← unPAUSED with Dr. Mary Claire Haver
unPAUSED with Dr. Mary Claire Haver
Mast Cells, Histamine, and Perimenopause Explained: MCAS, Anxiety, Estrogen
00:46:41
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- [00:03]
A
Today on Unpaused, I would like to share something a little bit different with you. I recently had the honor of interviewing Dr. Zachary Rubin, a double board certified allergist and immunologist and pediatrician and the New York Times best selling author of All About Allergies. We spoke about something that had completely taken over the Internet while I was on book tour for the new Perimenopause, the connection between histamine mast cells and women's hormonal health. What I did not fully appreciate until this interview is how much our immune system is wrapped up in all of it. Here's my conversation with Dr. Rubin. I'm Dr. Mary Claire Haver, a board certified obstetrician and gynecologist and certified menopause practitioner. I'm also an adjunct professor of obstetrics and gynecology at the University of Texas Medical branch of welcome to Unpaused, the podcast where we cut through the silence and talk about what it really takes for women to thrive in the second half of life. Hi everyone. And today I'm going to be interviewing Dr. Zachary Rubin, the New York Times bestselling author of All About Allergies. When I was on book tour in the last two to three weeks, something really exploded on the Internet. It was on my threads, it was all over TikTok and Instagram. I was telling everyone that this kind of topic exploded while I was on book tour. And as you know, having been a New York Times bestselling author yourself, you're a little busy during book launch. So I'm like in my brain, like, I'll get to that later. I'll see what's going on here. I wasn't really sure what was happening though in our menopause group chat, which is probably a hundred docs and we have a WhatsApp that we kind of share information on. I had seen a few mentions of MCAS and its relation to endometriosis and other things and I was like, okay, I'll get to that, you know, later. I'm still writing the book and you know, busy, but it has really taken over the Internet and like New York Times has written about it, it's in all the major news magazines. And then I saw you had posted on it as well. So as the expert, I am so excited to dig into this topic. But if people don't know who you are, you are a double board certified pediatrician and allergist immunologist, and you practice in Chicago. You trained at Case Western University of Illinois and wash U in St. Louis and you have a ginormous following of 5 million followers. And this is. I found you on the Internet as well. You are one of the most trusted voices in pediatrics and allergy and immunology, and I am so excited to have you here with us. Okay, so what are mast cells? What is histamine, and what is happening right now on the Internet?
- [02:58]
B
Yeah, well, thanks for having this conversation with me, because we've been talking on the sidelines for years and really appreciate that you helped promote my book. I have yours, by the way. So, you know, I just want to give a little context, too, because a lot of people were asking me about people's stories that were being shared online about taking certain medications to treat their pmdd. And this happened, actually, for the past couple of years. I saw some of this, and then I decided to do some more literature review over the past couple of years, see what's out there to help people kind of understand whether or not there's a connection between allergies and various women's health issues. So I'm glad that we're having this conversation. So we're gonna start at the basics here, which is talking about the mast cells, histamine, and what's going on there. So the mast cell is a part of your innate immune response. It's one of the first lines of defense. It kind of like sends off alarm bells if there's a foreign substance. And they're housed not just on your skin, but in various connective tissues, like in your gut. They're in your brain. And so they release various chemicals in response to different stimuli, like potential infection or even if you get a cut, any type of physical trauma. They're a part of the wound healing process. And so histamine is one of the ones that people are familiar with, because one of the most common allergy medications out there are antihistamines. So people hear of the brand names like Zyrtec, Claritin, Benadryl. We'll get into those in a minute. But histamine as a chemical is not just about allergies. And my book is all about allergies. But histamine as a chemical is much more than that. It is in your brain. It regulates your sleep, wake cycle. It can regulate your mood. It also regulates your gastric acid secretion and aid with digestion. So it's kind of a jack of all trades, which also makes it difficult to navigate this space, because a lot of the symptoms that people experience, they overlap. And as we talk more about some of these conditions, we're going to start to learn more but also be confused at the same time because there's so much overlap there.
- [05:07]
A
You know, I learned I knew histamine and its relation to allergies or the allergic response, but I did not realize until I started digging, like you that there's a bigger connection here to multiple organ systems, kind of like estrogen. So estrogen activates mast cells and progesterone calms them. Do I have that correct? Now, no one taught me this. Like, this was not medical school. This is not residency.
