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The Links Between Histamine, Oestrogen, and Cortisol with Georgia Marrion

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The Links Between Histamine, Oestrogen, and Cortisol with Georgia Marrion

What is the difference between histamine intolerance and mast cell activation syndrome (MCAS), and how does each present clinically?

Today we are joined by Georgia Marrion who discusses some of these differences, diving deep into the biochemistry of histamine in the body, and how it affects (and is affected by) the various hormones in our body, including oestrogen, progesterone, the thyroid hormones and cortisol. 

She also talks about some of the signs and symptoms our patients might present with if they have histamine intolerance and some of the key treatment considerations.

Covered in this episode

[00:49] Welcoming back Georgia Marrion
[01:20] Histamine intolerance vs mast cell activation syndrome
[03:36] Oestrogen and histamine intolerance 
[06:22] Oestrogen down regulates DAO
[08:58] Consuming high histamine foods
[10:38] Histamine, sex hormones and how they affect the menstrual cycle
[14:28] Clinical presentation
[16:53] Histamine producing bacteria
[18:08] How histamine impacts women
[20:01] The oral contraceptive pill and histamine
[21:05] Histamine and thyroid conditions
[24:14] Stress and histamine
[28:12] High histamine foods
[31:06] Emotionally supporting clients and where to begin treatment
[34:02] Addressing sleep issues
[35:32] Cravings and intolerances
[37:32] Clues your patient has histamine intolerance and treatment considerations
[44:09] Dosages
[47:53] Vitamin D testing and supplementation
[50:25] Using iodine and selenium
[53:06] Thanking Georgia and final remarks

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. Joining us again today is Georgia Marrion who's a naturopath and nutritionist with 15 years clinical experience, and who specialises in women's health, particularly hormone imbalances, fertility issues, and postpartum support. Today we'll be discussing the histamine, oestrogen, and cortisol link. 

Welcome back to FX Medicine, Georgia. How are you?

Georgia: Good, thank you. Thanks for having me, Andrew. It's great to be here.

Andrew: So, let's delve into your mind straight off. Let's firstly recap on histamine intolerance, because this is something that I still get confused about. This is a normal functioning compound which we require to adequately respond to danger signals.

Georgia: Yes.

Andrew: How do we get intolerant to it?

Georgia: Oh, wow. So histamine, obviously as you said, it's really important for lots of things in the body like your immune system, and it has a big role to play in inflammation. But it's also involved in digestion, and boosting exercise performance, and increasing attention, as well as getting nutrients and oxygen delivered to different parts of the body.

And obviously the problem occurs, as with anything with the body, is when there's too much histamine. And when your histamine levels increase, your tolerance decreases, if you like. And that is where you get a lot of the symptoms. What symptoms you get depends upon a lot of things including where it's released in the body. 

But that needs to be differentiated a little bit from the mast cell activation syndrome, and they tend to be confused because the symptoms can be similar, and someone can have either, or they can have both.

Andrew: Great, that really simplifies it. Thanks for that.

Georgia: This is the first question, right? So, essentially the difference really is in MCAS, is where mast cells don't just release histamine. Histamine intolerance is where they're releasing too much histamine for one reason or another, whereas MCAS is where they're releasing histamine along with hundreds of other substances, essentially a lot of inflammation and inflammatory mediators. And the symptoms can be can be quite similar to that. 

So, I guess why people become histamine intolerant or MCAS, it varies because there can be lots of different things that can lead to it or bring it on, really.

Andrew: Okay. So, we gave a hint in the title, and that was oestrogen. So, how does histamine intolerance affect women?

Georgia: So, before we answer that, just to speak broadly about, so too much histamine, so we're talking about histamine intolerance. That can be speaking broadly. Obviously, it can be brought on by external substances like things that we ate or things that we're exposed to, so like your pollen, and your dust mites, or your heavy metals, pesticides, glyphosate, and that sort of thing.

Internal processes like your gut health or intestinal microbiome, eating too much histamine-containing foods or foods that stimulate the body to produce too much histamine, and difficulty clearing it can also contribute it for one reason or another. And then nutrient deficiencies. 

But then hormone imbalances, as you said, can be a significant cause of histamine intolerance. And that's where really it comes in with females particularly, because when you talk about females in relation to this, there are differences generally in immune responses between males and females, such as antibody production and cell-mediated T cell counts and responses of that type of thing. And so these things are influenced by your sex hormones. So, generally speaking, oestrogen tends to be immune enhancing, and both oestrogen and progesterone tend to enhance type 1 and suppress type 2 responses in females. And obviously that's everything being imbalanced.

Andrew: When you're talking type 2 response, you're talking T helper cell?

Georgia: Yeah, that's right. And so it then follows from there is that mast cell reactivity, and histamine concentrations are also different between males and females largely because of this hormone picture that we have going on depending on where a woman is at hormonally, and in terms of her life stage and her hormonal health.

So, many of the conditions that are attributed to mast cell activity more commonly occur in females, which we can go into. And this is interesting because I think it's for lots of reasons, but histamine is present in most tissues, including the hypothalamus where, in the brain, mast cells are at the highest concentrations around the hypothalamus. And obviously the hypothalamus is closely involved in all of your sex hormones.

