Ep. 579: Normal Isn’t Optimal – The Shocking Truth About Progesterone, Brain Health & Hormone Timing with Dr. Felice Gersh | Menopause & HRT

Welcome to Everyday Wellness Podcast. I'm your host, Nurse Practitioner, Cynthia Thurlow. This podcast is designed to educate, empower, and inspire you to achieve your health and wellness goals. My goal and intent is to provide you with the best content and conversations from leaders in the health and wellness industry each week and impact over a million lives. This is part two of a prolific conversation that I had with Dr. Felice Gersh, who is a dear colleague and friend and also someone that I look up to as a mentor. She's a board-certified OBGYN in integrative medicine. She taught at the Keck USC School of Medicine for 12 years and is the founder and director of the integrative medical group of Irvine. Today we continue our conversation talking about the role of progesterone in brain health as well as brain health and cognition. The role of the liver and detoxification, different routes of administration for progesterone, not just oral but also rectal and vaginal, and the impact of allopregnant alone. Physiologic dosing of progesterone, the timing hypothesis, how to optimize hormones in perimenopause and menopause, and as she states, normal is not optimal. The impact of cycling hormones in menopause and optimal estradiol levels, which she likes to see greater than 100 pg per ml. The role of progesterone intolerance and paradoxical effects, growth factors in estrogen cycling, mitochondrial health and inflammation, the impact of shift work and circadian disruption and last but not least, immune system changes that we see in menopause and we know that inflammation accelerates. Again, one of these conversations you will want to listen to more than once. And to let everyone know, Dr. Gersh gave me a lot to think about with my 200 mg of oral progesterone that I take every night. This is definitely cutting edge ways of thinking about hormone replacement therapy. And as Dr. Gersh astutely states, we have to start thinking about the bigger picture. The neurotransmitters, I mentioned the neurotransmitter for the vagus nerve is acetylcholine. Well, that's what supports the vagus nerves function, which sometimes is called rest and digest. It should be the baseline status quo. It's sort of like peace and calmness. Your arteries are not constricted. Your temperature is good. Your pulse is good. Everything is working. Your bladder isn't going into spasms. You're having good digestion, motility of the gut, which is so problematic in women. Women have, you know, irritable bowel syndrome, 80% female. So a lot of problems after menopause. Men have more gurd gastroesophageal reflux than do men. Prior to menopause, men have more than women. The whole GI tract, the whole motility, the peristalsis, how things is altered. And while these same neurotransmitters, if you talk about, and we won't go into the sympathetic part, which is norepinephrine, epinephrine is modulated by estradiol. But in the brain, let's look at the neurotransmitters in the brain. Well, acetylcholine is in the brain. They call it the cold and allergic system. And it's modulated by estradiol. Okay? Now, there's another system in the brain that's called the serotonin. Well, serotonin, the receptors, the neurons, the production of serotonin is all modulated. The receptor function modulated by estradiol. And but it's not as simple as that. There's actually feedback systems with progesterone. So now we're finding that dopamine as well. So dopamine is very key in the brain as another neurotransmitter. And it is modulated by estradiol. But now we're finding that all of these also have input from progesterone. It's very complex. And sometimes it's in a pro, sometimes it's in a con. That's why it's really hard to micromanage things. And you should just try to give things in a physiologic way. Because these are also known as neurosteroids. The brain even can make them, but not enough as because women were designed to have the extra of these hormones, progesterone and estradiol coming from the ovaries. The brain does make these hormones and then they call them neurosteroids, but doesn't make enough. Okay? So there's a deficiency state after menopause of these precious neurotransmitters. And it's very complex and it's not always one direction. It could be a con at this point and a pro at this point. But it turns out originally I thought only estradiol was modulating these neurotransmitters, but that's not true. There's a role that's progesterone is playing as well in serotonin function, dopamine function. And then if we look at the sort of activating inhibiting sort of neurotransmitters, there's the glutamate. Okay? So glutamate is the excitatory. Now in terms of excitatory, think of it as making you more alert, awake, focused, memory. So there are drugs that activate the glutamate receptor function and make, and what is that? And make more glutamate. Those are called amphetamines. You probably heard of amphetamines. In fact, they're used, certain types of amphetamines are used for attention deficit disorder, right? To help people who can't focus. And that's another story, you know, if you want them or not want them, but that's what they're used for. That's a prescription drug like Ritalin, right? To help people. And that's amphetamine. They're also used in long haul truckers and people who are flying planes in the middle of the night, you know, so that they hopefully don't fall asleep at the wheel, right? We don't want long haul truckers falling asleep or pilots falling asleep in the middle of their flying, right? So that's, you know, I happen to know that they do that in the military too, because I have relatives. And so, you know, so they use amphetamines to try to keep people from falling asleep when they're doing crucial missions, you know, because stuff like that could happen. So anyway, we have the glutamate and the drug is amphetamine in terms of the hormone estradiol. So estradiol activates glutamate so that we have more focus. So estradiol is about memory and cognition and acetylcholine is predominantly estradiol also for creating memory and focus. And one