- [05:32]
B
Yeah, this is not something that I was taught in medical school either. And in my fellowship training, we do both allergy and clinical immunology. That's when I started to learn a little bit more it. But also as much as I tell people, yes, I'm a pediatrician. That's my first board certification as an allergist. I take care of all ages. So I do see a lot of women of all ages who will come to me with issues related to potentially MCAs, which we'll get into. And that's why I really started to learn more about this potential neuroendocrine immune kind of axis where a lot of the sex hormones are really connected to the immune system. And so, as you say, the general rule of thumb is that estrogen, we're getting more and more data to look at how it's interacting with mast cells. And so we know that estrogen can increase that activation. It could also decrease the degradation of histamine. So not only you're producing more, but it kind of lingers.
- [06:31]
A
Okay. You can't break down.
- [06:33]
B
Exactly. And then progesterone is kind of the. Putting the brakes on it. So there's two different levers, so to speak, with the mast cell just from sex hormones alone.
- [06:42]
A
So, you know, in the normal. This is for the audience. In a normal female biological cycle, before menopause enters the chat, we have natural undulations of these hormones. We peak mid cycle at ovulation for estrogen just after ovulation. And then progesterone kind of rises after that. In perimenopause, we lose that ability to predict what's going to happen. And it's very, very chaotic, these changes. So listening to women, you know, I HRT doesn't fix everything. Right. And so learning about this and realizing how related these to, you know, the histamine levels are to hormones and how things go just chaotic in perimenopause and seeing an increase in those symptoms does make a lot of sense to me. Clinically, from what I'm seeing in my patients, I just didn't know how to connect the dots.
- [07:29]
B
Yeah, absolutely.
- [07:30]
A
Okay, so receptor confusion in the media has been a little bit crazy. So H1 versus H2. Can you, in layman's terms, walk us through those two receptors?
- [07:40]
B
Right. So for folks in general, receptor is a word that's not always used in our vocabulary. And so I like to think of it like a lock in a key. And so the receptors are these proteins that sit on the surface of cells, and they're part of a signaling cascade, almost like your lock is very specific to a key. And so there's different substances like histamine that could bind to your cells through these receptors. And there are four subtypes, actually. So we hear about H1 and H2 a lot, but there's also H3 and H4. And the reason why people don't hear about those is we don't have clinically relevant medications that can work on those. And a lot of those are actually found in the brain. And I would love to see more research on H3 and H4, and can we develop some novel approaches to that? Because that could help with all sorts of different issues that we still haven't learned enough about. But H1 and H2. H1 is the classic one people think about with allergy, where histamine, when it's released during an allergic response, it could cause your blood vessels at the surface of your skin to become leakier, can lead to hives, swelling, also known as angioedema, itching, sneezing, runny nose, all the classic allergy symptoms. So when you take Benadryl or Claritin or allegra, those are H1 blockers versus H2 is actually famotidine or Pepcid, which is a common antacid medication, because H2 mainly sits in the gut and creates acid secretion for digestion. But H2 is also on mast cells, and it's in blood vessels as well, which is why, when patients have chronic hives, we not only give them Zyrtec to take every day, but we often give them Pepcid. And this is often why, as I've been taking care of a lot of patients and adult females over the years, I've noticed that some of my patients would report when I put them on the combo that we're talking about, right, the Allegra Pepsid combo or fexofenadine famotidine, respectively, that some of the women that I work with would report that some other symptoms Besides, hives would get better, like their mood, as an example. And so I would also see this reported online. And that's where I started to connect the dots from a mechanistic standpoint that H2 could be just as important with H1 blockers, and using them in combination may have some potential benefit. The challenge, though, and this is important when we communicate this on social media or with our patients, is we have absolutely no strong randomized control trials for the use of these two medications for any of these conditions. We're talking about pmdd, endometriosis, perimenopause, menopause, pregnancy, just PMS in general. I mean, there's so many different issues here that need to be explored. And I'm glad we're having these conversations and talking about this so that we can help raise awareness. And hopefully we can get some clinical researchers to start studying this and getting approval, which hopefully there'll be interest in funding from foundations to try to really look into this, to get a better understanding of. How can we use this in our clinical practice, because we're kind of just essentially mavericks in this. We're building the ship and riding it at the same time to try to do the best we can for our patients. And I really caution people, because as much as we talk about this online and we take that information in, we really need to look at the whole picture of each patient individually. Individually, to determine how much, how often, when, especially in the context of what other medications they're taking for potential interactions. So all of these different things need to be looked at, but by raising awareness and then saying, you know, it's really important that when women say that this is helpful, we believe them because we have the mechanism, that basic understanding why it makes sense. So we need to believe people when they're experiencing improvements, but then at the same time, monitoring this closely to see how can we optimize this and reduce risk at the same time. Right.
