Mast Cells, Histamine, and Perimenopause Explained: MCAS, Anxiety, Estrogen

0:00In business, there's no room for guesswork. Every shipment matters. Every deadline counts. When you're trying to keep operations running smoothly, the last thing you need is uncertainty. That's why reliability is at the core of USPS Ground Advantage. From the moment your package is first scanned in, it moves through a secure nationwide network, aiding in a timely and accurate delivery. You get near real-time tracking so you can keep up with your shipments. And with affordable, upfront pricing, there are no hidden fees or surprise surcharges to throw off your cost sheets. It all adds up to predictable deliveries you can depend on.

0:44Because knowing your logistics are handled lets you focus on everything else. Your customers, your team, and the future you're building. Visit usps.com forward slash ground advantage to start shipping with confidence. USPS Ground Advantage. We mean business. We talk a lot about the long game of health, steps, sleep, and nutrition. But when was the last time you saw your dentist as a key player in your wellness? It surprised me too. But your dentist might actually spot a health issue before your doctor does. It's all about the mouth-body connection. Smile Generation is a community of experts who know that what happens in your mouth affects your entire system.

1:26There are proven links between oral health and your heart, your brain, and conditions like diabetes. And for us women, this connection is vital. Oral health plays a significant role in women's wellness, impacting everything from hormonal shifts to pregnancy and bone density. Caring for your smile isn't just about aesthetics. It's about ensuring your body isn't holding you back. That's confidence unleashed. Regular screenings catch issues early, often before you feel a single symptom. Don't put your health on pause. Visit SmileGeneration.com slash unpaused. That's SmileGeneration.com slash unpaused to learn more about the mouth-body connection and find a trusted provider near you.

2:08When I'm looking for high-quality furniture that doesn't break the bank, I don't have to settle for subpar styles because I can find everything I need at Bob's Discount Furniture. At Bob's, I can score everyday low prices on pieces that real customers love, like Consumer Reports recommended mattresses, real marble dining sets, and the best-selling modular Bob's sectional, which has over 1 ,700 five-star reviews. So stock up on five-star style and visit Bob's, where America shops for furniture. Today on Unpaused, I would like to share something a little bit different with you. I recently had the honor of interviewing Dr.

2:44Zachary Rubin, a double board certified allergist and immunologist and pediatrician and the New York Times bestselling 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.

3:24I'm also an adjunct professor of obstetrics and gynecology at the University of Texas Medical Branch. 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.

3:50Hi, 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.

4:27Though in our menoplasi 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 later. I'm still writing the book and busy, but it is 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.

5:06You 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? 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.

5:43So, 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 mast cells, histamine, and what's going on there.

6:22So 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.

7:00So 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 the 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.

7:41You 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? And no one taught me this, like this was not medical school. This was not residency. 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 about it.

8:17But 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 where 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.

8:57It could also decrease the degradation of histamines. So not only are you producing more, but it kind of lingers. Okay, you can't break it down. Exactly. And then progesterone is kind of putting the brakes on it. So there's two different levers, so to speak, with the mast cell just from sex hormones alone. 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.

9:40So listening to women, you know, HRT doesn't fix everything, right? And so learning about this and realizing how related these two, 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. Yeah, absolutely. 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? Right. So for folks in general, receptor is a word that's not always used in our vocabulary.

10:19And so I like to think of it like a lock and 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, you know, 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.

10:54And I would love to see more research on H3 and H4, and can we develop some novel approaches to that? Because that can 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 of the surface of your skin to become leakier, can lead to hives, swelling, also known as angioedema, itching, sneezing, running nose, all the classic allergy symptoms. So when you take Benadryl or Claritin or Allegra, those are H1 blockers.

11:30Versus H2 is actually famotidine or Pepsid, 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 Pepsid. 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, the Allegra-Pepsid combo or fexofenadine-femotidine, 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.

12:22And 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.

13:02And 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 will 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 to determine how much, how often, when, especially in the context of what other medications they're taking for potential interactions.

13:50So 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. 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?

14:24My feeling is that it's because there's a predominance of estrogen. Okay. 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 distribution, kind of in early adulthood and later in life.

14:58But a lot of the times, it's actually in the 30s and 40s when those hormones are fluctuating. So if a patient comes into your office, Zach, and says, I started Pepsodin Zero Tech and my PMDD is gone, what do you do with that as a clinician? You talked about, you believe her. Right. 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 dealing with that and their loved ones around them because, you know, we don't really fully understand all this.

15:32right? But then... 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? Yeah. But we don't have any trials. Exactly. Exactly. So when they come into my office and they explain that, and we haven't really just heart to heart to say, I'm so happy this is making you feel better.

16:17Let's make sure we're not missing anything. Okay. I always want to make sure that people know that, you know, when we look at their entire our 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?

16:54And 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 six or seven thousand 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.

17:31It'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. Yeah. When we announced it, we had 11 ,000 likes on the post and we had 1 ,500 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 into a pharmacy. Which ones would I consider? How safe? How long? Can you talk about that a little bit? Right. So there's things that we know already, and there's things that we don't know about this issue.

18:07So the one that a lot of women are talking about that I often recommend with my patients is Allegra and Pepsid as the brand names. The generics are fexafenadine 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, Zizol, Zyrtec. The issue is that Zyrtec and Zizol are very similar medications. And for some women, it can actually cross the blood-brain barrier and make people sedated.

18:46For 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's a neurotransmitter called acetylcholine, and when that's blocked, there's other medications that 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.

19:24Claritin 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?

19:52and 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 appetite suppressant.

20:26So 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've got to gradually taper off.

21:03And 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 got to talk with your doctor about what's the proper way to do that. For famotidine is 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.

21:35And 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. So what exactly is MCAS for our followers here, you know, who don't understand what the condition is and how do we make that diagnosis? 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.

22:12And 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 is an example, or both, essentially. And so there are like primary and secondary disorders, you know, 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.

22:52So 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 like 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.

23:30There's a lot of malaise reported with POTS as an example. And there's different subclasses of it. We can get into the weeds with that. But cardiovascular-wise, it's 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.

24:00In my world, yeah, I start with menopause and work my way out from there. 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 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 as good. I don't know how to do it. And I'm going to tell you, because this is not easy.

24:33So 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.