of the reasons why loss of estradiol is associated with cognitive decline brainfuck. It's like universal as women transition into menopause that they have some especially noun recall. It's usually not too bad for adjectives and verbs and adjectives. So it's like a game of charades. What was the name of that? You know, I can describe it, but I can't remember the name real problem. That's been documented. It's pretty universal. It's not if it's how much. Okay. So what about progesterone? Well, we have everything in the body has like the yin yang, right? The hot cold push pull. So to counter the activation, okay, is the inhibitory. That's called GABA, right? Gabmoblutera amino acid. So it's like an amino acid. So GABA. So it turns out that progesterone through its metabolite called allopregnanolone can activate the GABA A receptor. And GABA is the inhibitory neurotransmitter that facilitates calmness and sleepiness, sedation and allopregnanolone as a metabolite. So it's a product of breakdown of a product of progesterone. And there are certain organs in the body that have enzymes like the liver and the brain that can turn progesterone into allopregnanolone, some of it. Okay. Allopregnanolone can activate the receptor on GABA to make more GABA and that facilitates sleep and calmness. And there's a drug that is a synthetic form of allopregnanolone. So it's like allopregnanolone. And those drugs are used for postpartum depression at very high doses, but just for like two weeks and they can be very effective. So we know that allopregnanolone is also an antidepressant, anti-anxiety, and there's some data that it can even potentially help with Alzheimer's and dementias. But once again, too much of a good thing is a bad thing. So if you have too much allopregnanolone, in rats, it's been shown that chronic allopregnanolone can induce dementia in rats. In humans, we do not have that data, but there is some data suggesting that it can impair memory formation. So it's like everything. It's just you don't want too much. You want just the right amount. And that's why I'm against giving lots and lots of high dose progesterone orally because when you give it orally, and this is like an important concept that is not yet talked about, but what's known, the infertility world never uses oral progesterone. There's no infertility doctor that's giving oral progesterone. They use shots occasionally. They used to use it a lot, not much now. And they give it vaginally. So vaginal progesterone is what all the infertility docs use on every IVF patient. And they're using a lot of it, okay, because they want to make the uterine lining, what they call complete secretory conversion. They want that uterine lining perfect for implantation of an embryo. Okay. Well, that's because they know that it works better when you give it vaginally. When you give progesterone orally, it goes, you know, right through the digestive tract and ends up in the liver. Now they make it micronized. Now, micronization of progesterone was a very important development because it allowed it to transverse the GI tract, like get through the stomach acid without being dissolved, but it doesn't mean it doesn't go right to the liver. It does go right to the liver. And in the liver, the liver is a metabolic powerhouse of transformation. They call it biotransformation. It changes one molecule into another molecule. For many purposes, it creates proteins and enzymes, all different things. And it changes different old things in the body so that they can be eliminated in the body through these different pathways, you know, conjugation, sulfation, methylation and all these different pathways so that they can go out the bile duct I call that the trachute into the intestine to be eliminated as stool, right, down the trachute. Or they become water soluble so they can go out the kidney as with water. The urine is like water, right? So when the progesterone ends up in the liver, up to 90% of it, 80, 90% of it is converted into other stuff. So you end up with very little progesterone left and you end up with a lot of other stuff. So what is this other stuff? It's like 30 different things, but the dominant one being allopregnanolone. And you get too much of it. Once again, too much of a good thing is a bad thing. You get multiple times the amount of allopregnanolone you'd ever naturally have in the body. And there are now women being given oral progesterone every single night, sometimes in very high doses, and they're getting really mega-dosed with allopregnanolone. And many of them think, oh, I love the way it makes me sleep. Well, it turns out that I mentioned amphetamines work to create the excitatory or, you know, activating neurotransmitter glutamate. Well, it turns out that tranquilizers, benzodiazepines like valium and, you know, ambien, xanax, they work in a little different receptor site, but it's exactly the same general mechanism as allopregnanolone on GABA to activate GABA. And so it's the same mechanism. And we now know, and there's data that you do not get good normal sleep when you get sleep, you're drugged. It's a drug sleep. It's not like a normal sleep. And allopregnanolone does not give you a normal sleep when you're overdosed with allopregnanolone as a sleeping pill. It's really not particularly different than if you were taking valium every single night for sleep, which is not good for the brain to do that. It doesn't. The whole system of clearing out the brain, the lymphatic system where you clear out the gunk, the junk metabolites and all the junk that's formed in the brain, it doesn't work properly. You're drugged, but you're not getting the brain clearage. And so that's why it can potentially increase cognitive decline over time, because it's you're not clearing out the junk from the brain. And that's what we're doing to women. And we're not even thinking about it, but that we're getting very small amounts of progesterone and we're getting large amounts of these metabolites, predominantly allopregnanolone, and we increase in GABA too much. You know, and that's why I'm saying it seems annoying. I know I can't help it, just how we're made, but we should use the progesterone that vaginally or this