Ep. 470 Your Midlife Hormone Survival Guide with Dr. Amy Killen

Today, I am delighted to reconnect with my friend and colleague, Dr. Amy B. Killen, a board-certified physician with expertise in bioidentical hormones, personalized medication, and cutting-edge rejuvenation techniques.

In our conversation, we dive into the spectrum of progesterone sensitivity, exploring why estrogen is considered the best longevity drug available and how it reduces the risk of heart disease. We discuss bone health and bioidenticals, outline ways to improve cognition, brain function, and cardiovascular health, and examine the ongoing debate around oral estrogen therapy. Dr. Amy also sheds light on slowing ovarian aging, explains the concept of hair pause and how to address it proactively, and offers her take on overrated or ineffective strategies for navigating perimenopause and beyond.

You will not want to miss this insightful episode with Dr. Amy Killen, and I look forward to having her back for another conversation.

IN THIS EPISODE, YOU WILL LEARN:

• Dr. Amy sheds light on the spectrum of progesterone sensitivity.

• Progesterone treatment options for women with progesterone sensitivity

• Why estrogen is crucial for longevity

• How estrogen protects the heart and blood vessels, reducing the risk of cardiovascular disease

• When is the best time to start taking estrogen for optimal cardiovascular benefits?

• Estrogen and bone strength and flexibility

• Can starting estrogen treatments early help prevent dementia and cognitive decline?

• Pros and cons of using a combination of estriol and estradiol

• Slow ovarian senescence and prevent hormonal changes from affecting your hair health.

Bio:

Dr. Amy B. Killen, M.D., is a leading physician in regenerative and hormone optimization medicine, specializing in women's health and helping patients navigate their "Queen PhaseTM" with evidence-based interventions. As a board-certified emergency physician turned longevity specialist, she combines cutting-edge treatments, such as stem cell therapy, hormone optimization, and peptides, with practical lifestyle wisdom at her clinics in Utah and Texas, while sharing her expertise through international speaking engagements and educational content creation.

Dr. Killen is the Chief Medical Officer of Humanaut Health, a longevity clinic franchise, and founder of the Human Optimization Project (HOP), a female-focused supplement company.

She lives in Salt Lake City with her family of five.

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“Nothing right now comes close to the benefits we see in the health span and lifespan of women taking estrogen.”

-Dr. Amy Killen

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Transcript:

Cynthia Thurlow: [00:00:01] 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. 

[00:00:29] Today, I had the honor of reconnecting with friend and colleague Amy B. Killen. She is a board-certified physician and expert in bioidentical hormones and personalized medication, as well as cutting edge rejuvenating medicine techniques. 

[00:00:46] Today, we spoke about the spectrum of progesterone sensitivity, why estradiol is the best longevity drug? And how estradiol impacts our risk for heart disease and how to work up our cardiovascular health, the impact of bone health and bioidenticals, as well as improving cognition and brain function, why there are so many opinions about oral estrogen therapy. Ways to slow ovarian senescence, what exactly is hair pause and how to proactively address it? And last but not least, overrated or ineffective strategies for navigating perimenopause and beyond. 

[00:01:28] This will be an invaluable conversation and I'll definitely have to have Dr. Amy back for an additional conversation.

[00:01:38] Welcome, Dr. Amy. So good to have you on the podcast again to unpack a lot of really cool things that you've been talking about on social media that I think my listeners need to learn more about. 

Dr. Amy Killen: [00:01:48] It's great to see you again always. 

Cynthia Thurlow: [00:01:50] Absolutely. So, let's talk about progesterone. And I say this with great love and respect that I think many individuals that are sensitive to progesterone feel like their symptoms are not really addressed. They're just told, “Okay, you don't tolerate progesterone, so you're going to just have to grin and bear it.” And you do a really beautiful job. If you are not subscribed to Amy's Substack, you need to be. I feel like I learn a lot and if I'm learning a lot, then I know there's a lot of incredible value that's there. Let's talk about the spectrum of progesterone sensitivity because this was fascinating. Absolutely fascinating. 

Dr. Amy Killen: [00:02:28] Well, so first of all, about 10% to 15% or so of women are sensitive in some way to progesterone, it doesn't work for them as well as everybody else. So, I think they get frustrated because all the rest of us are like “It's so wonderful. It’s helping me sleep.” We're all raving about it. And then there's this subset of people who, it just is not great. 

[00:02:49] So, of those people, there's three different types of progesterone is bad, whatever. It doesn't work for me. One type is called intolerance and that basically just means that you are more sensitive to it than other people. So, you have the same kinds of things, like instead of, it could help you sleep, but then you sleep too long and it can calm you down, but then your mood is too calm, you're too flat, you're depressed. So, it's like the same symptoms as regular progesterone, but people are very sensitive to it. 

[00:03:20] And then the second type is called paradoxical progesterone response. And that is essentially when one of the metabolites of progesterone called allopregnanolone, it goes to your brain and binds to your GABA receptor. And in most people, that causes this relaxation, this inhibition of the brain. In some people, though, that GABA receptor is configured differently. And so that binding actually causes excitation. So, it makes them wound up and they can't sleep and they're anxious and irritable. And so that's the second type. And that is also pretty common. Those first two are both pretty common. 

[00:03:54] The third type is a hypersensitivity, which is actually an allergic reaction, an IgE-mediated allergic reaction. So, it's an actual allergy, rash, hives, bronchospasm, swelling of the face. Very rare, less than 1% of people, but more serious also. 

Cynthia Thurlow: [00:04:11] Yeah, it's really interesting because I feel like for every 20 of us that are brave about progesterone and you're never going to have-- You're never going to stop taking progesterone because you feel the benefits, there are a few people that will say “I get it.” And what I typically hear from people is not so much that they feel like they can't wake up or they feel depressed. It's that they feel stimulated, so they get this glutamate receptor stimulation as opposed to GABA. And so all of a sudden, they're like the opposite. They're not falling asleep. They're totally irritable. 

