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Hormonal Contraception, Sex Hormones, Menstruation, Pregnancy, Puberty, Estrogens, Androgens

Updated: Aug 11, 2023

Full auto-generated transcript below. Beware of typos & mistranslations!

Adriene Beltz 3:57

Study Yeah, yeah, so I'm an associate professor of psychology at the University of Michigan. And I'm really interested in the development of gendered behaviors. So behaviors where on average, we see differences between boys and girls and men and women. I'm most interested though, in how go natural hormones hormones were exposed to naturally at puberty through the menstrual cycle hormones we try to modulate through hormonal contraceptive use, for instance, how they influenced those gender differences and how they do that in very unique ways for unique people.

Nick Jikomes 4:37

So you said, you said good Natl hormones. So what what are gonads?

Adriene Beltz 4:42

Yeah, so go natto hormones. mogil gonads are testes in men and ovaries and women so I focus a lot on the hormones produced by those by those organs. Although hormones we I kind of think of in this class like progesterone estrogens, testosterone, they also are produced and other organs of the body as well. So go natural hormones broadly, but not exclusively.

Nick Jikomes 5:16

And so pretty much everyone says he has heard of sex hormones. Everyone has heard of things like testosterone and estrogens. I don't wanna spend too much time on this, because because I've covered it on the podcast before and I think this audience probably has some grasp of this. But can you just go over the basics of what are the difference between androgens and estrogens? And what what are maybe some misconceptions about about those things that that we should clear up about, you know, the relative ratio, say in males versus females?

Adriene Beltz 5:45

Yeah. And that's a good question, because there is some movement and acknowledgement in the field right now that sex hormones that phrase maybe gives off the perception that like androgens are only for men, and estrogens are only for women. When you do see average differences, men have more androgens, and some more potent forms, and women with higher levels of estrogens, but these aren't exclusive. For instance. I mentioned hormones made by other organs besides the gonads, a key aspect of puberty is called ADRA. Anarchy, which is the awakening or the development of the adrenal glands which sit atop the kidneys. And the adrenal glands give out androgens and they're a particular type of androgens they're responsible for for instance, the development of body here in boys and girls, underarm hair, pubic hair. So androgens play a large role in pubertal development. So that's a key example of of how the sex hormone kind of overgeneralization is, is not quite accurate.

Nick Jikomes 6:57

I see. So, so both androgens and estrogens are found in everyone. They're just sort of differ in the relative ratios and exactly sort of when and how they're used. But the gonads are a key site where where some of these major sex hormones are produced. That's right. That's right. And then in terms of sex hormones, like testosterone, like estrogen, how do these things work at a cellular level? So they're producing the gonads, they get into the bloodstream? Where do they go? And when they actually exert their physiological effects? What exactly are they doing at the level of cells?

Adriene Beltz 7:31

Yeah, that's a another great question. They'll get into the bloodstream. And for a lot of the behaviors or the the types of phenomena that I'm interested in a key point or consideration, and that is that we know these hormones can actually cross the blood brain barrier. So they're active in and and they attach to many receptors throughout the peripheral nervous system, but also within the central nervous system, including in the brain. So there's receptors in the brain to which these hormones can attach themselves and through those means, modulate behaviors that those receptors play a role in. So in a lot of what I think about what we do, it's important to acknowledge then, that if we're if we're talking about hormone effects, or ovarian hormone effects, for instance, on a behavior, it's not just how much extra dial is in your blood, or how much we can assess through saliva, for instance. But the impact of those hormones is also modulated by how many receptors an individual has, where their individual receptors are located in different regions of the brain, for instance, and the sensitivity of those receptors to that hormone, because they're not, it's not necessarily an all or nothing, we can have different levels of receptor sensitivities as well. So it's not just about the hormones in the blood. But what the receptors are like that those that those molecules attached to,

Nick Jikomes 9:16

I see. And I would imagine that receptor densities and things how much of each type of receptor we have in a given part of the brain or given tissue in the body. Those things probably display a fair amount of individual variation naturally.

