Stress: The HPA Axis

Episode 97

The hypothalamic-pituitary-adrenal (HPA) axis is one of the two primary stress circuits in the body. Stress is one of the root causes of chronic disease, and it’s incredibly prevalent in our lives today. We can lower our risk of self-injury by moderating how our HPA axis responds to stressors. We discuss what the HPA axis is, how it works, and ways you can take control of this pathway to master stress.

Nimbus Healthcare

CBD Health Collection

Episode Transcript

It’s finally time y’all. I promise for so long. We’re gonna have an episode about the HPA Axis hypothalamus pituitary adrenal axis, and today is that day. This is one of the two major stress circuits in the body. We’re going to talk about what it is, how it works, what you can do to modify things to avoid things to do. We’re going to do a deep dive into this circuit. So it’s gonna be a longer episode, but I promise this for so long. It’s great to see that day is finally here. Are you ready to boost your health, EQ and IQ? Cue the music?


Join me Dr. Richard Harris as we strive to unlock the secret to the human body. Strive for Wellness strive for great health follow show on iTunes, Spotify, Google and Android.


And now a word from our sponsors. Our first sponsor is Nimbus healthcare, the company that I co founded personalized medicine personalized results. At Nimbus. We don’t believe that there’s a one size fits all when it comes to treatment. And the data is starting to show that there’s a large variety of how people respond to certain things. And we’re in the Age of Science where we can use things like genetic testing and biomarkers to truly customize a plan just for you. And that’s what we do at Nimbus healthcare. We are in the hair loss and the hormone space. And what we do is we use lifestyle medicine, supplements and compounded prescription medication to tailor and individualize a plan just for you. If that sounds like something that you’re looking for, you can check out Nimbus or click the link in the show notes. Our other sponsor is CBD health collection. CBD health collection is the CBD that we use in the house. We use it. Our dog uses it love CBD health collection, it meets all of the requirements that we set forth in our CBD episode, organic us grown. They do a lot of third party testing so you know exactly what you’re getting in the product. And it works. My ordering data is wonderful when I take the product for sleep, and then I also use it for inflammation and recovery. If you’re looking for a high quality CBD that is third party independently tested and who does research they work with universities to do research on their products to push the edge on CBD and make sure they’re staying current. Then CBD health collection is the CBD for you. You could check the link in the show notes, or head to our website, the GH and click CBD at the top. And now to this week’s episode. Welcome to strive for great health podcast with your host, Dr. Richard Harris, a podcast where we empower you to take control of your health with lifestyle medicine in the health mindset to live with purpose and joy. And today we’re talking about the HPA axis, something that we’ve talked about numerous times on this podcast with our old frenemy cortisol, we’re gonna figure out where that comes from. What you can do to modify this circuit how the circuit works. It’s going to be a long episode. So, you know, you’ve been asking for it, I’ve been promising it. Let’s dive in. What is the HPA axis, hypothalamus, pituitary adrenals. We’re gonna start with the hypothalamus. The hypothalamus is a small gland located at the base of the brain, in the intersection between the cortex cerebellum in the brainstem, it’s kind of the crossroads in the middle. And it is sometimes called the Godfather or the grandfather of the master of the endocrine system. It really is the coordinating center for the endocrine system for hormone systems. And it takes inputs from higher level brain circuits like the cerebral cortex, it takes autonomic inputs, meaning things like blood pressure, heart rate, gut function, it takes environmental cues like light and temperature. And it also has inputs from emotional circuits like the amygdala. And it integrates all of these signals. And what happens when a receives the signals it processes them. And then it releases several hormones depending on what’s going on in the body and what’s going on in our external environment. One of these hormones is corticotropin releasing hormone or CRH. And what this does is it activates a gene called the PL MC gene and goes to the to Attari to release ACTH. We’ll talk more about ACTH when we get to the pituitary in a minute, also causes the release of melanocytes stimulating hormone and the release of endorphins. Hypothalamus also will do growth hormone releasing hormone This tells the pituitary to release growth hormone and Another hormone called gonadotropin releasing hormone. As you can see, the theme here is releasing hormone. The hypothalamus will secrete these hormones to tell another Glenn in this case pituitary to release something. So gonadotropin releasing hormone tells the pituitary to release LH and FSH which are responsible for going to the ovaries and the testes and making sperm or testosterone or estrogen. Prolactin releasing hormone that tells the pituitary to make prolactin which is involved with lactation. Also somatic statin so that a statin is an inhibitor for growth hormone release. We don’t want growth hormone active all the time, because it’ll make everything grow. That’s not a good thing. Prolactin inhibiting factor. This is also known as dopamine, it inhibits the release of prolactin. So yeah, lactating all the time, I think that’s a good thing. And then it also has vasopressin and oxytocin, we’ve talked about these on the podcast before. They’re made in the hypothalamus and a release in the pituitary. But there’s a direct connection, there’s two parts of the pituitary, anterior posterior, that’s not something you really have to know unless you’re a science nerd. But the vasopressin and oxytocin are released from the pituitary, but they’re actually made in the hypothalamus. And there’s a direct track that links the two together. vasopressin is released in response to changes in blood concentration, blood pressure, and blood volume. And also in humans, there’s a small stimulatory effect on the pituitary to release ACTH. With vasopressin, other animals that’s actually a lot stronger. Oxytocin, we’re going to talk a little bit more about oxytocin later. But oxytocin is important and trust, cooperation, attachment love, it’s often called the love hormone because of its actions and making us feel connected.