[00:04:48] And so, for those that suspect they may be on this spectrum, what are some of the things that they can do? Now you talk about this in particular in your Substack article, which again, excellent, must go, subscribe to it. What are the options for people that feel like they get this magnification of symptoms. What are some of the options that they can do that still protect the uterus? Because there are concerns around there. What are some of the other options they have for treatment? 

Dr. Amy Killen: [00:05:13] So, probably the easiest option is just to change forms. So instead of doing oral-- like instead of doing a pill which is going to get metabolized heavily in to that allopregnanolone, change it out for a vaginal progesterone or even a rectal progesterone or even a troche, underneath the tongue. So, anything that's not a pill going into your stomach and then into your liver is going to create much less of that allopregnanolone. And so that is going to be much less excitatory, essentially, to your brain. 

[00:05:42] And the other option-- second option, is to actually either increase or decrease your progesterone dose if taking it orally. Because it turns out when it comes to the paradoxical response, there's this sweet spot in the middle of serum allopregnanolone level that causes disturbance. And if you're higher than that or lower than that, then it actually doesn't cause the same disturbance, which is weird.

Cynthia Thurlow: [00:06:08] It is. It's bizarre. So, for listeners benefit, typical progesterone route of administration is oral. Dosing somewhere between 50 to 200 mg depending on the individual. When you're talking about those that have this paradoxical response, are we talking about doses of 400 mg or are we talking about teeny tiny-- Like the range of doses? Teeny tiny, like 25 mg, is that typically what you're thinking? 

Dr. Amy Killen: [00:06:34] Usually, the worst doses for those people are between 100 and 200 mg orally. And then again, everyone's different, but if you can go lower than that, like if you're, 50 mg, unfortunately doesn't offer uterine protection at 50 mg a day. But if you're taking some other kind of progesterone also, then 50 mg is usually okay. And if you go up near like 400 mg, then that's also usually okay. But everyone's a little different. But that's the range that most people-- Most people, the worst range for them is the one that we give them, which is [Cynthia laughs] 200 mg. 

Cynthia Thurlow: [00:07:06] And if you're changing the route. So, if someone's taking it intravaginally, intrarectally, it does the-- Sorry, I don't know the answer to this question, does the dosage also correspondingly change? Because I would imagine rectal absorption is very different than intravaginal absorption I would imagine. 

Dr. Amy Killen: [00:07:22] Well, so most of the studies that we have are in vaginal. We don't have a lot of studies, at least in the hormone space. We have some in the fertility field. But most of our HRT studies are looking at vaginal progesterone. And that the uterus gets-- The progesterone goes into the uterus first, which is great because it's a uterus first pass effect. And the uterus gets up to 10x the concentration then it would-- I think you’re taking orally.

[00:07:48] In theory, you could go with a lower dose. If you take 200 mg orally, you could probably take 100 mg or even less vaginally. But the British Medical Society guidelines on this from 2022 are just take the same dose both ways. So, it's super simple. And what's kind of a cool trick is you can actually take your oral micronized progesterone gel caps, the one like the Prometrium. You could take that vaginally and then you could also take it instead. If it was easier, you could do it rectally. That's just not as well studied, but probably we can tell, it's similar. 

Cynthia Thurlow: [00:08:21] Yeah, it makes sense. And from years and years ago when I went through infertility treatments, I actually took intravaginal progesterone for the duration of my first trimester. And I remember what the irony is. I recall it made-- Well, it could have been a multiplicity of things. You could be pregnant and bloated. But I remember thinking, when I started taking oral progesterone as a perimenopausal female, I was like “Oh my God, I hope the bloating that I experienced years ago, it has not been problematic.” So, I'm happy to report that that was not an issue. But that's actually what my reproductive endocrinologist recommended was to take it intravaginally, obviously for a different purpose, but good absorption there as well. 

[00:08:57] Now, so that's progesterone. And you've done again, such a good job talking about the value of estrogen as a longevity drug. I think that there's a lot of focus on evolving research, things that we can do to slow ovarian senescence, ovarian aging. But in terms of longevity drugs, estrogen is really important here. And I'm so glad that the pendulum is swinging back to where we're having these conversations, because only 4% of women right now, at least that we can grab the data on, are actually on hormone replacement therapy.

Dr. Amy Killen: [00:09:31] Yeah, it's crazy. And I go to a lot of these longevity events, and I know you do too. And it's all these, mostly men talking about all these things that they're researching, cellular reprogramming and gene therapy and they're looking at all these other medications off label, rapamycin and all these things. And eventually these things are going to help. I'm very excited about them. But nothing right now comes close to the benefits that we see in both health span and lifespan in women taking estrogen. Nothing comes even close to it, and yet it's like crickets when you talk about it at these events, no one is talking about estrogen because it's been around forever and no one can make money on it. 

Cynthia Thurlow: [00:10:11] Yeah, it's not, “a sexy” kind of novel treatment. It is something that's an oldie but a goodie. And you talk about how 30% to 50% lower risk of heart disease. That is significant. The number one killer of women is atherosclerotic cardiovascular disease. Everyone listening should have this on their radar. Whether you appropriately can take estrogen or not, we should all be aware of our cardiovascular risk.

Dr. Amy Killen: [00:10:37] Yes. 

Cynthia Thurlow: [00:10:38] How does estrogen protect our hearts and our blood vessels? 

Dr. Amy Killen: So, it's really interesting. I think of it as direct effects on your blood vessels and indirect effects on your blood vessels. So, estrogen has actual direct effects like it causes nitric oxide to go up so you get vasodilation. So, you open up the blood vessel so you get more blood flow. It also has effects on keeping the blood vessels nice and supple, so prevents stiffening of the blood vessels. And it works directly on the endothelial lining. So, it actually has receptors inside the blood vessels where it binds directly to the blood vessels to keep the endothelium healthy directly.