- [11:40]
A
And we'll get into risk in a second. Why do women particularly have more mast cell related conditions than men? Do we have any ideas on why that happens?
- [11:50]
B
My feeling is, is that it's because there's a predominance of estrogen. Okay, Right, right. More estrogen compared to testosterone in women, compared to men. And also in the 30s and 40s, when a lot of these autoimmune conditions come out, we know the fluctuations that become more prevalent is associated with more autoreactive B cells that create the antibodies that create autoimmune diseases, like lupus as an example. So a Lot of autoimmune diseases show up in women in their 30s and 40s. There are some that could potentially have kind of a bimodal kind of in early adulthood and later in life. But a lot of the times, it's actually in the 30s and 40s when those hormones are fluctuating.
- [12:28]
A
So if a patient comes into your office, Zach, and says, I started Pepcid and Zyrtec and my PMDD is gone, what do you do with that? As a clinician, you talked about you believe her, right?
- [12:40]
B
Not only that, I celebrate that. Yeah. We smile. You know, sometimes, depending on the situation, we actually have a good cry, to be honest, because it can be really debilitating from a mental health standpoint for everyone that's. That's dealing with that, and those are in their loved ones around them. Because, you know, we don't really fully understand all this. Right.
- [12:59]
A
Oh, go ahead. Well, for everyone watching PMDD is premenstrual dysphoric disorder, what you might call PMS or premenstrual syndrome. So these are women who are debilitated by. It's that last week, last two weeks of their cycle, and they're having severe mental health issues, usually in depression or anxiety. So I just wanted to be clear. Everyone understood what we were talking about and how for a percentage of patients, these medications are alleviating that. And there is a mechanistic reason that makes sense, right?
- [13:32]
B
Yeah.
- [13:32]
A
But we don't have any trials.
- [13:34]
B
Exactly, Exactly. So when they come into my office and they explain that, and we have a really just heart to heart to say, I'm so happy this is making you feel better. Let's make sure we're not missing anything.
- [13:46]
A
Okay.
- [13:46]
B
I always want to make sure that people know that when we look at their entire health, is there something else that hasn't been looked at yet to make sure that we don't ignore everything else that could be playing a role with this? The one that I always worry about is thyroid disease, as an example. And so we make sure that we look at that, and then I look at, are there other symptoms that are being alleviated besides a mental health issue? Are they having a lot of gastrointestinal problems? Are they having a lot of skin issues? Because then we start wondering, is this becoming more predominantly a mast cell problem or is this a hormonal issue? And so I really would love to see more collaboration between OBGYN and allergy immunology on these types of issues, because we're often siloed. And part of that is because My specialty is so small compared to most other specialties. There's only about 6 or 7,000 of us in the country that are board certified, that regularly practice and we're not always in major academic institutions. So being able to have that academic collaborative effort to be able to do better clinical trials, or even just clinical trials to begin with, and then thinking about novel approaches I think would really help in the long run. It'll take some time to really see what effect this is having, but I believe women first and then I make sure that we're not missing something and then monitoring it.
- [15:06]
A
Yeah, we had, when we announced it, we had 11,000 likes on the post and we had 1500 questions. And a huge percentage of the questions centered around should I do this on my own without talking to a doctor? Because you can just walk to a pharmacy. Which ones would I consider? How safe? How long can you talk about that? A little bit.
