other thing is, I would question is they, if they're diagnosing based on t4 values, then I'd be curious if they would maybe see an increase in actual hypothyroid state in these ketogenic diet patients, because if they started to look at things like free t3 values and total t3 values, and then reverse t3 values in some of their ratios, and start to see like, maybe their t4 and their TSH values are fine, but their actual t3 values and the ratios of t3 t3 or total t3 and reverse t3 are skewed so they're actually at a cellular hypothyroid state, which would if you were diagnosing based on that, perhaps you'd have a higher proportion of patients that are that are in a hypothyroid state on this ketogenic diet. And then t3 therapy may possibly be better, although, again, growing t3 therapy on this low carb diet may not necessarily be ideal, because there's a reason the body is lowering that metabolic that metabolic rate, that metabolic set point with this, with this dietary setup.

Jay Feldman 46:53
Yeah, that's the whole it is a cohesive, systemic, intelligent, adaptive response, as they said in The quote, it mimics the ketogenic diet. Mimics the metabolic state of starvation. And we know that any removal of carbohydrates mimics that state, not any but if you remove carbohydrates enough, it mimics that state, it mimics the fasting state. This response is intentional, to turn the metabolism down. And so it should be like we want that to happen. And if you want to argue that a ketogenic diet is a good thing, then you have to argue that that is a good thing, that that is that the low metabolism and hormesis and stress is what leads to longevity and health, and that's why we spend a lot of time discussing that not being the case in our hormesis series and elsewhere. So yeah, it's it's a when looking at it through that context, and seeing the effects on the thyroid. It, it makes total sense. It's it's completely clear. The one thing I do want to come back to, which I mentioned before, is that insulin resistance, in contrast with just the presence of insulin, is associated with reduced t4 to t3 conversion. Now there's a couple of there's a couple of things to note here. For one, the reason I'm bringing this up is because if any time that you suggest that consuming carbohydrates can be beneficial and that increasing insulin during that temporary time can be beneficial, you get the response, which is that, isn't that going to cause insulin resistance to diabetes? The short answer is, no. We've discussed that again, pretty extensively. I'll link back to episodes where we discussed why those things don't cause its own resistance to diabetes, but that instead its own resistance is a state characterized where you by not being able to metabolize the glucose, not being able to convert that glucose to energy. When you're in that state, the response to consuming carbohydrates is very different, and because you're not using them efficiently, and also, the baseline response is different, and we've discussed this in that Robb wolf series, which is that insulin resistance is most effectively characterized, or at least equally effectively characterized by elevated glucagon. It's a hyperglycodenemic state, and in other words, it's a very high stress state. And so of course, high stress hormones are going to inhibit t4 to t3 conversion, despite high insulin in an insulin resistant state. And so that's why at least one of the main mechanisms through which you see that effect, but also the reduced energy production, and all of the other effects of that which we talked about, the oxidative stress, the cytokines, all of those things will also lead to impaired t4 to t3 conversion. So those are very different things, consuming carbohydrates that will increase insulin versus insulin resistance. Those are absolutely not the same. So I just wanted to make that clarification.

Mike 49:30
Yeah, and I think this, this like a parallel point that kind of exemplifies us a bit, is when we were talking about obesity and the mechanisms of obesity, they talk about this idea of leptin resistance versus an idea of hepatic ATP levels. So leptin resistance is that leptin essentially tells the body, hey, you know, we we're full. It's an appetite signal. It says we're full. And what they're seeing in obesity is you have this elevated leptin signaling, but people are still. Hungry to some extent or and they're still gaining body fat despite the elevated leptin levels. So they say, oh, it's leptin resistance. What they were talking about in that paper specifically was that perhaps the hepatic ATP levels, which are actual marker of the energy production at the cells, are at a lower level which is driving an increase in appetite despite what the leptin signaling is and so diabetes, I think you can see as kind of like a parallel state where the cells have a low ATP, a low ATP level, low at particularly low glucose oxidation, increased fatty acid oxidation, and they're despite having these high amounts of insulin, they're not effectively able to oxidize the carbohydrate and produce ATP appropriately from the carbohydrate because of the dysfunction that you have going on at the cell, specifically from multiple there's multiple different layers to that, obviously. So that's where I think it's kind of like a similar situation, where it's it's like you're seeing insulin resistance and you're seeing leptin resistance. But it's not like a paradox. It's because of what's specifically going on at the cells in these particular contexts, that's driving the cells altered responses to these different hormones, so the systems become dysregulated as a function of what's going on with the cells. Because, again, the hormones are messengers. They're basically broad. It's, it's kind of like a broadcast out from different areas of the body, saying, Hey, do this. But if all the cells are having this problem, it's like, you can't really, you can't really respond. You can't respond appropriately.