[00:11:15] And then the other way it works is on all of the risk factors for cardiovascular disease. So, estrogen helps your lipids, it helps your blood sugar, it helps your visceral fat, it can slightly help blood pressure in some people, so essentially, you're helping all the things that if you don't get them under control, can lead to cardiovascular disease. So, it's actually works in two ways. So, it's really cool, the effects that it has on the cardiovascular system. 

Cynthia Thurlow: [00:11:40] Yeah. And it's interesting because what many people probably don't realize is until women go through menopause, they're at a much reduced risk of developing heart disease, and it's because of the protective effects of estrogen. And I think about the thousands and thousands of patients I took care of years ago in Cardiology, and we would be having these conversations and saying, “These are the extra things we need to do,” really dialing in on lifestyle, and yet not having the conversation to say, because I was always told, “Stay in your lane, Cynthia, don't talk about hormones or stay in your lane in many different ways.” But helping women understand that the protective effects of estrogen really can be perpetuated if we are taking hormone replacement therapy, which then begs the question of-- 

[00:12:23] This is always the question that comes up is, some providers are pro checking labs to see levels of estrogen in the blood, others are not. Others base treatment on symptomatology only. Others do it labs plus symptoms. I know which camp you are in and I believe we're in alignment on this. What is the research demonstrating? Have there been any studies to show what levels we want our estrogen to be at to optimize for heart functionality.

Dr. Amy Killen: [00:12:56] Not really. I have estimated what levels they should be based on-- We have pharmaceutical data on what-- Essentially, like 1 mg of estradiol orally will give you a serum estradiol level of about 65, so we know what these pharmaceutical products will give us in terms of blood levels. And so, I've taken that information and then extrapolated what I believe the protective dose is. The data that we have is-- So that dose, I think, is about somewhere between 65 and 150 pg/mL of estradiol. 

[00:13:32] Now, unfortunately, most of the data that we have on cardiovascular disease is for oral estrogens, including both Premarin and oral estradiol. It's mostly an oral estrogen. In fact, all the randomized control trials are in oral estrogens that show benefit. And the only randomized control trial that we have on transdermal did not show benefit. But we don't know if that was because the dose wasn't high enough or because the route is important. But so that's what we know for sure. We know that oral estrogens at a certain dose are protective. We know also that we have to give those estrogens as early as possible that have to be given within ideally six years of menopause onset, but maybe up to 10 because you-- Unlike the bones in other systems, starting estrogen late does not seem to protect the cardiovascular system.

Cynthia Thurlow: [00:14:21] And I would imagine that has a lot to do with the inflammation in that low estrogen state, the oxidative stress, probably some degree of loss of insulin sensitivity that's probably contributing to this inflammatory state. I mean, that's my guess. 

Dr. Amy Killen: [00:14:37] Yeah. I mean we don't know for sure, but there's a couple of theories. One of them is that once you develop endothelial dysfunction, so once inside the blood vessels you start to accumulate plaque, that the receptors inside the blood vessels change and are not as effective, essentially when estrogen binds it's not as effective. 

[00:14:56] There are some other studies at least with blood vessels, not in people but in animal models that the estrogen actually works differently. It's anti-inflammatory when you give it early in menopause, but in some of these animal models it actually becomes inflammatory when it's given late on the blood vessels. I don't think it's a problem to give it late as long as you understand that it should be transdermal if you're giving it late and it may not have cardiovascular benefits, but you're still benefiting your bones, your pelvic floor, other areas like that.

Cynthia Thurlow: [00:15:25] Yeah. Which is certainly important. And you are a longevity expert, if a patient comes to you, they're within that six-year magic window. What are some of the tests if you're concerned about family history or symptomatology before evaluating oral estrogen therapies, are you doing clearly? I'm sure you're doing specific targeted lipoprotein analysis.

Dr. Amy Killen: [00:15:47] Yeah, I would do clearly if they had risk factors. So, Cleerly as you know is an AI-enabled CCTA. So, it's a CT Angio of the chest. So, it allows us to see the soft plaque inside the blood vessels. And it's one of these kind of newer tests. So, if there was concern like family history or risk factors for cardiovascular disease, even if they're early in menopause, I think a clearly scan is a great idea. 

[00:16:08] We also do this CIMT testing in the office, just ultrasound of the artery just to take a look at that. So, you can do certainly some of those things. We always ask about blood clot history and certainly if there's any family history or concerns about clotting disorders, doing a clotting disorder workup to look at Factor V Leiden and things like that in someone who's at risk. But if it's someone who is generally pretty low risk and is early in menopause onset. The risk of blood clot, even from Premarin, which is the synthetic estrogen, yes, it was twofold, so it's two times the high from placebo. But you're still only look at looking at about 17 extra patients per 10,000 patient years. So, 17 out of 10,000, pretty low risk actually. And an estradiol, the bi-identical form, the blood clot risk is lower than that for sure and we don't know exactly how much it is, but it's lower than that. So, it's still a pretty low risk, but I do ask those kinds of questions. 

Cynthia Thurlow: [00:17:05] Yeah, I would imagine and largely I feel like the podcast fields a ton of questions in this area. People who miss that magic 5- or 6-year window, people who are interested in bone benefits, brain benefits. So, let's talk about bones. Estrogen is very protective for bone metabolism. And what many people may or may not realize is that part of the challenges that occur in menopause is that, yes, you still build a little bit of bone, but you break it down faster than your body can rebuild it. 

Dr. Amy Killen: [00:17:35] Yes. 

Cynthia Thurlow: [00:17:36] And a lot of the conventional drugs that are used for osteoporosis, osteopenia, they are not without a lot of other side effects. And that is the concern that I have, is that there are people that may need those drugs. But just understanding that there are potential risk factors that come from those drugs, namely the poor-quality bone that is created. 