So you can see even just on the outset how that occurs and how you can see how it affects females more if that...do you know what I mean?

Andrew: Well, not just more, but also at different times of their cycle, and different times of life.

Georgia: Absolutely. And so, because oestrogen increases histamine, partly by downregulating DAO which helps break down histamine.

Andrew: What's DAO, please? Sorry.

Georgia: Diamine oxidase. There's a test in the end. 

And histamine causes the ovaries to make more oestrogen, so it becomes a bit of a vicious cycle. And women become, as you said, more vulnerable to hormone-associated histamine intolerance symptoms when oestrogen is high. So leaning into ovulation, and during perimenopause, and just before menstruation. Do you know what I mean?

So, you can see that clinically. It can also be seen, say, where allergies in which histamine is obviously closely involved. It's more prevalent in women with hormonal imbalance-related conditions like endometriosis, or when women are pregnant. Do you know sometimes they can have an alleviation or an improvement in allergic symptoms?

Andrew: I was thinking inflammatory symptoms as well.

Georgia: Yeah. That's right. And so hormonal associated fluctuations in asthma tend to be more prevalent in women of reproductive age compared to  postmenopausal women. And administration of antihistamine medication, it can influence your thyroid hormone levels. So, you can really see how it can get a little bit complicated with, it's not just a simple high histamine and that's it.

Andrew: I'm going to interject here. Everybody, this is how complicated Georgia's mind gets. But I love, like, when you're talking, I can see your cogs churning around, and I can see you joining dots and bringing in different systems, and concepts, and biochemical processes that are going on. It's such a great thing to watch, I've got to say.

Georgia: Well, I just think anyone in the area of clinic would be the same in terms of...and this is the industry they're in, you're not treating people just based on...I mean, there might be a particular focus depending on what their health priorities are and what's going on with them. Like you might be focusing on particular organ or system but you're not treating them just by this. So you need to be thinking about how all these things are connected to a greater or a lesser degree.

Andrew: Absolutely.

Georgia: And that's why I was curious about...

Andrew: Glad you said that. Yeah.

Georgia: That's it. It was like, okay, so there's high histamine. Yeah, okay. So, high histamine, obviously they need to be consuming less histamine, but then why do they have a high histamine? And how is that really throwing everything else out of balance?

Andrew: But you do make a very important point there, about consuming too much histamine. There's a big ground swell about fermented foods. But for those people that have an intolerance, they really got to be careful about what they're doing here.

Georgia: Yeah. They really do. That's right. So, for people who have...we can touch on this a little bit more later, but people who have, say, just histamine intolerance as opposed to MCAS, having a low histamine diet will tend to improve symptoms pretty significantly and fairly quickly. Whereas if someone has MCAS, it's a more complex process because there's lots of different triggers as to the root causes that are underlying it.

But, yeah, I agree. And I think that always comes back to the fermented foods. Obviously that can be amazing for a lot of people, but there's never a one-size-fits-all dietary approach, including fermented foods. There are other ways, also, to help support. And I'm a big fan of fermented foods for the right people.

Andrew: So it's this broad brush stroke. It's “healthy.”

Georgia: It can be, but it isn't always. It's healthy in the right system and the right person, if you process it, and absorb it, and metabolise it, and how their body responds to it. But, luckily, there's lots of different ways to improve your gut health. 

Andrew: So, I'm now going to ask that other question. How does histamine intolerance particularly affect females?

Georgia: So, to understand that, then we need to be looking at how they affect each other. So, oestrogen and progesterone receptors, they're both present on mast cells, and histamine and female reproductive tissue is derived from uterine and ovarian epithelium and mast cells, as well as other types of cells. So, functionally, this is where you see, like we're talking about before, and for anyone that actually could read my words on the diagram, the relationship between histamine and steroid hormones is bidirectional.

So, histamine plays a key role in ovulation and female reproduction. It stimulates the ovaries to produce more oestrogen by promoting the release of LH, which is obviously needed for ovulation. And histamine induces dose-dependent and that's relevant oestradiol synthesis through activation of one of the types of histamine receptors, your H1.

So it can have an additive effect on endogenous oestrogen levels, so you can even see just with that. So, obviously, you're automatically thinking when there's abnormal levels or excessive levels, for want of a better term, of oestrogen compared to progesterone, and where this is coming in, and they feed back on each other, and so the cycle can tend to go.

Andrew: I’m going to draw another box in there as well.

Georgia: See, I told you it wasn't finished.

Andrew: Well, you've got H1 and H2 as well. So you've got digestive issues.

Georgia: In different tissues. And oestrogen also has a pro-histamine effect. And then you look at the menstrual cycle. So during a menstrual cycle, obviously there’s, all things being in balance, there's a characteristic hormonal pattern that happens with your LH and FSH, as well as your oestrogen and progesterone. And there are cyclic variations in the endometrium immune cells such as the natural killer cells in the secretory phase.

