Effect of Hormone Imbalances on Energy, Sleep, Depression & Anxiety

This episode was pre recorded as part of a live continuing education webinar on demand. CEUs are still available for this presentation through all CEUs register@allceus.com counselortoolbox you I'd like to welcome everybody today's presentation on the biopsychosocial impact of hormone imbalances. I am Dr. Donnelly Snipes. We're going to review the sex hormones and their functions and not all of them. We're just going to hit the three big ones, estrogen, testosterone and progesterone. Today I really wanted to cover more, but there was no way to actually do that and do any of them any justice. So I have restricted it to those three. We're going to review the impact of sex hormones on the HPA axis and review causes and consequences of imbalances for estrogen, progesterone and testosterone, which obviously I'm alluding to the fact that hormone imbalances can cause mood symptoms. Most of us are not surprised by that. However, it is interesting to note that hormones work differently between the different sexes and they also work in concert with one another. All of us have estrogen, progesterone and testosterone, but it's just a matter of how much of each one. Let's start out with estrogen because that's the one that has had the most research done on it. I was really very surprised to see how little research has been done on progesterone and testosterone. But anyway, we'll get there in a minute. There are multiple forms of estrogen. The two that you're really going to want to focus on are estradiol, which is predominant prior to menopause, and estrone, which is a primary form post menopausal. Well, you can see right now, you know, think about when women go through menopause, how their moods change, how some of their reactions change. There is definitely a connection between levels of estradiol and cognitive and emotional reactions. Estrogen is synthesized by fatty tissue. What that means is people who don't have enough fatty tissue may not make enough estrogen. If you've got someone who is a dedicated athlete and maybe a bodybuilder, and you know how they want to get down to like 2% body fat or something before shows that is going to decrease their body's ability to synthesize estrogen. That's one thing that we need to know about. If you're working with someone who has an eating disorder and is significantly underweight, that may be an issue. If you are working with someone who just tends to be really thin. They don't have a eating disorder that's diagnosable by the dsm, but they are not hungry and they don't eat much. My best friend is like that. She is, you know, itty bitty. She doesn't literally have an ounce of fat on her, I swear. Which means, you know, her body's ability to produce estrogen is going to be different than mine because I tend to have a little more padding. It's important to know that for understanding or identifying when someone might have an estrogen imbalance or sex hormone imbalance. Estrogen works synergistically with many systems to promote physical, cognitive and affective functioning. It's not just mood. You know, we tend to think that when women develop PMS or pmdd, it's estrogen, it's estrogen's fault. Well, that's not necessarily true. We do want to recognize, though, that changes in estrogen levels can contribute to cognitive decline. It can contribute mood mobility. It can also contribute to things like fatigue and weight gain. Estrogens can modulate neuronal excitability through modifying serotonin, norepinephrine, dopamine and endorphins. Wow. So those are our big five. And actually it also modifies acetylcholine. I just didn't have that one in here. Our main neurotransmitters are all, all impacted by estrogen levels. If your estrogen levels are out of balance for your body, then you may start having a variety of different symptoms. I know there's a lot of women who may go off. They may be on birth control and then go off birth control while they're trying to get pregnant. Then obviously while they're pregnant. You know, those are three very distinct, distinct periods where hormones are in different balances and it can affect their mood, their cognitive functioning, and their physical functioning. Estrogen supplementation can decrease both systolic and diastolic blood pressures and reduce norepinephrine levels. Let's think about when somebody's depressed. What are some of the drugs that they take? Ssri, selective serotonin reuptake inhibitors. But the other one that is often prescribed are SNRIs, selective norepinephrine reuptake inhibitors. When norepinephrine levels go low, you tend to have blood pressure that goes down. But you also may have other things like energy and mood that tend to go down as well. Norepinephrine is one of our main excitatory neurochemicals. When we don't have enough norepinephrine we're not going to have that focus, we're not going to have that energy, if you will. Glutamate is our other one. But let's just focus on norepinephrine here. And as I said, obesity can increase estrogen levels. There's been a marked increase or there is a marked increase in people who are over fat, not necessarily, you know, oversized or according to the bmi, which, you know, you all know I don't like the BMI measure, but if people have in excess of 30% body fat, their estrogen levels tend to go up, which can promote estrogen dominance. We're going to talk about what that looks like in a little while. It's not always the case, but it is one of those risk factors for high estrogen. Estrogen modulates mood via the serotonergic system. It also contributes to the downregulation of, of 5 HT2. Remember, there are about 17, I think, different types of serotonin receptors. 5 HT1A is the one that your antidepressants are going to target. 