The hypothalamus is also important in regulation of temperature, the autonomic nervous system, so sympathetic, parasympathetic, and control of appetite and thirst, we’re not really going to talk about those mechanisms. Here. We’re mostly focused on the stress access and the HPA access. The pituitary, the hypothalamus are in close proximity, and they have a coordinated blood supply. And this is important because in order for the pituitary to release these hormones that it does, it needs a really concentrated amount of the hypothalamus hormones. So the hypothalamus hormones really, when they’re released, are working mostly in the local circulation. Their hypothalamus hormones are small proteins, they function locally, they receive pituitary in high concentrations. Now, back to the CRH. Because this is what the focus of this podcast is about. It’s about the HPA axis. Typically, this system is suppressed. And what do I mean by that is that it is not tonically activated, it’s tonically suppressed. And it’s done by neural inhibitor called GABA, we’ve talked about GABA before on the podcast, what happens is the system is not default, on its default off. And it’s activated by excitation. And this is done in the brain by a neural modulator called glutamate. And you’ll get a release of glutamate to the system during periods of stress. And this could be all different types of stress. Overall, we’re going to say this is stress. And we can even break it down into distress distress as things that causes the system that activate you stress are things that cause resilience, and we’ll talk about that more later in the podcast. So it’s activated by social stress, by toxins. Alcohol activates this system, by low blood sugars, low blood pressure, pain activates this system, anything that puts us under physiological stress. It’s also secreted in a circadian rhythm. And we’ll talk about this more later, we’ll talk about the cortisol awakening response. And it’s also secreted in ultradian rhythm, and we’ll talk about that more in a minute as well, in ultradian, rhythms are shorter rhythms throughout the day. These are like 90 minute rhythms that we have. The circadian rhythm is our 24 hour rhythm. It’s activated by arousal. And I’m not talking sexual arousal, I mean stuff that calls our attention, stuff that makes us focus on it. It’s also activated by serotonin. And what happens during chronic stress is things get kind of wonky, and chronic stress, GABA actually activates this pathway. And this is why this can be such a horrible scenario, because normally the thing that’s going to shut off this pathway is now feeding it. It’s like feeding the fire. And that’s why it’s so important to have stress mitigation and also to build disease. illogical resilience. This system is also activated by the anticipation of stress. So remember, just briefly, we mentioned that higher level of brain circuits, the cerebral cortex, the decision making part has inputs to the hypothalamus. And so if you anticipate stress, this will actually activate this pathway. And it will activate it stronger when you encounter that stressor. So this is why spoiler alert, things like meditation are so important for moderating our stress response to control the higher level circuits. As we age, this is a feedback loop. And we’ll talk about that feedback loop. It’s basically that cortisol inhibits the hypothalamus. So cortisol is the instream product of this pathway. And as those levels increase, it actually shuts down this pathway, then we’ll talk about how that happens.


But as we age, that feedback loop, meaning that cortisol, what we call negative inhibition, that cortisol increasing, shutting down this pathway becomes less potent. And as we age basal production, meaning just the general background, production of cortisol increases, and then cortisol levels to stressors increases, well, now there’s a process called facilitation. If stressors are sufficiently strong, it will override the feedback loop and increase ACTH released or promote the adrenal glands being more sensitive to this. We’ve talked about a couple ways here, that the system can progress forward, in spite of the checks and balances that are put in place, as we age, and as we get a sufficiently strong physiological stimulus, bypassing the inhibitory signals that are in place, like most things, intensity, and duration of the stressors matter, high intensity, long stress, prolongs this response, you get a higher response to a higher intensity stress, and then you get a longer response to long stress. That makes sense, because the system is constantly scanning and checking our environment, checking cues, and it will respond depending on what’s going on. So the more intense a stressor, the more response, you’re gonna get different response if you get shot versus if you stub your toe, which makes sense because one of those is going to be more stressful than the other. And then it also depends on if the stressor is long, like say, you lose your job and you’re out of work for eight months. That’s a pretty long stressor. Versus if you get an email saying, hey, I need you to draft up a one page document for me real quick. There’s going to be different response. We mentioned briefly that cortisol is the inhibitor of this feedback loop. So hypothalamus, secretes CRH, to the pituitary secretes ACTH to the adrenals secretes cortisol. And then as cortisol levels increase, it’ll go back to the hypothalamus and tell the hypothalamus Hey, bro, we’ve got enough cortisol, shut it down. There’s enough people in the club club is full. We’re not letting any more people in. And this process is actually mediated through our old friend, the ECS, the endocannabinoid system, and we talked about this in the CBD episode. But the endocannabinoid system really works as a sensing system, kind of making sure that things are where they should be that things aren’t too high, things are too low. It really is a regulatory and overall balancing system. And what happens is when the ECS is activated by this cortisol feedback loop, it prevents the release of glutamate. Well, this feedback can also be inhibited by other neuro peptides and neuropeptides are similar to neurotransmitters they often are in the same areas as these neurotransmitters and they work to potentiate or inhibit them. One of them is in caffeine and caffeine is similar to endorphins. Testosterone also downplays the HPA access, high levels of estradiol are associated with lower cortisol levels. And as estrogen levels change during the cycle, stress response can change. And some people theorize that cyclic fluctuations in the cycles may contribute to higher levels of stress disorders in women. And because of those fluctuations, you’re getting different stress responses physiologically at different times. And then that can affect the top down processing from the cortex. Overall, we know unequivocally that women have higher rates of stress disorders. And this could be one of the contributing factors to that is because of the variance in estrogen levels throughout a woman’s cycle before menopause. Let’s move on to the pituitary. It’s a small gland it lies in something called the Selah it’s like directly behind your eyes really. And when people have pituitary tumors, it can be surgically accessed through the bones at the back of the nose, and I’ve actually seen these surgeries before. It’s really cool. What the pituitary does in this pathway is it secretes ACTH and ACTH adrenocorticotropic hormone. This hormone goes to the adrenal gland, and tells it to produce cortisol to produce DHEA. And a little bit of the sympathetic hormones as well.