There's an increase in neutrophils at the start of the menstrual tissue breakdown phase, and there's a significant number of macrophages. That's relevant in terms of a menstrual cycle, is influencing our immune cells within obviously systemically, but particularly in our reproductive organs. And it's really interesting as well because, so when you're talking about mast cells, endometrial mast cells numbers don't seem to fluctuate so much throughout the menstrual cycle, but the degranulation of histamine does appear to fluctuate with menstrual hormone secretions, if that makes sense.

Andrew: Do you know what I'm pondering? I wonder...I don't know, I wonder if this might be a possible link or explanation for those people that think that endometriosis has an autoimmune factor? Maybe this might be that link between the inflammatory situation that's going on with endometriosis, the hormonal drivers of it, and the histaminergic actions on inflammatory mediators.

Georgia: Yeah. And I think endometriosis, it's a complicated condition, but it's an immune-mediated condition.

Andrew: Here's a Leah Hechtman question.

Georgia: So, as far as the particular cell drivers for it, and do you know what comes first? Do you know what I mean? Obviously, that all still needs to be elucidated, but, possibly, yeah. I find that interesting.

Andrew: I need to get Leah Hechtman, Donna Ciccia, and Lara Briden on a panel.

Georgia: Yes. So, in terms of then when you're looking at how it presents clinically, obviously we need to touch on thyroid and cortisol, but when you're looking at how this can present clinically, so obviously it can vary depending on where a woman is at. If she's premenopausal or if she's perimenopausal. And with premenopausal women, it's particularly relevant in women who obviously present clinically with your low progesterone and elevated oestrogen relative to each other in terms of the histamine stimulating the effect of oestrogen. And progesterone tends to have a more inhibiting effect on histamine. 

So, you can see how when things are out of balance, that can contribute to things, what we're talking about before. So they can tend to have more severe symptoms when your oestrogen is high, so during ovulation just prior to menstruation as we said before, so heavy menstrual flow. It can cause period pain to be much worse, and to the point of dysmenorrhea and other PMS-type symptoms to be worse, like PMS, and brain fog, and headaches, and anxiety, and bloating, and insomnia depending on how it's presenting for someone.

Andrew: Wow.

Georgia: Yeah. It can also contribute to ovarian cysts because of the inflammatory process that's happening. Migraines, and premenstrual migraines. So that could be pretty common as well, menstrual migraines and non-migraine headaches as well, partly to do with inflammation and muscle tension, along with other types of things.

And then you can look at it can also be associated with things like interstitial cystitis because there's chronic inflammation of the bladder wall, and so activation of mast cells is a key player in that process. And there's over-expression of mast cells in the bladder, so obviously in histamine-producing bacteria as well.

Andrew: That's interesting.

Georgia: And then obviously it's not the only factor because there's other metabolic factors driving it, with PCOS. And this is more to do with the oestrogen dominance and low progesterone thing, again, that we've been talking about. And it can trigger the production of histamine from your mast cells, and so essentially it can be one reason behind PCOS symptoms, are driven by oestrogen.

Andrew: When you're talking about histamine-producing bacteria, which genera are more prevalent at doing this?

Georgia: I'm going to have to get back to you on that one?

Andrew: Is it Proteus, or E. coli? Or is it typically UTI bugs, or is it other ones involved in interstitial cystitis?

Georgia: I'm pretty sure E. coli is one of the ones that's pretty significantly involved, and I think, S. aureus can also be involved as well. And there are also obviously things like parasites. Certain parasites can also bring that sort of stuff. So, as with anything with the gut, I don't think that's the whole picture, but, yeah, so that was some of the...

Andrew: So, that would be interesting to delve into why they do that. Like, what's their function for doing it? Is it the way that they attach to walls, or create a biofilm, or something like that?

Georgia: Yeah. That's probably a question for someone with more...

Andrew: Ten seconds to answer me.

Georgia: It's very broad topic. Answer this. Immunology. Go. And so, when we're talking about premenopausal women, endometriosis before, like we mentioned there's associated high numbers of activated mast cells which increase in response to stress, which exacerbates the condition. So potentially not the whole story, but definitely not helping the picture when there's inflammation and there's dysregulated immunity going on in these sort of areas. And so histamine intolerance and MCAS are more also common in women with gut issues like IBS, and IBD, and celiac disease, and SIBO, and that type of thing. So, yeah, that's it, exactly. 

So, with perimenopausal women, obviously the fluctuating hormone picture is where, I guess, it's really comes about. So their symptoms tend to be more severe during things like brain fog, and hives, and nasal congestion. And if they had previously existing allergies, the allergies can feel like they're getting worse. And then you add in the impact of cortisol and the adrenals, and then also gut health in terms of metabolising your oestrogen and how that is. And so that can help present for those types of women.

And then with postmenopausal women, obviously their hormonal picture is not really contributing as much as perimenopausal women. But if they're on HRT, they might, for example, have...

Andrew: Was my next question.

Georgia: Yeah. I was going to say that there can be a higher risk or incidence of new onset asthma when they previously haven't had it before when they're taking HRT. So I think it can really affect women at any life stage. This is depending on, say, how much of it is hormonally driven and how much other processes contributing to it.