5 HT2 tends to be more stimulating. It down regulates those. And the monoamine oxidase receptors, well, when, when somebody is depressed, then one of the drugs, old drugs they used to take were those MAOIs, monoamine oxidase inhibitors. We do want to recognize that estrogen is in there, monkeying with all those things. Estrogen Also down regulates 5 HT1A receptors presynaptically, but not postsynaptically. And the take home message from all that, because none of you are neurobiochemists, I don't think it's just that estrogen really is intensely interwoven into this serotonergic system. So changes in estrogen levels because of monthly cycles, because of birth control, because of pregnancy, because of stress, can all alter estrogen levels, which can have an effect on cognition, mood and physical symptoms. In one study, 80% of women were given estradiol and they reported a significant decrease in mood symptoms after three or six weeks compared to only 22% of women on placebo. That is interesting. It's not. Don't take that and run with it and go, hey, that means most of the people just need to take estradiol. No, no, no, no, no. We don't want to jump to that. That is way overly simplistic. But that is some good news for people who have tried SSRIs and have not achieved the results that they're looking for. Maybe having a blood test easy to Test hormone levels to identify if their estradiol levels are low. And if that's true, then supplementation may help. Estradiol resulted in an improvement in 68% of perimenopausal women with depressive disorders, whereas only 20% of women on placebo experienced a similar benefit. We're seeing that 20, 25% that are not responding, which means their symptoms are probably not caused by a hormone imbalance. But we are seeing a large portion of women, especially perimenopausal, when that estradiol level is starting to drop, kind of like a rock, and estrone is starting to become more dominant and women are starting to experience mood symptoms. This is one of the reasons we do want to pay attention. I know it seems personal to ask questions about when was your last monthly cycle? Or are you pregnant, Are you on birth control? But these are all things that may be useful to put into the clinical formulation. Estrogen also regulates glucose metabolism and energy production. Think diabetes. If estrogen is out of whack, people tend to be at a higher risk for diabetes. Declines in these processes, glucose metabolism and energy production, are also characteristic of neurodegenerative diseases like Alzheimer's disease. Who knew? Well, I guess the scientists knew, but that's not something I was ever taught in graduate school that estrogen imbalances can contribute to cognitive decline. Estrogens can be really awesome in the right balance, because in the right balance, in the. In the soup, in the neurotransmitter soup, they exert neuroprotective actions to maintain cerebrovascular health, including prevention of glutamate induced excitotoxicity and hippocampus shrinkage. Okay, I could hardly say that for all the big words. What does that mean? If you think back to the HPA axis, the stress response system, when we experience a stressor, that fight or flight reaction kicks off. When it kicks off, glutamate is released into the system. Glutamate is our main excitatory get up and go, fight or flee neurochemical. Excessive exposure to glutamate actually is toxic to our brain cells and we start losing. We do actually start losing brain cells, which leads to shrinkage in the hippocampus, which is one of those areas that's responsible for learning, memory, and emotion. Estrogens protect against that flood of glutamate, if you will. So we want to have estrogen. We don't want to get rid of it. I know a lot of people get stressed out because certain cancers are, you know, Estrogen positive and all that kind of stuff. We don't. We need estrogen in a certain amount, we need testosterone in a certain amount. We don't want to get rid of it. We don't want to have too much. It's about finding that appropriate balance for the person. Estrogens can exert some anti inflammatory effects, which is good and naturally occurring. Higher levels of estrone, remember, not estradiol but estrone were associated with poorer cognition and specifically problems with working memory. So when your estrogen goes up and your estradiol goes down, people tend to have poorer cognition and difficulty with working memory. Estradiol acts in part with nitric oxide to increase extracellular dopamine levels. Why did I put that one in here? Well, a lot of workout supplements and some of your energy drinks now contain nitric oxide, which is made from arginine or made with arginine. And when those two things get together, they can increase dopamine levels. If people have enough nitric oxide and stuff in their system, but they don't have enough estrogen, then they may still have difficulty in some parts of the body producing enough dopamine. We know dopamine is our perseveration chemical, if you will. It's the chemical that says I want to do that again, I want to keep doing that. Premenopausal females have a better response than males to serotonergic antidepressants, indicating that female hormones may improve the efficacy of SSRIs. Estrogen, serotonin are intense, intimately intertwined. We saw in the research studies that there's a percentage of women out there who respond favorably to estradiol supplementation, which means that part of their symptoms may be caused by estrogen imbalances. Not necessarily just serotonin. But putting that estrogen in there may help the system function better. Depressed postmenopausal females on supplemental estrogen plus SSRIs showed improved responses compared with depressed postmenopausal females without estrogen. Remember, and what we're talking about with this estrogen is the estradiol. After menopause, that estradiol level goes way down. When