Let’s move on to the adrenals cortisol. We’ve talked about cortisol before, let’s go over some basics. Again, cortisol is a steroid hormone made from cholesterol. So what actually ACTH does is it tells the adrenals to up regulate cholesterol production to make more of these adrenal steroids like cortisol. When we have dysfunction in the HPA axis, we can have either excess cortisol, which is actually the more common, sometimes you can get a relative cortisol deficiency. We’ll talk about that more in a minute. But symptoms of excess cortisol are brain fog, central obesity, elevated blood sugars, increased infections, skin rashes, muscle weakness, mood swings, digestive issues, symptoms of deficiency or lethargy, muscle weakness, mood changes, low appetite, diarrhea, weakness, low blood pressure, low sodium, we’ll talk about the mechanisms behind these things in a minute. We mentioned earlier that cortisol has a circadian secretion, meaning there are certain times in the day where there’s more or less, and it also has an ultradian secretion, meaning there’s a pulsatile amount throughout the day, let’s dive into this. Around midnight cortisol levels are the lowest, and then they slowly start to increase to about 30 to 60 minutes after awakening, you get a surge in cortisol levels. This is called the cortisol awakening response. And this is mainly to help us deal with the stressors of the day, it also makes us feel more alert and more awake. Cortisol levels then start to decline throughout the day, but we’ll get smaller pulses about 15 to 18 pulses throughout the day. This is that ultradian rhythm. And in fact, if you catch a stressor during a peak, so one of these ultradian 15 to 18 pulses throughout the day, you will actually get a higher response. And what this means is that as you go throughout the day will have different susceptibility to stress. If we catch a stressful event during one of these ultradian pulses, then you get a stronger response than if it’s at the lower end. If it’s not during one of these ultradian pulses, you can get an increase cortisol awakening response in Multiple Sclerosis with upper respiratory infections with obesity with metabolic syndrome with depression. You can get a decreased cortisol awakening response with diabetes with chronic fatigue syndrome, hypertension with GI disorders. So you can actually look at someone’s cortisol awakening response. And it will tell you what is going on underlying system and their underlying biology because, again, some disease states are associated with a higher some disease states are associated with the lower. So it’s a way you can see how someone’s body’s interacting with other parts of the physiology like insulin resistance or autoimmune disease. Acute elevations in cortisol have analytic effects, meaning that acutely, cortisol is actually supposed to make us feel more calm in a stressful event. If the system is working correctly. These elevations in cortisol, the stress are transient, they should elevate during a stressful event, stay high for a little bit and then come back down to baseline. But like most things in the body, there’s a difference between acute and chronic chronic elevations and cortisol, actually potentiate Well, we call angiogenesis meaning making you more anxious, through sensitizing the amygdala. We’ve talked about this before, the amygdala you can think of as the fear center in the brain. And the amygdala sends inputs to the hypothalamus. And what happens here was with chronic cortisol elevations, you get a sensitized amygdala. What that means is, you will start to see things as threatening that you may not have seen threatening before, and you will also rate them as more threatening than you would before. So you get more activation of the system in that like we talked about, the more the system is activated, the more the brakes stop working. So it’s like if you use your brakes more, you know your pump your brakes, pump your brakes, pump the brakes all the time. those brakes were out faster, eventually they stopped working. And this is what happens with this system. And this is why stress is so insidious. Because if we’re in a state of chronic stress over time, we lose our ability to regulate this system, and it impacts so much of our everyday life.