is an alternative. It sounds weird until it stops sounding weird. You know, everything initially sounds weird, but when you get over it, it's not weird anymore. And that is rectal insertion. If you'll loop it all up, it's just think of mouth opposite. OK. And that's actually another alternative. And there's actually good published data on it. It's absorbed extremely well that way. But taking it orally, do we don't give oral estrogen anymore? Did you notice that we use like transdermal is always the thing? Why do we use transdermal estrogen? Duh, because we don't want to convert it into estrone in the liver. If you're in perimenopause or menopause and are feeling more fatigued, dizzy, lightheaded, struggling with headaches or noticing your workouts feel harder than they used to, electrolytes may be part of the missing piece. As estrogen declines, we lose some of the fluid regulating and vascular protective effects that hormones once provided. 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Because I'm sure people are wondering, like, am I taking too much? And how do you... How do we find, like, the right balance? Well, number one, I used to give it all the time, oral, because I fell into that same trap of... I mean, it's like, why are we doing this? Why is no one, like, thinking about this? We don't... It's like the same process that goes through the liver. You know, it's sort of craziness that, like, it's so obvious. When you... Once you know it, it's like, duh, what the heck, you know? But so I believe in giving physiologic doses of estradiol. By that, I mean... And this is a very simple thinking. You remember I said in the beginning, we're not smart enough to create new paradigms of how to give hormones that never existed in human nature, in humans, females, ever, ever, ever. So if you look at what hormones are doing, and I didn't mention, but I'll just quickly, that these hormones in a cycle, like a human female menstrual cycle is not static. And you have the first half, which is the... From the uterine lining perspective is the proliferative phase. The uterine lining is growing. And then after ovulation, it's called secretory. Progesterone comes on the scene along with estradiol, which is then produced at a slightly higher amount in the luteal phase. And it was in the first half. So you have more progester... You have more estradiol produced in the second half of the cycle. And you also have progesterone. And that's called secretory. The uterine lining stops growing. And then it blossoms. Okay, it's like... It's just like... It's like a teenage boy. He grows like a weed and he's all lanky. And then he stops growing and all these muscles come out, you know? So that's like the uterine lining growing like a weed. And then, poof, it just fills out. Okay, that's secretory. And it's a beautiful combination. And it's not just affecting the uterine lining. It's affecting everything. You're turning on and off receptors. During the first half, estradiol is up-regulating its own receptors, progesterone receptors. It's also up-regulating. It's making more functional. Testosterone receptors, thyroid receptors, all these things are happening. Then when progesterone comes on the scene, progesterone down-regulates testosterone receptors. That's why sex drive tends to be less in the luteal phase. And that's understandable. You can't get pregnant. Everything is about, everything in nature is about making children, babies, you know, conceptions in every species. Okay? So nature doesn't care about having sex when you can't conceive. So testosterone goes down in terms of its receptor function when progesterone comes on the scene. So don't you want to never have a sex drive? So give progesterone every day. Okay, good luck, ladies. Okay? Just telling you. That's just what it is. Now, progesterone also down-regulates the estrogen receptor alpha. Now, there's like different receptors. We won't go into all of that. But the alpha receptor is the one that's involved in growth factors. I mentioned growth factors. You want to have growth factors. That's how you repair, maintain, replace all those things. Well, how do you grow the uterine lining? Like in the first part, the proliferative phase. Well, you need growth factors. Okay? Now, I told you that in the secretory phase, growth stops, you know, it stops. And then it fills out and blossoms. So what stops it from growing? The progesterone down-regulating the alpha receptor of estradiol. So and that receptor is the same one that's involved in breast cancer, that proliferation, overgrowth of any kind of cancer. So progesterone down-regulates the estrogen receptor alpha. But we don't want it always down-regulated. Then it's things are not going to have proper growth and repair. And it's like this beautiful balance. That's why you don't want progesterone in any form every single day. Because you're perpetually down-regulating the receptor alpha, which is not only about growth factors. How about mitochondrial function, vascular function? In fact, they're talking about, maybe we can do this another time, the whole thing of the timing hypothesis. And like, why is it said that if you're over 60 or more than 10 years out that you missed the boat lady, you can't go on hormones now. Now, suddenly hormones went from being good to bad. What the heck is that all about, you know? But one of the theories, which I do intend to talk about, as this can be also debunked in certain ways, but I'm not going to say it's all bunk, you know, because there's something to it. But in terms of the estrogen receptor alpha, that with aging, the estrogen receptor alpha becomes less functional. So the last thing you want is a less functional estrogen receptor alpha. But that's what you're getting when you constantly give progesterone. That's one of the reasons they haven't been able to show giving hormones in these regimens that are currently being utilized are doing anything long-term that is beneficial, you know, in terms of healthy longevity. Well, you know, niche and so on. Well, duh, if you give things in the wrong way, in the wrong doses, you're going to get the wrong outcome, right? The long-term outcome is not going to be what you hoped. So