Typically a woman will go in to see her doctor, and if she complains of any symptoms related to hormone balance, it seems to me that one of two things will happen. This is an oversimplification, but one is nothing. Nothing happens. There’s actually no investigation into hormone levels as a possible cause of her issues or anything that could affect hormone levels directly. Maybe two is that an antidepressant gets prescribed. Or three, if the practitioner is maybe a little bit more progressive than most, they might recommend hormone replacement, estrogen perhaps if the woman is in menopause or maybe estrogen and/or progesterone if she’s still menstruating. What’s wrong with that as a model?
In this episode, we cover:
3:30 Biggest mistakes in mainstream treatment model
9:23 Post birth control syndrome
22:43 What hormone treatment should look like
49:35 Three things most women with hormone problems would benefit from
55:35 Sara’s next book
Chris Kresser: I’m Chris Kresser and this is Revolution Health Radio.
Hey, everyone, it’s Chris Kresser. Welcome to another episode of Revolution Health Radio. I’m really excited to welcome Dr. Sara Gottfried as our guest today. She is the New York Times bestselling author of The Hormone Cure and The Hormone Reset Diet. After graduating from Harvard Medical School and MIT, Dr. Gottfried completed her residency at the University of California at San Francisco. She is a board-certified gynecologist who teaches natural hormone balancing in her novel online programs so that women can lose weight, detoxify, and slow down aging. Dr. Gottfried lives in Berkeley, California, with her husband and two daughters.
I met Sara a few years ago. I was on my book tour, actually, in Chicago, and I got a text from her. I think she was there also on one of her book tours, and we had dinner and hit it off and became fast friends. I have tremendous respect for Sara and her work. She’s one of the brightest practitioners that I know and just has a really holistic and informed perspective on functional medicine and nutrition and, of course, hormone balancing, which is an area that she has a lot of expertise in. In fact, if I have a question about hormones or hormone balance or anything to do with testing and diagnosis and treatment of hormone issues, I’m almost certainly going to ask Sara about it. There aren’t that many practitioners that I have that kind of respect for and collaborate with on a regular basis, and Sara is definitely one of them, so I’m really excited to do this episode. I’ve talked about hormones and hormone balancing to some extent in the past, but we haven’t really taken a deep dive, and I thought Sara would be the perfect person to do that with, so let’s jump in.
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OK, now back to the show.
Chris Kresser: Sara, I’m so happy we finally made this happen. I can’t believe we waited so long.
Sara Gottfried, MD: Hey, Chris. I’m so happy to be here.
Chris Kresser: Let’s kick things off by talking about the biggest mistakes that are made in the mainstream medicine model when it comes to addressing hormone imbalance. Typically a woman will go in to see her doctor, and if she complains of any symptoms related to hormone balance, it seems to me that one of two things will happen. This is an oversimplification, but one is nothing. Nothing happens. There’s actually no investigation into hormone levels as a possible cause of her issues or anything that could affect hormone levels directly. Maybe two is that an antidepressant gets prescribed. Or three, if the practitioner is maybe a little bit more progressive than most, they might recommend hormone replacement, estrogen perhaps if the woman is in menopause or maybe estrogen and/or progesterone if she’s still menstruating. What’s wrong with that as a model?
Sara Gottfried, MD: What’s wrong with this picture? Chris, you and I have met a lot of mainstream hormonal refuges over the years, and so I think there are many problems with the mainstream model. I’ll just rattle off a few of them, and we can drill deeper if you want.
First, I would say, is there’s a lack of regard for root cause, especially if you’re seeing a primary care doctor who works by algorithm, by kind of rote algorithm. There’s this kneejerk quality to it. So if you’re 17 and you have acne, you end up with a prescription for a birth control pill, and there’s no careful assessment of the control system that could be leading to the high androgens or the food intolerances or the gut issues that could be at the root of the acne. And as you’ve described, if you’re 25 and you have painful periods, the pill, yet again, is considered the solution.
What I think is a problem here is that women are getting put on synthetic hormones or, in some cases, bioidentical hormones for almost any issue well into their 50s, 60s, and 70s, and there’s often a cost to it. There are long-term alterations to the control system for hormones, which I assume we’re going to get into today, and I just see this lack of regard for root cause, so that’s one.
A second mistake is the financial motive, and this one is really troubling. When you look at birth control pills and how they first started in the 1960s and maybe initially were thought to be an instrument of female empowerment, it’s now this gigantic moneymaker for Big Pharma. Just with the birth control pills that are on patent, it makes more than a billion dollars per year for pharmaceutical companies, and I have to say that I think the pill is the number-one endocrinopathy for women—which is totally caused by the prescriber—in the developed world.
Chris Kresser: An iatrogenic problem.
Sara Gottfried, MD: Iatrogenic, absolutely. And the same is true for hormone therapy, for hormone replacement therapy for older women. Premarin or conjugated equine estrogens synthesized from pregnant horses, that was the number-one prescription in the US for a long time. Even in 2002, when the Women’s Health Initiative was published, it was the number-four prescription in the US. We then had data from the Women’s Health Initiative about how it’s dangerous and provocative to the female body, leads to a greater risk of stroke and together with synthetic progestin increases a woman’s risk of heart disease and breast cancer.
And this then leads to a third mistake, which is a lack of rigorous evidence behind the mainstream approaches to hormone problems, and maybe even more insidious, the lack of awareness of the lack of evidence by folks in mainstream medicine. Premarin was prescribed for 57 years before we finally had a randomized trial to show that it was a problem, and this is a shameful part of our past in American medicine.