- [15:28]
B
Right. So there's things that we know already and there's things that we don't know about this issue. So the one that a lot of women are talking about that I often recommend with my patients is Allegra and Pepcid as the brand names. The generics are fexofenadine and Famotidine. So when we look at the H2 side of things, you're pretty much with Famotidine for the most part. There's not really many other alternatives at this point. And then with the antihistamine H1 side, there's different choices for sure. I mean, you've got Claritin, Allegra, Zyzol, Zyrtec. The issue is that Zyrtec and Zyzole are very similar medications. And for some women it can actually cross the blood brain barrier and make people sedated. For me specifically, if I take even half of a Zyrtec, it's like Benadryl for me, basically. I never recommend Benadryl for this approach. The reason being is that Benadryl can really sedate people. And also chronic long term use is associated with dementia later in life because as an older first generation antihistamine, it has anticholinergic effects. So there is a neurotransmitter called acetylcholine. And when that's blocked, there's other medications that we have seen we are seeing this association with when we have medications that are less likely to do that and don't have the anticholinergic effects. Allegra is a good choice. Claritin is also potentially a good choice. As well, but I always believe when you're going to be taking these for a while and you're trying to make sure that you're fiscally responsible with this, you know, generics are fine, you can get them in bulk, that's fine. And then how you use it is going to vary from person to person that we have to kind of experiment. So some people may use it for about two weeks before their period starts, or they're using it chronically. And that depends on what other issues are going on. So are they having chronic hives? Are they having other things on top of this? And so how much you take of it really comes down to person to person. Do we take, you know, theoretically you can take quadruple the over the counter dose, but I don't recommend that openly for people. You shouldn't. You need to talk with your doctor about this to see if that's the right amount for you or not. Especially with what other medications you are on. Now fortunately, we know that the newer antihistamines like Allegra are generally safe long term. But there are two issues I want people to be aware of. Number one is that when you take it chronically, histamine also acts as an, an appetite suppressant. So when you take antihistamines, you may increase your hunger and indirectly gain weight. I've seen that. I've seen some women gain 10 to 20 pounds taking these medications. Not very common. The FDA has started to make some announcements fairly recently, like a year or two ago about this. And the other issue which is very concerning for some people is when they decide, hey, I want to stop this. After a few months of taking it every day, they may get this kind of withdrawal effect where they have a severe itch. It is like ants crawling on their skin from taking that antihistamine off. So when you do it, you gotta gradually taper off. And the tapering protocols are not, there's not like a one size fits all approach to this. There's different ways you can do it and that's something. Again, you gotta talk with your doctor about what's the proper way to do that. For famotidine as the H2, again, generally safe long term. But there have been some post marketing surveillance that have showed rare severe side effects with it. And I've never seen any of those, so I can't even really comment on it because I've never seen it. But if you look at the package insert, you'll see that there's some scary sounding things, but it's very Rare for something like that. And in general, taking something all the time, year in, year out is not something I'm generally a fan of. So we have to always revisit this to decide if this is something that has to be continued or not.
- [19:12]
A
So what exactly is MCAS for our followers here who don't understand what the condition is and how do we make that diagnosis?
- [19:20]
B
Right. So MCAs. I have an entire chapter in my book where I discuss this. It stands for MAST cell activation syndrome, and it's being talked about a lot on social media as a potential diagnosis. I'm going to question people that we don't fully understand it, and we don't understand how many people have it, and. And we're really starting to scratch the surface on our understanding of it. But here's the concept. We talked about. Mast cells that are all over the body, and there are a bunch of different disorders that are underneath this that are related to either making too many of these cells, they're essentially twitchy, to benign stimuli like stress, as an example, or both, essentially. And so there are like primary and secondary disorders, you know, and I'll go through the workup on it, but there's three main criteria that we think about that can cause these severe problems. Number one is that you're experiencing severe recurrent symptoms that involve two or more organ systems. So examples include somebody who has chronic hives, swelling, and flushing. That means histamine is being released in the skin, causing those symptoms, as well as your gut having a lot of bloating, abdominal pain, and diarrhea. So that's like your skin and gastrointestinal tract. A lot of people have overlapping postural orthostatic tachycardia syndrome, or pots, where their heart rate is going really fast inappropriately when they change their position relative to gravity. So when you sit down and you get up, your heart rate does go up a little bit. But for folks with pots, it goes really fast to the point that you get dizzy, faint, and weak, and it can make you feel really, really sick. There's a lot of malaise reported with POTS as an example, and there's different subclasses of it. You know, we can get into the weeds with that, but cardiovascular wise is another one of those organ systems that could be involved. And a lot of folks report brain fog and fatigue. That is with this. That's not necessarily diagnostic criteria, but those are the symptoms. And most patients who come to me, they check those boxes off. And the problem is that it overlaps with a lot of other Diseases, a lot of things you're probably saying, oh yeah, this sounds like perimenopause. A lot of it sounds very similar.
- [21:26]
A
Yeah, I start with menopause and work my way out.