people were given SSRIs postmenopausally, it may have helped a little. It wasn't super influencing, but when they bumped that estradiol level back up to premenopausal levels, all of a sudden we started seeing improvements in mood. Estrogen alone though did not relieve depression. So there is something going on with the serotonergic system that is still out of whack but adding estrogen is sort of enhancer to the treatment protocol. One of the downsides with estrogen, the largest clinical trial of hormone therapy ever conducted revealed an increased risk of cancer, dementia and cognitive decline with prolonged administration of conjugated equine estrogen or cee for a long time, this, the estrogen supplements that women were taking were conjugated equine estrogen. We're wanting to look for other more natural, more bioidentical hormone replacement therapies. Higher levels of estradiol produce a stronger HPA axis response. Okay, so that's kind of interesting. It increases serotonin or works with the serotonin system to help people feel calmer and exert some neuroprotective effects. But high levels of estradiol also produce a strong stress response, even during non threatening situations. And during and after stressors, if people have estradiol levels ratio to estrone, estradiol levels higher than what is what they need. You know, I hate to use the word normal, so I'm trying to not to use it then. Excessively higher level, excessively high levels of estradiol can produce HPA axis dysregulation. So when somebody gets stressed out, they go from 0 to 200 in 1.2 seconds. Under conditions of anxiety and stress, this is interesting. Women tend to threat differently depending on their endogenous estradiol levels. When their estradiol is lower, when their estrogen is lower, they tend to be avoidant of stressful situations. When their estradiol is higher, when their estrogen is higher, they tend to be more vigilant. If you've, you know, if you're female or you've worked around people who are female or worked with female clients, you've probably seen this. It's easier to avoid, ignore, let go of things. When estradiol levels are lower, when it's, when estradiol levels are higher, people tend to be a little bit touchier. Now, I will pause here. I didn't do a lot of discussion because there's not a lot of research out there on the impact of people who are transgender that are going through hormone replacement therapy. The lion's share of the research focuses on the effects of estrogen in women and the effects of testosterone in men. The effects of estrogen supplementation, for example, on adolescent males or juvenile males who are trying to go through gender transition. We're not speaking to that right now, but it is definitely something to consider that when we start artificially altering the levels of those hormones, regardless of the person's birth sex, it is going to have an effect. Estradiol increases the activation of corticotropin, releasing hormone and base levels of ACTH back to that HPA axis. When we get stressed, the brain releases corticotropin releasing hormone, which causes the release of cortisol. And ACTH is another one of those chemicals that's involved in releasing norepinephrine and adrenaline. So estradiol increases the activation of those chemicals, which goes in sync with the fact that when estradiol levels are higher, we tend to have a more potent HPA axis response. But chronic stress produces a hyporesponsive HPA axis, just like chronic stress with ptsd. You know, we've talked about this over and over again. Chronic stress. Eventually the brain says, I can't be bathed in all that stimulation all the time. I need to, you know, reserve my energy for when there's really a threat and the receptors become less receptive to the cortisol. Just like when somebody who has an addiction, you know, they're constantly flooding their brain with endorphins and dopamine and eventually they develop a tolerance and they need more of the drug to get the same high, same sort of thing. When you're under chronic stress, eventually the body becomes desensitized or hyper responsive to that cortisol, and you need more cortisol to get the same boost. So it really has to be an intense stressor to get that boost. So chronic stress produces a hyper responsive HPA axis. We've called that hypocortisolism. That is hypersensitive to the modulating effects of estrogen. You have an HPA axis that's in reserve mode. It's trying to protect itself. But then when estrogen is introduced, it causes an even more dramatic HPA axis response. Changes in HT1A receptor binding in the hippocampus and hypothalamus are restored by estrogen replacement. HT1A, remember, is serotonin. And serotonin tends to be our calming chemical. If estrogen levels are rebalanced, they're finding that serotonin system. The serotonin system tends to be rebalanced, but that also means getting rid of that chronic stress. We can't continue to bathe the system in stress chemicals. Treatment with estradiol could inhibit negative feedback effects of cortisol and increasing cortisol levels. Remember, estrogen increases that HPA axis. So if we're providing estrogen treatment, there is the concern that it actually itself could be a stressor that contributes to hypercortisolism eventually or increase cortisol levels. Estradiol treatment has been shown to increase corticosteroid binding globulin cbg, which inactivates cortisol in males. Now, it hasn't been found to be the same way in females, but in males, which is very interesting, when estrogen is given to males, it reduces cortisol levels. Crosstalk between the hypothalamic pituitary gonadal axis and the HPA axis could lead to abnormalities of stress responses and as a result exacerbate protein peripheral pathologies. Which basically means if your hormones are out of whack or your HPA axis is