Adriene Beltz 9:29

Yeah, yeah, like a lot of things. You can see some average effects, some average differences in genders or by different clinical conditions, for instance, but there's a lot of what we would say individual differences in this space as well. Not just differing across people, but also differing within a person over time, right where puberty is a key element of this we see changes in receptor sensitivities and densities with puberty, even within a person

Nick Jikomes 9:59

and then You know, when an androgen or an estrogen like testosterone, or estradiol when it gets where it's going, and it's binding that receptor on a cell somewhere in the body? Are those always intra within, within the nucleus, receptors that then go on to affect gene transcription, or literally in the cell? Where are the receptors located? And what's sort of the immediate effect of activating that receptor?

Adriene Beltz 10:26

Yeah, those are really good questions. And we the best evidence from those are regarding those processes we get from animal models, right? This is much harder work to do in humans where I focus. And yeah, so I think when it comes to animal models, and thinking about how they generalize to humans, there's a lot of caveats. For instance, there's the representation of androgen and estrogen receptors in the brain are different in rodent models, where we do most of this work and versus human models, for instance. And so at least how we think about it in my group is we can borrow, we can be informed by those animal models. But when we get to humans, we actually have to work at like a bit of a higher level of analysis.

Nick Jikomes 11:16

And, you know, more broadly speaking, like what is a hormone as opposed to some other kinds of molecules circulating throughout the body? You know, we've got nutrients in our bloodstream, they go everywhere they get inside cells, we've got other things, what differentiates a hormone is its ability to act systemically to sort of orchestrate coordinated changes across tissues. How exactly do we finally define hormone?

Adriene Beltz 11:40

Yeah, I mean, hormones are just broadly chemical messengers. And they come in, you know, we're talking about go Natl or, you know, it'd be said sex hormones. But there's a lot of other hormones as well, for instance, in cortisol and in responses to stress. So they're just different ways that our bodies, body signal and communicate that information.

Nick Jikomes 12:02

And so, you know, a lot of what we'll talk about today will have to do with female physiology, I think we'll we'll talk about difference between males and females as well, insofar as it helps us understand the female side of this. But you know, when it comes to, you know, change, systematic changes and hormone levels across developmental time, I just want to start with puberty. So you've got a girl, puberty initiates somehow, and that's gonna lead to all sorts of changes. What are some of the key hormonal changes that are occurring in females at the onset of puberty? Or what is actually triggering that onset?

Adriene Beltz 12:39

Yeah. What is triggering it is broadly changes in the pituitary and hypothalamus. And what leads to those changes, some of that is debated right now, clearly, there's some biological components, right? The best indicator of when a girl is going to begin puberty is when her mother began puberty. So there is biological influence, but we also know at more of a population level, that pubertal timing is kind of getting earlier, it's shifting down, compared to where it's been historically. And there's lots of questions about what players might be in in that progression, aspects of diet right aspects of different chemicals, potentially blocking or impacting those hormone receptors, we were just talking about potential roles for obesity, and, and some some of the estradiol production that can come along with that. So so that's kind of how puberty begins, or parts of it begin, but we typically think of puberty having three different axes of development. One is changes or growth in height. Another is the Adron archy, the maturation of the adrenal glands that I that I mentioned earlier, and the adrenal and androgens and their roles in secondary sex characteristics like body hair development, and then gonad archy, which for girls is maturation of the ovaries, and the ovarian hormones progesterone and estradiol, that that come from that. So going at archaean girls the secondary sex characteristics associated with the roles of the that awakening of the gonads is breast development, as well as eventual monarchy or girls. First period. For boys. The growth axis is the same as anarchy is the same, but obviously going at archy is different. That's the the awakening of the gonads there would be the development of the testes And then you'll see roles of androgen and secondary sex characteristics more like facial hair and voice changing and cracking, as well as development of the of the penis and testes growth and enlargement as well. So some similarities and some differences in those axes of maturation for males and females. And one of my favorite things in studying puberty is that the time course of these axes also differs on average between boys and girls. For instance, in the progression of puberty for girls, the growth in height is among the first things to begin as well as breast development. And so that's why you'll see girls with their growth spurt, right, and maybe the third, fourth, fifth grade. But for boys, the growth spurt isn't one of the first stages of puberty, or one of the first events of puberty. Instead, it's development of the testes, for instance. And that growth, the the change, or the growth spurt doesn't happen till the very end of puberty for boys. And so that's why you'll hear some men say, like, yeah, I grew an inch in my senior year of high school or even grew, you know, a couple inches in college. So I think that's a fun perspective on even though both girls and boys have the growth spurt as a key element of puberty, when it happens in kind of the process of puberty differs, differs for them.