Chris Kresser: It’s bizarre, really. These chemicals, including drugs, are innocent until proven guilty. Obviously there’s a process for determining the safety of a drug before it’s introduced, but in cases of hormones, it seems like that process failed—early on, at least.
Sara Gottfried, MD: It certainly did. I think there’s another issue here, maybe a little more subtle than a mistake, but a sociocultural problem. This one is kind of creepy. I think there’s a patriarchal quality to how hormones are addressed. I’ll mention this just briefly so we can get to some solutions, but I was taught in my conventional training that you don’t need to check a woman’s hormones because they vary too much, with one exception—if she’s trying to get pregnant. And in that case, if she’s having trouble getting pregnant, then you check everything. You do a thyroid panel, you do a day-three estradiol, you look at her FSH and day-21 progesterone, her androgens, her cortisol, her cortisol metabolites. That’s a total double standard.
Chris Kresser: If she’s trying to procreate, we can get involved, but if not, forget about it.
Sara Gottfried, MD: If not, you’re on your own, or why don’t you take this nice birth control pill?
Chris Kresser: Yeah. Let’s talk a little bit more about that, what we might call post birth control syndrome, because you alluded to it a couple of times, that birth control is the number-one endocrinopathy and it causes a problem with our natural hormone regulation. I just had a patient last week that fits into this category, so it’s at the top of my mind, and I think it’s always helpful to use these kinds of examples so that folks who are listening know what we’re talking about and it’s not just theoretical.
This is a 23-year-old female, and from the beginning of her cycles, they were painful and difficult. She had skin issues and a lot of problems associated with that, and so, of course, not surprisingly, she was prescribed birth control and took it. Fast forward eight years later, she’s a patient in my office with numerous complaints. I tested her hormones, using both urine and blood, and found that her total estrogens were high with altered estrogen metabolism, so she was metabolizing estrogens down a proliferative pathway that can increase the risk of breast cancer. She had cortisol dysregulation, so inappropriate secretion of cortisol through the day and also high cortisol overall. Her androgens were high, so not only DHEA, but also etiocholanolone and androsterone and then testosterone and DHT. Her copper/zinc balance was totally out of whack, out-of-the-reference-range high copper and below-the-reference-range zinc. And then iron deficiency and a number of other problems. If you look at the scientific literature, pretty much everything that I just mentioned can be traced to birth control pills, but she was never told that this could be a problem.
Sara Gottfried, MD: Yeah, well, this is so troubling, and before we dive into this, is she now off the pill? Please tell me she’s off the pill!
Chris Kresser: Yeah, she went off of the pill, like, three or four months before seeing me. She knew that would be the recommendation and did it and then wanted to see where her hormones were after being off the pill for a few months. So, yes, she is off.
Sara Gottfried, MD: Yeah. Good. Well, I think this is a great example, unfortunately, of the endocrinopathy that can happen, as well as micronutrient deficiencies. I know you’ve talked about this with your listeners before, but just taking a step back, we know that the birth control pill makes the control system less flexible. The control system for hormone regulation, this feedback loop, which some people call the HPA, the hypothalamic-pituitary-adrenal axis—I like to think of it a little more broadly as the HPATG, the hypothalamic-pituitary-adrenal-thyroid-gonadal axis—that system becomes a lot less flexible when you go on the birth control pill. There are numerous micronutrient deficiencies, and what troubles me is that I doubt this woman ever got full informed consent.
Chris Kresser: No way.
Sara Gottfried, MD: No way, right?! This is kind of that mistake that we were just talking about, where I think so many prescribing health professionals aren’t aware of these potential risks.
Chris Kresser: Right.
Sara Gottfried, MD: They don’t know that 20 to 25 percent of women on the pill have vaginal dryness. That’s, like, the greatest irony ever, right?! Especially if you go on the pill because you want to have more sex! You have vaginal dryness, and you’re just like, “What’s going on?!” It can shrink the clitoris up to 20 percent. It just has a number of effects that may not be completely reversed when you go off the pill. That should be part of the informed consent.
There’s a study from Claudia Panzer where she looked at… you know, one thing that happens when you go on the birth control pill is that it raises this intermediary, sex hormone-binding globulin. I think of it as a sponge that kind of soaks up your androgens, and that’s one of the reasons why going on the pill can reduce your androgen levels and then reduce acne. But by the same token, when you stop the pill, up to a year later, women still have elevated sex hormone-binding globulin. There are these persistent changes to the matrix of the body that really disturb me.
Chris Kresser: Yeah. I’ve tested so many women now at various stages in that process, people who have just gotten off birth control maybe a month ago, people who have been off it for two years but were taking it for 15 years and still have abnormal hormones and either oligomenorrhea or dysmenorrhea or amenorrhea. They’re on different parts of the spectrum in terms of issues with the menstrual cycle, and maybe still, if they’re trying to conceive and that’s why they’ve come off the pill, they’re not able to because their hormone system is so dysregulated. That’s one of the saddest… “side effect” seems insufficient as a term for that, but that’s one of the most devastating potential effects of long-term use of the birth control pill.
Sara Gottfried, MD: Well, it’s a tragedy. I’ve seen a number of patients—I don’t know what the numerator and denominator are here because I just haven’t seen good data on it, but I’ve seen at least 10 people over my lifetime of taking care of patients who have ovarian insufficiency. Like, they just stop having their period. They’re in their 20s or 30s, and they have the hormones of a menopausal woman, and they want to make babies and they can’t. In fact, I think I sent you one of these women recently.