- [21:28]
B
Exactly, exactly. And so for me, people come to me saying, I think I've MCAs. And then I have to work my way out to rule out other potential issues and make sure. Have you seen all the other physicians who have done these different workups? They come in oftentimes with many papers, pages of labs to go through. Usually, number two, they need to have laboratory data that supports mast cell activations occurring. And this is the hardest part because the testing is not always there. And I'm going to tell you, I'm going to tell you because this is not easy. So a lot of the testing is fraught with inaccuracies and difficulties of getting the proper positive test. So the one that's most reliable is a blood test called Tryptase. And I encourage people to get used to ordering this type of test ahead of time before sending to an allergist or somebody who does this on a regular basis because we often need multiple levels to try to prove what's going on. So Tryptase is another protein released from mast cells that linger for about four to six hours after activation. And so when somebody has anaphylaxis, a severe allergic reaction, and you're in the emergency room, I encourage my emergency doctors to get these tests because if they see a high level during this response, it helps confirm anaphylaxis. Because sometimes anaphylaxis could be vocal cord dysfunction or something else is going on. And there are great mimickers for that. And we really need to do a better job getting that objective data to rule out other issues. And so Tryptase often needs to be repeated. Same thing with these other tests that I'm going to go over. They have to do with urine tests. So there's leukotriene E4 and prostaglandin 2 PGD2. These are urine tests that you can get as spot tests to measure mast cell activation. They're essentially like a little bit of broken down products that spill into the urine because it's excreted in the urine. The problem is that if the lab doesn't get it at the right time and they don't run it quickly, it often is falsely negative. That's really annoying. There's a 24 hour N methyl histamine urine test where women have to have a jug and I've had a few men but mostly women, they carry a jug, they have to urinate in it for 24 hours and keep it on ice.
- [23:45]
A
We did that in pregnancy all the time for 24. A urine collection for protein, you know, for pre plants yet. So I'm very familiar with that.
- [23:52]
B
It's not fun. It's not fun. And again, again, if, if you're not tad to it tied to an academic center, it's hard to know how reliable it is. So the, the most commonly positive test I see in my practice is the prostaglandin urine test. For all these different urine tests, I, I've almost never seen a 24 hour or a leukotriene test pop positive. I'm in the community, I'm not in an academic center. So that, so I often send my labs to quest. And so I get, I get some, some good results for the prostaglandins. The other ones I just don't, I don't know really.
- [24:24]
A
Okay.
- [24:24]
B
So it can be challenging to do that, but if you repeat it multiple times, especially when a patient is feeling sick, you may increase the likelihood that they end up being truly positive, which can help. So, so I often don't, I don't want people to feel written off because they've had normal tests one time. And that's true for autoimmune disease too. But autoantibodies don't always give us enough information and we may have to repeat it multiple times over years before it's really clear, oh, that's what's going on. And that's really a major challenge with a lot of issues related to women's health. Autoimmune disease, mast cell activation, it's all overlapping in that same level of frustration that we have where we don't always have the laboratory criteria to settle things. And that's why I think a lot of people feel like medicine, healthcare are not necessarily doing the best job. And I think it's really just if we have a little bit more patience and try to try and try again, we may be able to get better results with that. The third criteria, which is the last one, which is one that I see most commonly positive, is we treat mast cell activation syndrome and their symptoms go away or they get much better. And so we talk about the H1, H2 blockade, but there's other medications that I may use, example cromolyn. It is a stabilizer of the mast cell membrane that can be taken orally before meals and before bed, and it essentially coats the gastrointestinal tract to stop those Mast cells from activating to decrease the abdominal complaints that people experience. And I find a tremendous amount of success with that. If they're truly an MCAS patient where they've had all these non specific symptoms with eating, it's like ibs, but then they take it and they feel a lot better. The problem is that you have to titrate this medicine slowly because if you give them the full required doses, they will have diarrhea. As much as you're trying to prevent that, it will cause it because it's not absorbed systemically that much. It's just a coating essentially. So you have to slowly build it in so that you're not causing that problem. There's also Montelukast. It's a leukotrine receptor blocker also known as Singulair. I tend to use this as one of my later treatments because there's a black box warning for as much as we're trying to help with mood stabilization with this, it can cause neuropsychiatric events, it can cause bad nightmares, mood swings, anxiety, depression, even thoughts of self harm. It's likely. The FDA came out a few years ago and did some studies that we believe that there's off target effects that it goes into the brain and it can actually interact with serotonin receptors as an example, and dopamine. And so if you take the medicine away, in my experience, those symptoms do go away. So. So you have to really counsel your patients on this.
- [27:04]
A
To watch for those.