I believe that we should just somewhat, somewhat mimic nature and give hormone levels that are sort of typical for a normal menstrual cycle. And by the way, I'm very encouraged to see some of the academics now are coming out saying premature menopause, which is before the age, well, even early menopause. So normal is starts at 45. Early is 40, up to 45 and premature is before 40. That they're saying that even the premature and the early, that they should have not only have hormones, but maybe hormones that are into the physiologic range. But then when you hit around 50, you should stop that. Or 52. That doesn't make any sense to me. It doesn't make any sense to just stop it. You're actually advocating for physiologic dosing up until 52 for the women who are going into early onset of menopause. So I'm saying do that, but do it forever and do it cyclically so that you're turning on and off genes, you're up and down regulating receptors. I didn't mention genes, but yes, that you're turning on and off gene expression when you have the hormones coming and going. And these are including tumor suppressor genes. Our own hormones did not evolve to give us cancer. That's why cancer is much less in younger women than in older women. And much of the cancer in younger women is because of endocrine disruptor exposures, essentially poison exposures, chemicals at critical stages of development and life. So, you know, we didn't evolve to have our hormones hurt us, but we need to use human hormones and we need to go some in ways that are aligned with human physiology, which means like it or not, it's how we're made that you have a cycle. And if you have a uterus, you'll have a pretend period, but it's real blood. But, you know, we know how I know how to deal with this to make it so that it's livable. It has to be livable and, you know, so that that it's a person's individual choice. But all I want is what I call and it's not me calling it this. It's what it is. It's called informed consent. Because as an MD, I did as an OBGYN, not the current chapter of my life. But in a former chapter, I was an incredibly prolific surgeon. I did surgery virtually every single day and every patient had its assigned consent form that was informed consent. I told them the pros and cons of everything I was going to do in surgery. And so they went into it making a choice. They chose to have the surgery and they knew that everything has inherent risks. I don't see that happening when people are told to take progesterone every night. I don't see anyone being told, well, you know, here's the problem. I'm with oral progesterone. And, you know, why did this even evolve to give progesterone every single night? Well, because the idea is not to bleed this belief that while bleeding after menopause is dangerous and abnormal, well, number one, it is abnormal. But so is everything else we do in medicine. You know, if you call everything we do, every drug is abnormal. Every surgical procedure is abnormal. Every joint replacement is abnormal. So get over abnormal if you want any medical care because everything, if you're going to use the word abnormal, you know, it's certainly unnatural. You know, that's what we do. You know, natural is let's see if you live or die. Good luck. You know, so, you know, that's in medicine we intervene. But I say intervene in a way that's consistent with the way the body was evolved. Right. So if we're going to try to keep hormones going because we know they're wonderful and they do wonderful things throughout the body, then let's give them in a way that's aligned with the way the body is adjusted, you know, to evolve, to receive them, which is that you have estrogen and then you have progesterone. And then you have no progesterone and then you have estrogen, you know, so it's a cycle and I'm working on some different other additional ways to modify it to be a little bit more aligned with physiology. But right now, having most patients use a level amount of estrogen. It doesn't matter what the dose is, it matters what your level is, right? And the conventional world doesn't even believe in levels because they don't believe in healthy longevity use of hormones. They believe in hormones for the sole purpose of suppressing night sweats and hot flashes, which is important, necessary, but not sufficient in my view. OK, but everyone has their own choice. Somebody says, I don't want to have a period, then don't, you know. But here's the sacrifice, here's the decision that you're making is going to potentially create for you all the sequela. So to try to not have a period, what did they do? They give very, very small doses of estradiol, very small. It can't be enough to grow the uterine lining much. Dr. Gersh, one of the questions that people will have out of curiosity and I'm not asking you to share any information that you feel uncomfortable sharing. I would imagine if patients are cycling in menopause, we're talking about higher levels, estradiol, than what the conventional patch or gels are providing. Is that correct? No, not always. It depends. So I mentioned that the conventional world is not looking at levels at all. Well, the data is so many of the women who are getting conventional treatment are getting patches. We talked about patches, the point 025, milligram is often where it started, and then maybe they'll go up to the next one, the point 0375 and maybe just maybe the point 05 and rarely higher than that. Occasionally, but rarely and very, very rarely up to the point one. So it's individualized because once you recognize the skin is a barrier, it's actually not supposed to be a sieve. It's not supposed to have things come through. In fact, that's what they patented on the patch is how to get it through the skin. You can't patent estradiol. It's a natural hormone. So they patent how to get it in. OK, that's why when you look at doses, they're really different, whether it's the patch in terms of milligrams, the patch or the commercial gel or compounded creams. And a lot of people don't know that. So they'll dose the compounded creams to be similar to like, say, the the commercial gel. But that's not accurate because in general, the the compounded creams, because