Nick Jikomes 16:36

I see. So, you know, there's there's sex differences in terms of when these changes commence. And there also seemed to be some kind of unknown environmental influence that that's shifting the time course here systematically across the population.

Adriene Beltz 16:51

That's right. That's right. It's harder to know whether puberty is happening earlier for boys as well. Because some of those earlier markers for puberty are just not as well studied. It's harder to measure and assess puberty and boys, at least in the behavioral sciences, which is, which is where I work. So we know less about that shifting time course for boys. But for girls, it seems to be there.

Nick Jikomes 17:18

And so, you know, obviously one of the changes that females exhibit is they start menstruating. One of the one thing I want you to clear up at the beginning, too, I talk mostly to basic researchers from from the animal world. What's between ministration the menstrual cycle and the estrus cycle?

Adriene Beltz 17:36

Yeah, different species. Right. So the menstrual cycle humans, the estrus cycle in a lot of rodent species, and the estrus cycle is shorter and can be more frequent. You know, in humans, the the menstrual cycle is roughly 24 to 35 days, kind of any range in there would be considered typical. And, yeah, and from there, and from there, we'll cycle

Nick Jikomes 18:05

and how does so how does the Metro cycle in humans differ from other animals, but my understanding is, you know, one of the ways that the human did certain other animals are different from any other mammalian species is, you know, for many species, the females simply are not at all interested in sexual activity, except basically, when they're ovulating, there's very clear, visually clear physical changes that that allow everyone in the species to see when that is. But in human beings, and I think maybe some other primates or a few other species, that's not the case, we still have the cycle. But you know, females engage in sexual activity throughout throughout the cycle. And there aren't as many crystal clear sensory cues to kind of specifics as to you know, where she is in that phase.

Adriene Beltz 18:53

Yep. And I think you've said it well, and even for an individual herself. Read we, and perhaps you're gonna ask about this coming up. But the menstrual cycle is often discussed as different phases. And ovulation is one of those phases, but delineating what those phases are in humans is actually quite a challenge, and doing so well. And reliably I don't think we're great at as a field because it does require constant monitoring of a person. You know, like I said earlier, and really capitalizing on some of these ideas of like individual differences or variability that we mentioned earlier. You know, there's any, there's a variety of different cycle lengths that that would be considered healthy and typical, usually 24 to 35 days. But even an individual doesn't always have a cycle. That's those same numbers of days that can vary within a person and you'll hear you know, some kind of rule of thumb for where ovulation occurs like in a in a quote unquote typical cycle, whatever that means. You know where ovulation occurs, you know, usually within like a two or three day kind of period in the teens somewhere. But so if day one is usually defined as the first day of bleeding, so when there's bleeding that's considered day one. And when you get to the leader teams, you know, you'd have two or three days when ovulation is occurring. The best indicator of ovulation is like luteinizing hormone spike, I'm not really the estradiol or progestin changes that a lot of folks use. But even within a person when ovulation occurs can differ across cycles. And another thing we don't consider broadly in research, although it's getting much better, is that many cycles can be an ovulate Tori. So that means no egg was released during that cycle.

Nick Jikomes 21:01

So the cycle still happening. And just that that part of it simply doesn't happen for some reason.

Adriene Beltz 21:05

Right? Right. So in terms of changes to the uterine lining, and in terms of bleeding and hormone fluctuations, they can be happening might be a bit blunted, if an egg isn't released, and that would be considered then in an ambulatory cycle, but they're, they're really relatively common. And so if you're working with populations and women where you're trying to bring folks in, during like a certain phase of the menstrual cycle, which like I said, is very loosely defined hard to do changes across people different across people. The awareness that some cycles are, you know, and Avi LaTorre, is also important to consider. And so you

Nick Jikomes 21:45

know, you've mentioned you've mentioned estradiol, progestin luteinizing, hormone, follicle stimulating hormone, or am I missing any there? Are those sort of the key handful that fluctuate? And who's you know, relative phases? Define who's relative, you know, peaks and troughs in terms of blood levels? define these different phases?