Chris Kresser: Yeah.
Sara Gottfried, MD: It’s just awful. It’s totally awful, and it’s very hard to reset the system. It’s not quite as flexible as we would like it to be.
Chris Kresser: No. With those patients, I’m definitely careful to set expectations up front because it is possible, and in most cases we’ve been successful, but it’s not something that’s going to happen overnight, and it requires really digging into all of the various mechanisms that can affect hormone function and to really reset and kickstart normal hormone production again.
So that’s the problem with the conventional medicine model—or one of the problems or some of the problems! Then there’s another world, which is this anti-aging medicine world, where the kind of prevailing idea is that… it’s kind of like the deficiency replacement model.
Sara Gottfried, MD: Yeah.
Chris Kresser: If the hormones are low, simple—just give hormones, whether that’s estrogen or progesterone or testosterone. That’s not even really necessarily the mainstream model. That more kind of fits in the kind of integrative, anti-aging medicine model. Let’s talk a little bit about the issues there.
Sara Gottfried, MD: Oh, yes. Well, I sometimes call this the topping-off model.
Chris Kresser: Right!
Sara Gottfried, MD: Where you’re taking the tank of all these different sex hormones and you’re topping them off. To me, this is a really unskillful way of working with the intelligence of the hormonal feedback system. It’s a sledgehammer instead of a nudge. And I find, after taking care of patients for the past 25 years, a nudge works a lot better! At least at the beginning and in the middle. This more anti-aging school of thought is almost like spray-and-pray.
Chris Kresser: Right.
Sara Gottfried, MD: Like, let’s top off every single hormone—pregnenolone, growth hormone, estrogen, progesterone. How about some testosterone? And, oh, a little DHEA, too. I think when you do that, it’s very hard to understand how you’re changing the feedback mechanisms, and there’s a total lack of regard for evidence, long-term safety, and other consequences. So I want to be careful not to get totally binary about how anti-aging is bad and functional medicine is the best approach, and I think the way to do that is to look at some of the evidence. So could we talk about Suzanne Somers?
Chris Kresser: Sure. Sounds fun! I don’t think I’ve ever talked about Suzanne Somers on my podcast, so it’ll be a first!
Sara Gottfried, MD: Good. Well, I think everyone can kind of visualize Three’s Company, or if you can’t visualize that, you’ve seen some of Suzanne’s blockbuster books. I’ve tracked her really carefully. I don’t know her personally, I don’t know kind of the backstory, but she started off in menopause with pretty hefty doses of what was then called hormone replacement therapy—estrogen, progesterone, and testosterone. And she took them to deal with what she famously called the Seven Dwarves of Menopause—Itchy, Bitchy, Sleepy, Sweaty, Bloaty, Forgetful, All Dried Up. I think those are the seven. That’s kind of cute, but lo and behold, within a few years, she was diagnosed with breast cancer. I don’t know if anyone was checking her estrogen metabolism, but it seems unlikely.
Chris Kresser: Yeah.
Sara Gottfried, MD: So she then left the care of the endocrinologist that she was seeing, and she started the Wiley Protocol, which is a series of different doses of estrogen and progesterone cream that you apply to your arms in order to mimic the hormone levels of a woman in her 20s.
When I first heard this concept, I was like, are you crazy?! Why would you want to take a 50 or 60 or 70-year-old woman and give her the hormones of someone in their 20s?! That makes no sense to me! But more important than that is there are no long-term randomized trials. The Wiley Protocol gives you this whopping dose of estrogen that’s about four-fold what the FDA has approved as a safe upper limit, and so it sets you up for estrogen dominance, for high estrogens relative to progesterone. And then, maybe not surprisingly, Suzanne Somers was then diagnosed with endometrial cancer. Endometrial cancer. Is that surprising? No. Is it preventable? Probably. Endometrial cancer usually is.
So what’s wrong with giving people these massive doses of estrogen and progesterone and testosterone in pellets, etc.? I think the biggest problem is there are no long-term randomized trials showing that it’s a good idea. And they’re often prescribed by people with limited training. Like, they did a weekend workshop and they’re actually emergency medicine physicians.
Chris Kresser: Right.
Sara Gottfried, MD: There’s kind of a blithe disregard of the skeptics. You know, just fill up the hormonal tank, and that will help you not get old before your time. I just think there’s a real danger here to the lack of robust data.
Chris Kresser: Yeah, when you look at it from an evolutionary perspective, which I often, of course, do in these situations, it doesn’t make a whole lot of sense, as you pointed out. It’s not like throughout most of human history women had the same hormone levels all the way throughout their lives, whether they were in premenopause or menopause, but then there was something about the modern lifestyle that dropped women’s hormone levels in menopause, and so giving hormones is like getting us back to a natural state. It’s a totally artificial construct, this idea that a menopausal woman’s hormones should be the same as they are prior to menopause. That’s just a notion that no one has ever really explained, at least that I’ve seen, how that makes sense or why that would even be a good idea.
Sara Gottfried, MD: Right, and I think there are many layers to it. I think some of it is valuing women as wombs and sort of saying, OK, let’s replace her back to what she was like in her prime, in her 20s.