Acute elevations also caused an increase in arousal, basically excitement, meaning that we are able to focus our attention on something. Cortisol, its main job is to mobilize energy stores. When we go through a stressful event our ancestors did something was probably trying to kill them. And you know, you either fight or flee. And to do either, you need energy. And so cortisol, what it does is, it causes the release of amino acids from the muscle of causes the release of glucose from the liver, causes the liver to make new glucose. And it causes us to make new fatty acids, we’re literally trying to free up energy. So our brain can function hyperdrive, our muscles can function in the hyperdrive. This is great for running red Tiger. But chronic elevations of this think about it, you’re breaking down your muscle, that’s not good. You’re increasing sugar in your blood, that’s not good. You’re increasing fatty acids in your blood, that’s not good. It’s associated with insulin resistance and weight gain, if chronically elevated and muscle wasting. Also, this system will increase ghrelin, because our ancestors again, fight, flee, something’s trying to kill them, or the other major thing they had to deal with was famine. We used to go through periods of starvation all the time. And what happens is, instead of going to the starvation and wasting away and you know, not fighting it, our body will literally try to make us more motivated to go seek out food. And what happens is you increase ghrelin, and we’ve talked about ghrelin before, you can think of ghrelin as ghrelin, the hunger hormone, ghrelin then stimulates the release of cortisol in rat models. And so what can happen is, is that you get more feed forward again, you’re getting cortisol, increasing ghrelin, ghrelin increase in cortisol, and this system just continues to spiral out of control without brakes. Leptin will act as a brake at the level of the hypothalamus and the adrenal gland. But if we’re obese, if we’re insulin resistant, if we are constantly over consuming calories, we have leptin resistance, we lose those breaks, which is why it’s so important to not count calories. You know, we’ve talked about this on the podcast before I don’t count my calories. But I ensure that I’m not over consuming calories through time restricted eating or have a 24 hour fast through exercise, increasing my muscle mass increasing my metabolism. overconsumption of calories is a big problem. leptin resistance is a big problem, leptin resistance, we lose the brakes on this system. Cortisol elevations can also affect memory. What happens is it potentiate memory formation, but it impairs recall. And this is something that seems kind of weird when I say that. But what this basically means is you have two different processes from memory. You can form memories without being able to recall memories. This is one of the things that can happen with chronic stress conditions where people get a stress response to something. And they’re wondering why it’s because their memory their mind, has formed a memory associated with that thing causes a stress response. But that person has a blunted recall,


chronically elevated levels are associated with impaired memory, and actually lower brain volumes. And the reason for this is it’s actually trying to protect your brain. What it’s trying to do is say, Hey, this is important. We need to store this, but we don’t want to cause the host emotional distress by making a recall of this. In fact, we actually try to do something similar in the ER and when people come in with for stressful events, ketamine is approved, and why is that? It makes it so that you can recall a memory but you don’t get emotional attachment to it. And that’s why ketamine is used for people when they come in the ER who had been through really stressful events. You recall it the memory, but there’s no emotional attachment to that memory. Cortisol is also important in electrolyte maintenance. chronically elevated cortisol can lead to sodium retention and potassium wasting. Cortisol also stimulates bone resorption and decreases bone growth. Both it decreases gut calcium absorption. In general, cortisol is not interested in growing things, it’s interested in breaking things down to provide raw materials. Cortisol also is an immune suppressant synthetic versions, like prednisone, or soggy, Medrol, or dexamethasone. These are used to suppress the immune system. And what cortisol does is it induces what we call apoptosis, or cell death, and suppression of the immune system. We’ve talked about this before in the immune system balance episode that you want cortisol later in the infection, to tell the immune cells to go home and chill out. You don’t want that early in the infection. You also don’t want this chronically elevated suppressing your immune system. And this is why we often see viral infections happen when people are stressed. Herpes. What do we tell people, this will come back? Likely when you’re stressed because of that suppression on the immune system. We talked about how it increases ghrelin. Well, it increases seeking of foods that contain sugar, salt, and fat. Again, these usually tell our brain these are high calorie foods. These are foods that can help sustain us during high energy demands or low food intake states. This is why when you’re stressed you’ll seek out food, especially food that you know is not good for you. And that’s why it’s so important to moderate that with that top down processing, that higher level cortical centers. Chronic elevation and cortisol also increases vulnerability to addiction and cravings. Chronic elevations cause an increase in the growth of the adrenal gland and makes the gland more sensitive to ACTH. Again, it’s a feed forward system. So let’s talk about DHEA for a second DHEA is another steroid hormone DHEA is used a lot by bodybuilders and they’re trying to grow muscle ACTH and cortisol was stimulate DHEA release. Mostly it exists as DHEA sulfate, the sulfate group is removed and tissues to make it active there. But the half life is much shorter. So you’ll see most people when they supplement this they supplement DHEA s because it is more stable to transport. It lasts in the body longer. And then that sulfate group that S is removed when it gets to the tissue to work. It’s a hormone with weak estrogen and androgen like activity, but it’s mostly it’s converted into estrogen and testosterone. It’s made from a conversion of cholesterol to something called pregnenolone. We’ll talk about pregnenolone more later, DHA will also bind to the same receptors as nerve growth factors. So DHEA is actually very important for mental health. And very important for that. In women. It’s also the source of most of the androgens, women absolutely need testosterone, it helps with sex drive, helps with energy, it helps with bones. Osteoporosis is a big thing. We’re going to talk about osteoporosis on the podcast, I promise. Hopefully it won’t be another year but it’s on our list.