- [27:05]
B
To watch for the. Yeah. And another way to think about it is like you have a kid in an elevator with a hundred buttons and they're supposed to press 1, but they press 20. Once you get the kid out of the elevator, the buttons go back to normal. That's the way I think about it. And then another Mast cell stabilizing medications, Ketotifen is one that has to usually get compounded by the pharmacy. It can be helpful, but it can cause a lot of sedation. So I generally try to shy away from that as much as possible. And now there are two other off label medications that are very expensive, but if we can get it approved, they could potentially help. So there's something called Omalizumab or Zolair, which is an antibody that blocks IGE antibodies. Those are the allergy antibodies and that decreases mast cell activation. But it's not entirely effective for everybody. Again, this is all stuff that we have to talk about. There's not clinical trials for this. And then the other one that's a newer medication is called Rapido or Remibrutinib. This is an oral BTK inhibitor, Brutons tyrosine kinase, that's taken twice a day. It's approved for adults with chronic hives, but it stops mast cell activation. So this is something that I'm using for my patients with chronic hives. I'm looking into kind of off label privately, you know, testing out with my patients and seeing how it's going. And. And there's variable success with it right now.
- [28:28]
A
Okay, so on my quick review of what people are stacking on the Internet, we talked about H1 and H2 blockers. What about quercetin? And we're having a few questions on that. And what about low histamine diets? Is there any.
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B
Right.
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A
Is that realistic?
- [28:42]
B
So quercetin is a supplement. I don't even know if I'm pronouncing that.
- [28:47]
A
I don't know.
- [28:48]
B
It's one of those ones. I've heard it said five different ways, so no worries. This supplement has not been well studied. We know in the lab, in vitro, it has antihistaminic properties. The problem is that we don't know how much you need to take and when and the full safety profile. Plus, with any supplements, we always have to tell folks, you have to be careful where you're getting it from because you can't guarantee that you're actually getting the number of milligrams that you're going to get. So it's always something that I say, if it's working for you and we're not seeing any untoward side effects. I mean, you could talk about it, but I can't generally recommend it for the public on social media when there's all these potential safety issues. It's not FDA regulated, so I always caution people with that not to say that it can't work, but we have to always use it with caution.
- [29:38]
A
And what about dao?
- [29:40]
B
Dao is the same kind of thing. So diamine oxidase. Dao is an enzyme that helps break down histamine and metabolize it. And so there is a concept called histamine intolerance where some folks, when they have foods that are high in histamine, like sausages, sauerkraut, pickled items that accumulate this, just a few examples, they start having a lot of different symptoms, not just gastrointestinal, but they'll complain of joint pain, headaches, fatigue, nausea. And so Dao supplements for some people might help, but the current clinical evidence towards it is not great. And there's actually one study that I always look at where they did a randomized placebo controlled trial for people who thought they had histamine intolerance. And they said, we're gonna give you a substance, it's either a placebo or histamine and you don't know what you're getting and we're gonna see what symptoms you experience. And when they did it that way, double blinded, randomized and placebo controlled, there was really almost no difference between the two groups. So it may be something else that's going on when people think they have histamine intolerance. So MCAs could still fit that as an example where it's really not that the histamine is lingering around. You're making too much of it is what it could be as an example or something else for all we know. And so Dao, I'm not a huge fan of same thing with low histamine diet. So I do feel that when we look at the evidence for low histamine, again, not a lot of it, we don't really have much to go off of and some people may report having success with it. But if we overly rely on a very restrictive diet, it could cause more anxiety, it could potentially cause nutritional problems. It doesn't mean that you can't do single food elimination diets and slowly, methodically take things out to see how that interacts with your body. Not just digestive, but does it? Is there an immunological basis for it that is, I think, appropriate, but if you start taking a bunch of things out at the same time, you don't even know what's helping. Right? And a lot of these low histamine diets, if you look, they're not even the same. Like when people talk about it, we don't know what is a true standardized low histamine diet that's been well validated. And that's where it becomes really difficult to be able to give good advice on it.
- [32:04]
A
When for anyone listening, would self experimentation be reasonable and somewhat safe versus you need to go immediately to an allergist, right?
- [32:14]
B
So I don't mind people trying these things. They're over the counter, right? I mean, it's safe enough for most people that it's worth doing a short trial, but one step at a time. You don't want to do 20 different things at once. You'll never know what's actually helping you. But if these symptoms are, are, you know, controlling your everyday life, you really need to talk with a physician. And here's the Challenge though, like with my specialty, I mentioned earlier, we have very few of us to go around. There are some communities, especially rural ones, where you may not be able to find an allergist for like 4 or 5 hour drive. I have patients that will drive hours to see me sometimes and they'll be, you know, waiting just to get in to see someone like me. You know, in Canada, as an example, I went to a conference recently and in Newfoundland, that entire province has five allergists and their wait list is about two years in some places to even get in. Right. So. So a lot of people turn to social media because they can't even get access to a physician. And that's a big issue that we're really needing to have a call to action to figure out. How can we bridge the gap? Because yes, people are turning to social media, they're getting their information. Some of it's good, some of it's not good. And when you self experiment, you do have to know that there's potential risks. So slowly adding these things in and then if you can get a chance to talk with people that are professionals, that's really, really important to make sure that yeah, if you're feeling better, great. But we don't want to overstack these things to the point that they're interacting with other issues with your health that I can't even get into because I don't know what people like. I know you do too. We get tons of messages from people all the time asking for medical advice and it's something we can't do.