You and I have talked also about, you know, when you look at a woman’s hormones, context is so important because often low estrogen, low progesterone, there may not be any symptoms associated with that. It may not be a bad thing. In fact, it may be associated with greater healthspan, and so what’s the innocent bystander versus a potentially pathological situation that we can address and improve quality of life and improve other outcomes that are important, like breast cancer, heart disease, so on.
Chris Kresser: Right, and as we’ve also discussed, even if the hormones are pathologically out of range, it doesn’t necessarily follow that addressing the hormones directly is the best way to remedy that, which leads us into the next topic, which is what is the best way to approach hormone issues from a functional medicine perspective.
Sara Gottfried, MD: Yes, well, I want to riff on this with you because I think we have different approaches. There’s a lot of similarity, but I think… what I’ve learned to do over the years is to start with root cause analysis. I’m going to kind of reveal myself here as an engineer! I feel like you get the best results when you approach hormone issues like a medical detective and you really work through a particular sequence of modules.
You and I have talked about this as kind of a root-and-branch approach. Do you want to say anything about that? I think that was your language, and I think that it’s so valuable here.
Chris Kresser: Sure. Anyone who’s been listening to this show for any length of time or following my blog will know this, but in functional medicine we try to address the underlying cause of illness rather than just suppressing symptoms. If you think of it as a tree, that would be looking at the roots of the problem. When you do that, it’s very often the case that the branches, which really kind of represent the manifestations of the underlying dysfunction, and if you think of a tree that branches out in a number of different directions, you can have many different manifestations—or symptoms, as we call them—of a fundamental cause that may seem like they’re unrelated if you’re only looking at the branches because one branch is going off in that direction, another branch is going off in the other direction, and they don’t really look related, but if you trace them back to the roots, you see that they’re related.
That’s one aspect of the root-branch model, but the other is—and I think this is the one we were talking about, Sara—is that although it’s true that the best approach to long-term healing is to address the underlying cause, it’s also true that sometimes symptoms can be so problematic and difficult to live with that you have to address the branch at the same time as the root just so that the patient can have the wherewithal to stick around and stay with the process long enough to deal with the root. For example, if a woman is having hot flashes multiple times every hour and is soaking the bed at night because of this and not sleeping at all, well, yeah, it’s all well and good to deal with the long-term underlying causes, but if that process if going to take months, you better do something right away to help her to sleep and stop sweating as much.
Sara Gottfried, MD: Yeah, that’s a great example. I think that often with hormonal symptoms, women especially are suffering, and they can’t take on some of the lifestyle redesign, the changes to the diet, and we want you to exercise this much and stop sitting so much. They can’t take it on when they’re exhausted and hot-flashing constantly, so I totally agree with that.
What I talked about in my first book, The Hormone Cure, is a really simple functional medicine approach, and we can talk about that. We can also get into some more details, but what I start with, which I think is probably self-evident, is with an initial assessment and really kind of understanding the symptoms, looking at all those branches, and also getting a sense of the relative weight that the patient places on them. That piece, I think, is especially important because it’s so different from person to person, and I can give you some examples of that in a moment. That’s the piece that I think is often missing in the mainstream medical appointment of whatever it is, 7.5 minutes.
Chris Kresser: Yeah.
Sara Gottfried, MD: I used to work at a health maintenance organization where I was expected to see 30 to 40 patients a day. You can’t sit for an hour and learn about every branch and every root in 7.5 minutes.
Chris Kresser: No.
Sara Gottfried, MD: Then I do confirmatory testing, and what I’ve found over time is that I can predict most hormone levels just by looking and talking to somebody. Occasionally I’ll be surprised, such as with cortisol. I think that’s sort of a less predictable hormonal character, but for the most part, you can sort of predict what’s happening hormonally and sort of what pattern somebody fits in. Then the approach that I talked about in The Hormone Cure is to start first with lifestyle redesign. You talk about this a lot—addressing the food, the movement, filling the micronutrient gaps. Most hormones take six weeks to reach a new steady state, so I’ll often start people on these targeted lifestyle protocols for six weeks, and then we measure progress, both symptoms and also laboratory tests.
Step two is herbal therapies. You have a long experience with Chinese medicine. I have been studying Ayurveda for a long time. I feel like this is the nudge that a lot of people need—with some exceptions.
Step three is bioidentical hormone therapy, but at the lowest dose and for the shortest duration, almost like small experiments, kind of these n-of-1 experiments, when the first two steps don’t yield results.
But going back to that woman who is miserable, having hot flashes every hour, often what I’ll do is we’ll start the lifestyle redesign. I know that the chance that herbal therapies are going to help her with having hot flashes once every hour is so slim—on the order of, like, 10 to 20 percent!—that it’s probably worthwhile to do some of the baseline testing and get her started on even a small dose of bioidentical hormone therapy, just to kind of get her through that initial period of time.
Chris Kresser: Yeah. Another analogy I like to use for this is a raft that helps you get from one side of the river to the other. It’s really useful, but once you get to that other side of the river, you generally don’t drag the raft around with you anymore. If we think of bioidentical hormone replacement as a raft, it can fulfill that kind of function.