DHEA tends to decrease as we age. When we’re at we have about 80% of what it was when we were 25 and low levels are associated with heart disease, depression, neurodegenerative diseases, we talked about how it binds to the same receptors as nerve growth factors, will it make sense of the levels are low, that’s going to be associated with diseases of degeneration in the brain by neuro degenerative diseases as things like Alzheimer’s, things like Parkinson’s, that’s associated with low bone density and an increase in all cause mortality. Another adrenal product is adrenaline or epinephrine, you can use the terms synonymously you know, different scientists name these different things. We use them interchangeably. So the adrenal gland mostly releases adrenaline, it also releases a small amount of noradrenaline, then these are sympathetic hormones. They activate our sympathetic nervous system, they cause an increase in heart rate increase in blood pressure, increase in focus in the brain. noradrenaline makes us agitated, not angry, but it tends to make us want to move. It’s made from the conversion of tyrosine to L dopa, and then to dopamine and then, noradrenaline, norepinephrine also stimulates the hypothalamus to release CRH. And initially after a stressful event, norepinephrine increases in the brain. It’s actually the first signal. What happens is we get a stressful event our sympathetic nervous system activates. We get in norepinephrine, norepinephrine goes to the hypothalamus tells the hypothalamus to release CRH. And then the to work together to enhance consolidation of relevant information and prevent encoding of novel information. This is what we talked about earlier, prevent recall, but still keep the relevant information from what happened. The two work together, there’s other stress response accesses. But the two main ones are the sympathetic and the HPA access and the sympathetic acts first. It’s kind of that first wave. And then the HPA axis is the second wave, it’s the longer way, and then the two work together to potentiate the stress response. Well, how do we test these things? You can do salivary cortisol testing, it measures free cortisol, you can also do blood testing for cortisol. Oftentimes, this will be done at four times throughout the day, to see the overall secretion pattern, is it matching what it should be? Are the levels higher in the morning during that cortisol awakening response? Are you getting a blood response? Are they too high throughout the rest of the day, there’s something called Dutch dried urine testing. Dutch is really cool for measuring the response to the HPA access, because you can take a look at cortisol and you can also take a look at all the cortisol metabolites. And this lets you know where in the process something may be going wrong. And you can better fine tune what you’re going to use to treat these people. Because you can use targeted therapy for whatever is going wrong in the pathway. And the patterns can vary. There’s also a dosterone, we’re not going to really talk about aldosterone much, but I’ll dosterone is important for regulating sodium and causes the reabsorption of sodium in the kidneys, it causes us to lose potassium through the kidneys. And then it’s also important for fluid balance, it increases water absorption, aldosterone is mostly regulated by angiotensin two and potassium concentrations. ACTH causes a small release of aldosterone. Now, the reason we don’t call this adrenal fatigue, because adrenal fatigue makes it seem like the adrenals have burned out and that they’re not producing cortisol anymore. And that’s typically not seen. Typically, we see higher cortisol levels. Now there of course, there are cases of low cortisol, there’s a disease called Addison’s disease where this happens.


But what actually happens is, you get a down regulation of receptors. Again, with most hormones, if you bombard the system, the body tries to protect itself from that. And you get resistance. So this is one of the pathways for cortisol resistance, you get down regulation, or you remove receptors from the pool, these receptors are on the outside of cells. And if you’re getting cortisol resistance, then what happens is say there’s 10 receptors out there binding cortisol for it to do his thing. Maybe now you only put five out there, then there’s actual resistance at the level of the receptor. Now, we’re not removing receptors, but now the receptors, they’re not binding that cortisol is strongly. And this is called receptor sensitivity. So maybe they’re only binding the cortisol when it’s around 20% of the time instead of 100%. Or maybe the receptor itself is not causing the downstream changes. There’s a lot of things that can happen in that regard. Another thing is decreased cortisol bile availability. And this can happen if lots of cortisol is being metabolized to cortisone, and getting rid of that cortisol. Now we’re just processing a lot more of it. And cortisone is a less active form. In this increases the binding protein, there’s something called CBG. And this is a protein that binds most of our cortisol, only about 5% of the cortisol is free to interact with the receptor 80 to 90% is bound to CBG and five to 15%, are bound to albumin and CBD levels are increased by estrogen. They’re decreased by cortisol itself, under conditions of stress, all of these things here can impact this system, what causes dysregulation of the system? Obviously, number one, physiologic stress, or mental stress. We’ve talked about the mechanism there. Sleep deprivation, sleep deprivation can lead to more secretion of cortisol. When we’re sleep deprived, we are in a stressful state. Look at what happens when you’re sleep deprived, you’re insulin resistant, your heart rate goes up, your heart rate variability goes down, your blood pressure goes up. These are all physiological signs of stress. Of course, our body’s gonna respond With more cortisol, poor nutrition, if we’re eating a lot of processed foods, we’ve talked about this 65% of the caloric intake by the average American is processed foods, refined sugars, if we’re eating a nutrition plan that’s low in fruits and veggies, these are all associated with higher cortisol levels. nutrient deficiencies can exacerbate this especially vitamin C, the B vitamins and magnesium. We’ll talk about that more at the end. inflammation. Inflammation can impact this system from multiple different ways. inflammation can directly trigger the sympathetic nervous system, you trigger the sympathetic nervous system, you increase norepinephrine, you increase cortisol. And these inflammatory mediators can also activate the hypothalamus pathways through our old friend NfkB. If you remember NfkB is the master genetic switch for inflammation, things like TNF alpha, il one cyclooxygenase, CD 14, these are these actual mediators that can increase inflammation, they can activate hypothalamic pathways directly. Activation of micro glial cells in the brain leads to many maladaptive responses. We talked about these micro glial cells in the Alzheimer’s episode. This can lead to tissue damage directly an activation of the stress response. And then they can also activate HPA independent pathways. Again, there are independent pathways, we’re just talking about the major two today. These independent pathways can be directly stimulated by inflammatory mediators to cause cortisol release, independent of this HPA access. We know that previous trauma is associated with abnormalities in the system. trauma can either lower or elevate cortisol, for example, Holocaust survivors, sexual assault victims or abuse victims, African Americans who experienced racism, we’ve seen elevations and cortisol levels in these populations.