- [33:53]
A
Unfortunately, we can't do it. We try to provide resources, books, blogs, podcasts, you know, but I give them personal medical information.
- [34:02]
B
Right.
- [34:03]
A
The. Where do you think medicine, you know, when we're going for mood symptoms and that's really big. And we know like across the menopause transition and we're assigning a lot of it to fluctuating hormones, we see 40% increase in either depression or anxiety and that's new diagnosis or someone who was previously well controlled with their therapy medications and now they've lost that resilience. And you know, what I'm worried about or what this makes me more think about is how much of that could be what's happening with your immune system being involved in this as well.
- [34:42]
B
Right. We know that with PMDD as an example, one of the standards of care is using SSRIs because there is utility in that and that's where we probably have the greatest evidence. But if people aren't getting Optimal control with just that alone as an example, or with cbt. This is where we need to have this conversation about how much the immune system is really playing a role in all of this. And hearing that a lot of women are reporting success with taking, like, this combination H1, H2 blockade, can we start developing new treatments that look at the immune system's involvement with all this? These are questions that will take time to answer. And so if people are finding success with it, again, we're all very happy for those folks, and we want to continue that success. We also want to understand it better and be able to give the best advice possible and find ways to supplement this and be able to address this holistically. Because I think there's a lot of room for growth in this area that, you know, you and I and other allergists, immunologists, OB GYNs, we need to partner more on this to be able to do a better job with this and to provide better care.
- [35:57]
A
So what we're seeing in our group chat is there's a percentage, small, but there is a percentage of patients who seem to develop MCAs or MCAs, like, symptoms when they start hormone therapy. There's something about the formulation, the dose, you know, not all HRT is equal. Right? We have, like, any medication, we have transdermal, we have oral, we have transmucal soul, we have, you know, and it does seem to make a difference. Are you seeing that in your practice as well?
- [36:28]
B
A little bit. So I've had a few patients come to me thinking they're having allergic reactions to hrt. And so the question becomes, you know, what is actually really happening there? I can't say I know for certain. This is speculative. I wanna make that very clear for folks. Anything that I'm saying right now is purely speculative. We don't know enough about this. But as we look at some of these mechanistic studies and how estrogen is involved with mast cells, estrogen, I think, is kind of the key here. And the question is, is it because we're giving too much? Is there something cyclically happening there? I don't know. I really don't. But, you know, I talked to somebody recently about this, and I said, you really gotta talk to your prescriber and see, can we try a different formulation? That's actually what I told somebody recently. Yeah.
- [37:17]
A
And that's what we typically say is, let's go with a totally different formulation.
- [37:21]
B
And have you personally seen kind of follow up with that? Because right now, again, this is kind of new Fresh for me, with hrt for people coming in to see me about it. But have you seen that the change in formulation or the delivery mechanism makes a difference for some people?
- [37:37]
A
Yes. When, if it's not tolerated, we see, I think, a lot more of it on the progesterone side with a paradoxical reaction to progesterone, which is supposed to be a little bit sedating. Either they'll just feel completely grogged out or they'll have a big mental health change. With the oral micronized progesterone, typically, and the synthetic versions like the norithendrone that's in the patches, they actually tolerate a lot better, probably because it converts to ethanol estradiol in the metabolism process, so they get a little estrogen. That's all very endocrine coated, you know, complicated stuff. The good news is we have multiple ways to get this into your system to figure out what's going to work. And sometimes we just throw spaghetti at the wall and just keep trying until we get better and so. And never really understanding what's going on in the background, you know?
- [38:26]
B
Right, right.
- [38:27]
A
So I think that's what I love about the Internet, you know, in women's health, one thing I know that social media changed was getting pain control for gynecologic procedures. When you have millions of women screaming on the Internet that they thought they were going to die during their IUD placement, where I was taught there's no reason to give any kind of pain control for an iud, and then I start doing them, I'm like, wait a minute, 20% of my patients are not okay with this. And so really fighting to make that change, which has happened.