Jay Feldman 51:27
Yeah, and it always comes back to energy, energy availability, energy production, as you're saying with the and with the leptin resistance, example. And I'll link back to either the citation or the places where we discussed that prior. So yeah, it's a great point to continue on the same line of thinking, very parallel to the starvation state induced by ketogenic diet. You have equivalent effects with caloric restriction, whether this is dieting or just mild caloric restriction, and whatever it is, and you see that it has those same effects on thyroid status. So and then you see the opposite too. So you also see that a high calorie diet, or an overfeeding diet, will increase t3 levels. And of course, we don't think so overfeeding is, is another one of those circularly defined words, kind of like a calorie deficit, where it's just defined by the outcome. In other words, it just a it makes it a almost impossible to use it scientifically and like where the process is is defined by the outcome. But anyway, we wouldn't suggest that somebody overeats to the point where they're gaining weight to increase thyroid activity. But the point here is that if we are getting sufficient calorie intake, it will increase t3 and if we're not getting sufficient calorie intake, it will lower t3 and one thing that is brought up anytime we bring up the concerns with caloric restriction, and sometimes when it's brought up in the research as well, is that if there are adequate micronutrients and protein, then a low calorie diet is not a problem. And this has actually not been found to be the case specifically in terms of thyroid activity. So this paper is titled effect of long term calorie restriction with adequate protein and micronutrients on thyroid hormones, and they state that long term caloric restriction with adequate protein and micronutrient intake in Lean and weight stable healthy humans is associated with a sustained reduction in serum t3 concentration similar to that found in calorically restricted rodents and monkeys. This effect is likely due to caloric restriction itself, rather than to a decrease in body fat mass, and could be involved in slowing the rate of aging. Of course, we will kind of ignore that last line there about slowing the rate of aging. We've discussed that in those aging episodes, and we've referred back to we've referred back to a couple times, but the important part here being that the caloric restriction directly reduced t3 and this had nothing to do with protein intake or micronutrients, and is something that's seen across species, not just in humans, and they were able to parse out that it's actually due to the caloric restriction itself, rather than any decrease in body fat mass or body mass overall, which is also something that's often pointed to...

Mike 54:04
Yeah, and I mean, it's not only t3 that you'll see alteration. I know they're testing that specifically here, but you can see changes in steroids. You can see changes in glucocorticoids, etc, over long with the long term exposure of with caloric restriction. And I know we did talk about there, I think you just linked to the episodes where we talked about, like, diet quality and things like that. So, but here you're basically showing, even with supposedly a decent diet, you're still seeing alterations in these hormones.

Jay Feldman 54:35
And again, it's because of that decreased that decreased energy intake so you don't have an adequate energy over time. Yeah, exactly, exactly. That's what's being sensed. And it is interesting. There's also research looking at different calorically restricted diets. The ones that are lowest in carbohydrates have the most thyroid inhibiting effect. So you'll see the lowest t3 if you're on a reduced calorie diet that's low carb, whereas if you're on a reduced calorie diet that's high carb, you'll have less of a reduction in t3 Three. So that's, of course, noteworthy as well. Yep, in terms of diet, there's one other aspect that I want to mention, which is fasting and feeding and blood sugar regulation. And essentially here we see the same thing that we're seeing in all these other situations, which is that if you go a long time without eating, then that will also reduce the conversion of t4 to t3 and increased reverse t3 we see this in all sorts of different fasting studies, both long term ones and also the short term ones. The typical 16 eight will cause these effects on thyroid hormone same way as a low carb diet. They're all working through parallel mechanisms, which of course, makes sense when considering that the whole point of thyroid status is to sense the energetic availability of our environment. So that's a another point here, and I'll I can mix to some citations in the in the show notes as well.

Mike 55:52
Yeah,I think they all go hand in hand. I think you're kind of seeing low carb, low calorie, decreased eating windows, etc, driving this the same type of profile and with essentially carbs being carbs indicating energy availability and energy status.

Jay Feldman 56:09
So the one other thing that I wanted to mention when it comes to the fasting and food or meal frequency side of things is that even if we're not fully fasting, on the other side, if we're eating relatively consistently every several hours to avoid the big spikes in stress hormones. Then that's also going to minimize any conversion from t4 to reverse t3 and maximize conversion from t4 to t3 so it all goes hand in hand, along with a good carbohydrate containing diet and all that, all the hormonal state will shift toward improving the thyroid state. So that was the last thing I wanted to mention as far as the kind of fasting, feeding blood sugar side. But there's one other thing that I think is worth talking about very briefly, in terms of just general energy and fuel availability and its effects on thyroid hormone production and conversion. And that's that t3 the presence of t3 will have a positive feedback on its own production. So if you have t3 it actually increases the activity of d1 the diode and Ace one enzyme that converts t4 to t3 so what this means is that as you're increasing your metabolic rate, there's positive feedback to continue doing so, and so as long as we aren't preventing that from happening with stress hormones and everything else, we have this feed forward reaction. This is part of why supplementing with t3 can actually help to reverse issues with conversion, is because it'll actually increase its own production, increase its own conversion from t4 so not only is it just incredibly beneficial, but it's also one of these situations where, if we are doing the kind of quote right things, and we're not doing the low carb diet, and we're not restricting calories or fasting or anything, we can fix the conversion issues that could be underlying our herbal thyroid state, and we'll have this kind of feed forward positive feedback loop that will continue to raise our metabolism and oppose stress, decrease stress.