Dr. Amy Killen: [00:17:55] Yes. Yeah. I think of it like the bisphosphonates, for instance. Estrogen, we know builds healthy bone, so it builds the bone that you currently have. It helps-- Bone is a metabolic organ. So, it's always building and absorbing and building. It's always like this process. And estrogen helps with both the mineralization of bones, so getting the calcium and the magnesium and all the things in the bones. And it also helps with the collagen and keeping the collagen in the bones because we know that also goes away as we lose estrogen. So, it's helpful not just for strength, but also flexibility. 

[00:18:30] Bisphosphonates they essentially kind of like mummify the bone. It prevents the bone from-- It's like we're just going to keep you just like this so they can stop the bone from breaking down, but they're also not helping you build bone. So, you've got these mummy bones that are much more likely to fracture. You get all these weird things that can happen with the bone and there's not really that good of evidence. And this is why we don't-- Doctors don't give them for more than a couple of years because they're pretty dangerous if you give them for very long. And estrogen is not dangerous. And so, it's baffling to me why we're not using it more, especially when women who are at risk for osteoporosis. 

Cynthia Thurlow: [00:19:05] Yes. And it's interesting how many of my dentist friends will talk about those drugs, the biphosphates, how much they dislike them. They said “Anytime, if I'm going through a patient history and they mention they're taking one of these drugs, having to have that conversation about some degree, a very rare side effect is this mandibular necrosis that people can develop, which is bad.” 

Dr. Amy Killen: [00:19:25] Yeah. It's the rotting away of your jawbone. Your jawbone rots in the middle of your head. It's horrible. 

Cynthia Thurlow: [00:19:33] Yes. It's a terrible, terrible side effect. Another super important function of estrogen is brain function. And I think the older I get, the more I'm genuinely concerned about preserving cognitive function and doing all the things to make sure that I am not developing any of the sequelae that can happen with those shifts in sex hormones, in particular estrogen.

Dr. Amy Killen: Yes. I love Lisa Mosconi’s work in this. I’m looking at some of the studies that she's done. The pictures of the brain as it's going through perimenopause, even your brain energy goes down by 30% from premenopause to perimenopause. And I just think about, like all of us are doing so many things, we're used to having a 100% brain energy and even that's not enough sometimes. And then without warning, your energy goes down to 30, you’re down by 30%. And so, it's like your light bulb literally just dims 

[00:20:26] And what's interesting in her work is she's found that as estrogen's going down, the cells increase the number of estrogen receptors. And so, the cells are like little plants in a little shop of horrors. They're like “Feed me. Feed me” they really want estrogen. [laughter]

Cynthia Thurlow: [00:20:42] Well, and I really think it really speaks to the body, is looking for a workable solution to a problem. And so, I think for a lot of people, it's like what are the things we can be doing as we're getting older to help preserve cognitive function. I have a loved one that last year passed away. It wasn't because of Alzheimer's. It's the sequela related to that. And I recall being in this Alzheimer's unit, there were 10 patients, 9 of whom were females. And the staff saying to me, like, “We all typically only have maybe one, possibly two male patients. But it is always women and it's always women who have outlived everyone in their lives. Their spouse, their siblings and they have this long-term sequelae of neurocognitive decline, whether it's related to Lewy Body dementia or Parkinson's or Alzheimer's. But more often than not, it's women and not men.” And so, I think it's become a particular interest of mine of like what are the things I need to be doing proactively? 

[00:21:39] I was just mentioning on my last podcast that my husband and I have started doing pickleball because- 

Dr. Amy Killen: [00:21:44] Oh yeah. 

Cynthia Thurlow: [00:21:45] -how important it is for cerebellar health and just finding new things to stimulate your brain, how important that is. Do we have any data? And I'm sure Lisa Mosconi is probably working on this because it's a burning question that I have. We know that there are levels to help with bone protection. At least that's my understanding. I think everyone's curious to know how do we-- Well, we probably aren't at a point now where we're doing it, but how do we measure the estrogen levels in the brain? I don't think we're there yet or at least not conventionally, but I know a lot of people are curious about that. 

Dr. Amy Killen: [00:22:15] As far as I know, I haven't seen anyone actually looking at levels. The research on the brain is interesting because you've got a lot of mixed studies. We know for sure that starting synthetic estrogens late, after 10 years, menopause onset is a bad idea. We know that can worsen dementia, so we know that. 

[00:22:36] And certainly there's a number of studies that looks like mostly again, on oral estrogens, both bioidentical and synthetic. But looks like if we start those things early, then we can decrease dementia and cognitive disease, and I think both vascular dementia and Alzheimer's dementia can be affected. But I haven't seen anyone looking at what's the estrogen, serum estradiol level. There's only even a few studies that have used transdermal estradiol and those are pretty small studies. We certainly don't have randomized controlled trials. They're just kind of small observation. So, I'm assuming that it's probably similar to the cardiovascular disease numbers, but that's completely just theoretical. 

Cynthia Thurlow: [00:23:16] Yeah, I think it's challenging because obviously it's a whole lot easier to draw serum labs than it is to have a sense of what's going on in the brain, because the brain is protected. There's the blood brain barrier. There's ways to do it, but they tend to be very invasive. They're not things that people are doing as outpatients. And so, I think that it'll be interesting to see what Lisa's research continues to evolve and share. And certainly, I'm so grateful that she's at the forefront of a lot of the research that's going on. 

[00:23:44] So, I feel oral estrogen in many ways has probably gotten a really bad rap, given the fact that I think many people equate it to oral estradiol, which is the predominant form of estrogen our body makes prior to menopause. People equate that with conjugated equine estrogen, which is Premarin versus oral contraceptives, which again, that's a synthetic estrogen. Help us understand how oral estrogen has gotten a bad rap and why there are more of us that are starting to talk about some of the benefits for the right patient. 

Dr. Amy Killen: [00:24:19] Yeah, when you say estrogen, you have to understand that's an entire whole group of different types of estrogen. Estrogen is a group, it is not a single thing. And so, as you mentioned, Premarin, which is the CEE, is the synthetic estrogen that was used in the Women's Health Initiative. And then, of course, birth control or synthetic estrogens use at much higher doses, usually two to four or more times that what we use for HRT. And then oral estradiol, which is the one I use and you would use, I'm assuming is bioidentical estrogen. 