Exercise Exercise can be a double edged sword. If the system is already dysregulated, the intensity of the exercise matters. moderate and high intensity exercise in cardio can increase cortisol production. This is when you’re at a vo to max of 60 to 80%. However, low intensity exercise about 40% of our vo to max does not if your system is healthy. It’s okay to be at that 60 to 80% vo two Max because that imparts physiological resilience. We’ll talk about that more in a minute. Now you’re telling me okay, what’s vo two max right you’re telling me if my system is dysregulated I need to keep my vo two Max low. Well, you can go measure your VO two Max through organizations there are all kinds of places that will measure this I’ve measured mine. But a quick and dirty way to do this is 40% deal to max is 64% of your max heart rate 60% via to max is 75% of your max heart rate. And 80% vo two Max is 88% of your max heart rate. How To calculate your max heart rate takes 217 minus point eight five times your age. For me, if I’m feeling super burnt out super stressed, I would want to keep my heart rate below 117 Because that’s 40% of my vo to max fasting. You want to be aware with prolonged fast if you have HPA Axis dysfunction, because if you get hypoglycemic, it’s going to activate the system. Hunger activates the system is 100% okay to be in a small caloric deficit, you know 5% This actually can increase DHEA in primates, so it’s may increase your DHEA levels. A systemic meta analysis showed that a slight calorie deficit increased cortisol levels initially but levels returned to normal after a few weeks. If you’re doing time restricted eating you want to keep that fasting window for no more than 10 hours time restricted eating is okay you just don’t want to do it for too long. Being in a calorie deficit is okay. You just don’t want to make that deficit too large. But you don’t want to do prolonged fasting. Obesity, obesity increases that CBG that corticosteroid binding globulin, it decreases the amount of free cortisol available so a dysregulates this system dysbiosis we’ve talked about dysbiosis before dysbiosis can change neuromodulators which can affect the hypothalamus. leaky gut, leaky gut more toxic molecules can cause inflammation in the brain. You can get an increase in LPS lipid polysaccharides more inflammation, you can get a decrease in short chain fatty acid butyrate is anti inflammatory. It also helps regulate microglial cell function. We’ve talked about all this on the podcast before. Insulin resistance is associated with HPA Axis dysfunction. And then genetics, of course, anything that we’ve talked about in this pathway can have a genetic influence. You could have just genetically more cortisol released, you could have a genetically more sensitive hypothalamus, you could have a genetically more sensitive ACTH receptor, the opposite, you can have less sensitive as well. So genetics always play a role. But it’s the old conversation nature versus nurture. We can overcome what our genetics say by epigenetics, how we interact with our environment. Other ways that you can tell these things, your blood sugar response? Do you have an exaggerated blood sugar response? Are you getting more than a 30 milligram increase in blood sugar after you eat? What’s your heart rate doing? Is your heart rate trending up? Is it higher than it normally is? Everyone should know their baseline heart rate when they’re feeling great. My heart rate is usually between 60 to 70. If I start seeing my heart rate in the 70s, I know something’s up. Heart rate variability, we talked about heart rate variability on the how do you know your healthy podcast, if your heart rate variability sucks, if it’s super low, you our stress heart rate variability is a direct measure of the balance between your sympathetic fight or flight or your parasympathetic rest and digest system. A low heart rate variability means the sympathetic system is dominant because most people, the parasympathetic is not going to dominate. low heart rate variability could mean the parasympathetic is dominating. But that just doesn’t really happen. Not in our stressful day and age. low heart rate variability means that one system is dominating, likely the sympathetic system. And this is increasing our overall physiological stress.


If you’re gaining central body fat, that could be due to hormones, and preeminently. It could be due to cortisol because cortisol tends to lead to deposition of central body fat. If we’re having fatigue, if we’re having brain fog, if you come to me as a patient when I was taking patients, I’m not anymore, right, unless you are coming through Nimbus, but we’re not doing this stuff through numbers yet. And if someone told me, you know, what the same level of stimulus is causing a far greater response, like if something that didn’t used to piss me off is now sending me to the moon every single time. I know there’s something wrong with the system. That’s an easy, quick way to tell, are you getting more angry, more upset and more sad by things that didn’t use to move the needle that much? lifestyle interventions. Now the main goal of these interventions is to impart resilience. And what do I mean by resilience? So this stress response is not all or none, it’s not zero or 100. It’s zero to 100. And so what resilience does is, it makes it so when we encounter a stressor, because we’re always going to encounter stressors, this is life, you’re not going to have a no stress life. Instead of going to 100, maybe your response goes to 20. And by going to 20, the system isn’t activated as long, and then it goes back to normal. That’s what resilience is. It’s our ability to appropriately deal with the stressors that come through our lives. Sleep. Sleep regulates our circadian rhythm, it regulates our hormone cycles. One night, a poor sleep can increase cortisol levels for two days. So it’s very important to get good sleep, restorative sleep, to balance that cortisol awakening response in the morning, it sets the pathway, right? Nutrition, whole food nutrition plan, we talked about processed foods, high calorie intake, low fruits and vegetables all causing an increase in cortisol release a whole food nutrition plan will actually balance the system balance the hormone pathways, and then if you are trying to lose weight, or body fat because like you know, I hate that term weight, then you want a slight caloric deficit. You don’t want to do prolonged fasting by prolonged I mean, have your fasting window, your non food intake window longer than 10 hours strength training and aerobic exercise. This can improve physiologic and mental resilience. This is why resistance training and HIIT type exercise is so great, because not only does it improve your physiology. So it imparts that physiological resilience making you better able to deal with stress. This is what we call a huge stressor instead of a Distressor. You stress is stress that causes an increase in norepinephrine or adrenaline, maybe a release of dopamine, but it doesn’t cause an increase in cortisol with it. Or if it does cause an increase in cortisol with it that cortisol release is short lived and appropriate in response to the stimulus. What exercise does is it allows your body from a physiological standpoint to have physiological resilience at the level of the cells, it makes the cells more resilient to stress. But it also imparts mental resilience that top down processing. So you’re better able when you exercise to be able to control the mental aspect of the stress pathways. This is what we call habituation. Exposure to low levels of certain stressors decreases our overall stress response when we encounter a stressor by improving resilience. Now, what the data shows is that in those who are chronically trained, you get a reduction in cortisol, heart rate and heart rate variability when exposed to a stressor. That’s what we want. Now, we talked about earlier that exercise can increase your cortisol Yes, but it’s not a dysregulated increase. And then it imparts this double resilience, mental and physiological. So when you do encounter a stressor, later on, you get a reduction in that cortisol so that stressor is not going up as high, it’s going to, you know, 20, instead of 70, or 80, mindfulness, non sleep deep breath, breath work, also imparts physiological because it helps control the balance between the parasympathetic and sympathetic nervous system. And it imparts mental resilience.