Adriene Beltz 22:04

Yes, yes, really, you know, follicle stimulating and luteinizing hormone, you know, surrounding ovulation. And then there's some like typical, again, typical, saying very loosely with air quotes, levels of estradiol and progesterone, that kind of mark the phases. So for instance, when bleeding is occurring at the very beginning of the cycle, both estradiol and progesterone will be quite low. And then progesterone will stay relatively low, and they'll start to be a peak or an increase in Astra dial. And that's usually what's considered the follicular phase of the cycle. And then estradiol will come down a little bit, but still stay elevated, and there'll be a big increase in progesterone. And that's the luteal phase that happens. Right around or right, right, following depending on the individual person, ovulation, and then if the egg is not fertilized, then both progesterone and estradiol will decrease. And menstruation world will occur again. So that's, that's the general patterning. But what those levels and cut offs are and how long they last, right, that's quite variable.

Nick Jikomes 23:28

And so, you know, there's obviously some variation, but there has to be some phase locking here. You know, generally there is a, you know, a somewhat predictable cycle, thinking, you know, I'm gonna ask you like, where that comes from, you know, thinking by analogy, we say, with a circadian rhythm, it's pretty easy to think about, you know, where the phase locking in a circadian rhythm comes from, because, you know, we've got eyeballs, they detect the light fluctuations that are, you know, happening as the sun goes up and down every day. And you know, from there, you you get the 24 hour circadian rhythm that's tied to the sun going up and down every day. Where Where does the phase locking for all these hormone changes come from? What's what's actually coordinating them? Yeah.

Adriene Beltz 24:08

Again, another fabulous question. And, you know, my, my training is in development. So, you know, when you ask a question like that, it'll be like, Oh, well, it depends. And it changes drastically across the lifespan to even within a person and with other reproductive events. For instance, we know that after menarche so the first, the first period are first bleeding and adolescence, it takes usually two to three years before there's some predictability within a person for those phases. So, you know, there can be really long cycle really short and condensed, there can be missed cycles early on, right? So you know, as the system is really developing, and then the same thing happens obviously surrounding pregnancy and Um, and breastfeeding, if if folks breastfeed, you know, post birth, that often the, the menstrual cycle, you know, won't be there or at least enough to, to instigate bleeding that we can see for some period of time, but that changes across folks. And then the same thing when you get up to menopause, you know, menopause is when those cycles become irregular again, but you menopause is defined as not having a menstrual bleed for 12 months. And so sometimes folks can go six months, you know, or three months or there's, there's some sort of inconsistencies there. So this idea of other phase locking is a fun one to think about. But these are really dynamic, dynamic events and rate can be highly modulated as well by things like diet by other reproductive events or conditions, polycystic ovary and Demetrio says, and of course, right hormonal contraceptives can influence this cycle as well.

Nick Jikomes 26:08

Are there other like social sensory cues that can regulate when when menstruation is happening? So for example, I know that in other species, you know, females can pick up on pheromones released by the presence or the absence of them from males, and for other things like this. And there's folklore at least. And I don't actually know if this is truly folklore or this is true that females humans can synchronize their cycles by you know, living or cohabitating together, which would imply some some kind of, you know, sensory based synchronization. Is that true at all? Do it. The females?

Adriene Beltz 26:47

Yeah, I don't think there's strong evidence. Now. I don't think there's strong evidence. But of course, right. There's, there's folklore and you a couple of studies or reports out there, but I don't think it's overwhelming now.

Nick Jikomes 27:01

And okay, so you've you've already alluded to the question somewhat, but and I know this is fairly broad, with no, probably specific answer, but how, how much variation is there between women of a comparable age and developmental stage in terms of their menstrual cycles in terms of how the hormones are fluctuating? And how consistent they are? And how long they last? is? You know, is the is there just is it all over the map? Or is there a fair amount of consistency?