they're not specially formulated or patented for absorption, you need much higher amounts. So and you need to and ideally you really should, if you're doing compounded creams, use them twice a day because they're not time release. OK, so you're going to have to do and do, you know, so you don't want that. So, you know, you want to have a little bit more consistency. You know, I mean, I wish we had like an insulin pump for estrogen pump. We don't have that. So we have to make do, you know, but you can't compare the doses to these different systems. But if you look at the point one patch in many, but not all women, you can get levels of estradiol that are around 100, 100 pg per ml. Now, that is a reasonable amount. Even in like so, what do I think is a good level? Well, probably ideally somewhere. But I will vary it based on tolerability, because some women are so sensitive, they'll get breast tenderness, galore, they just think I mean, it has to be livable. Can't, you know, so you can't just go by a level. You have to go by clinical outcome, you know, how the patient feels always matters, you know, that's why I don't even measure levels right at first. When I give it, I say, I want to see how you feel and what happens, because I don't care what the level is. If you're bleeding randomly, if you're feeling horrible, your breast tenderness, I can't do that. OK, so, you know, clinical manifestations of how you feel is the number one thing. And then, you know, I try to optimize the dose to get the level. But many women will get a level of about 100, which is adequate. It's good. And I usually like anywhere from about 80 to 150. Now, in a normal menstrual cycle, it usually in the first part, the proliferative, it starts, it can be quite low. It could be like 40. OK, and we're talking the measurement is what they call picograms per mill. But it starts at 40 and then it can go up to like, say, 80 or so. And then in the luteal phase, it can go up over 200. OK, so it goes higher in the luteal phase. Now, why is that? It's an incredible balance between the negative effect of progesterone on estrogen receptors and the need to have enough estrogen to do all the things that estrogen does. So it's a beautiful balance between these two. And now there's different theories on PMS. But one of the newer theories is that it's not enough estradiol to counter some of the effects of progesterone. So anyway, it's and there's others, you know, that it could be. Some people, it's occasional and they call it progesterone intolerance. You probably, I'm sure you've heard of that, where women say, I can't take progesterone, it makes me feel horrible. Well, if it's taken orally, it's virtually always a paradoxical effect of the allopregnanolone. And this can also happen even when you'd give it vaginally or just naturally produced by the ovaries, that normally allopregnanolone is a calming thing working on GABA, but in some people, we don't know why. It has what's called a paradoxical effect and it makes people feel anxious and wired like the opposite of calm. OK. And so that is maybe a part of what causes progesterone intolerance. But the other part of progesterone intolerance, if you take it orally, is that it's potentially just over sedating women. They feel drugged, they feel drunk, you know, they feel in the morning like, what is happening? Like I'm on a boat and I feel like my head is in a big fog. And I've had so many patients when I've switched them from oral progesterone to vaginal progesterone, say I had no idea how foggy my brain was until it's like the fog lifted when I got off the oral progesterone. It's like, oh, my gosh, I feel like my head is cleared now. And it's like and we talked about sleep when I mentioned serotonin. Well, estradiol and progesterone also has an effect on serotonin. Serotonin, the field called the feel good neurotransmitter, makes you feel happy and also and calm. And from serotonin comes melatonin, essential. That's why sleep is so essential for, you know, being healthy. But as I mentioned, but you can't sleep without melatonin and you can't make melatonin unless you make serotonin. And I'm not talking about taking melatonin, you know, from naturally in the body. All melatonin comes from serotonin and you can't properly have make serotonin and have adequate function of serotonin without having estradiol. And so you need to have adequate dose matters. I give them dose matters, dose matters. And so the current policy of giving these tiny doses and when you measure them, like in the keep study, that was one of the studies everyone was looking forward to, because they were going to use estradiol and progesterone. And the problem was they did use estradiol, but they even said they were doing the philosophy of less is best. Like the legacy of the women's health initiative is that hormones are intrinsically dangerous, so you want to give the lowest possible amount. And that's what they followed in the keep study. So when they actually measured the number of picograms per mill, the highest they got was like about 40. So anything under 50 is considered still in menopausal level. So they actually never got above menopausal level. The interesting thing is that even a whiff of estradiol, like even if you go from like 20 to 30 picograms in that while, you can still feel better. It's like it's like the body loves it so much that even a whiff of estradiol can over time, over time, it can take 12 weeks or so, you know, can suppress night sweats and hot flashes and cause women to feel better. So even in the keep study, the women who took the hormones felt better, but they didn't show cardiovascular benefit. Like, well, first of all, they were young in this study, only one for a few years. And women are typically not having heart attacks and strokes at age 30, you know, 53, which thank goodness. But the bottom line is they never got out of the menopausal range. We know for vaginal health, you cannot do anything for vaginal atrophy, which they now call, you know, genitourinary syndrome of the menopause, unless the estradiol level gets over 50, it has to be over 50 to do anything. So they never that's why giving menopausal estrogen to the vagina is such a