This is also associated with reductions in cortisol reductions in heart rate reductions in heart rate variability, when exposed to an acute stressor, I always say in moments of strength prepare for moments of weakness, you cannot just say, oh, you know, someday I won’t have any stress. If this is gone from my plate, I just won’t have stress, you will all waise have stress in your life. What you need to do is do the work to prepare you for when that stress comes. And that’s things like nutrition, things like sleep, things like exercise, things like mindfulness. And, you know, this may seem like a broken record, because we talk about these things with every single podcast. But that’s because they impact every single biological system. The growth mindset, we did a whole podcast episode on the growth mindset, our limbic system, our emotional centers in the brain, our thoughts and our thought patterns can influence stress responses. So it’s very important to make sure that you have the right mindset and that growth mindset that challenges or opportunities for growth, everything we talked about in that podcast, is the way that you can improve that top down process of the HPA axis, but also, it helps control the amygdala in your fear response, because that’s another input into the system. So what this does is it decreases the anticipatory factor of the stress response, social connection, or apparel, a dog oxytocin can reduce cortisol levels when we feel like love and social connection, we can actually decrease our stress response why is it that pets are such great emotional support animals because they increase oxytocin you pet a dog you get an increase in oxytocin the dog gets an increase in oxytocin we talked about this in the man’s best friend episode. I think that’s the name of it. I’ve got so many episodes, I can’t even remember the name because the home now I guess that’s a good problem to have. Another thing and human loves these things, shout out to to human. I don’t know if you still listen to my stuff or not probably not here too big now. But periodic heat and cold exposure deliberately can improve physiologic and mental resilience. We talked about in the infrared episode, heat actually mimics the effects of exercise on the body. So heat after exercise can actually improve your heat tolerance, so you don’t feel as hot when exposed to high heat temperatures. It will actually help you endurance wise when you exercise because the enzymes in your body can only work. In certain temperatures. There’s a temperature effect there and especially for metabolism. There’s a specific pathway that’s very impacted by heat, and you will basically show doubt your ability to metabolize for energy generation when your body heats up outside of certain range. And so by increasing your heat tolerance, this basically means that when you’re exposed to the certain stimulant, your body temperature won’t increase as much. You get more efficient at generating energy without generating heat. And we talked about this in the metabolism podcast, cold showers in the morning. So cold exposure has been shown to increase norepinephrine, epinephrine and dopamine without increasing cortisol. This will help you wake up, it’ll help you feel more alert, you’ll feel better because you have dopamine, you’ll feel more motivated, then this will impart physiologic and mental resilience, supplements, there’s a lot of different things that you can use on the supplement front. I typically start with adaptogens. Well backup, I always start with the lifestyle stuff, the All you got to do the lifestyle stuff, supplements are just meant to augment the lifestyle stuff. But adaptogens adaptogens by definition are substances that increase the ability to adapt to environmental factors and avoid damage caused by those factors. Now, there are several of these things. My favorite is ashwagandha ashwagandha has been found to lower cortisol levels improve sleep, increased stress resilience, I personally take 500 milligrams a day, if I have a more stressful day I take 1000 We have ashwagandha in our alpha male x and alpha female products. You can find out more about those at Nimbus Others include Rhodiola ginseng, holy basil eleutherococcus, which we talked about in the podcast before, these are all different adaptogens certain species of mushrooms are adaptogens as well. There are several different ways that you can get adaptogens is just my personal favorites ashwagandha. As far as I know, it’s the most studied one of the adaptogens vitamin C,