Sara Gottfried, MD: For sure, and I think another helpful part, when you look at hormone issues from a functional perspective, is this mnemonic that I learned at IFM. I mean, it’s something I learned way before that, but they put it together in a way that I think is easy to remember. I don’t know if you’ve heard of this, Chris, before, but they use the mnemonic PTSD. Sort of an unfortunate mnemonic, but the P is production, synthesis, and secretion of that particular hormone. T is transport of conversion, distribution, interaction with other hormones—the crosstalk that happens with hormones. S is sensitivity to the hormone signal. Most people have heard of insulin resistance, and from you, they’ve heard about cortisol resistance, thyroid resistance. And then the D stands for detoxification, metabolism of the hormone, and then excretion of the hormone. I think that’s a helpful mnemonic to kind of think about some of those root causes that need to be addressed when you have hormone issues.
Chris Kresser: Yeah. As you say, my approach, I think it’s, of course, impossible to talk about hormone function without talking about all of the other body systems that affect hormones, the PTSD, every aspect of hormone production and metabolism. By that, I mean things like blood sugar regulation, other hormones like insulin and leptin sensitivity. Gut function, for sure, plays a big role. If there’s some kind of inflammatory gut condition, that’s going to affect hormone balance. Toxins, like heavy metal toxicity. I’ve been certainly spending a lot more time learning about biotoxins like mold and their potential effect. Then we have the liver. It’s part of the gastrointestinal system, but liver function, liver capacity and detox capacity, which obviously has a big impact on hormone balance and is something you have spent a lot of time addressing in your detox programs and in your books and your writing in general.
It’s kind of a good-news/bad-news thing, right? If a woman comes in and says, “I’ve got a hormone issue,” and you say, “No, you don’t. You have a gut, blood sugar, detox, heavy metal, potential mold toxin, gut-brain axis issue.” They’re like, “Whoa! Wait! What are you talking about?! I have a hormone issue!” Hormones are kind of the tip of the iceberg in that respect, but the good news is that the model for addressing hormones in the way that you and I are talking about is basically the model for addressing overall health. The goal is improving your health, and the hormones come along for the ride and naturally correct themselves when you restore homeostasis.
Sara Gottfried, MD: Totally. Yeah, I totally agree with that, and I think there’s kind of a cadence, sort of a right pace with uncovering, unraveling the reasons why someone has a hormone imbalance. And just as you described, when you have someone who’s sitting in front of you who’s a bit of a cortisol junkie—like I used to be—and they have high cortisol and you’re rattling off all these potential root causes, they want to go running from the room! They’re just like, “Aaaaa!” The good news is that when you have this integrated, functional approach, people feel better. Often it’s in that first six weeks or the first 12 weeks that people get better, and if they don’t, then you start looking for the zebras. You start doing the ERMI, the test for mold. You start looking at heavy metals, or in your case, you get referred people who are pretty complex, and so I think you frontload more of the testing.
Chris Kresser: Yeah.
Sara Gottfried, MD: But there’s a way to do it that is more kind of adjusted to the individual and how much they can take on.
Chris Kresser: Yeah, exactly. One of the things I know that you’ve gotten really interested in… Can I spill the beans here about the third book?
Sara Gottfried, MD: Yes!
Chris Kresser: Your next book that you’re working on is really focused on this. It’s the role of genetics in longevity and health in general and epigenetics, and so I’m curious where that research has led in terms of the hormone regulation specifically. Are there genes that you’re looking at that you think play a pretty big role in affecting predisposition to hormone imbalance? Or is it more of an epigenetic and an environmental, exposome-related influence? What’s the relative contribution of all of those things, in your mind?
Sara Gottfried, MD: That’s a great question, and I’m totally immersed in this data. It’s so much fun, and I feel like we’re at this tipping point with our understanding of genetics and what can be done, kind of the promise, the leverage of epigenetics, but the amount of data on the topic is increasing exponentially, so it’s a challenge to keep track of it.
But to answer your question… maybe I’ll start with your second question first. I’ve heard you talk because I think I’ve listened obsessively to every single podcast you’ve had, Chris!
Chris Kresser: Thank you!
Sara Gottfried, MD: My husband put me on a limit for how many I can listen to.
Chris Kresser: I’ll be speaking to him about that.
Sara Gottfried, MD: Please, talk to him. You’ve talked about this point that genes load the gun and epigenetics pulls the trigger, and I think that’s a really valuable way to look at it. I wish we had a good ratio that I could just rattle off when it comes to hormone balance. I think when we look at degenerative disease or kind of the disease of aging, we think the number is somewhere around 10 percent genetics, 90 percent exposure/exposome/epigenetics, and I don’t know if that same ratio applies to hormones. My instinct is probably that it’s more like 20/80 or 30/70, something like that.
I’ll talk about a couple of genes that have my curiosity right now. Frankly, there are about 50 of them, but maybe we can start with three!
Chris Kresser: Yeah.
Sara Gottfried, MD: I’ll open the kimono on myself first because it’s the genome that I know the best. The first one is CYP1B1. All these genes kind of sound like license plates.
Chris Kresser: Right!
Sara Gottfried, MD: They have ridiculous names and ridiculous abbreviations, but this is a SNP, a single-nucleotide polymorphism, and I am homozygous, which I think of as kind of a red light. I have the bad version of this gene. My genotype is CG, and that means I’m at an increased risk with my particular SNP for procarcinogenic activation of my estrogens.
Chris Kresser: Mm-hmm.