dysregulated, it's going to. Both of them are going to affect each other synergistically and can cause a whole host of other problems. Low estrogen, for example, can cause a blunted HPA axis response that hypocortisolism, which often looks like depression. High estrogen can be, can exacerbate an HPA axis response, produce sustained higher levels of stress chemicals which produce anxiety, inflammation and autoimmune responses. That's, you know, you want to go back to the class on the HPA axis for more information into that. But just looking at the influence of this one chemical, which is, well, there's multiple types of estrogen, but this one family of chemicals in our health and well being, it's not just our mood, it's not just our cognition, it's our brain health, it's our body health, it affects our blood pressure. Hormone therapy administered at or around the time of menopause may improve cognition. But hormone therapy initiated five years or more after menopause shows no cognitive benefit and even may produce cognitive decline. If people are wanting to start hormone therapy, then it looks like it's best. There's a window of opportunity, you know, less than five years after menopause to begin that hormone therapy. The shorter the time between menopause and initiation of hormone therapy was associated with larger hippocampal volume. Remember, estrogen protects against hippocampal shrinkage because of glutamate induced excitotoxicity. We want to make sure that people have enough estrogen to protect themselves or have other skills available. My stepmother, for example, you know, she had a hysterectomy many, many, many, many years ago. And this was probably back when they were using the conjugated equine estrogen or whatever. But she can't take it and, you know, it was horrible, horrible experience. For her. So she couldn't take that. Does that mean she's going to have cognitive decline because she doesn't have the same the premenopausal levels of estradiol? No. You know, it's been 20, 30 years since she had her hysterectomy and she's doing just fine. But we do want to pay attention to the fact that that can be a risk factor. Hormone therapy using estradiol more effectively recalibrates the estradiol estrone ratio to approximate premenopausal levels. Basically, they found in a lot of these studies single hormone estradiol replacement appears to be more effective and have less side effects than multiple hormones like estrogen and progestins and you know, putting multiple things in the body at once. Estrogen's actions, this is just an interesting fact, skew immune responses toward allergy and autoimmune responses, which seems counterintuitive since estrogen can have some anti inflammatory effects. It depends on where the estrogen receptors are and how they're working in the lungs. It can actually increase asthma and inflammation. Not only do endogenous estrogens appear to play a role, but environmental estrogens also have been implicated, including bpa, phthiolates and both of those enhance allergic sensitization and may enhance asthma in humans. There's been a lot of research that has shown that there are definitely some chemicals we're using and exposed to on a daily basis that are endocrine disruptors. And we'll talk about that at the end of the presentation. There was a study that came out a while back that has since been pretty much debunked that said that exposure to essential oil of lavender could, or tea tree oil could increase estrogen levels and promote gynomastia in men. They've since debunked that or yeah, I guess you want to say debunked that study and found that there were some flaws in the methodology and there's very little support for those two essential oils being problematic. But there was another study that showed that the essential oils of geranium or essential oil of rose increased estrogen levels compared to a control odor. Now, it was one of those. It wasn't clinically significant, it was just statistically significant. But it is interesting to note that things like smells can increase estrogen levels. So I want you to think, you know, I know sounds, for example, when I hear a baby crying, you know, that can trigger, that triggers my maternal response. I love babies. Other smells, like the smells of baby powder Other things like that may trigger estrogen responses in some people, and I don't want to say just women, but, you know, it may trigger increase in estrogen or an increase in hormones that are geared towards preservation of the species, etc. It may not just be essential oils. Something to think about. Progesterone. Finally, we're done with estrogen progesterone, and that falls into the family of progestins, which regulate cognitive functions as well as social behavior and mood. Some of the progestins currently used in clinical practice exert neuroprotective and anti inflammatory effects in the nervous system. Again, this is a good thing. We want to see anti inflammatory because inflammation is associated with depression and chronic pain and autoimmune issues. Anti inflammation is associated with good health and good mental health. Progesterone is synthesized by the ovaries and the adrenal glands and it has widely distributed receptors and is antagonistic to estrogen. So when one goes up, the other one goes down. And we see this in monthly cycles. We see this in pregnancy. We see this a lot. The progestogenic component in combined hormone therapy was found to potentially counteract the beneficial influence of estrogen on on mood and even induce negative mood symptoms. So like I was saying earlier, using combined hormones tends to have worse effects, according to the research, on people's mood and cognitive abilities. That's going to be something for the woman to discuss with her prescribing physician, but it is something to pay attention to and it's one of the reasons