we don’t make vitamin C, we need to consume vitamin C, we need about 200 to 300 milligrams of vitamin C per day from food. To maintain adequate levels and stress situations our need for vitamin C can go even higher. The adrenal gland actually has one of the highest concentrations of vitamin C in the body. It is a cofactor for catecholamine, catecholamines or norepinephrine, epinephrine synthesis and for the adrenal steroid, so to make these we need adequate vitamin C, there is data showing that vitamin C at 500 to 1000 milligrams a day can decrease stress and anxiety. I personally take 300 milligrams of vitamin C daily, but I’ll take it up to 600 If I have acute issues, B vitamins, all the B vitamins are used at some point in making the adrenal hormones but especially B three B five and B six B vitamins and combination with mineral supplements have been shown to reduce stress, enhance performance on cognitive tests also reduce mental fatigue and symptoms of anxiety and depression. I take a B complex every day. I’ll take two on days that I feel more stress. Magnesium, we’ve talked about magnesium a lot on the podcast 40% of the population is deficient 60% Get inadequate intake. Symptoms of magnesium deficiency include fatigue, irritability, anxiety, muscle weakness, gi spasm, muscle cramps, headaches, sleep issues. Now if you remember early in the podcast that sounds a lot like the symptoms associated with abnormalities and cortisol. So abnormalities in the stress access seem to have the same symptoms abnormalities in magnesium. The human body contains about 21 to 28 grams of magnesium about half of that is in the bones. Magnesium is involved in hundreds of reactions in the body, protein and DNA synthesis metabolism neuromodulators heart function, electrolyte balance, it activates vitamin D. The brain uses magnesium to inhibit glutamate. So we talked about how glutamate is necessary to activate the hypothalamus. It’s also used to activate GABA we talked about how GABA tonically inhibits this HPA access so you inhibit ACTH release. It’s also needed for serotonin action, and the synthesis of serotonin. It increases BDNF brain derived neurotrophic factor which is like brain growth food. It decreases free radicals so you’re not getting inflammatory damage in the brain. Initially what happens if we are stressed our body starts pumping magnesium into the bloodstream from the bones. But if we don’t repeat it, we will get depleted and magnesium in low magnesium levels are associated with increased norepinephrine, catecholamines and cortisol. Now I’ll take 200 to 400 milligrams a day when under stress. One study showed that 300 milligrams of magnesium daily showed a positive response on stress. 400 milligrams a day showed improvement in HRV during muscle endurance training To the daily mount for magnesium is about 400 for men 300. For women, that’s what’s recommended that we get probiotics. If you’re having a lot of gut issues associated with stress, things like lactobacillus acidophilus, Bifidobacterium, bifidum, bacterium, long GM and l KCI. These are all things that are associated with improvement in the stress response. Now the Bifidobacterium are associated with increased GABA. We’ve talked about why that would be helpful, and the lactobacillus acidophilus and the Rudra. They increase oxytocin, we talked about why that would be helpful. studies do show reduction in stress and anxiety with the specific strains. The ECS endocannabinoid. The ECS system helps regulate brain function in multiple areas. Data shows that the ECS can either activate or inhibit the HPA axis. And what’s interesting here is it seems that endogenous meaning the cannabinoids that we make naturally, the to ag and in the anandamide. These seem to suppress the HPA axis, while exogenous cannabinoids like THC seem to activate it. Now here’s the interesting thing about CBD. CBD is an exogenous cannabinoid.


But it is a really poor activator of our ECS system. How CBD actually works, is by potentiate ing the body’s own endocannabinoid system. And this is why you can see that studies using higher doses of CBD have shown an analytic meaning improvement and anxiety. data also shows that people with stress disorders have lower levels of endogenous cannabinoids, so boosting those endogenous cannabinoids can improve this system. Now, if things are really really bad in the system, people are doing things and you just can’t improve it, you may need to actually replace some of these hormones. DHEA DHEA may increase muscle mass and decreased fat mass in the elderly with low levels. It may help with mental functioning and depression may improve sexual function and libido. Typically, we’ll see 25 to 50 milligrams a day as a starting dose. Some people advocate for 17 keto DHEA in women, as it’s not readily converted to testosterone, it also seems to cross more readily into the brain, because it’s not bound up by those binding proteins that we talked about. The side effects of DHEA are usually androgenic, meaning they’re androgen like they cause male typically, like what you’d see is like male type symptoms. So like greasy skin acne, increase hair growth and pubic areas. And then sometimes you’ll do pregnenolone pregnenolone is a precursor to all the adrenal hormones. It’s a compounded prescription, but it can be used as a last resort and people who are just not responding. They’re Dutch Testa looks all over the place. And you just need something to get all of those hormone access. He’s right. This is something that has to be done under a physician who is very knowledgeable about the HPA axis. Okay. Woof. Hit the hour, Mark. Man, I feel like Cuba man, I don’t know how he goes for two hours on this stuff. I’m exhausted. All right, y’all. That was our HPA access episode. Hope you enjoyed it. Hope you found it informative. It’s a very complicated system. But it’s one that we can exert a lot of control over. By doing the things we mentioned in this podcast, I can control how I respond to the stress and that is 100% under my control. Thank you guys for listening to the strive for great health podcast with your host Dr. Richard Harris. Have a blessed day. Thank you for listening in to strive for great health podcast with your host Dr. Richard Harris. It’s our mission and goal at the podcast to impact as many lives as possible to empower individuals to take control of their health and live a life full of joy and purpose. You may help us achieve this mission by leaving a five star rating and review on your preferred podcast platform. And by sharing this podcast with anyone you think it may help. You can also support the podcast by making a donation to your favorite charity. If you do so and send us an email. We’ll give you a shout out on the podcast because here’s the strive for great health podcasts. We’re all about charitable giving and making the world a better place. Thank you for listening and God bless

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