Andrew: Is there any data on the oral contraceptive pills and the progestogens, their actions or interactions with histamine?

Georgia: Well, progesterone...

Andrew: Progestogens.

Georgia: Progestogens. See, this is the thing. To be honest, I'd have to look into that side a little bit more, but progesterone is one of the processes, and encouraging its production through obviously ovulation. But if it's needed to be taking micronised progesterone as part of the process, if hormone imbalances are driving a lot of these histamine-type symptoms. So, given that progesterone has histamine-inhibiting effects, I would be thinking that progestins don't have the same effect because it's not the same thing.

Andrew: Yeah. Well, it's you change one stick on that molecule and it's not the same action.

Georgia: Yeah. That's it. So I wouldn't have thought that it would have the same effect in terms of that.

Andrew: Interesting to look into. So, what about the effects of thyroid? You mentioned it before. Now I can see this as a huge player.

Georgia: Yeah. So, with thyroid is really interesting, and this is one of the areas I think that so much research is only just really coming out about it in terms of the effect of it. And it seems to be...from what they understand, so far it's twofold because T3 effects can be modulated by mast cells, and mast cells can modulate thyroid function. So your histamine...and, yeah, this is another one of those cycles. And mast cells can be secreted together with other mediators including thyroid hormones, so TSH and T3. So mast cells, they express T3 receptors, and they can store T3. 

So, we talked about the hypothalamus before in terms of there's a high concentration of mast cells in the brain around the hypothalamus. And the hypothalamus can stimulate your mast cells and T3, which is stored along with histamine in mast cell granules, or it can be broken down into T3 metabolites. And these metabolites can trigger mast cell degranulation, releasing T3 and histamine.

So that can mediate a lot of the classical type of symptoms that you associate with histamine.

Andrew: Yeah.

Georgia: But histamine can also activate TSH receptors and can control the release of TSH. So it has a possible role in thyroxin regulation, which then begs the question, having high histamine, does that then have an effect on thyroid medication? I would be surprised if it didn't because of that...

Andrew: What about Hashimoto's? What about clinical hypothyroidism?

Georgia: So, the clinical relevance here to be looking at least is that because of the ability of mast cells to modulate thyroid function, this is potentially relevant in things like early-stage thyroiditis because it's an inflammatory process, as well as inflammatory intestinal diseases like we mentioned before, and Hashimoto's thyroiditis. Particularly, if you've got someone with Hashimoto's with particular skin presentations, like your chronic urticaria, and alopecia, and atopic dermatitis, you'd definitely be looking at that as a comorbidity.

Graves' disease, and non-thyroidal illness, because changes in this HPT axis in patients suffering from these types of illnesses that are not originating in the thyroid, right, which is what that is. So, characterised by a particular hormone pattern. And then you'd also be looking at this for bacterial-induced hypothyroidism. 

So I think there's more to come with the impact, like this interaction between mast cells and thyroid, and how that all echoes also with, they've also seen that thyroid antibodies can cause mast cell activation and degranulation, so obviously which is where the Hashimoto's link comes in.

Andrew: I wonder if the orthodox allergy clinics are looking at this. I mean, this is just so far-ranging, the effects of an allergy or an intolerance. Now, allergy clinics are very pretty cut and dried with what they call an allergy and intolerance, but this could open up a whole world of consideration or reconsideration of what was marked to be that, and may indeed be influenced by histamine.

Georgia: Well, this is right because everyone is… So we're talking about females here, but, say, if a female has MCAS, and there's a whole list of triggers and root causes for that, so generally there would be multiple ones. And then when there's multiple triggers, there's likely to be multiple clinical presentations for that that are beyond the classic, they have skin issues. Or they react immediately after having a particular food that's high in histamine.

So I'm glad that there's becoming more an awareness like...so, obviously I specialise in women's health, but like, to do with women and histamine, and how this affect...because it can have a pretty significant on a woman's quality of life when she's experiencing histamine-related issues in relation to hormone imbalances. But there's a lot more to come in terms of how this is all interacting. Because then you look at the role of stress and cortisol in this interaction, which is really interesting...

Andrew: Absolutely.

Georgia: ...because stress and adrenal dysfunction are one of the main drivers of histamine intolerance. And thinking about stress, you've got to be thinking more broadly than just psychological stress. Obviously, that's a factor.

Andrew: That’s awful.

Georgia: Yeah, that's it because human mast cells release more CRH than the brain does, which is interesting. And mast cells obviously have a very strong affinity for CRH...

Andrew: Corticotraphic-releasing hormone.

Georgia: That's it. So mast cells are activated, so then you get your CRH released, and that then acts back on mast cells. So then, essentially mast cells are more susceptible to stress. And I think this is particularly the case with MCAS where they may not be releasing histamine, but they're more responsive to stress. And stress can then be chronic stress. So it can be anything obviously the sort of psychological stress to nutritional status, and heavy metals, and pesticides, and moulds, and...

Andrew: And infections.