Adriene Beltz 27:29

When you're comparing between people on this? Yeah, I think it's quite diverse. And like I said, even within a person over time, so to give you a sense of this, for instance, some of the best approaches if we were to bring someone into the lab, and most of my work is on hormonal contraceptives, but I collaborate quite a bit a bit on our menstrual cycle studies. And so some of the best approaches, if you really want to, say, make an association with the follicular phase are with ovulation, and some sets of behavior. So if you really wanted to investigate, you know, whether these hormone fluctuations seem to have consequences for how we think and act, we would start by assessing someone or asking someone to track their cycle, if they're not already doing that quite regularly. So when did you start bleeding? How long were you bleeding for, then track the number of days until they started bleeding again, to do this for two or three cycles to get a sense about how long is this person cycle at least recently. And then, in a best case scenario, we would assess hormones across those cycles as well. Because the best way to tell if someone really is in a different a different phase of the cycle, is to look at changes within a person over time. So if we can have those hormone assessments, and compare them relative to hormones on other days in the same cycle, and relative to other cycles, we can say, then we can map per person, okay, I can see like the increase in extra dial, I see that a coincides with when bleeding ended. And right here is when progesterone started to increase. So yeah, I can say pretty confidently for this person, you know, the follicular phase was days, you know, eight through 10. And you could do that for other people as well. And the follicular phase might be eight through 10, might be five through seven might be eight through 12. But that's the best way we can map these things is by asking someone to track themselves hopefully have hormone levels and then look at those hormone levels within a person and really, like quite literally map their cycle maps that map to peaks.

Nick Jikomes 30:04

And next one asked about variation within individuals. So we've mentioned that there's this interesting population effect happening, we're puberty and females are shifting early and early time points, presumably, presumably, that involves some set of environmental inputs. We know that there's variation between individuals. We, how do things like physical activity, and as a consequence of the amount of physical activity, you know, BMI or body fat composition, how to things like that, how to things like diet impact, the dynamics of menstruation.

Adriene Beltz 30:39

Yeah, they can definitely have impacts. And I'm gonna start to sound like a broken record, it really depends on the person. You know, we know for instance, with high intensity, physical activity, especially in an endurance linked to physical activity, menstruation can can stop or be interrupted. Right? If caloric intake isn't matching physical demands, for instance, and right, that's called amenorrhea, when menstruation stops, and it can be due to food restriction, it can be due to high caloric output a combination of both of these things or rate to a variety of other conditions as well. So so we know those those things have impacts. And there's, I think we're beginning a little bit to understand some of the unique links with you know, with higher BMI is, for instance, some hormonal contraceptives, we know don't will work as well, in individuals with higher weight. And that's important to consider to make sure that everybody has options that are working for them.

Nick Jikomes 31:50

And then, you know, we've mentioned that these, you know, the sex hormones are very powerful, they get into the bloodstream, they can cross the blood brain barrier, they activate their receptors, wherever they're present, including in the brain, including neurons, this is going to lead to lead to changes in gene expression, and all sorts of other cellular changes. So from that perspective, you would expect that different aspects of brain function are going to track with where you are in the menstrual cycle. And then again, we've got another area where there's lots of folklore, and I'm not even sure how much of it is folklore where women are perceived to have changes in personality and mood, and even cognition in terms of where they are in that cycle. So to what extent is, is that folklore true? Or has it been studied at all? And to what extent do we know that there are any clear sort of systematic changes in cognition, or mood or anything like that, in terms of what phase of the menstrual cycle someone said?

Adriene Beltz 32:46

Yeah. These are fun questions, because unlike in animal models, we can't experimentally control nearly as much in humans, right? We're not even sure we have to go to great lengths to make sure we're measuring the menstrual cycle Well, before we can even begin to look at things that it might be associated with. And then when we do look at things that the menstrual cycle is associated with, and you named some of them that, that, you know, folks think about a lot, emotion, you know, mood, cognition, well, emotion, mood, cognition. These are also you know, behaviors that are influenced by a variety of things, hormones certainly play a role. And emotion hormones certainly seem to play a role in cognition. But they're not the only things that play a role in emotion and in cognition. So when we when we try to understand what role hormones might be playing, we need to make sure that we're considering all of those other multifaceted influences as well. I can tell you a study that my group did to really address this. And this this issue and like you said, Is it is it folklores are some scientific evidence for it? There's scientific evidence that hormones influence mood that hormones influence cognition, but there's not scientific evidence that when women are more variable in mood or cognition than our men, right, they just similarly variable but for different reasons. And this is critical because for decades in a lot of biomedical including animal and human research, women weren't considered as research participants. They weren't recruited. They didn't serve as research participants, because there was this notion that the menstrual cycle makes behavior and women variable. And what we're trying to do as scientists is control variation. And so this menstrual cycle is getting in the way of us seeing how our experience demand, how this medication how this situation really influences behavior. So women were excluded from the search as a way to kind of control or maybe understand the question better. That's what the thinking was, there was a

Nick Jikomes 35:14

way to try and control for something that was presumed to be a source of variability.