Sara Gottfried, MD: So if you look at my estrogen pathway—you talked about this a little bit with the patient that you described—if you look at how estrogen is used in my body, I make too much of 4-hydroxyestrone. Then, just to add insult to injury, I don’t methylate it to a safer estrogen. I don’t take that bad estrogen and then make it safer, which is 4-methoxyestrone. So I have to track my estrogen metabolism, especially now that I’m in perimenopause. It’s something that I learned about when I first started doing genotype testing related to hormone balance, and I started that in about 2006 with Genova. They have a couple of panels that I found to be worthwhile. So it just means that I have to be super-attentive to how much 4-hydroxyestrone I’m making, and then I need to sort of nudge my body along with how much I methylate that to make it safer.
Then, speaking of methylation, I’m a lousy methylator. If you just look at MTHFR, for me, I’m heterozygous for MTHFR, so I have about a 35 percent reduced MTHFR enzyme activity. That means I need to take certain supplements that kind of help me, and then I track about once a quarter my estrogen metabolism.
Chris Kresser: Mm-hmm.
Sara Gottfried, MD: Then a third one I’ll mention. This is maybe a little less complicated. I have two genes, GSTT1 and GSTM1, and these make me low in vitamin C. The interesting connection here is that vitamin C is a micronutrient that is really important for your progesterone levels, and so I have a tendency to not make enough progesterone. It’s kind of related to being crazy stress girl in my 30s because I was monomaniacally making cortisol. It’s kind of how I survived through my medical training, and my high cortisol would then block my progesterone receptors, and then my poor body could hardly make any progesterone because I didn’t have enough vitamin C.
Chris Kresser: Right.
Sara Gottfried, MD: We know that taking vitamin C can raise your progesterone level. So that’s just an example of three kind of sets of genes that I’ve been paying attention to.
Chris Kresser: It’s a really good example because everything that you mentioned is a combination of your genetic predisposition and then the particular lifestyle circumstances that you had.
Sara Gottfried, MD: Right.
Chris Kresser: It’s not like it’s set in stone that you have these genes and you’re for sure going to have low progesterone and you’re for sure going to have all of the issues that you mentioned, but if you combine that genetic predisposition with the modern lifestyle, that’s why you get these issues whereas somebody else gets different issues. I think it’s really important for people to understand that. We’re not talking about single-gene diseases here, where if you have a genetic mutation, you for sure are going to have a disease. We’re talking about patterns and probabilities.
Sara Gottfried, MD: That’s right. Yeah, that’s a really important point. Since we’ve been talking about birth control pills, can we talk a little bit about the genetics of the androgen receptor? That’s kind of a fun story.
Chris Kresser: Yeah, sure.
Sara Gottfried, MD: I feel like in the next 10 to 20 years we’re really going to change the way that we approach hormone balancing, and I hope that we get, at some point, to a place where you go see your clinician, you pull out a card from your wallet that has your genome on it, and we can say to that person, “You know what? A birth control pill is not a good idea for you because of these three SNPs.” In the meantime, it’s also kind of a spray-and-pray approach, especially when it comes to birth control pills. When I talk about birth control pills as being the number-one endocrinopathy, what I see is that women and men have differences in their androgen receptor.
I have a friend named Andrew Goldstein who’s a gynecologist back East, and he has a great analogy here. He talks about how some women have the Hummer version of the androgen receptor. When they go on the birth control pill and their tank of testosterone goes down because their sex hormone-binding globulin goes up and is like a sponge soaking up their free testosterone, they have all kinds of symptoms. They’re part of that 25 percent that has vaginal dryness, maybe decreased arousal, maybe even pain. And there are other people who have the Prius type of androgen receptor, and they can go for miles with a low tank of testosterone. They don’t notice symptoms. They sort of don’t know what all the fuss is about. If you’re one of those people with a Prius androgen receptor and you’re listening to us right now, you may be thinking, “Why are they talking endlessly about the birth control pill? I went on it and I had no problems.”
Chris Kresser: Yeah.
Sara Gottfried, MD: There are these different phenotypes that people have when it comes to hormone receptors, and it can really make a difference in how you respond, especially to synthetic hormones.
Chris Kresser: Yeah, and what’s really interesting, too—this is a subject for another podcast entirely—but with cortisol and the whole three-stage model of adrenal fatigue, which was never really based in any solid peer-reviewed evidence, one of the main things that that completely ignores is the role of cortisol receptors. Some of the more recent research suggests that a lot of the issues that we see with cortisol are not related to the overall production of cortisol being high or low—or even necessarily a disruption of the diurnal rhythm of cortisol—but instead with cortisol receptors on cells losing their sensitivity. Just like we can have insulin resistance and leptin resistance, we have cortisol resistance. And what you’re saying is some people may have relative resistance to testosterone or other androgens versus another person who has more sensitive receptors, and that is something that can make a huge difference but is really not being looked for at all by anyone in any approach.
Sara Gottfried, MD: That’s right. Yeah, I’m glad you raised this point about Hans Selye and the stages of adrenal dysregulation because I think that it was way oversimplified, and I think it’s confusing for a lot of people because they just think they need to crank up or down their cortisol levels when there’s this much more sophisticated biochemistry happening in the background.
Chris Kresser: Yeah.
Sara Gottfried, MD: I think we’re still pretty early in understanding hormone receptors and sensitivity. There’s some data, for instance, on the oxytocin receptor, and having a certain SNP for the oxytocin receptor makes you more likely to have autism. I just think it’s a very interesting topic. There are some genes like the short serotonin transporter gene that make you more likely to have cortisol resistance, and I feel like that’s the direction that we’re heading, where you kind of have a sense of, “Oh, I am a short serotonin transporter. I need to manage my cortisol 10 times better than my spouse,” for instance.