why it is important. And like I said, sometimes it feels weird because it's a really personal question to ask. But it is important to have people try to chart women chart their monthly cycles, even if they're irregular cycles. Let's chart them so we can see what the hormone fluctuations are and compare them with your mood symptoms. That can give us a lot of information about whether some of the mood symptoms may be hormone induced or due to hormone imbalances. Women with higher average progesterone levels across their cycles reported higher levels of anxiety. Progesterone has also been shown to decrease gastric emptying, which has the potential to modify any antidepressants. Pharmacokinetics. You know, you get the pill in your system and it stays in your stomach for longer. It can be absorbed. More of it can be absorbed instead of being passed through, for example. So people with higher progesterone levels may need less or lower doses of antidepressants or other medications, but not necessarily Use of combined hormone therapy in the previous month was associated with worse depression and anxiety among 6,000 peri and postmenopausal women. So again, combined hormone therapy just really doesn't seem to be something that is helpful. Like I said, the information and research on estrogen was prolific. The research and information on progesterone and testosterone, much less so. But we're still going to hit those because we've got them and they do influence our mood. Testosterone is essential for maintaining virilization and muscle mass and may also affect libido, mood regulation, bone health and cardiac disease. Now, if you didn't know it, women also have testosterone and testosterone levels actually increase in women during pregnancy. Who knew? I didn't know that until I was preparing this particular class because of that. Because we have testosterone, it means it serves a function. Obviously it serves the function in men too, hypogonadal men, which means men with low testosterone levels exhibit significantly higher levels of anxiety disorders and major depressive disorders disorder. There's a lot of buzz out there right now about low testosterone and low t. And you know, take a pill for this and you know, take this supplement, it'll increase your testosterone. Again. I really, I do want to know about that when we're doing the assessment because that taking those supplements themselves can have side effects. Altering testosterone levels without really knowing what your base was can be kind of a sticky wicket too. Certain chemotherapies can reduce testosterone and increase anxiety. Most of these chemotherapies that reduce testosterone tend to be centered around prostate cancer and other testosterone oriented cancers. But any chemotherapy is exceptionally stressful on the body and, and can reduce testosterone levels. Testosterone, like estrogen, can enhance dopamine and serotonin release in the mesolimbic system. Remember, limbic system is where our emotions are. So these hormones are actually directly responsible for increasing dopamine in our emotional brain centers. We want to make sure that we've got enough but not too much. Testosterone also can enhance gaba, which is our main endogenous volume, if you will. And it's our main calming chemical. Serotonin tends to be more mood stabilization. It can promote relaxation and is responsible also for pain perception in part. But GABA tends to be the real heavy, heavy duty lifter for, for relaxation. Gonadal dysfunction appears to impair dopamine release, but not synthesis. This is important to consider, especially if you're working with transgender individuals, because once somebody who's transgender starts taking hormones in order to alter their hormone levels, it can reduce testosterone levels which can be considered gonadal dysfunction and impair dopamine release. We know that lack of dopamine can be can produce feelings of depression. We also know that altered levels of dopamine are related to things like restless leg syndrome and schizophrenia. You know, high and low levels of dopamine. So dopamine does a lot. And when we start monkeying with testosterone, we also start monkeying with dopamine levels. Testosterone acting in the hippocampus has a number of anxiolytic, antidepressant, and protective cellular functions, just like estrogen does. Testosterone can influence the degree of amygdala activation in relation to fear. And with a positive correlation observed between testosterone levels and amygdala activation, the more testosterone, the more the amygdala, which is our primitive fear area, fight or flight area. The more testosterone is up, the more the amygdala gets activated. Interestingly, there's a negative correlation in women. The higher a woman's testosterone level is, the less their amygdala is active. Gonadal steroids impact the HPA axis reactivity differently. Testosterone replacement blunts the cortisol and ACTH response to stress. So testosterone actually reduces the HPA axis response. Some estradiol actually increases the reactivity of the HPA axis. So when you think of women, you know, when you think of sex hormones for women, your first thought is estrogen. Well, estrogen increases HPA axis activity. The main hormone you think of for men is testosterone. It actually reduces HPA axis activity, which is interesting. To maintain homeostasis, the neuroendocrine system continuously monitors the level of gonadal steroids. That's, you know, gonadal steroids includes all of your sex hormones. Using estrogen and androgen receptors in the hypothalamus, Dysregulation of either or both of these axes, the HPA axis, your stress response system, or the HPG axis, the hypothalamic pituitary gonadal axis, can result in compromised responses to stressful life events. And as just a little aside, testosterone is suppressed with long term opioid