Mike 58:03
 Yeah, so it can be a possible like therapeutic modality for people when they're trying to come out of these stress states, which is what we kind of touched on before a few times, is that you can possibly use thyroid hormone, whether that's t3 or t3, t4, combination or natural desiccated thyroid to kind of get your dig yourself out of the hole a bit and kickstart the system in the right direction, assuming you're also trying to push the other pieces together. The one thing that I think is important to say, and I don't think that we ever presented this way, is that it's not like thyroid or t3 supplementation is like the single cure all, but it is one tool in the toolbox that we have to dig ourselves out of a metabolic hole and try to push things in the right direction, especially if you've gone through low carb, you've gone through keto, a lot of intermittent fasting, long term caloric restriction, or you're just stuck in that cycle of yo yo dieting, where you're dieting down and You're gaining weight, and you're dieting down and gaining weight, and at the back end, you've just, essentially, you've ballooned up because of these. Again, every time you you do these types of things, you have this hormonal impairment. And this, we don't have the studies here to discuss it, but there are some studies talking about an overshooting and fat gain because of some of the hormonal aberrations that occur during some of these dieting cycles, where following an extended period of dieting or caloric restriction, or some of these things, where you're likely to put on weight and you will overshoot in terms of fat, and again, it's a function of these alterations in the hormonal profile. So using something like t3 can be helpful to overcome that while build bolstering your nutrition and also building out a nutrient dense diet and adjusting some other factors in the lifestyle simultaneously.

Jay Feldman 59:49
Yep, absolutely. And we'll come back to that and where we place or when we want to use the supplementary hormones in the context of healing from a low metabolic or hypometabolic or hypothyroid state. So there are a few other things to touch on here, as far as factors that are going to affect our thyroid hormone production, conversion status. One is the polyunsaturated fats. We talk about these all the time, and of course, they rear their head here when it comes to thyroid. We mentioned that if you have high levels of free fatty acids that are highly polyunsaturated, they'll inhibit the binding of the thyroid hormone to the thyroid binding globulin. So that's one factor, but there are some other interesting studies also showing that the presence of the polyunsaturated fatty acids actually interfere with the binding of t3 to its nuclear binding sites, and they can also interfere with the conversion of t4 to t3 so this isn't surprising, again, considering the larger context of the polyunsaturated fats, of course, in every level, whether it's driving hibernation or reducing the efficiency of energy production, or, in this case, reducing thyroid hormone production or activity and conversion, it's going to have metabolism depressing effects. And we just see that again here. And that's paralleled also by endotoxin, which again, is something that we talk about all the time as one of the major drivers of inflammation, major drivers of inhibited energy production, and major drivers of issues with health. And so again, it rears its head here in terms of thyroid as well. And interestingly, we talked about how inflammatory cytokines can inhibit thyroid hormone conversion and production and also the stress hormones, and of course, endotoxin will increase both of those things. But interestingly, there are some studies looking at endotoxin and actually showing that it will lower thyroid hormone production and inhibit TSH independently of the inflammatory cytokines, and at the same time, it'll increase reverse t3 so it has these effects on conversion and production somehow independently. I don't think the mechanisms are entirely parsed out, but it's just an interesting thing to note here as well. Of course, not surprising, considering that we see endotoxin in all of the same areas as a primary driver of every disease state.

Mike 1:02:03
Yeah, it's one of those ubiquitous poisons. Kind of, there's like a couple things you can look at here, but you have the stress hormones, endotoxin, excess polyunsaturated fat, so you can kind of see across the board, elevated in all of these disease states, and driving some of these disease states through multiple mechanisms and kind of working together with each other, specifically on PUFA, just kind of an interesting point is you can either address your thyroid function, have your thyroid functioning appropriately, and bring your cholesterol down through a mechanism where your thyroid hormone is driving the cholesterol into the cell and then into the mitochondria to produce steroid hormones, or you can just supplement with large doses of t3 and basically impair your liver's ability to export cholesterol and produce the apple lipoproteins that are necessary for LDL and bldl production. So kind of just like this. I think the reason I bring it up, I know I'm kind of saying it tongue in cheek, is that it's like understanding these mechanisms and working through like these different mechanisms and and understanding why we're doing what we're doing can become quite important. Instead of just looking at the overall effect, where it's like, oh, T uh, omega threes, they they lower, they lower cholesterol levels, so and triglyceride. So if you take, you know, three grams a day, you get x, y and z benefit. It's like, or you can just optimize thyroid function, and then the instead of impairing that production of the the cholesterol at the liver, you can be turning that cholesterol into steroid hormones.