Chris Kresser: Right. Yeah, you can’t just look at someone else and say, “See? Look what they’re doing. I can do that, too!”
Sara Gottfried, MD: Right.
Chris Kresser: It doesn’t work that way. And of course, a lot of people figure this stuff out without even knowing their genome. If they’re paying attention and they observe their reactions to various stimuli and circumstances, they determine this stuff on their own.
Like for me, I’ve known for years that I’m relatively sensitive to caffeine compared to other people. I would just look at people who would order an espresso after dinner and just think, “What in the hell? What?! How is that even possible? If I did that, I would be awake the entire night, like, wide awake the entire night.” I just couldn’t even comprehend that that person was the same species as me because we’re so bizarrely different.
Then recently I had you take a look at my genes, and of course, there is a reason that I’m sensitive to caffeine like that—I’m a slow metabolizer of it.
Again, this is all fascinating, and I really do look forward to the time where we have that kind of information. And I want to remind people that you can learn a lot through observation and self-awareness until we come to that point in time where we have that level of knowledge and understanding.
Sara Gottfried, MD: Yeah, that’s such a good point. Fifty-one percent of people in the US are slow metabolizers of caffeine. You and I share that particular SNP. So chances are that at least half of you have this! And it’s not just clearing caffeine. It’s also clearing stress, and maybe it’s part of the reason why you and I have contemplative practices that we’ve developed along with our professional work.
Chris Kresser: Yeah. We’re getting off on a little tangent here—which is permitted on my podcast, even though people do frequently complain about it. That’s too bad! That’s just what happens!
Sara Gottfried, MD: You’re just trying to work with your genome.
Chris Kresser: Right! So you said 51 percent are slow metabolizers. That’s perhaps especially disturbing in light of the recent study, the caffeine study. Did you see that, about the effects of caffeine on circadian rhythm when it’s consumed in the afternoon or evening?
Sara Gottfried, MD: Hmm.
Chris Kresser: I’ll send it to you if you haven’t.
Sara Gottfried, MD: Yeah, send it to me.
Chris Kresser: In the intro, what they said—that blew me away. I mean, I guess I had some idea, but 90 percent of individuals consume caffeine in the afternoon, between 12 and 6 p.m., and 69 percent of people consume caffeine between the hours of 6 p.m. and 12 a.m.! I’m like, wait! We wonder why we have a sleep epidemic! This is crazy! Fifty-one percent are slow metabolizers of caffeine, but 69 percent are unable to metabolize that caffeine. And of course, this study found exactly what you would expect it to find, which is that, overall, consuming caffeine that late at night does adversely affect sleep, but the effects were varied.
Sara Gottfried, MD: Yes.
Chris Kresser: And they didn’t get into why they vary, but we know why they vary—because of the differences in caffeine metabolism that are genetically determined.
Sara Gottfried, MD: Exactly. If you look at the literature on caffeine, this one certainly makes sense and kind of adds to the story. Very few of the studies looking at caffeine have broken people into categories based on their SNPs, but when you do that, when you look at the people who are the slow metabolizers, they’re the ones who have the increased heart disease. They’re the ones who have to keep their caffeine less than 200 mg a day and certainly before 6 p.m. and, in my case, like, before 7 a.m.
Chris Kresser: Right!
Sara Gottfried, MD: I think that’s what we’re going to be seeing in the literature, is more of this, OK, let’s take this population-based model and now break people into categories according to their SNPs so that we can be a little smarter about how we approach this.
Chris Kresser: Right. OK, so we’re coming to an end here. I just want to kind of summarize and say again that the bad news is we can’t say here are three simple steps that every person can take to improve their hormone balance. I mean, we can get close to that, and I’m going to ask you that question, actually, in a second! But I think the overarching message here is that hormone balance is largely determined by many other aspects that affect our health, like our diet and our metabolism and our gut function and our liver detox capacity. So to really address hormones from a holistic or functional perspective, that’s what you have to be looking at.
Having said that, because I’m talking to the author of the bestselling The Hormone Cure, which has helped a lot of women recover their hormone balance, what are maybe three things that most women—no matter what the root cause of their hormone problem is—would benefit from in terms of helping to regulate hormones?
Sara Gottfried, MD: Well, I have to start with cortisol because I feel like… I mean, you’ve heard me joke before that cortisol is like the bad boyfriend.
Chris Kresser: Mm-hmm.
Sara Gottfried, MD: There’s a way that it needs to be wrangled. I think most of us don’t learn how to wrangle stress, and so we end up with this sort of chronic stress that’s very hard to clear in the body. I find that to be the root cause of hormone imbalance in, say, 98, 99 percent of the people that I work with.
Chris Kresser: Yeah. I would agree with.
Sara Gottfried, MD: The unfortunate part is when you start talking about stress management, people’s eyes glaze over, right? It’s like saying you need to stretch more.
Chris Kresser: They stop listening entirely.
Sara Gottfried, MD: “I’m on my iPhone now. Do you have anything else for me. I’m waiting for numbers two and three.”
Chris Kresser: Yeah.
Sara Gottfried, MD: To me, what is important is to develop what some people call the witness self, separating from the self-talk and sort of the mental chatter and the way that we get caught up in our modern lives, and finding a way to actively pause—by whatever means possible. I’m a yoga teacher. I had to become a yoga teacher just to wrangle my cortisol.
Chris Kresser: We teach what we need to learn, right?