use doesn't necessarily mean somebody who is abusing opioids. There are a lot of people who are on pain management regimens in which they are taking opioids over an extended period of time. I worked with a lot of veterans who are on a lot of opioids, but there's also people who are on methadone, for example, and whether it's methadone to help them get off heroin or if it's Methadone as a treatment for pain that is thought to be less potentially dangerous than other opioids. Whatever the reason, it's not uncommon to run into people who are on some type of opioid for an extended period of time, which will suppress testosterone. Testosterone treatment in hypogonadal men has beneficial effects on depressed mood. Again, when you've got someone who comes in and they've got depressed mood, well, a lot of the buzz right now is if you don't feel like you have the energy anymore, you don't feel virile anymore, you don't have that get up and go, you need to take this supplement to increase your testosterone or you need to go to your doctor and get testosterone supplementation. My question would be, why is the testosterone low in the first place? What's causing that? And we need to look at what's causing the dysfunction in HPG axis. However, when testosterone levels are restored to a level that's adequate for that person, mood symptoms tend to abate quite a bit. Now here's a little interesting thing. During the postpartum period, men's Testosterone levels drop 30%. And if they are engaged with their infant, their testosterone levels drop even more. Why is this, we wonder? Well, there's a strong correlation between men developing postpartum depression and they're the birth mother also having postpartum depression. So when there's stress, then it's likely that the man's postpartum depression and testosterone is going to go down and cortisol levels are going to go up. He's stressed, he's in this fight or flight, got to protect, you know, caveman mode, which, you know, testosterone and cortisol seem to be inversely related to. But we do know that, you know, in most fathers around the three to six month period, not the immediate postpartum period, but around the three to six month period, testosterone levels seem to really plummet and we start to see postpartum depression in men. Testosterone levels, they found in other studies, tend to increase in a reproductive context. So when they're trying to procreate, testosterone levels are high. But when they've, they've procreated, they've been successful and they have this new little being. Testosterone levels go down because the body says, you know what, we don't need to procreate. Procreate right now, we need to protect. So let's protect what we have. That can also explain some of the increase in irritability. As testosterone goes down, cortisol goes up. And because they're in that protective mode, in sort of a mini fight or flight or a mild fight or flight status most of the time. Chronic activation of the HPA axis, that stress response system, has an inhibitory effect on estrogen and testosterone secretion. Cortisol's high. Sex hormones are going to go down. Stress is high, threat is high. Not the time to procreate, basically is what the scientists have figured out. Stress in adulthood continues to mediate the HPG activity in females through activation of a sympathetic neural pathway originating in the hypothalamus and releasing norepinephrine into the ovaries. Now, that's the part that I wanted you to focus on. The first part was important to understand why all this is important. Chronic stress causes the release of norepinephrine into the ovaries, which tell the ovaries, you know what, there's a threat out here. This is not the time to procreate. The ovary does not ovulate, which produces cysts, which has been linked to the development of polycystic ovarian syndrome in a lot of women. People who have been exposed to childhood trauma, adverse childhood experiences or, or early trauma, again, are typically have a stronger stress response and, you know, maybe struggling with hypocortisolism. They are primed, if you will, to have that norepinephrine pumped into their ovaries because their body is hypervigilant a lot of the time, which, again, they've found may contribute to the development of pcos. Polycystic ovarian syndrome in women. Obviously, in women you can see people tend to gain weight, they tend to have oilier skin, they tend to lose a lot of hair, they tend to have thinning hair, dramatically thinning a lot more facial hair, higher levels of testosterone. There are treatments for polycystic ovarian syndrome, but it is something. There are a lot of very marked physical symptoms of pcos. Chronic social stress in females may lead to low estradiol and hypersensitivity and estradiol replacement. We already talked about that. But it can be chronic social stress. It's not just trauma. Chronic social stress can be enough to keep that low level of HPA axis activation going to the point that it causes hypersensitivity, that hypocortisolism. And then when you add the estrogen back, it's. It goes from 0 to 60. In people who have experienced chronic social stress who decide to try adding estradiol replacement with their SSRI or whatever. The recommendations seem to be start low and go slow because a little Bit maybe way more than what they need. The ability to modulate the HPA axis to ramp it up when it needs to be and to tone it down when the thread is gone is significantly reduced in over rectomized females. So people who've had hysterectomies suggesting a hyporesponsive HPA phenotype resembling that observed in several human psychopathologies, including ptsd. Basically they're saying once you take out the ovaries and you start altering that, that because you don't have the estrogen project production, then you start seeing more hypocortisolism. So