big deal because women are not on adequate systemic levels of estradiol and progesterone to actually improve vaginal health because the levels stay in the menopausal range. If you think about this, does a healthy 25 year old woman need vaginal estrogen? No, unless she's on birth control pills. That's another story. Or Artem, I think a lot of people who are pregnant or postpartum or breastfeeding definitely have those symptoms for sure. Oh, yeah. But I'm saying like cycling. So let me make it a cycling, nonpregnant, nonbirth control cycling. Normal 25 year old woman. OK, she's just having normal menstrual cycles. Everything's great. She's healthy. She does not need to supplement hormones in her body. She makes enough to support every organ system, including the genital urinary system. OK, so she doesn't need it. Now, I can change that and say, well, what if she remembered like what if she has an IUD? Well, I'm saying, no, this is not that woman. OK, this is a woman who's having natural healthy cycles. OK, so if you have a woman in menopause and you can think of it as the canary in the coal mine, no matter what estrogen dose you're giving, she never gets any improvement vaginally. So you have to really give her the vaginal, not against it at all, you know, giving vaginal estrogen. But it's a sign that they're obviously not getting adequate systemic amounts to deal with that organ system. So think of it this way, if you're not on enough hormones to support the genital urinary system so that you're still getting a lot of vaginal dryness, problems, painful intercourse, bladder problems, you know, like urgency, bladder infections. If you're getting all those symptoms, then what do you think is happening to other organ systems? You think they're getting enough? If the vagina and the bladder are not getting enough, you think your brain is getting enough, your bones are getting enough, your arteries are getting enough, your skin is getting enough. Why would you think that? Because it's one body, it sinks or swims as a whole. So if you have to supplement hormones in one part, you probably, ideally, should supplement it in all parts, which probably means you should get up your dose, right? You should give more. But then the problem is, and it is, you know, nobody wants this. I understand that I'm a female too, you know, that when you give more physiologic levels, you will have growth factors. Now, I love growth factors because growth factors are controlling building bone and rejuvenating and restoring. And it also controls, it maintains mitochondrial function and mitochondria control the cell cycle, which means they tell when cells should die, like the old senescent cells, you mentioned senescence. Well, when you get old cells, they should commit cell suicide, apoptosis. Get rid of those old guys, you know, because they can become the zombie cells that can do you all kinds of harm, create inflammation and cancer. So, well, what controls that? What tells the cells you're old and yucky, you should die. OK, it's the mitochondria. And what is influencing the mitochondria? It's these vital life hormones. And what about men? So you think, well, what about men? Well, a lot of the testosterone effect is actually by converting into estradiol. The enzyme to make to convert tests, all estradiol comes from testosterone. That enzyme exists all over the place. And a lot of the action, of course, they're direct testosterone receptors as well. But a lot of the testosterone receptors are right next to estradiol receptors. They're right neighbors, because a lot of the testosterone is actually locally, locally, intracran in the cell or paracran in the organ converted into estradiol right there and then and then it affects it. So men should love estradiol too. But you can't men can't get enough estradiol unless they have enough testosterone. That's why low T and men is bad, bad, bad. Right. So we want every human to have the right hormone balance and giving hormones so that you can't bleed or try not. By the way, close to 50 percent of women on these constant dosing, you know what we call static constant dosing will have breakthrough bleeding at some point. So it's like a drip, drip, drip, even a tiny drip from the faucet. If the drain is plugged, eventually the sink basin will overflow. Right. So eventually even a little bit of estrogen may cause enough growth factors to outweigh the negative effect on the receptors of the progesterone and cause some breakthrough bleeding. So it's very common. 40 to 50 percent eventually will have some breakthrough bleeding or spotting. And then everyone freaks out. So and as a gynecologist, I don't because I know what to do. You know, I can do uterine biopsies, you know, in a split second, you know, and make it not too bad so we can confirm you can get ultrasounds. You can you can test. The other thing is it's important to know if you're on physiologic levels of estradiol enough to create growth factors which will grow the uterine lining. And if you grow it, you must shed it and then you use, you know, sequential. So like anywhere like 12 to 14 days of progesterone every month. And then when you stop it, you bleed, you shed the lining and think of it as a purge. It's a total body purge of yuck cells. OK, you're purging the yuck. And that's what we do. And, you know, so if you view the period as a purge as opposed to an annoyance, you know, it's how you everything's how you frame it, right? And that it also means that you're making growth factors. You're making if you're growing your uterine lining, then you're growing everything. You're maintaining your rejuvenating everything. And we, you know, you're going to get rid of your old senescent zombie cells. It will lower your risk of cancer. They now shown how much more data do we need to show that estradiol lowers breast cancer risk, lowers it. That's come out now. Like it was like causing it. Now they say it lowers it and progesterone also when you give it properly. Remember, it down regulates estrogen receptor alpha. There's a lot of data on the benefits of as progesterone and cancers, multiple different kinds of cancers by reducing chronic proliferation. So what causes cancer