Jay Feldman 1:03:40
So just an interesting point, specifically with the PUFA, a slight a little bit tangential, but I think important to keep in mind, and again, to highlight not just, they aren't just impairing or reducing cholesterol production, they're doing it via oxidative stress, and we talked about that in the fatty liver series. So I'll link back to that episode where, yeah, you're told that is so beneficial, but when you actually look at the mechanisms, it's directly causing an oxidatively stressful environment, you know, driving inflammation, driving inflammation, and those inflammatory cytokines we were talking about. So certainly, does it sound like something that would be a good thing?

Mike 1:04:07
Definitely not. We also talked about in terms like the some of the immunosuppressive effects as well, which wouldn't want to be optimizing, lowering thyroid function, also creating oxidative stress to the liver, possibly having an immunosuppressive effect at the gut, but your cholesterol is lower, so it's all good.

Jay Feldman 1:04:24
Exactly, exactly kind of like what happens with looking at just TSH levels, which we'll talk about. So some other factors that affect thyroid hormone production and conversion. We've talked about the micronutrients here. There's a couple that I want to highlight. So outside of just the many that are involved in thyroid hormone production and conversion. There are certain balances to be had. So we talked about this in terms of, I would say the three major ones, which are iodine, vitamin A and iron. And when I say three major, it's because A, they're majorly involved in thyroid hormone production and activity, but B Major, in terms of wanting to make sure that there's sufficiency, not deficiency. But also that there's not excess, because excess of any of those has thyro suppressive effects. And so when it comes to iron we I don't know if we talked about how thyroid peroxidase is iron dependent, and that's what's required for producing thyroid hormone. And when we have an iron deficiency, it reduces the ability to produce thyroid hormone. It also ends up reducing thyroid hormone binding to its nuclear receptors, much like vitamin A. We need vitamin A for that as well, and then the iron is also involved in t4 to t3 conversion. But of course, in a case of excess iron, that's going to be a primary driver of oxidative stress, and we talked about how that's going to do the opposite, that's going to impair thyroid hormone production and conversion. So that's one where we definitely want to be careful of balance, and also all the other co factors that go with it, so it's being used properly. You mentioned copper earlier, which is a major factor there. And you know, the same thing will can be said for vitamin A and iodine. So when it comes to iodine, you mentioned earlier, how, how? Because iodine is involved and necessary for thyroid hormone production, people suggest taking massive amounts of iodine, but there's actually research showing that, and this was, I don't remember what I want to say, this was over weeks. It could have been over months, but what they found was that supplementing iodine, at 1.5 milligrams per day, lowered sour hormone production. That's high compared to what you would get in the diet, but it's not high compared to what a lot of people supplement with. And also this was, again, not like a lifetime, long study. So if you're supplementing with even lower amounts of iodine for a long period of time, that could also be something that inhibits thyroid hormone production. So that's one to be aware of. And the reason why it does that is because the iodine. When you have excessive amounts, it actually prevents iodine uptake at the thyroid, so it actually ends up preventing the whole reason why you're wanting to take it.