Georgia: Infections and makeup, particular compounds in makeup. And then there's nervous system imbalances that women can present with, so difficulty handling stress, and relaxing, and getting enough sleep. And these are all really common clinical presentations in women that I see, and a lot of women say feeling wired after being around people too much, and talking too much, and then also things like chronic infections and reactions to food, startling easily, things like that. 

And, also, when you're doing a clinical case on someone, if in the last few years they've had major life stresses happening such as divorce, or job change, and that sort of thing, because all this is coming from, because cortisol obviously has an effect on mast cells. And that can release inflammatory chemicals which then releases more cortisol, which then releases more mast cells, and that can trigger your symptoms. So even just stress alone, so we're talking about thyroid and cortisol.

And this is where I see with a lot of women with this type of presentation, obviously there's a lot of different things to consider, but hormone balances, and stress, and thyroid, and gut health are often playing a pretty significant role in how this is presenting. It's usually not always just histamine intolerance as a standalone. They're having too much histamine in their diet, and that is it.

Andrew: So, I'm just pondering this again, and that is, you've got a glass of water there. So here's a good analogy. In some instances, you reach a very small threshold, and you get a full initiation, heart muscle initiation, that electrical impulse. It reaches a threshold and you get a heartbeat. In other situations, for instance, immunity, allergy is one where you've got a glass of water, and you have a sip of genetics, and a sip of dust mite, and a sip of cold air, and a sip of something else, and suddenly you've overflowed and you get the allergic symptoms. 

So, when we're talking about stressors, is this a case where you can work on, actually first identify which stressors are the major culprits in initiation of a histamine intolerance? And then, do you stratify or strategise to say, "Let's work on this one first, that one second?"

Georgia: Yeah. So, I guess probably the first thing, I mean, probably the easiest place to start is putting someone on a low-histamine diet because it is just...

Andrew: That's the biggest.

Georgia: If it's mainly histamine intolerance, well then it's going to produce pretty significant effects. And if it's MCAS, it will still help. So, either way, you're going to get an improvement in someone's clinical presentation initially, which is what I want.

Andrew: How quick do you find effects and how good do you find compliance?

Georgia: I will say this is the thing with histamine intolerance and foods is that often there can be a bit of misinformation out there about what actually constitutes high-histamine foods. And if someone has... obviously there are ones that we definitely know. So, like your fermented foods and certain types of your old, aged foods, and fermented alcohol...

Andrew: Sauerkraut.

Georgia: ...all that sort of thing, artificial additives and that type of thing. But then, if someone has, say, MCAS or histamine intolerance, either of those or a combination of those, they might also be reacting to things like lectins, or oxalates, or salicylates, or FODMAPs. So, if it was just histamine intolerance, you can get pretty quick results.

If someone has MCAS, you probably get some improvement, but not significant and not quickly necessarily. Like, there'd be some alleviation of symptoms, but there's probably other intolerances or things that the body is reacting to food-wise. So it's a matter of unpacking those and then going further.

Andrew: How well then do you find the instigation of emotional support? Because we know that naturopathic practitioners, one of the reasons they have such a great reputation is because the patient feels heard. And this is vastly different from the 8-Minute Medicare Australia consultation, the doctors are working in the little mouse treadmill. So it's almost like naturopaths have this beautiful arena to actually allow the patient to express all of their anxieties, and that just in itself may be a major de-stressor.

Georgia: Yeah. I'm inclined to agree and I think a lot of other naturopaths would agree is that by the time they've come to see us, usually they've been through a fair few different types of modalities, and may not feel like they've been...not in all cases, but may not feel like they've been listened to or their particular issues haven't been addressed. And if it was, they probably wouldn't come to us. A lot of naturopaths tend to see people when they're at a certain point of being a little bit at the end of their tether.

So, if you're at that stage and you go to see someone, and they're actually listening and delving in deep, and asking all the questions, and all the things you do as a clinician, I agree that they do tend to feel that sense of, "Someone's actually listening to me," and that they're not just carrying this bag of health issues on their own. They can share that load a bit with someone who understands and cares about them being able to get where they want to be with their health.

So, I think, definitely, particularly if it's MCAS, and if there's hormone imbalance issues to do with it, addressing stress and nervous system imbalances has to be, along with the dietary approach that we spoke about, so reducing intake of histamine foods, and exposure for at least four weeks to see if you're going to get an effect or not, is we're really looking at stress.

And I think it's like, because stress activates your mast cells, as we spoke about. So, supporting the HPA axis, addressing what is the cause of someone's actual stress? Really looking at that and someone being honest, coming to an awareness about that, and looking at how they can alleviate that, taking in particular, and I put my hand up here as well, taking regular time to yourself to do things that you enjoy.

Andrew: That's why women might be more affected than males?

Georgia: Oh, I don't know. That's right, yeah. Possibly. Someone needs to do a really perfect study to confirm that.

Andrew: Okay. You said four weeks. How quick an effect, and how great an effect do you find just dietary modulation has on symptoms?