Adriene Beltz 35:19

That's right. That's right. But there's not good evidence that it was really a systematic source of variability that needed controlling. And that an example from my group is that we followed folks with a natural menstrual cycle, we followed men, and then we followed folks using hormonal contraceptive everyday for 75 days, and at the end of each day, ask them to reflect on a set of 20 emotions, you know, how interested were you today? How scared were you today? How irritable were you today. And then across those 75 days, and we did it intentionally, because that would be two cycles for most people to menstrual cycles for most people. We use some statistics to quantify how much within a person, their emotions really did go up and down both their positive emotions and their negative emotions. And when we did that, and then we compared the groups of naturally cycling women to men, they didn't differ in these emotional variability indices.

Nick Jikomes 36:27

That's actually um, did you see the recent paper? There's a recent paper in rodents, where they did 3d imaging and did unsupervised clustering of spontaneous behaviors of rodents, males versus females. And I think the basic results in the basic question was, are females, in fact, more behaviorally variable? And what they found was no,

Adriene Beltz 36:45

yep. Yep. I saw that one. And there was one earlier by Joe Becker, who's actually my colleague here at Michigan and her collaborators. Where we did, they did the same thing with physiological signals in rodents, looking at things like basal body temperature and other physiological indices to see if there were differences in variability.

Nick Jikomes 37:06

So So one thing that's kind of interesting here is, on the one hand, you know, we know as you said that, you know, hormones have a very profound impact on Cellular Physiology on the brain and behavior. We know that these things cycle, the menstrual cycle and and other cycles that change throughout life. It would be shocking if there weren't behavioral and cognitive changes to some extent that track with the systematic fluctuations in hormones. And yet, you've just said that we've got evidence that there's not more variability for women as compared to men. But on the other hand, we've got this expectation that there should be some changes as these hormones fluctuate. So does that imply that? Do those two things together imply that there are comparable fluctuations in men? So so it's not that women aren't varying across the estrus across the menstrual cycle? And in terms of things, it's that men are also varying at that timescale?

Adriene Beltz 38:02

It could be at that timescale. I think that's one plausible explanation. Another plausible explanation is things like emotions are complex, and emotions matter for them, or sorry, hormones matter for emotions, but maybe in different ways for different people, right. And here's the big one in different contexts. Right? It matters. If you have a high stress day, if you're in the office, if you're traveling, you know, if you slept well, if you ate well, that when it comes to things like emotion, there's, there's lots of different reasons people could fluctuate, it could be, you know, and you mentioned timescale, you know, we assessed emotions every day in that study every day for 75 days. And like I said, intentionally across two cycles, but you could imagine assessing emotions at a shorter timescale, and looking at variation there. So I think, and some kind of some of the commentary that came out of our study on that topic was really, you know, men and women ride the same emotional roller coaster, you might have gotten on the roller coaster for different reasons. And your experience on the roller coaster might be a bit different, but were nonetheless kind of on the same emotional roller coaster. So I think the other explanation, right, is that emotions are complex and these things in the gendered behaviors of i that I study a lot, they don't have one cause and they don't have one consequence. They're really multifaceted, you know, complex human traits.

Nick Jikomes 39:40

Are there any like obvious physiological changes that track with ministration? Beyond the obvious so for example, you know, when we look at some of the species differences, it's not you know, we don't we don't look like a baboons or other species. We're the females have these sort of very, they're literally It looks sort of like science to conspecifics to say I'm ovulating right now, I may be receptive to sexual behavior right now, are there any physiological, physiological changes in terms of you know, skin or anything else that track with, you know where you are in terms of the menstrual cycle.