anyway? OK, well, not getting to the like the layers of the onion will say like the more immediate, OK, because it could be toxins, it could be biological. It means all kinds of things can create the setting for cancer. But essentially it's too much inflammation combined with too much proliferation. OK, so if you have a chronic state of inflammation, unrelenting inflammation and unrelenting proliferation, then that's the perfect scenario for having DNA breakage and then creating growth of cancer. Well, inflammation up regulates the enzyme aromatase like in fat tissue. So you make you convert androgens predominantly from the adrenal gland into estrone. Now, estrone is an estrogen that predominantly affects and activates the alpha receptor, the one that creates growth factors. It's not the balanced estrogen of the ovaries or what we give in menopause, which is estradiol. So we got to stop the confusion of the estrogens, right? That's a family of hormones. And estrone is an estrogen that creates growth factors and also activates the innate immune cells that can create inflammation. OK, estradiol actually modulates the whole system. So it turns on and off inflammation as needed. And it creates growth factors as needed. It's like the grand modulator alpha receptor that's estrone just is like the on switch. It's the on switch for inflammation and for growth and proliferation. So that's the perfect scenario, chronic inflammation and chronic activation of growth factors, breast cancer, that's estrogen receptor positive. It's always alpha. It's always alpha. And when you have inflammation in the breast, remember, you're going to have inflammation everywhere. I mentioned in the ovaries, you're going to have inflammation in the breast, inflammation in the breast. Well, it activates the enzyme aroma taste in the breast and the breast has a lot of fat, OK, a lot of fat in breast tissue and stroma. And those tissues have the enzyme aroma taste and make estrone. So breast cancer can make is very pro inflammatory. So the breast is making estrone. And then if breast cancer develops because you have DNA breakage and you have all that inflammation, which creates instability of the DNA. And remember, NAD, I mentioned NAD is really has different functions involving the mitochondria and DNA stability. So it's about like energy and it's about stability. And, you know, that's a very simplification because it's much more complex. But one of the big roles of NAD, DNA stability. Well, when you have inflammation, you destroy your NAD. Right. I just I told you about that. So now you have like loss of control and you have uncontrolled DNA, you know, proliferation, instability. And that's the start of cancer. What about estradiol? Estradiol modulates all that it reduces inflammation. It controls the systems, you know, and so you don't get that whole environment that creates the perfect scenario for the development of breast cancer. So and then progesterone, when it's given properly as well, it's down regulating that alpha receptor every time you have progesterone. So it's the perfect blend of hormones to lower the risk of breast cancer. And nature also put in, I mentioned that it activates tumor suppressor genes. So you're doing everything when you have a normal menstrual cycle to suppress breast cancer and other cancer developing. So, you know, and but this is now at least established that estradiol does not cause breast cancer. It actually lowers the risk of breast cancer, but it's really hard to get that into the psyche of everybody because they've been so brainwashed into that these hormones cause cancer when they actually reduce cancer. You know, it's like everything is like opposites, right? Everything is opposite. Everything you were taught was wrong. It was the opposite, you know, you know. And so I'm just trying to show the science of it. I'm very science oriented and what is the mechanism? How is the what's the pathway? How is this working so that it's not just we like hormones, they make us feel better, but we don't want to have periods. So we'll give them this way. That doesn't make sense. You know, we just have to accept who we are as females, how we evolved as, you know, cyclic beings. We have to accept our circadian rhythms, right? You know, we know that if you work at night, that's a problem. I did it. It was a problem for me, you know. So, you know, we hope that, yeah, night work is very harmful and or self-imposed night work, you know, like you're doing something at night, even though you don't have to. And so you have very, you know, erratic sleep schedules and so you have very erratic sleep schedules and so on. So it's really important to like align ourselves with how we evolved, except that we're cyclic, except that if we have a uterus, we'll just, if we want optimal hormones, we're going to have periods and we can make them manageable. But I always tell people, if you're going on a vacation, just skip the progesterone that month. By the way, nobody gets uterine cancer in a month. It doesn't work that way. Remember, it's not even common at all. But, you know, it's not that we don't think about it. I'm always like on alert for it. But like you can skip a month of progesterone and just not bleed on your vacation, it's totally OK, you know, and just do it the next month or, you know, reschedule it a little bit because it's, you know, we have control over. We did, we've done that with birth control pills forever, right? Timing things with birth control so you don't have a period to get married or what? I've done it all, you know. So, you know, it's just, you know, progesterone is wonderful. And just as a last thing, I just want to mention about progesterone. I mentioned the immune system and, you know, everything is interconnected to the immune system, everything. And progesterone is inherently anti-inflammatory. And if you think about pregnancy, I think of a lot of things I learned. I just think about what happens in pregnancy, what would this hormone have to do in pregnancy if we're just looking at it from the pregnancy point of view? In pregnancy, you don't want your immune system to destroy your fetus. You don't want it to do that. But it's an alien. It has antigens