- [38:59]
B
So, and I, and I, and on the allergy side, we've talked a lot about moving away from Benadryl as a common. This is the first thing you do for allergic reactions. Like, no, no, no, there's actually better, safer alternatives now that we know more about what's going on with this. And so I agree we have the power to be able to change the discussion on these things and also normalizing it too. I think that's really important. But also I always caution people, how we communicate this information online needs to be nuanced and always with the caveat that we have to always leave the discussion open to your providers, your healthcare providers, and make sure that it's a full team, that you can't just like take what's online. And that's going to be your only bit of medical advice because there's so many different issues that, especially for women that overlap, that we may be overlooking. And I see this constantly where people already come in with an MCAS diagnosis and it's like, wait a second, hold on. We need to make sure that that's actually what it is before we go down the rabbit holes.
- [40:02]
A
Because both can be true at the same time.
- [40:04]
B
Yeah, there's also. Exactly. They could be both and we could have this and then miss something else that's happening at the same time. So we always have to revisit that. But having a forum, a discussion that can really disseminate to people to say, okay, we're asking these new questions. Can we spur on this discussion to start to either have a policy change or have more research funding into something you start to have interest in all this. I think it's just wonderful.
- [40:31]
A
Yeah, I agree. So let's on our wrap up. So if a woman wants to test whether histamine might be a part of what's happening in her body, where should she start? What's a reasonable way to start?
- [40:43]
B
The first thing I always tell folks is to make sure that you're journaling what's going on and say, hey, what are the symptoms specifically that you're experiencing and when are they happening? Are there any potential triggers, aggravating factors, alleviating factors? These are things that medical students are taught to ask patients on a regular basis when we get their history of present illness. So patients really need to take all that data in first and start to map out, is there a cyclical nature to this? Could this be influencing with my menstrual cycle as an example, because a lot of people's allergies get worse in the luteal phase right before the period. It's so common. In fact, I'm making a video on it right now to help people get a better understanding and raise awareness towards that. And so then you could say, look, you've got over the counter medications. You can certainly try some of these things and see does it significantly get better and then bring it to your doctor to say, hey, this is what's happened to me. And depending on if there's a lot of different things going on, a tryptase may be helpful in starting that discussion about whether you have a mast cell disorder.
- [41:46]
A
He has an entire chapter on mcas, mast cell activation syndrome. And you have all of the tests listed and medication, everything is there so, so worth your while, you know, to do your own research. He wrote it all for you right there. And of course, follow him. If my followers are Watching this, I just want to touch on endometriosis. We had so many questions. What do we know?
- [42:10]
B
Right. So we have a better understanding of kind of the immune system's response with endometriotic tissue than before. And so we realize there's a lot in the estrogen production and histamine is ramped up in those tissues, and also it lingers quite a bit. And that may be playing a role in the amount of pain that women are experiencing, which is why I've also withdraw this journey that I've been having lately of raising awareness to this and discussing it. A lot of women have been saying, yeah, this combo therapy has actually been helping with those symptoms as well. And so it's just fascinating to me the connections between histamine and all these different issues that we've been talking about lately. And I'm hoping that we can continue to have this discussion and that it will enact some change and more research into it so that we can provide better care for our patients.
- [43:05]
A
Awesome. Well, thank you so much for joining us. It was so wonderful. So, everybody who doesn't follow him, Dr. Zachary Rubin. He's. What's your handle on.
- [43:15]
B
It's Rubenallergy.
- [43:18]
A
Okay. And please buy his book. It's amazing. You can find full episodes of unpaused on YouTube at Dr. Mary click claire. I'd love to hear from you about this topic and anything else that's on your mind. You can find me on Instagram @Doctor Mary Claire and get honest and accurate information on health, fitness, and navigating midlife@thepauselife.com My new book, the New Perimenopause, is available everywhere you buy books. If you're loving this podcast, I have an important request. Please take a moment to follow Unpaused on your favorite podcast app. Following and listening is what pushes this information to more women who need it. So if this podcast has helped you feel seen, understood, or supported, hit follow right now so you never miss an episode. Thank you for being here with me. Let's keep going. Unpaused. Unpaused is presented by Odysee in conjunction with pod people. I'm your host. Host, Dr. Mary Claire Haver. The views and opinions expressed on Unpaused are those of the talent and guests alone and are provided for informational and entertainment purposes only. No part of this podcast or any related materials are intended to be a substitute for professional medical advice, diagnosis, or treatment.