Adriene Beltz 40:17

There certainly are. And like most things, it depends on a person, but basal body temperature is one base. And, and again, you have to know, as an individual, like what your basal body temperature is, you have to track yourself over time in order to detect these changes. You know, you can't necessarily do a check one time and know what your cycle is, you know, but you can over time, you know, see some patterns of fluctuations. Things like progesterone, they, they affect different people differently. But depending on things like we discussed, like cell, or sorry, receptor location, density sensitivity, but you can sometimes see skin changes associated, you know, increased oil and acne for some folks at certain phases of the cycle. And there certainly are consistent reports often nearing menstruation and right this is associated with things like PMDD, premenstrual or premenstrual dysphoric disorder, that there can be some mood and negative changes that negative emotional changes that some people feel very strongly proceeding, preceding menstruation, and right, these are very real and very common. But they're not what you see within a person and what a person knows of themselves right? After having this like cyclical experience for most of their reproductive life, where individuals can detect these changes for themselves, it doesn't mean, you know, like we were talking about with our fluctuations and comparisons to others, that there aren't other big indicators, big events that influence emotion for other people in different ways, you go to a big sporting event, you know, the emotions go high, low all over the place, you know, different folks kind of have different cues for themselves when it comes to things like emotion. So it doesn't like I said, it doesn't mean that hormones don't matter. They do and very strongly for some folks. But there's a lot of other things that matter to

Nick Jikomes 42:34

so when a woman becomes pregnant, so at the point, the egg is fertilized, what are some of the the key hormonal changes that that start to take effect, and maybe this will be a good lead into starting to talk about hormonal contraception?

Adriene Beltz 42:51

Yeah, in terms of a lot of the hormones that we've been talking about, you'll start to see or they'll start to be like large spikes in estradiol, and especially in progesterone levels, like unlike, especially for progesterone much beyond what would be seen in in typical menstrual cycle. There's a lot of other hormones at play, too. And those are the types of hormones that a pregnancy test would pick up on, for instance. But in terms of what we've been talking about large spikes in extra dial and especially progesterone,

Nick Jikomes 43:23

and are those are those spikes are they sustained?

Adriene Beltz 43:28

Like most things, that would be like a cycle within a pregnancy. So you'll see you'll see rising levels, and I say spikes, because sometimes it depends on the person, it depends what number pregnancy this is, and age and other characteristics of the pregnancy. But sometimes those initial increases that kind of surpass levels the individual has been exposed to before, they're very noticeable to the person. But then once they are sustained a bit, the body the individual kind of adapts to, to some of those sensations. But then there can be other consequences for you know, a more prolonged exposure. So I think it it puts under a magnifying glass pregnancy does some of these phenomena that we think about a lot with behavioral links to hormones, such as going back to puberty, at puberty, hormone levels, right? Individuals are exposed to hormone levels that they haven't been exposed to before. So puberty is this transition in that in the level and then adjusting to the maintenance of that level. And so I think what I'm trying to say is, in terms of hormone exposures, we think of things like activation effects. Sometimes folks think that if the hormone is present, the behavior is on and Still hormone is not present, the behavior is off. That could be the case for some hormones and for some behaviors. But it's more complicated in that it matters whether it's the first presentation of that hormone, it matters how long that hormone has been there. It and other factors in the context matter as well. So So hormones aren't as simple as on and off when and for how long? And how intense also matter. Yeah,

Nick Jikomes 45:29

I think I can think of some examples from the animal from the nonhuman animal world, I think, right? Like, in rodents, I know this is well worked out in other species that, you know, you might have maternal care behavior exhibited by a female who was pregnant at least once before, but it's not even her offspring. But that first sort of spike that lasted for some period of time when she initially got pregnant has flipped some circuit in the brain. So that, you know, the presence of pups now just triggers that maternal that maternal care behavior or you get, you know, changes after, through and after pregnancy that leads to an increase in say, defensive aggression, you know, to protect the pups that are upcoming, and things like that. Do we see things like that in human females? I would guess that we do, but But you know, perhaps I toxin has that stuff been been measured or studied?

Adriene Beltz 46:18

Yeah, so those are organizational effects, right? That hormone, presence or intensity of a hormone at a sensitive period of development, seem to organize or maybe make permanent, right not make transient and this on and off way, but make permanent, some behaviors that that hormone was linked to. And in humans, we see the best evidence for that actually, with prenatal hormone exposures, so a fetus in utero being exposed. All fetuses in utero are exposed to relatively high levels of estradiol from from their parent or from their mother. But androgen presents in utero, right. That's what determines the appearance of the external genitalia for instance, if androgens are there, then verily verily zation occurs, which means the ovaries kind of form into testes and the labia fuses. And the testes descend into it. So So androgens organize how aspects of the physical body look prenatally. And we also know that the brain is sensitive to those androgens prenatally as well. And there's some behaviors that we see that differ on average between boys and girls and men and women that seem to be linked to prenatal exposure to androgen. So we do see those organizational effects in humans. I think some of the best evidence comes from from the work I just mentioned, on, you know, prenatal androgen exposures. But there's a lot of hypotheses right now that maybe puberty is another period of brain organization. So if you go through puberty earlier, the brain is thought to be more sensitive to those hormones earlier in development. And so for whatever behaviors, those hormones matter, for, you'll get more of them. And maybe permanently, pregnancy is thought in a similar way. And in some of our work, we're thinking of hormonal contraceptives in the same way. It's an exogenous hormone influence a certain period of time.