[00:24:46] The reason is that the synthetic estrogens got a bad rap is because of-- The Women's Health Initiative certainly didn't help. They saw increased dementia, increased heart attacks, increased strokes in the group getting oral estrogens, especially if the progestin was added. And, we have a lot of studies that show us that oral estrogens can increase blood clotting risk and things, and so that-- When people say estrogen, they think about that. They think about all the things that those synthetic estrogens can do.

[00:25:13] Unfortunately, they don't talk about-- People don't talk enough about the fact that oral estradiol is actually really safe. And we have three randomized controlled trials that show that oral estradiol reduces cardiovascular disease in women. And we have-- These are good studies. Hundreds of women or more over many years and none of those patients in those studies got blood clots. None of those patients in those studies got any other risk, any other issues. So, I think there's a place for transdermal estradiol. There's a place for oral estradiol. 

[00:25:41] Oral estradiol is actually a lot better for your lipids, the transdermal in general, it's worse for triglycerides, but it's better for everything else. And so, there are certain patients. For instance, if you have elevated Lp(a), which is a genetic thing that can cause your-- It's an atherogenic, bad genetic thing to have, and oral estradiol is one of the few things that will reduce Lp(a). We don't actually have other drugs that do that very well. So, there's some things like that, you have to understand the nuances, but I do think that it's been-- Oral estradiol has been thrown under the bus and really, it shouldn't be. 

Cynthia Thurlow: [00:26:17] Yeah, no. And you do such a beautiful job of explaining why there's a need to have these conversations, these subtle conversations that are explaining the nuance. Now, I am someone that has the crappy genetic lottery, and so I have high Lp(a), I have high ApoB, if I'm not treating it with Zetia because I'm a hyper absorber. And so, we, I say we as in my functional med doc and I have done everything that you can imagine to get that Lp(a) down without starting a statin without starting oral estrogen only because we were trying a bunch of different things first. 

[00:26:55] But I think for the right patient and certainly, the genetic lottery that we get, it's not a lifestyle-mediated thing. It doesn't mean that you're not taking care of yourself. It's just the genetic dice that you were thrown. I think for the right patient, that can certainly be a viable option. 

[00:27:14] There are two other major players in the estrogen family, and as you appropriately stated, it is an estrogen family. Let's talk about estrone and estriol because I feel like there's also a lot of differing opinions, I'm going to say this very respectfully, [Dr. Killen laughs] differing opinions about the value of one over another. Should we be doing Bi-Est, Tri-Est? I think is has totally fallen out of favor. But there are definitely people that speak to Bi-Est having breast protective effects. And so, what is the research showing? And again, why is there so much confusion? I feel like there's a lot of confusion because of the post WHI phenomenon. And then, I think there's growing knowledge and growing curiosity about determining what's the right approach to take with each patient.

Dr. Amy Killen: [00:27:59] So, yeah, so estradiol, which is called E2, is the most potent form of estrogen. It's the type-- This is what your body makes throughout most of your reproductive life. The next most potent type is estrone. And I remember that's E1. I remember that because it has the word one in its name, otherwise, I forget. But estrone is our-- It's one-tenth as strong as estradiol. And estrone is what's generally made, it's the primary estrogen made after menopause, when your ovaries have shut down. Estrone can get made, peripheral fat conversion and adrenal gland, things like that. 

[00:28:34] And estrone actually is has a bad rap also. People think of it as being this like inflammatory estrogen, but it's not actually inflammatory. It's just that it hangs out with inflammation. And so, it has its friends with inflammation, but it's not a bad estrogen. The benefit to estrone actually is that it can get a-- a sulfate group will bind to it and it becomes like this invisible estrogen that's traveling around in your body. It's not binding to receptors. But if a part of your body needs estrogen, like your brain is like, “I need some more estrogen.” Then your body, as smart as it is, it will cleave off that sulfate group, and then the estrone will get turned into estradiol, and then your brain can use it. So estrone actually has some benefits to it in that it's able to stick around for a long time, be this like secret agent kind of estrogen. 

[00:29:25] And then the third kind of estrogen is estriol, which is E3, and that's about a hundredth as strong as estradiol. And so, when you ask about Bi-Est. Bi-Est of course, is a combination of E3 and estradiol usually. Long story short, I don't think that Bi-Est is-- I don't use it, and I don't think it's dangerous. I just think it's like watering down-- It's just paying more to water down your estrogen. And we have no really good evidence that estriol, it's not good for bones. It does do anything for bones. It's good for skin if you want to put it on your skin or even vaginally, but systemically, you have to use very high doses and to me it's not worth it. 

Cynthia Thurlow: [00:30:01] Yeah. And I think this conversation is so interesting because, again, it's that nuance when we're talking about hormones. It's not an all or nothing. It's like a platter. Like what is the platter? What are the things that you specifically need? And what is going to be of greatest benefit to you? Now, I know a lot of your focus as a longevity physician is on senescence and in particular, ovarian senescence. The aging of our ovaries. Our ovaries set the tone for aging in our bodies. And I find it utterly fascinating the things that can positively or negatively impact ovarian senescence, like smoking can obviously hasten ovarian senescence. Trauma can hasten ovarian senescence. What are some of the cutting-edge things that you find really interesting? Obviously, you have an amazing supplement line called HOP Box with a lot of these agents in there. What are the things that you think are most beneficial for slowing ovarian senescence, slowing the aging process of the ovaries, which, that is what, again, defines the aging of our bodies as females?

Dr. Amy Killen: [00:31:04] It does. Well, I wish I had a single answer and could say we should all go out and do this, because it's going to help us live longer because I do think that if we can slow down our ovarian aging or ovarian senescence, that as a group of women, that means that we will live potentially longer but definitely healthier.