Georgia: Well, I think it comes back to when it's just histamine intolerance, it's pretty quick. But you'll be doing the four weeks just because obviously it depends on how long someone's had this for, and therefore what else the high histamine might be affecting in the body? And bringing that back to a certain amount of baseline, so to speak.

So, when you're looking at then the stress, so then you're adding in the other things as well we've spoken about. So with stress, sleep is a big one for women. So, addressing why someone is not sleeping, whether it is stress or whether it's allergies and food intolerances, or whether it's gut issues. And it's interesting to do with sleep because the brain releases, I think, the highest amount of histamine at about 3:00 in the morning. So, if you can imagine...

Andrew: So, women should wake up at 3:00?

Georgia: Or if women are...no. Waking regularly at 3:00, and it's not related to kids.

Andrew: I’m going to get shot for this. I was being glib. 

Georgia: Like, with stress, and then they might have toxicity, and they might have gut issues. And then they've got hormone imbalance, so it's no wonder that a lot of women don't get very effective sleep. We're looking at addressing why they're not sleeping. Do they have the right nutrient support to be able to sleep in terms of they're having enough protein? Now, what are they eating during the day and before bed as far as what they're eating enough of, or what they're not eating enough of? Do you know what I mean?

Andrew: Still on that, on eating enough, do you find that the histamine intolerance, like the food intolerances that we see, I'm always at a quandary with this, inner quandary, and that is, the notion that you either avoid or crave things that you either need or are intolerant to. 

You know how people talk about people crave the things that they're intolerant to? But then in another sentence, other people say that you crave the things that you need. And I'm like, well, do you need it because you're intolerant to it but it's setting up a crutch?

Georgia: I think that's a bit of a mixed bag of a response because I think, in some cases, because our relationship with food, especially when there's stress involved, is complicated. And so, in our minds, if we really feel like that chocolate...we can justify anything that that's a craving and not an intolerance. 

Andrew: I can.

Georgia: Absolutely. You can justify anything to do with food, really.

Andrew: Let's be positive here. I do.

Georgia: Yeah. Absolutely. That's it. Whereas for, in other cases, it might actually be women might not be having enough protein sort of things, so they're really feeling like they need to have, say, more. If they're iron-deficient, they're feeling like they really need to have more meat or that sort of thing. So I think in some cases, it can be driving an actual area where nutrients are out of balance, but not always.

So, I think you need to take that with a little bit of a grain of salt and be looking at clinically, “Okay, if someone's craving certain foods, what's driving that? What's that about?” Before you're saying, "Yeah. Well, they're craving chocolate, so therefore they must eat that all the time to get a lot of antioxidants in their diet."

Andrew: Are there any clues to presentation that you can give us? You spoke about anxiety, for instance, and it's like, well, what condition doesn't present with anxiety? Heart disease, autoimmune disease, pregnancy, infertility, methylation issues, depression, where do you stop? So, are there any clues that you go, "Wait a minute, I should be going this track?"

Georgia: How long's a piece of string? This is one of those questions.

Andrew: I want that on this diagram, Georgia.

Georgia: It's only a one-page diagram. It's not a journal. So, in regards to clues, I think first of all you need to be considering where a woman is at in terms of her hormonal life. Is she premenopausal? Is she perimenopausal, or is she postmenopausal? And then, obviously, then you're looking at, okay, let's look at the easy stuff first. Is it that she's just having too much histamine for one reason or another? And reducing that. And, does that make a difference? And then clinically from there.

So, I think once you narrow those things down, then you can start looking at particular clues as far as if a woman is experiencing all your classic oestrogen, progesterone, histamine type of symptoms that we spoke about before, then obviously you're going to go, clinically down that track is going to be your focus type thing. But if a woman is experiencing that kind of thing, there's always going to be stress, and often adrenal and thyroid along with that as well, and usually you've got to address gut as well. So I'm not sure if I've answered the question quite as clearly because it's not...

Andrew: Well, to me, it's really interesting. Like, listening to Datis Kharrazian in the BioCeuticals Symposium. And it was, you got the notion that the thyroid was the master of everything. And we know that it regulates the rate and rhythm of every cell in the body, we get it. But what he was alluding to is that it's the master culprit and target for a lot of autoimmune conditions. And if you can settle that down, that you settle everything else down. 

I've spoken to people in the past, integrative doctors in old eras, over a decade ago where it was cortisol. Everything was cortisol. Cortisol was the panacea for everything. And it was a very wise Andrew Heyman that said, "Hang on, if you've got a latent infection and you don't know about it, you give somebody cortisol. What are you going to do there? You're not going to kill the bug. You're just going to kill the symptoms." So it was a real awakening for many people in that room. So, I'm wondering whether...I think it goes back to the old stress management, being heard, and dietary manipulation.

Georgia: Yeah. So, generally the process I would take is obviously, like we mentioned, looking at your dietary approach. So looking at histamine foods. How much are they having? All of that sort of stuff, addressing that, minimising that. Reducing exposure, depending on how some response to that, and to other things they potentially it would be treated by, like your lectins, oxalates, salicylates, FODMAPs, that type of thing.