that are not human, identical to yours, right? It's different from you. So you have changes in the production of estrogen by the placenta. That's very different from ovarian production of estrogens. And you have dominant estriol. Estriol is down regulates the alpha receptor, which is on the innate immune cells like the attack cells, the macrophages, mass cells, neutrophils. So you're down regulating them just like an immune modulator would, just like if you're on humera. OK, that's why a lot of autoimmune diseases actually go into remission during pregnancy, because the estriol acts like an immune modulator. It down regulates the attack immune cells. And so it's calming to the immune system, you could say. But it also makes pregnant women more vulnerable to outcomes that are more severe if they get infected, like with chickenpox or COVID or the flu, because their innate immune system is down regulated so it doesn't kill an attack. You know, the embryo and then the fetus. Well, progesterone is very, very anti-inflammatory. It has to be for the same reason. Well, when we have progesterone and it comes and goes in a beautiful sequence, it is also very anti-inflammatory for our body. And we keep talking about inflammation, inflammation. But it's dose related. When you take it orally, you get tiny amounts, really tiny, you know, because most of it's converted into this other stuff by the liver. So you need to have an adequate amount of progesterone in the body for this beautiful anti-inflammatory type of scenario to take place. And, you know, for another time, another day, you know, it interconnects with another system called the endocannabinoid system, which is critical. And that's why CBD, you know, which is from the cannabis or hemp, you know, just the CBD part is very anti-inflammatory. Well, it acts through the endocannabinoid system, which progesterone does as well. And it's just amazing, you know, how anti-inflammatory, how important progesterone is for regulating the immune system and preventing that chronic inflammation, the inflammation of aging. So like three cheers for a progesterone. What does comfort that carries you from morning to night feel like? This March, cozy earth crass every piece with care from soft, supportive socks for your steps through the day to breathable comforters that help you rest deeply at night. And let's be clear, in perimenopause and menopause, our sleep is precious. Every detail with cozy earth is intentional. So your everyday feels quietly elevated. Their designs focus on comfort in the details because small choices make a lasting difference. 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This product I've used exclusively for the last five years is the only digestive enzyme that I recommend. It is incredibly effective. No, it's such an important hormone and you've given me so much to think about in terms of physiologic dosing of hormone replacement therapy. I'm sure it will lead to more questions, but for now, a truly invaluable conversation. As always, Dr. Gersh, please let listeners know how to connect with you outside of the podcast, how to learn more about your work, obtain your books or if you live in California, work directly with Dr. Gersh because she is still, as she astutely states, I am still in the trenches. She's still seeing patients and has a vibrant integrative gynecology practice. Yes, I consider myself an outlier. I still love working with patients and it's a number of love. So I have a practice. It's called the integrative medical group of Irvine where I see patients pretty much every day, sometimes on weekends, but definitely Monday through Friday, unless I'm out there lecturing or doing something else, but mostly I'm there. And, you know, I can see patients like anywhere in California, including with telemedicine, out of staters. They have the joy of having a little mini vacation in Southern California because I'm in Irvine, California. That's in the beautiful O.C. Orange County, California. I'm nestled between Laguna Beach and Port Beach. Oh, you have a great seat. They touched them. They're like two seconds from them. So, you know, it's a lovely place and Disneyland is like 15 minutes away. So you come and visit me and then you get a nice little mini vacation. And then we can do some telemedicine thereafter, but I need to see my other out of staters from in person for the initial visit. And California is not required, though I do like it if I can see people in person. And I have three books, two on PCOS, my PCOS series and the PCOS SOS. I guess I could call it series PCOS SOS and PCOS SOS fertility fast track. And my newer book and I have new books, I hope that I'll be writing and I'll join you on the book circuit with a new book coming up in 2026. But I have one that is I'd like a little encyclopedia on. It's called menopause. Fifty things you need to know. And I really think it should be required reading for every female because it tells you all the things that are happening to you and it gives you some ideas of what you can do in addition to hormone therapy. So it gives you sort of the lifestyle approach because I always say hormones are necessary, but not sufficient at any age. You can have a 25 year old. I mentioned 25 year old before, but they can be very unhealthy. You know, they can be infertile, they could be obese, they could have all kinds of other autoimmune diseases. So just being young doesn't mean you're healthy anymore. So it's necessary to have hormones, though. It's foundational to your health, but it's not sufficient. You have to do all the lifestyle things. So I'm very big on lifestyle medicine and I use supplements, nutraceuticals as exactly what they are supplements to a healthy lifestyle to optimize health at every age that a woman goes through. Well, thank you again. Oh, and I also have a YouTube and I have a YouTube and an Instagram. Yes. And she does a lot of very gracious teaching just like she did today. Thank you again. I love these conversations. I feel very grateful that we are friends and colleagues and you're such a gift to women and their families. If you love this podcast episode, please leave a rating and review, subscribe and tell a friend.