[00:31:21] In animal research, all the kinds of things that have been researched for longevity in general and have shown some benefits in animals have shown similar benefits for ovarian aging. So, some of the supplements like Alpha-ketoglutarate and NAD precursors and CoQ10 and some of these antioxidants, Resveratrol in animals have been shown to be helpful. Rapamycin, which of course is this sort of longevity drug potentially that's been looked at a lot by this community, has also been shown to help with that Metformin as well for slowing down ovarian aging. I think that all we can say right now is that the best thing you can do is be as healthy as possible. So don't drink too much, don't smoke, don't be too overweight, like all the same things that are bad for our whole body are bad for our ovaries. 

[00:32:04] I will say that there's some interesting companies out there. And in fact, I'm an advisor for one of them, it's called Timeless Biotech which has a-- They're bringing to market a time to menopause product essentially where you can-- It's a combination of blood test and family history and you know questionnaire where if you're within 15 years of menopause onset, they can tell you essentially within about a year when menopause- 

Cynthia Thurlow: [00:32:29] No way.

Dr. Amy Killen: [00:32:30] -is likely to start. Yeah. 

Cynthia Thurlow: [00:32:31] That's amazing. 

Dr. Amy Killen: [00:32:32] It's pretty cool. And there's another company as well that's called Life Ahead that I know about that they're using ultrasound and some other questionnaire for the same kind of thing. But essentially, the good thing is we have some tools now that even if you're in your [unintelligible 00:32:44] and you're like, “I wonder how long I have,” there's some tools out there that are coming to market here pretty soon to be able to help, so you can do family planning and things like that. 

Cynthia Thurlow: [00:32:54] I find it fascinating. I think the addition of AI to these metrics I think is going to be really interesting. I know that-- And I promise I don't stalk you on social media, but you're in my feed all the time. [Dr. Killen laughs] I'm usually seeing what you're putting out there, but you were mentioning you had done ChatGPT, you’ve plugged in, I guess your AMH level-

Dr. Amy Killen: [00:33:13] Yeah. 

Cynthia Thurlow: [00:33:13] -how long is it to menopause? And it was like spat out one year and you were like, “Wow, fascinating.” So yeah, AI is getting involved in the prediction of ovarian senescence. 

Dr. Amy Killen: [00:33:27] Yeah. I think a combination of things like your FSH, your AMH, your estradiol level on day two to five of your cycle, as well as family history and reproductive history are some of the pieces that can be useful with the right tools to understand what to do with those pieces. 

Cynthia Thurlow: [00:33:44] Yeah. What are your thoughts on GLP-1s when I'm saying this, the concept of microdosing, not per se, the people that need to lose 50 pounds to 100 pounds where I mean there's obviously benefits there as well, but the anti-inflammatory, anti-aging benefits of GLP-1s because I feel like we're getting to the point where I could probably, if I look at a cross section of the population, make an indication for just about anyone who's interested in partaking in the GLP-1 discussion. 

Dr. Amy Killen: [00:34:10] Yeah, I think that there's-- I don't think that we know for sure. A lot of this is speculation based on what we know from the study, so we don't know exactly what dose for instance is going to not cause weight loss, but is going to be anti-inflammatory or is going to be helpful for your kidneys. We know that in the studies that they were done at the doses that the FDA ended up approving, those did have all these systemic benefits, brain benefits, heart benefits, kidneys, like everything. So, we're assuming that if we decrease the dose we can still have some of those benefits, but we don't know what dose exactly. 

[00:34:46] But I think it's a good idea at least for some people especially if nothing else is working. I've seen it. People, for instance, who have like a lot of joint pain, people who have autoimmune disorders, I've seen a lot of benefit. People with PCOS, I've seen a lot of benefit. So, I think that certainly there are some special populations that there's-- We could definitely use these drugs now. 

Cynthia Thurlow: [00:35:06] Yeah, it makes so much sense. And how about-- what are your thoughts on low-dose naltrexone? 

Dr. Amy Killen: [00:35:11] Yeah, I like it. It's good for inflammation as well. So, we use it a lot for people who have autoimmune disorders, Hashimoto's or things like that, where you're trying to reduce inflammation, you're using this little baby dose. And it can be helpful for that purpose. So, I think that's another nice trick that functional medicine doctors or people in this space that have been doing this for a while know about, but it hasn't really made the traditional medicine scene. 

Cynthia Thurlow: [00:35:35] If you want to freak out an anesthesiologist, you just mentioned the word naltrexone. [Dr. Killen laughs] Now for listeners that may not know this, it's a drug that at higher-- much higher doses can be used for people that have an opiate addiction. And so, I remember I had to have a colonoscopy and I mentioned-- And I said low dose naltrexone and all they heard was naltrexone. And I was like, “No, no, I've never had.” And I was like “There's no judgment, but I've never had a problem. I have autoimmune conditions.” 

Dr. Amy Killen: [00:36:02] Yeah. 

Cynthia Thurlow: [00:36:03] But I just remember they looked at me like I was crazy. They're, like “Wait, you willingly take a very low dose of naltrexone?” I said, “Yes, and it helps my thyroid.” And they were like, “Interesting.” But yes, it was definitely starting to become more popular. But I think for the traditional allopathic medicine set, they hear naltrexone, they don't hear the low dose. And then they're like thinking you've got a whole other conversation about your social history.

Dr. Amy Killen: [00:36:27] Yeah, totally true. I think that's true of a lot of these sort of drugs that are used off label. There're so many things from Metformin and rapamycin to the SGLT2 inhibitors. Now, canagliflozin and things like that, which also have a crazy amount of benefits, potentially system wide, but they're diabetes medications. And so, I have to say whenever-- Like I got a colonoscopy last year, I don't even write this stuff down anymore. [laughter] I'm not putting all this down because then I have to explain everything. I'm sure this is not advice, don't do what I'm doing. But then people are like “Why are you taking all these? Do you have diabetes? Do you have this?” And they're very confused by all of this. 