the. Estrogen is not protecting and balancing out that HPA axis anymore. Depression and anxiety commonly associated with dysregulation of the mesolimbic system, the hypothalamic pituitary adrenal axis, the hypothalamic areas, hippocampus and the medial prefrontal cortex. Dysfunction and hormone symptoms. Synthesis, release or reuptake. So you can have estrogen and maybe the body can't produce it, maybe the body can't isn't releasing it like it should, it's just sitting there in storage. Or the body releases it and the receptors aren't receiving it. Any breakdown in that system can disrupt the hormone balance and impact the HPA axis via the HPG axis. Which takes us back to that first statement. When that HPA axis is dysregulated, it can dysregulate the HPG axis. But when the HPG axis is dysregulated, the hypothalamic pituitary gonadal axis is dysregulated. It is going to likely cause dysregulation in that HPA axis, which is likely going to cause mood symptoms. Basically, to be overly simplistic, variances in body fat, hormone levels and liver metabolism between the sexes have been shown to affect the pharmacokinetics of antidepressants and oral hormone replacement. Someone who is heavier, someone who has a greater percentage of body fat, someone who has a less efficient liver, maybe because they have a history of alcoholism, whatever, is going to respond differently than someone who is of average weight and has a fully functioning liver. Also, I should point out, as we get older, our liver function decreases. People who are considered older adults or geriatric, I hate that word, but they tend to have impaired hepatic clearance. Their liver is a lot slower at removing the toxins and getting the stuff out of our body. Which means toxic levels of things like benzodiazepines can Build up in the system. A lot of the people who are exploring hormone therapy tend to be older. Maybe not to the level of where they're considered geriatric, but. But as we get older, our liver functioning does slow and it's at a varying rate depending on your lifestyle factors. But that is important to consider when looking at hormone levels and everything else. Obviously this is something that the primary care physician is going to be focusing on. It's not something that we really need to be concerned with, but it is important, interesting at least if not important for us to recognize that as we get older, our body responds differently to medications. The stuff you were taking when you were 20 is probably going to be way too strong when you are 60. The biopsychosocial impact I told you we'd get here. HPA, the physical aspect, HPA axis activation. When those hormones are out of whack, it causes the body to perceive a stressor. And when there's a perception of a stressor, then that HPA axis gets activated. Persistent HPA axis activation. Really cool. When there's a threat, it secretes cortisol, which actually is sort of an anti inflammatory. It's a. But when the threat is passed, our body secretes inflammatory cytokines in order to encourage the body to repair anything that got damaged. Which is why when you're working out, you know, you're not feeling pain, you're just pumping that iron. You're getting a little micro tears and stuff, but you're not feeling the inflammation. It's, you know, a couple hours later or the next day that you're like, oh, this hurts. Those inflammatory cytokines have gotten out into the system. When the HPA axis is persistently activated, eventually those inflammatory cytokines are just constantly there, which leads to persistent systemic inflammation, which leads to autoimmune disorders. Disruption of hormones can also affect people's ability to regulate their blood pressure. They may have insomnia, fatigue, hypervigilance and altered libido. When you're tired, well, we'll keep going. When hormones are altered, it can contribute to irritability, anxiety and, and depression, which you know, when you're irritable, anxious or depressed, you really generally don't want to spend a lot of time with people and it can impair your work product. And when you're anxious, it's hard to sleep. When you're depressed, it's hard to stay awake. Either way, you're getting your circadian rhythms out of whack, which can cause more mood problems. People who are Irritable, anxious, depressed are at an increased risk for addiction. And if they end up trying to self medicate. And socially, when you're depressed, anxious, tired, you know, hyper vigilant, you may not want to spend a lot of time with people, which can lead to social withdrawal, which can have a negative impact on relationships, which removes one of those great buffers against stress. It can increase a sense of guilt because, you know, you don't really even want to go out with people, but you feel guilty because you think you should, and goes round and round. There can be impaired relationships due to irritability. We've all heard the stories of people who, when their hormones are out of whack, can be more irritable. And I'm treading lightly and choosing my words. I had a friend of mine that actually would go, they had a cabin, and when she would start getting pmse, she would go stay at the cabin for three days because she's like, I'm intolerable to be around. I don't even like being around myself. Wow. You know, imagine feeling like that every month. And it can contribute to work impairment. If you're exhausted all the time, if you're depressed, if you're anxious, if you're not wanting to get out of bed, not wanting to deal with people, if you're irritable, you know, it's probably going to affect your relationships with people at work as well as your work product, which is why it's so easy, so simple for people to go have a blood test done to get their sex hormones and their thyroid hormones tested to see if they're in normal limits. They're in normal