And then adding in the nutritionally dense, whole food approach, to making sure they're getting enough the nutrients to support all these processes that can be affected when there's histamine intolerance and MCAS. So, like with your vegetables and your protein, your good-quality, whole-food protein, and your fats, and that type of thing. And just being careful with carbohydrates.

So in some people inflammation can be triggered by grains, and so that's not going to work for them. And in particular, tips like avoiding slow cooking because that can increase histamine foods. Like, if you're going to have leftovers, freeze them, because unless you're going to eat them within a few hours, that can increase histamine in foods, things like that. And then you'll be looking at improving the body's capacity to clear histamine. So things like B6, and vitamin C, and quercetin, and then beyond that, supporting progesterone production, because that has an antihistamine mediating effect, if you like. So then that's we’re tying in where you're looking at your oestrogen and hormone balancing, and what's going on with that? Where is that at? 

And, so if you're supporting progesterone, reducing inflammation with your dairy, and your gluten, and your sugar type of approach. Addressing, like you said, thyroid, and if there's blood sugar imbalances particularly, eating enough the macronutrients that we talk a lot about with women, and having enough of certain nutrients like your zinc, and your iodine, and your magnesium, and selenium.

And then, with your oestrogen, improving your oestrogen metabolism with your microbiome and gut support. Looking at what medications are they taking? Are they eating a lot of sugar and wheat? Is alcohol something that's high in their diet? The stress we spoke about, sleep we spoke about. Do they need digestive enzymes to support this process?

And then liver support. Things like an N-acetylcysteine, and liposomal glutathione, and then your herbs like your milk thistle and your turmeric, that type of thing. And then addressing inflammation, obviously, because that affects oestrogen detoxification, and then adding nutrients in there. And then you'd be looking at your stress like we spoke about. Before stress, and so your thyroid, adrenal kind of processes, and what's happening there, and then your parasympathetic nervous system as well. 

So that's generally the sort of approach that I would follow, obviously, and then beyond that you'd be looking at things like traumas or significant emotional triggers from the past or present sort of thing that are driving this, or is it things like mould? And then going down that rabbit hole of...

Andrew: There’s a rabbit hole. That old fight.

Georgia: And so it's always a matter of, as with anything, helping someone symptomatically in terms of...because then that can help them keep going with your treatment process, if you're helping them with their symptoms as quick as you're able to, without inhibiting the process of addressing why they're getting it, and then working on those things along with that. And then going further down the rabbit hole if you need to, depending what their clinical presentation is.

Andrew: What about dosages? Like quercetin, I've used it as an antihistamine, and I've had to take exceedingly high dosages to get any sort of real effect. I've drunk Baikal skullcap in years gone by. I would not recommend that. It's like hazelnuts times 10,000, and that woodiness. I am a bit weird, though. I am weird in that I was drinking it straight.

But I was drinking it straight, and this was a full-blown rhinorrhoea. Like, this was just snot fest, and watery eyes, and the whole symptomatology of an acute histamine release. And I remember it was really quick, but I was drinking it like, I would never be able to recommend this for patients. 

So, what sort of clinical dosages do you use, and what sort of tricks can you give us as to what you mix together, and which way you address it?

Georgia: With quercetin, again, it's one of those things people either respond to it and they respond to it well, or they won't. So I'll probably tend to use a dose of about 500 milligrams a day, because you're going to be careful with too many phenols, too. 

Andrew: Right.

Georgia: So, with supplements, you're only going to get that dose for supplements. So just making sure it's not derived from peanut shells or fava beans because if someone might react to that, sometimes it can be sourced from that.

And, also, with any supplements, you've also got to be careful with any sort of additives and stuff that are in there because, for some people, particularly in MCAS, this can trigger some of what they're presenting with. So, beyond the dietary that we spoke about, so dosages-wise, with B6, I'd be looking at, so when we're talking about histamine clearing effects, generally use up 50 milligrams, twice daily is the dose that I would do.

With vitamin C, I think you can go below bowel tolerance, obviously, with someone, and that can be quite different for everyone with what it'll be. But vitamin C is one of those ones you can't really go too far wrong with it beyond bowel issues.

Andrew: We’ll know.

Georgia: Yeah. You definitely know. It's like if you take too many probiotics, it's like it's...

Andrew: You know.

Georgia: ...guess work. And then, so with your hormone support, like we were talking before, so magnesium glycinate, I'd be looking at 300 milligrams a day, and selenium, about 150 micrograms a day, that kind of dosage. 

If you're using N-acetyl cysteine, which is fantastic for a lot of different parts of this process, it depends upon the person, but at least 500 to 2,000 milligrams a day depending on how someone can tolerate it. With your liposomal glutathione, I'd be looking between 100 and 400 milligrams a day, really, I guess they’re kind of doses that I would tend to use.

And then, so with D3, obviously it's an anti-allergic, and it can have an effect, and it can tend to be low with people with these types of issues. So you'd be starting it...I mean, obviously you're testing for it to see how low they are. And if someone has Hashimoto's, thyroid issues, well, they can tend to have a lot of issues when they take vitamin D and getting their levels up because they tend to have SNPs with vitamin D. So you'd be starting at 2,000 IU and obviously monitoring what their results are with vitamin D. So they're the dosages I would tend to use.