Cynthia Thurlow: [00:37:04] Yes, yes, no. And I too have done that on occasion where it has not impacted the quality of care I've received. I'm like if I sit down and write down all my supplements and explain what I'm taking, your eyes are going to glaze over and you're going to think I'm crazy, but I'm not- 

Dr. Amy Killen: [00:37:18] Exactly. [laughs] 

Cynthia Thurlow: [00:37:19] -crazy. Yes, exactly. 

Dr. Amy Killen: [00:37:21] But also to your listeners, you should definitely disclose all your-- [laughs]  

Cynthia Thurlow: [00:37:24] Yes absolutely every single supplement, every medication. Please share with your provider so they can deliver you the best of care for sure. 

Dr. Amy Killen: [00:37:31] Exactly [laughs] 

Cynthia Thurlow: [00:37:32] Big concern for many women in middle age is hair loss and/or hair pause or whatever type of pause we want to call it. What is happening to our hair follicles with the aging process along with everything else? 

Dr. Amy Killen: [00:37:45] Well, I have a Substack series going on this right now. 

Cynthia Thurlow: [00:37:48] I’ve seen it and It's excellent. 

Dr. Amy Killen: [00:37:50] I have a series. There's another one coming out next week. So yeah, there's essentially what we think is it's almost like a menopause of the hair follicle. Although oftentimes in women starts well before menopause, 10 years earlier kind of thing. But more than 50% of women notice hair shedding in midlife and it's probably a combination of hormonal changes and metabolic changes and all of it happening at one time. The hormonal changes, the main ones are estrogen going down because estrogen is actually very protective of your hair follicles. It protects it from inflammation. It keeps the blood flow to your scalp. It's protective in general and it helps to keep the ratio of estrogen to androgens appropriate when estrogen is high. So, when that goes away then your androgens are up. And that's testosterone, DHT, which we know-- Well, we think is potentially dangerous in some people to the hair follicle, not all people.

[00:38:44] But other hormones as well like we know thyroid goes down oftentimes in midlife and that's important for hair. Melatonin is another one. That's something else that is going down in midlife. This is why you're not sleeping as well potentially. But it's that melatonin is very anti-inflammatory and very good for your hair follicles. So, there's all these hormonal things and then you add on top of it just aging things like mitochondrial dysfunction. Your mitochondria don't have enough energy and it turns out your hair follicles require a lot of energy. So, tons of things happening and yeah, leading to this hair pause as I said in my articles. And it's a big drag. None of us like it. 

Cynthia Thurlow: [00:39:18] No. And it's interesting. I had someone, I was at an event and I was getting my hair blown out and before they started drying my hair, I don't know why, because they had just washed my hair, they would know if I had extensions. They said, “You have hair extensions?” And I was like, “No, I do not need one more high maintenance thing.” But how many of my friends have started to consider getting extensions or having extensions for a special event because they're just so unhappy with the amount of hair loss. 

[00:39:45] And one thing that I found interesting in your article was you were talking about our hair growth phase shortens in menopause just like everything else. The follicles shrink which leads to finer, thinner hair and then this reduced blood flow piece along with nutrient deficiencies. So, I feel like in many ways a lot of the themes about each body system that's impacted by menopause are similar, like decreased blood flow, decreased nutrients, really honing in on nutrient depletion. Are you a fan of tests like NutrEval by Genova or tests like that that are looking at micro and macronutrient depletion that can occur for anyone, but in particular middle-aged people. 

Dr. Amy Killen: [00:40:26] Personally use them a lot with my patients. However, a lot of the doctors in Humanaut, like my kind of co-doctor who is just a lot of like deep functional medicine, he definitely uses a lot of those tests. And I think that-- I don't think that necessarily everyone needs every functional medicine test. 

Cynthia Thurlow: [00:40:40] I agree. 

Dr. Amy Killen: [00:40:41] I do think that we go overboard and I think that unfortunately that makes this care a little bit inaccessible to some people because they're-- If you have to order $3,000 of test to even get started with the patient, then that's a pretty high bar for most people. But I do think that there are special patient populations where more detailed testing is definitely beneficial. Whether it's things like that where you're looking at micronutrients or heavy metal testing or all the things like there's a place for all of it, I think. 

Cynthia Thurlow: [00:41:10] Yeah, it's interesting because one of the things that has stood out to me and I don't order that test all that often, but if I have someone that's got autoimmunity, we know they've already got leaky gut. They're starting to have this constellation of hair growth issues, thyroid issues. It's like, okay, what are some-- Like no, it's not an inexpensive test, but can it yield good information that ultimately will help us fine tune like what vitamins or minerals do you actually really need? And then going from there. I cannot tell you how many people I've worked with who have omega 3 fatty acid deficiencies. Probably not surprising given the fact that we have so much inflammatory oils in our diets, but just these relative imbalances of fatty acids that can really exacerbate skin issues, hair issues can really be surprisingly problematic. What are your thoughts on progesterone's role in hair pause?

Dr. Amy Killen: [00:42:00] So progesterone is a weak 5 alpha reductase inhibitor. So it is-- it weakly blocks the conversion of testosterone to dihydrotestosterone. And certainly, medications that are used in men like Propecia or finasteride, which is a very strong blocker. Those medications work really well for men's hair loss. They may have problems, but they do work well for hair loss. So, progesterone has some of that weak activity where it's a little unclear what else progesterone is doing in the hair for the hair follicle. 

[00:42:30] Estrogen is pretty strong. We know estrogen is very important for the hair follicle. Progesterone we're not quite sure about, and we're also not quite sure about DHT and androgens. If anything, they're probably not great, but even that evidence is a little bit confusing. 

Cynthia Thurlow: [00:42:46] Yeah, no, certainly helpful to have that. And when you're talking about lab work that you think is beneficial to evaluate hair loss, I think a lot of people just automatically jump to sex hormones, but you do a really nice job in that Substack talking about, like these are accessible labs for everyone. These are not unusual labs. These are not functional integrative medicine labs. What are some of the labs that you think are important to do to evaluate hair loss issues? 