limits, then great. If they're not, then we've got something to work with, potential hidden culprits. I told you we would get here. There are things in the environment called, well, and things that we're exposed to, called endocrine disruptors, which means there are things that we take that are not hormone replacement therapy that actually alter the levels of the hormones in our body. Triclosan, which is an antibacterial agent. If you look at any of your antibacterial soaps, it's in a lot of them. It disrupts estrogen, testosterone and thyroid hormones. According to the Natural Resources Defense Council. And obviously where these hyperlinks are, links to all the different studies. The interesting thing is our skin. Our skin, basically one big endocrine receptor. So if you're using antibacterial soap, you know, on your hands, okay, you know that that's you know, you do what you do, but if you're using it on your hands, plus you're bathing in it and putting triclosan throughout all over your body and it's being absorbed through your skin, you're being exposed to much greater amounts of it. It's also found in certain toothpastes and we all know that most people don't spit out 100% of their toothpaste. So that's one of those things to look at. Other things that increase estrogen, BPA and phthalates, which are found in water, water bottles, PVC pipes, food wrapping. Oh, I didn't like that when I heard it. You know, the stuff they wrap your meat in or any of those plastics that they use to wrap canned foods. Did you know that they line cans, especially acidic foods like tomato paste? They line those cans with BPA to prevent the acid from the food from deteriorating the can. And other plastics, like the plastic Tupperware that you might be putting your, your food in, make sure that you're getting stuff that's BPA free. And you know, if it says don't microwave it, don't microwave it because it may, when it gets hot, it may leach other chemicals into your food. PFAs and PFOAs, basically Teflon, your non stick foods or your non stick ware also can disrupt estrogen when you're using it. As long as it's not flaking off. You know, theoretically it's not. You're not getting enough of it in your system to be a problem. But if you're like me, you know, my pans when I was using those used to flake off pretty quickly and pretty easily. Certain essential oils may increase estrogen. The jury's out on that. And phytoestrogens also can increase estrogen. And there's a lot of debate about phytoestrogens because they are less potent than our endogenous estrogens. So when they get into your body and, and take up those receptors, they pack less of a punch, which may be protecting your body in some cases from the more powerful endogenous receptors. And this, these would be your soy based foods primarily. But there is a lot of research on both sides of the aisle about whether women who are at risk for breast cancer, for example, should eat soy or avoid soy. Not making a recommendation. I'm just saying they do know that plant estrogens do interact with the estrogen receptors. Other things in the environment that may lower testosterone, opioids. We already talked about that. Tagamet, which is a and any of the medications pretty much that are prescribed for gastric esophageal reflux disease can lower testosterone. Antidepressants can lower testosterone. Statins, which are the medications to lower cholesterol, actually can lower testosterone. Obesity, diabetes and childbirth can also well, childbirth can lower testosterone in men. It actually increases it in women. But it is interesting to recognize that there are certain environmental or behavioral factors that can lower our hormones or raise our hormones. And there are also certain hidden culprits that we don't even realize are monkeying with our endocrine system. It's interesting. I mean, you can get very concerned about it and, you know, go through and take everything out of your house or you can, you know, go with the FDA guidelines and say, well, the FDA says it's safe or this is just more for informational if you want to be err on the side of extreme caution. These are some of the things that have been identified as potentially problems in disrupting the endocrine system to treat depression or anxiety by increasing serotonin, norepinephrine and or dopamine is overly simplistic. Mood and physical symptoms may result from impaired reuptake or one or more of the monoamines, your neurotransmitters or sex hormones or other things too. It should be noted that when sex hormones or monoamines are artificially replaced, it impacts the balance of the whole system. So if you throw estrogen into the mix, it's going to alter norepinephrine, dopamine, serotonin, and not necessarily all to the same degree. It's going to be important to balance it all out. Estrogen and testosterone have neuroprotective effects, but excess can also cause problems with monoamine balance. And monoamines are the things we typically call neurotransmitters. Too much testosterone can cause mood swings, irritability, anxiety and impaired judgment. Too much estrogen can cause anxiety, insomnia, fatigue, cognitive decline, mood swings and weight gain. Too little estrogen can cause mood swings, hot flashes, depression, fatigue and difficulty concentrating. And too little testosterone can cause depressive symptoms, cognitive decline, fatigue and weakness. I want you to really hone in on this and recognize how many of these symptoms overlap with depression and generalized anxiety disorder. There is definitely a interrelationship. Between writing notes, filing insurance claims and scheduling with clients. It can be hard to stay organized. That's why I recommend TherapyNotes. Their easy to use platform lets you manage your practice securely and efficiently. 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