Andrew: Can I just interject, sorry? Can I just make a point about vitamin D and testing? We did waste millions and millions of Australian healthcare dollars, and we certainly can't afford this in the new era of COVID-19. We just simply can't afford it. Even though it's been taken off the NHS as a screening tool, so it's basically user pays. Having said that, it's a cheap test. So there's two ways of thinking about this. One way is Professor Michael Holick says that it's pointless testing, it's a waste of money. Simply supplement. That's it.

It's so cheap the cost of the supplement outweighs any cost of the testing. It's so safe. If you go 3,000 to 5,000 units, and 3 to 5 times that for obese people, and certain medications like steroids and...what was it? Anti-seizure medication, there was a few medications, anti-HIV medication, that you need to increase the dose for. Just dose. So there's his way, and the other way is, as you're saying, which is probably, in certain sensitive patient populations, you might go, "No. I need to get a baseline." But I think...

Georgia: Yeah. It depends upon the person. It depends. Like, D wouldn't be the first thing. In all of this going on, it wouldn't be the first thing I would test for. But it would just be a consideration. If someone presented with Hashimoto's thyroiditis, the first thing you're thinking of is, more often than not, they don't tend to respond well to vitamin D, particularly at the more, say, 2,000 to 4,000 IU.

So that's where you're probably looking at, okay, well then, you probably wanted to test to see what their baseline is because then you're probably wanting to go more significant doses, and just seeing what doses actually they are responding to. So I think it wouldn't be…

Andrew: The other point I was going to say about vitamin D testing is, just know that the test you take today is really representing the vitamin D intake from three odd months ago, because there's this lag. And so, just be aware of when you take it during seasons.

Georgia: Yeah. That's right. So, to me, it's more appropriate to test someone this time of year during winter, to see what the actual levels actually are.

Andrew: Yeah. Well, I'd be taking it early spring, and then you'll get an idea of how low they were in winter.

Georgia: Yeah. That's right.

Andrew: Okay. What other clues and tips can you give us with regards to management, and even caveats? What do we have to be careful of? Datis Kharrazian was extraordinarily conservative with his iodine dosing.

Georgia: Yeah. Iodine is where you'd be looking more at where there's the hormone imbalance side of things. And I would tend to agree with him as far as being somewhat conservative with iodine because it's pretty widespread now in terms of food, and not fermented foods, in fortified foods. It's one of those things you've got to be careful with because when there's too much of it, it can certainly cause a lot of issues.

Andrew: Having said that, it was the first vitamin supplement rather than fortified foods, it was the first supplement which was encouraged in guidelines, I think it was January, 2010, for all pregnant women to receive a supplement of iodine of 150 micrograms, because diet alone could not make up the difference for the lack of iodine in our diet.

Georgia: Yeah. I agree, but then I mean that might be something, again, not to say everyone needs to be tested for everything, but you don't necessarily want to give just iodine, because you'd have to be giving other nutrients as well, otherwise the process it'll...like you want to making sure you're getting things like your...or that they're having enough selenium, and having enough iodine, those sort of things.

Andrew: Selenium seems to be the magic one, isn't it?

Georgia: Yeah. That's right. But beyond that, I think it's, I guess, the way...any other tips is, depending on the person that you've got in front of you and where they're at with their histamine intolerance or MCAS is just...so, if someone are histamine-intolerant are starting fairly simple. You're always starting with the diet and the approach that we spoke about. But if someone is more likely presenting with MCAS, it’ s just like, okay, this is the sort of thing that we're doing. These are all the different steps we're probably going to have to look at, because it's a multi-faceted approach.

But it's definitely possible to help people feel a lot better, but it's probably like ulcerative colitis in that there are general things that will help most people with it, but there's always going to be different tweaks to that depending on their particular triggers for it. So that's why you really need to be taking a broad approach to this, because as we touched on in the beginning, histamine and mast cells, it's not a simple topic because there's still so much...because it has a positive and negative effect on the body depending on its level.

Andrew: But it's also evolving. I mean, I can't thank you enough, Georgia, for taking us through just some of the issues today. I mean, as we say, this is evolving. I mean, this paper you sent me, that I only scanned through, was 29th of March, 2019, and that's looking at the mast cell interaction with thyroid hormone. So it'd be very interesting to revisit this with you in, like, another year or two years and see what's come out in the research.

Georgia: For sure. Yeah. It will be interesting.

Andrew: Thank you so much for taking us through this. I mean, this is really important stuff. It's given me a new appreciation of what might be a linking pin between different disorders that we'd not thought separate, but we didn't know why they were so linked. We didn't know why it was. So this is one possible answer. It's very interesting.

Georgia: It is, yeah. It's a really interesting topic, and this is why clinic's interesting, because it's never…there’s always something to learn.

Andrew: Yeah. That's right. And I thank you for your expertise and your care for your patients. Thanks so much for joining us on FX Medicine today.

Georgia: Thanks, Andrew.

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook.

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