Dr. Amy Killen: [00:43:12] Some of the key labs are thyroid and including obviously all the TSH, free T3, free T4 at the minimum, at least get those three. And making sure that you're in that sweet spot, hopefully towards the upper end on the T3 and T4 of the reference range versus the lower end. And that can make a big difference. And then ferritin is also another really Important lab to get. A lot of women when you're menstruating, you're losing blood every month and that of course you're losing iron. And ferritin is just the stored iron form. 

[00:43:44] And hair-- There's a number of good studies that show that you want to have a ferritin of at least 50 to 80’ish for hair-- for good quality hair in women and in men as well. But a lot of women, their ferritin is like 20, but no one's checking it because it's not like you're not anemic, your hemoglobin, hematocrit are normal on like the basic test your doctor does. And unless you do just add on a ferritin test, no one know that-- You don't know about it. So that's another big one. And pretty easily treated with just high iron foods and supplements if needed. So those are two certainly the hormones. All the hormones we talked about, estrogen, testosterone, those kinds of things. And then sometimes, I don't tend to check all the micronutrients, but you can check B vitamins, you can check selenium and cadmium if you have specialized tests for those. I do omega 3 fatty acids also in that. And then also just general inflammation markers, getting a CRP or some sort of test. And I think it's important to do anyway CRP, blood sugar test, we know that any metabolic diseases of all-- Any kind of inflammation that's bad for your body is also bad for your hair, so you got to think about those things too.

Cynthia Thurlow: [00:44:54] Well, I think a lot of people don't realize if you're chronically stressed, if you go through a stressful period, like when I spent 13 days in the hospital in 2019, I had so much hair loss after losing 15 pounds that I didn't need or want to lose, then I remember my hair person was like, “You may need to think about extensions.” And I was like “absolutely not.” Because that will then become another long-term thing, but chronic cortisol elevation can actually impact the hair follicle quite significantly.

Dr. Amy Killen: [00:45:25] Yeah, absolutely. Whether it's physical stress, like you're sick or emotional stress, emotional mental stress, anything that's causing that cortisol to be up over time. And the thing is that the hair loss usually starts like three to six months after the stress. So, it's not like you're stressed out and your hair starts falling out. It starts six months later and you're just like “What is going,” it comes out of nowhere, and so it's difficult to pin down sometimes what's causing the hair loss because who knows what was happening six months ago. 

[00:45:55] And also similarly, when you get to treating it usually takes three to six months before you start to see benefits also. So, it's very difficult because who wants to be on a medication or whatever for six months and not know if it's even working or not? 

Cynthia Thurlow: [00:46:07] Yeah, that can be super frustrating. I'd love to end the conversation today talking about things that you feel like are overrated or even ineffective in the longevity space. And by this I mean things that you kind of-- because you understand the science at such a deep level, you look at it and say, okay, well there's a-- It could be one of those like pop up IV places that's administering things that are ineffective, you can't actually absorb them or these detox teas or professionals that are still prescribing oral contraceptives as HRT, which is not HRT.

Dr. Amy Killen: [00:46:43] Yes, well, all of those things that you just said. I don't think that detox teas, pills. There is a way to detox your body, but I do think you have to have-- You have to be very strategic with the provider who knows what they're doing to really do that properly. I am not a fan of alkaline water. I think it's a total scam, the water that you're drinking to try to alkalize, that's ridiculous. Your body is not so easily tricked, if you will. 

[00:47:09] I don't think NAD IV is really all that-- I think it's expensive. Who wants to pay a $1000 for something that really doesn't have good evidence behind it? And if you want to increase NAD, you can just take a supplement like NR or NMN or other similar supplements and those work just fine to do that and they're much less expensive. So yeah, don't like that. I don't love progesterone cream and I especially don't love like the yam creams that you can get over the counter. It turns out that rubbing yam cream on your skin gets absolutely zero progesterone made into your body. So that is a total waste of time. It is all placebo effect if that works for you. 

Cynthia Thurlow: [00:47:49] Yeah, I think it's important to have these conversations and what's interesting is I did a podcast on NAD with a physician researcher and learned so much getting prepped for that podcast. I thought to myself, I've never gotten IV NAD or NAD, but I'm so glad that I never did because now I understand it's too large of a molecule to get intracellularly, you need the precursors that you mentioned, the NR, NMN. And I love that you brought up the progesterone cream because without naming names, I will just suffice it to say you can eat all the yams and sweet potatoes in the world and it's not going to raise your progesterone. 

Dr. Amy Killen: [00:48:22] It is not. Progesterone can be made from a specific type of Mexican yam in a laboratory. There's a molecule called Diosgenin in there that can be made into progesterone, but the thing is your body cannot do that conversion. It has to be done in a laboratory. So, eating yams, put them on your body, none of that-- Yams are fine, they're delicious, but it's not going to help your progesterone. 

Cynthia Thurlow: [00:48:46] Well, I always enjoy our conversations, Amy. Please let listeners know how to connect with you, how to subscribe to your site Substack or learn more about your work. 

Dr. Amy Killen: [00:48:55] So, Substack is Dr. Amy B. Killen and I do have both a paid and a free subscription there. My website is dramykillen.com, and actually if you go to my website, I have a free supplement guide for perimenopausal kind of midlife women that you just sign up for my newsletter and you'll get that in your inbox. Has lots of information in terms of like favorite things and doses and different brands and things like that. And then if you are interested in supplements, check out HOP Box, which is my supplement company. It's hopbox.life. I've got a female focus easy twice-a-day little supplement pack, but it's pretty awesome as well. 

Cynthia Thurlow: [00:49:27] Thank you so much for your time. 

Dr. Amy Killen: [00:49:30] Thank you. 

Cynthia Thurlow: [00:49:33] If you love this podcast episode, please leave a rating and review. Subscribe and tell a friend.

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