Mike 1:06:48
And that's also it's function. It's doing that as a protective mechanism to the thyroid so that it doesn't it's not overloaded with iodine and starting to produce large amounts of oxidative stress to try to increase this hormone production through TPO. Now it's also not good, because it that thyroid suppressive effect, like what you see in the rat studies with excess iodine intake is it will increase TSH. So the body it the body with the excess iodine, like there's a local protective effect from the I think it's the wolf checkoff effect. But then at the same time, the body starts to sense that there's a lowered amount of thyroid hormones, and then it starts to elevate TSH, which, again, acutely, maybe not a bad thing, considering circumstances, but in the long term, can actually lead to increased oxidative stress at the thyroid gland. So again, it's isn't, as you already mentioned, it's important to have sufficient intakes, not excessive or inadequate intakes. And something that I did want to just bring up briefly, to particularly on the iron pieces. We on the bioenergetic helpline recently, we had just discussed, there's a woman who had reached out, and she had said that she had some hemorrhaging, and then her her baritone and her iron values were low, and then she started to experience, like a whole host of some of these other symptoms and what we talked about there is correcting her iron as kind of a first step, because that, as we're talking about here, you need adequate iron, not only for TPO, but for a whole bunch of the enzymes. For example, cytochrome c oxidase, I think it has a heme component, which is iron dependent inside the mitochondria as well. So iron is and this kind of, let me finish the statement. So iron is extremely important inside the body for tons of enzymatic functions, as a very basic example for carrying oxygen in the blood. However, as we discuss, excess or or deficiency are quite problematic. Now, just to point out here, there's this, a lot of this going around in some of the spheres of like, iron being this, like, ubiquitous, bad player overall, and that we just need to, like, keep unloading iron as much as possible. And that's been, like, kind of bleeding into some of the bioenergetic sphere. I don't think that's a necessarily ideal view to hold on iron as much as the sufficiency view is. Because, again, like the arguments like, well, Copper has all this function and 300 enzymes and yada yada and things along those lines. And it's like iron is just as absolutely essential to a lot of these enzymatic processes, to thyroid hormone production, to energy metabolism at the cell, to oxygen carrying also to antioxidant defense. Is involved in quite a few of the antioxidant enzymes, and it has functions there. So depleting iron can lead to a degree of oxidative stress because of the lack of that enzymatic function, as well as having an excess. So again, it's important to have an adequate amount of the iron specifically, and to not view it as like this primary negative factor, unless you have an excess. Now, I have people come off carnivore who that are like, quite iron overloaded, women included, not just men. And it's like, yeah, in that situation you caught, you're probably going to want to fix that iron overload. But in circumstances where, like, again, you have your ferritin is less than your ferritin is like, 20. And your hemoglobin matter, could or borderline, you're probably going to want to make sure that you're eating adequate iron to to bring those levels back up to sufficiency. So yeah, all of these, these nutrients are important. And then I think another one, just that's quite important is but again, you don't want to have an excess as well as Selenium. Selenium is involved, and we kind of touched on this already, but selenium is involved in the deiodinase enzymes directly, but it's also involved in antioxidant enzymes through the glutathione system. So you it's man, it's helping with the activation and utilization of thyroid hormone as well as helping with antioxidant function. So it's important to have adequate selenium diet and the foods that are dense in iodine or, or, and selenium and iron and manganese and copper, etc, are going to be, those are going to be your organ meats. Those are going to be your egg yolks. Those are going to be your shellfish. These are going to be, and I know what kind of I guess we're going to touch on this a little bit lower, but it's a lot of those general foods that you know we would that we usually talk about as kind of being like nature's multivitamins, to some extent, because they are very rich in these and iodine as well these various foods. You don't have to supplement with a milligram of of iodine every day. You could just, you know, you can have some seafood on a regular basis, and some egg yolks and things along those lines.

Jay Feldman 1:11:20
Yeah. Milk, too. Milk, yeah, yeah. And you were touching on on the kind of fear around iron, again, some of it warranted. Some of it not, kind of just saying, we need to have a we need to be aware of both aspects here, and that low iron can be a real issue. And low iron is involved in tons of enzymatic processes as well, including vital processes like energy production and again, same thing with vitamin A. So a lot of the there's a big influence as well that is very pro vitamin A, pro retinol. And this is also such. And I guess I should also say there's also a camp that's very much in favor of very low vitamin A. In views, vitamin A is extremely problematic. And I would say that we see very clearly with thyroid, like looking at it through this lens of what's going on at the thyroid or with the thyroid hormones, also becomes clear with vitamin A, where, if you don't have enough vitamin A, it causes hypothyroidism. It prevents the activity of t3 in terms of its binding effects in the nucleus, but at the same time, excess vitamin A will also lower thyroid activity and cause a hypothyroid state. So you can have it both ways, if you have excess vitamin A versus low vitamin A. And it totally makes sense, because A, firstly, vitamin A is vital for a lot of of thyroid functions, and because of that, if there's low thyroid, you're not using as much of the vitamin A, those vitamin A levels will go up, and you'll also potentially get the keratinia, where your hands and feet can start to become orange, especially if you're having beta carotene. But it's also especially true if you're not converting or using the vitamin A due to a lack of thyroid. So that is part of the reason why excess vitamin A causes hypothyroidism is because it is a signal of a lack of usage of vitamin A. At the same time, vitamin A is necessary, so not having enough will also create a hypothyroid state. So we have these things that maybe kind of seem like paradoxes, but I think in reality, just require, in this case, a quote, balanced perspective of recognizing that there is a necessary sufficiency for these things, but excess or too little can be a problem. I do also not want to make the caveat anytime I say something like that. This is not a situation where we're saying everything in moderation or like you just need the you know, like you just need that. Yeah, I guess it's just everything in moderation. Like we should not fans of that idea, because it's just a cop out that isn't actually describing the physiology at all, and doesn't apply to a lot of scenarios. Like, would it be a fan of a moderate amount of fasting, or moderate amount of ketogenic diet or anything like that, or a moderate amount of marathons, you know?