Sara Gottfried, MD: Totally. And that’s not the solution for everybody. I have lots of people who will come to see me in my practice and they’ll say, “I just want to get this off my chest at the beginning. I’m not going to yoga. I hate yoga. It makes me want to shoot myself. Don’t tell me to go to yoga.” Those people do better with a guided visualization or a long vacation.
Chris Kresser: CBT or who knows.
Sara Gottfried, MD: CBT, vacation more often, surfing, saunas, hormesis, whatever.
Chris Kresser: Yeah.
Sara Gottfried, MD: That’s the first thing. The second thing is the microbiome, to pay attention to the microbiome. We haven’t talked about this yet—we have offline—but we are at this place, which I think is really fascinating, where you can think of the gut microbiota and their DNA as a separate endocrine organ. It’s controlling, modulating your estrogen levels, your testosterone levels. I wasn’t reading that article on caffeine and the circadian rhythm. Instead I was reading an article in Science today about the role of these subcultures within the microbiome and how they affect autoimmunity and lead to a greater predisposition, for instance, in women for autoimmune conditions.
Chris Kresser: And then we have the estrobolome, of course, right?
Sara Gottfried, MD: The estrobolome—what do you do to take care of that? Well, unfortunately it’s not as simple as many of us would like it to be. I remember I was reading a book a couple of years ago that was positioning certain microbes as, like, the Homer Simpson microbes that you need to get rid of and then others that you want to populate, kind of your ratio of Firmicutes to Bacteroides, and it’s not quite as simple as that. That ended up getting disproven… or at least called into question. But it’s something that we want to pay attention to, and so some simple solutions are things like fiber, resistant starch. Some people think taking a supplement like calcium D-glucarate can help you with getting rid of the bad estrogens in your body so that they don’t endlessly recycle in your enterohepatic system like bad karma.
Chris Kresser: I like that!
Sara Gottfried, MD: And then the third thing that I would say is humor. How’s that?
Chris Kresser: Yeah, perfect.
Sara Gottfried, MD: I think humor is essential to… Like, this topic of hormone imbalance, my husband, I’ve been with him a long time, and he’s a businessman. He’s just like, “Why did you specialize in hormone imbalance?!” It’s tough, it’s complex, and it brings up a lot of stuff. It’s not a walk in the park, and so I think humor is kind of a great way to manage it and to have as much fun as possible when you’re talking about the complex biochemistry and to sort of draw parallels and see patterns and have some fun with it.
Chris Kresser: That’s great, and I think those are three really powerful and far-reaching things that people can focus on because each of those things will not only affect hormone balance, but pretty much every other aspect of health.
The other thing I would like to recommend is go out and pick up a copy of The Hormone Cure. If this is something that you’re really serious about and you are suffering from hormone issues, it’s the best resource that I know of for helping you to figure this out, especially if you don’t have a skilled practitioner to work with. I have a copy of it sitting on my shelf, and so do, apparently, about 100,000 other people, I hear. You’re approaching a really fabulous milestone in the number of copies you’ve sold, so I want to congratulate you on that. That’s quite an accomplishment and well deserved because that’s 100,000 people that you’ve really helped with this message.
Sara Gottfried, MD: Thanks, Chris. I appreciate that. We can definitely make the world a better place if we reset these hormones.
Chris Kresser: I kind of spilled the beans a little bit earlier on what you’re working on or what you’re interested in now, but maybe you can tell us in your own words what this next book that you have cooking is about and what other things you’re working on or interested in.
Sara Gottfried, MD: Sure. My next book is about DNA and how to leverage epigenetics. This aging process, hormone imbalance, the challenges that we’re facing—many of them present these opportunities to change your epigenetic influence. It’s kind of a complicated topic. My agent says to me, “How do you get people to care about their DNA?” That feels like a really interesting challenge. How you really make this feel relevant and part of someone’s daily life and not, like, “OK, I’m only 40. Why should I care about having a longer healthspan when I’m 80 or 90 or 100?” But the truth is you have to address it now.
Chris Kresser: Yeah.
Sara Gottfried, MD: The problems in the gut, as you well know, the issues with accelerated aging, they start in middle age. They start 35 to 55, and so that’s what my next book is about. It’s super yummy, and of course, it has proven solutions from the wisdom traditions like Ayurveda and Chinese medicine and how to modulate your exposome with simple daily actions, like how you floss—which, by the way, no one does correctly, I’ve learned!
Chris Kresser: Right!
Sara Gottfried, MD: To taking a sauna. I am a total convert now to taking a sauna. It’s amazing how it turns on your longevity genes, your FOXO3. Super-exciting data just published in JAMA about it.
Chris Kresser: Yeah, we got an infrared sauna a while back, as you know, and I’ve spent a lot of time in there. It’s so great.
Sara Gottfried, MD: It’s totally great. And then a side project has been starting to wrap my head around mold and biotoxins. Oh, my gosh… that’s a big project.
Chris Kresser: Absolutely. I’m so glad we finally made this work. I’m surprised it took us so long, but better late than never. I’m really grateful to have you on the show. I think it’s going to help a lot of people, and I would love to have you back sometime.
Sara Gottfried, MD: Thank you, Chris. Such a pleasure to be here. Thanks, everybody.
Chris Kresser: That’s the end of this episode of Revolution Health Radio. If you appreciate the show and want to help me create a healthier and happier world, please head over to iTunes and leave us a review. They really do make a difference.
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Thanks so much for listening. Talk to you next time.