Mike 1:13:58
But yeah, so anyway, that's like, kind of the point here with the micronutrient, the question is optimal amount, right? We're shooting for, what is the amount that you need for, and the other so we shooting for what is the amount that you need on a regular basis to optimize thyroid function without causing like a suppressive effect on the thyroid. And the other thing too is these targets can be moving a little bit as energy metabolism improves and thyroid function improves, and you start to have it, you may need to increase your thyroid. And this is something that Ray has talked about. Talked about, and he kinds of alludes to at sometimes, and it's when you I remember, when I first listened to him, he was like, Oh, I increased my vitamin A dose during the summer because I realized X, Y and Z with my thyroid. And then at first it's like, kind of, it seems like it was willy nilly, you know. And then you go, and you look in the research, you're like, oh, as you you have you increase your thyroid hormone, as thyroid hormone function increases, which tends to happen in in the summer months or in warmer climates, etc, then you may have an increased requirement for vitamin A. So Ray was like, describing those things. But then you start going in the research, and it's like, Oh, yeah. It's kind of corral. Rating, what, what exactly Ray was saying. So that stuff, that stuff is really, really cool to see. But yeah, there's, it's not about moderation. It's about what is, what are these optimal ranges? And that's then, this is why the this is why you do research. This is why researchers are doing research. This is why people are trying to test down and find, okay, so what is this adequate amount of vitamin A for like in serum, and these different reasons for the in these different measures. And why do we need it? What's its functioning? It's trying to narrow down these kind of like ranges and ideas and how these things adjust in different ways. So it's with the nutrients, with the L and with these different elements. Is not Oh, again, I also wouldn't recommend that everything in moderation element, it's more it maybe it kind of can seem like that when you start talking about building out a diet, like you're going to want plant foods, you want animal foods. It's not about moderation. It's about that these different elements have different beneficial effects, and you need them to optimize health in these different in these different areas. So it winds up looking like, oh, you having all these different things, but it's like, you know, all it's just all these things are needed right?

Jay Feldman 1:16:08
 It's about optimal, and the moderation just depends on where you draw lines. Like, do you draw a line between plant and animal food? And then, I guess, sure, moderate amounts of both were amounts of both. But it's not because it's 5050, or anything like that. And we're also not talking about moderate amounts of nuts or seeds or vegetable oils or, you know, poorly, like unprocessed grains or again, all depending in context. But yeah, yeah, I think, I think that's clear, but you did bring up a really good point that I wanted to come back to, which is that increased sour activity increases micronutrient needs and new and macronutrient needs, and increases our needs for calories, for carbs and fats, potentially protein as well, and it will also increase our need for different vitamins and minerals. So that is something to keep in mind as somebody progresses through increasing thyroid status at the same time, another dichotomy or paradox, very low thyroid status can also increase nutrient needs because of a reduced ability to retain those nutrients. So this is something that Ray had talked about a lot, in terms of magnesium. We're basically in a low thyroid, hypometabolic state. You're not able to effectively retain magnesium. So you can take grams and grams to get a desired effect. But as you actually improve the underlying state, improve your metabolic state, thyroid state, you won't need anywhere near as much magnesium to have the same effect and still be functional. So again, that's another principle that can be helpful. It applies in some cases, not to everything, but yeah, just worth mentioning there.

Mike 1:17:29
Yeah, that one actually, I remember when Bray was saying that again, like, I when he first, when I first heard him say that as like, okay, but I didn't understand the mechanism. But then when you start to go through, you understand, okay, increased thyroid hormone increases ATP production, and then ATP and magnesium are bound together in the cell. And so it's like, oh, that's why, that's what, that's what he's talking about with retaining magnesium. It wasn't just like, you it like, it wasn't this, like, Willy, this kind of obscure thing. Was like, No, there's actually specific understanding that magnesium in the cell is or ATP in the cells bound to magnesium, and obviously thyroid hormone is increasing ATP production, increasing energy production overall. So those are, yeah, those are really, that's a really great point, and also really interesting when you start to put the piece together and you read the studies, because it's not, it's not like there's a direct study showing that, like thyroid, specifically, like, hypothyroidism is wasting magnesium is kind of like Ray discussing, like, understanding these things across a broad context, and then putting the pieces together. And then you start, when you see it, it's like, wow, this is great. This is amazing.

Jay Feldman 1:18:35
Yeah, yeah. There's a lot of, there's a lot of like, systemic complexities there, outside of just the ATP magnesium complexing, but you also have general increased activity of different stress systems, like the RAS system, and when you have increased aldosterone, that's going to cause the wasting of potassium and magnesium. Also, when the cell is less energy, it's not going to be able to literally retain it in its structure, the potassium and magnesium and it's going to allow sodium and calcium in, and the potassium and magnesium will get pushed out, and you'll have a lot of bulk water in there. Won't be well structured. So that's another factor too. So it's, yeah, it's, it's really cool to see all the layers there behind, behind these things. But anyway, bit of a digression. So the last grouping of factors that I want to touch on here is environmental toxins and their capacity to affect thyroid hormone conversion and activity and production. So environmental toxins encapsulates a wide range of different factors that we're exposed to, or chemicals that we're exposed to in our environment, from plastics, from adhesives, from all sorts of industrial products, from our furniture with the flame retardants to the plastic water bottles you might be drinking from, to the exposure to heavy metals in food that we're eating or in our water supply, or in our cookie utensils, all sorts of things like that, and a lot of these different industrial chemicals, pesticides. Is another big category as well. Will have effects here, and so it could vary between all of them, but a lot of them have the ability to reduce t4 to t3 conversion. Some of them will inhibit iodine intake at the thyroid. Some of them will impair the binding to of the thyroid hormones to the transport proteins. Some of them will reduce thyroid hormone uptake of the cells. Some of them will actually increase the excretion of thyroid hormone. Again, these are not none of this is surprising, considering that our thyroid is just our metabolic response to the metabolic sensing of the environment, what the energy availability is, and knowing that all of these things create equivalent shifts. They shift us toward estrogenicity. They shift us toward hypo like a hypometabolic state, increased stress, some of them directly impairability to produce energy. So yeah, it's a very broad category, but another one to keep in mind, as far as something that can really affect not only our thyroid status, but our health as a whole, which, of course, those are one in the same, and something to be aware of when it comes to literally anything that we are exposing ourselves to in our environment, again, whether it's the pesticides on the food that we eat or in in our lawn, heavy metals in again, food or water or different utensils we're using plastics and plastic In our water, plastic in everything, like plastic everywhere, yeah. I mean, just touching it, you know, through your skin, all the things that we put on our skin and our skin care products, the paint that's on our walls, the, as I mentioned, the flame retardants that are in our furniture, it gets you can really like it's it's really everywhere. So it can be overwhelming to start to address these things. But it doesn't mean that it's not worth being aware of and slowly or comfortably addressing them.

Mike 1:21:47
Yeah. I mean, there's even so a couple things as a per as a nice example. Let me start off with this. It would be nice if there was some, like pesticides or chemicals or something that had like this positive effect, right? It's like the pro thyroid pesticide class that just makes the insects. So, um,

Jay Feldman 1:22:06
what's the hyperthyroid?

Mike 1:22:07
Well, not hyperthyroid. It makes them, uh, what's the word I'm looking for? I can't, not moralistic, but like, so altruistic that they choose not to eat our crops. Locust to grasshoppers. Yeah, it turns the locus to grasshoppers. That we need those anti serotonergic..

Jay Feldman 1:22:24
yeah, anti serotonergic pesticide, yeah

Mike 1:22:27
So that, I think that's, that's, that's our next business venture, Jay is we're going to make the anti serotonergic, pro thyroid, anti estrogenic pesticides. But on a more serious note, as an example, like just BPA in general. I did a couple articles on this in my newsletter, and essentially BPA is...

Jay Feldman 1:22:46
We went over it in an episode, by the way, yeah, I don't know if you remember, but we did Yeah. So

Mike 1:22:50
Yeah. So there's, there's some interesting research showing that the BPA not only upregulates glucocorticoid signaling, it blocks degradation. It's then it has estrogenic signaling, and then it has anti androgenic signaling, and then it has anti thyroid signaling. So it's like the alt, like the ultimate endocrine disrupting chemical. So it's, it's just out of control, like the the and then it also has functions and altering different like signaling within the brain, around learning and NMDA receptors and things along those lines. So it can be, it's quite a toxic substance, and it has broad, ranging effects. So they, they the the toxins really can have quite a negative effect on a hormonal profile. And basically, there's, it's kind of like a buzz thing now, but they talk about fertility, particularly male fertility, declining significantly, and that being a function of some of the toxins and the pests, not necessarily pesticides, but the plasticizing agents that were exposed to, and basically degrading, or degrading the the endocrine system of males and also females as well. Just it's they're seeing it specifically in like a decline in in sperm count and function, etc. So these things do exist, they definitely have a negative effect. It's not like woo, woo or anything like that. I know it's not massively discussed in a lot of circles, even even in some of the like health circles, but they are things to to keep in mind and to try to avoid, to some extent, like, I'm like, I would say some of the worst things could be, like drinking out of plastic water bottles that have been sitting out in the sun, things along those lines, there's, there's, like, a whole host of things that you could do to address these things. But I would it is something to give, to give attention to in this overall context, because we're, we're sitting over here, we're trying to adjust all these factors to improve thyroid function, androgens and progestions and steroids and lower the stress hormones. And it's like these things are directly working against those elements at every step of the way. And also, even with thyroid like the you can have adequate thyroid levels, adequate thyroid production, et cetera. But then if you have a if. Loaded up on a whole bunch of chemicals that are blocking T three's ability to interact with the cell, or altering t4 conversion into reverse t3 rather than t3 Well, it's kind of shooting yourself in the foot, foot, even if everything else is, you know, in the right place.

Jay Feldman 1:25:14
So definitely something to consider, yeah, yeah, that's that's definitely a good point. One other factor to discuss here when it comes to, I guess, one last thing to discuss when it comes to factors that can affect thyroid hormone production, conversion, everything related there would be sleep. So there's some good research showing that over time, a lack of sleep is going to cause low t3 and low t4 despite TSH remaining normal. So it seems to have some effects in reducing the t3 and t4 production, possibly t4 to t3 conversion as well. That's in the long term. In the short term, you'll actually see that TSH increases in response to short term sleep deprivation, and this is basically a stress response, similar to a lot of others, that would help to increase thyroid hormones to make up for the lack of sleep. But of course, long term, we see a dichotomous effect there. So and one last point is that normally at night, and this is something that repeated talked about as well, is that sleep or night itself will increase the production of stress hormones and things like TSH. And so you will see TSH increases as a part of its normal circadian rhythm to help deal with the stress of night.

Mike 1:26:33
Yeah, you see it peaks around the same time that cortisol does. So you kind of like, have these series of stress hormones all peaking at like the last portion of the night, so kind of starts here, and then as the night goes on, it slowly increases into a peak. And then as the sun starts to come up and whatnot, the hormones will start to drop back down the and a lot of those stress hormones include a decent amount of the pituitary hormones, you'll see peak in the very more early morning hours. But yeah, the also, something with the sleep pieces disrupted circadian rhythm can also alter thyroid function pretty significantly as well, because a lot of the neurons in the brain that are directly involved in thyroid and hormonal regulation, which is the, I think it's the suit, the are directly tied to the suprachiasmatic nucleus, which is the part of the brain that deals with circadian rhythm. So strong circadian rhythm dysfunction can alter signaling in those neurons which project down into different areas of the hypothalamus and then subsequently the pituitary, which kind of has a master control over a large degree of the hormonal systems of the body. So if you have circadian disruption, like night shift, or you're going to sleep super late on a consistent basis, or you're, you're you like shifted time zones consistently, those are all actually pretty significant stressors and then altered something that's very important. They call them the zeitgebers, which are the the different elements involved in regulating circadian function. So light exposure, meal timing, bedtime, waking time, having like a very inconsistent element in those can also create a degree of stress by shifting circadian rhythm to some extent as well. So ideally, you'd want to have kind of like organized daily structure to some extent to allow for a consistent sleeping cycle and getting light on a regular basis, and part of the stress of winter, and you can see this with seasonal affective disorder, is that lack of adequate light exposure, and it's in the light exposure is directly involved with that super key as Matic nucleus, and which again ties in directly with the different areas of the hypothalamus and subsequently the pituitary. So very important to have circadian rhythm organized to some extent as well. And sleep, yeah,

Jay Feldman 1:28:50
And sleep, yeah, yeah, absolutely. And we did have some podcast episodes discussing sleep as well, so I'll link back to those. Yeah.

Mike 1:28:57
Well, with the sleep to brain energy metabolism through the glymphatic system, which what we talked about. So if the brain cells need to kind of get rid of the metabolic waste from their day through the sleeping process, and so that will directly alter energy metabolism to some extent as well, which, as we're talking about is quite key here in terms of, like overall health in general. Yeah, yeah, absolutely.

Jay Feldman 1:29:25
All right, we're going to end that episode there and pick back up in part three, where we'll be discussing what causes Hashimotos hypothyroidism, how to properly interpret your thyroid blood work, and what your doctor likely doesn't know about thyroid testing, how your cholesterol values can be used as markers of thyroid status. How symptoms like metabolic rate, body temperature and pulse rate can be more helpful to blood tests when identifying thyroid status and the ideal blood test values for optimal thyroid function. If you did enjoy today's episode, please leave a like or comment if you're watching on YouTube and if you're listening elsewhere. Please leave a review or five star rating on iTunes. All of those things really do a lot to help support the podcast, and are very much appreciated. As always. To check out the show notes for today's episode, head over to Jay Feldman wellness.com/podcast where I'll link to the articles and studies and anything else that we referenced throughout today's episode. And if you're looking to reverse your hypothyroidism with clear action steps and strategies, along with personalized guidance from me, head over to Jay Feldman wellness.com solution, where you can find all the information for the energy balance Solution Program. This program includes customized health coaching, a video library, including a video that talks specifically about how to evaluate your thyroid status using blood work and symptoms, as well as when you should supplement with thyroid hormones, how to dose them properly and how to pick the right product. The program also includes resources like a sample meal plan and supplement guide, as well as access to a private community. So head over to Jay Feldman wellness.com/solution, to check out all the details, and I'll see you in the next episode.