Nick Jikomes 48:34

Yeah, I mean, there's, I mean, there's a lot of fascinating questions there. So to sort of summarize some of what you said, basically, you know, when it comes to many of these hormones, having the right level of the right hormone, or the right combination of them at the right developmental time point, can lead to organizational changes, or persistent changes in tissue structure and architecture, or persistent changes in behavior via changes to neural circuits that outlast the hormone so that even when the hormone levels go back down or fluctuate to a different level, you get a persistent, you know, the tissues are gonna still be there, or the behavior is still going to persist. They are potentially irreversibly.

Adriene Beltz 49:10

Yep. Yep. And so we would call those, like I said, organizational effects. And we know there's certain we call them sensitive periods in development, when hormone exposures, you know, can't can do that. And right, there's a lot of interesting work right now, in what qualifies those effects. Can you reverse those effects? Or how long do they last? When do they fade away? But it starts to create this picture. And like I said, I'm in developmentalist. And this is what really interests me, and that kind of hormone exposures across a lifespan then, you know, layer on each other. And that's why we have these great individual differences and behaviors that we now see. You have this hormone layering across development, plus all the fabulous content So that humans live in, that influences those same behaviors.

Nick Jikomes 50:04

Yeah, so I mean, so this would imply that if you were to introduce exogenous levels of some hormone, in the prenatal environment and the postnatal environment in the adolescent environment, that could have potentially profound and persistent effects on the trajectory of tissues developing including the brain.

Adriene Beltz 50:21

Yes, it's possible. Yeah. And for for good, or maybe not.

Nick Jikomes 50:26

Yeah. So you know, maybe we'll keep that in mind. But now let's, as we talk about hormonal contraception and how it works and when it's used and what phases of development. Let's just start out with a very simple question. How do hormonal contraception contraceptives used by women, the most common ones say, how do they work? Yeah.

Adriene Beltz 50:48

A fun question because they work in different ways, depending on what the form of hormonal contraceptive is. And I think sometimes that's not realized. For instance, in oral contraceptive the pill will have, on average, the more common or the more common, the most commonly used pill is a combined oral contraceptive, and combined, meaning it contains both exogenous levels of estradiol and progesterone, as we call those progestin. So it's got synthetic estradiol, synthetic progestin. And when taken at the same time, every day, it basically suppresses ovarian function, it stops the ovaries from, you know, secreting those same endogenous levels of estradiol and progesterone. Because the system senses that those exogenous levels are already present in the bloodstream. So some down regulation occurs,

Nick Jikomes 51:52

so progestin estradiol taken every day, you're going to have a boost in the levels of those that's going to shut down ovarian function is that what people mean when they say that these things basically are supposed to mimic pregnancy is that the direction of the hormonal changes you would see in a pregnancy?

Adriene Beltz 52:08

The these things are really, really difficult to map. Because the endogenous, it's hard to compare the, the potencies of the exogenous hormones to the endogenous hormones, I see. So we know the exogenous ones are potent enough to,

Nick Jikomes 52:30

to do that to shut down

Adriene Beltz 52:33

and basically take over the cycle through this kind of external regulation. Right. And so combined oral contraceptives, they have an active pill phase, active meaning these are the pills that contain those hormones for 21 ish days, usually. And then there'll be some placebo pill or maybe placebo supplemented with some iron or something like this for four to seven days. And when, when the placebo pill is taken, it's not menstruation that occurs, but there is a withdrawal bleed. And so that's kind of how the cycle is mimicked. But we can't compare well, to the exogenous levels.

Nick Jikomes 53:15

What's the point of doing that, to mimicking the cycle in that way, by having a placebo? Why not just not have placebo?

Adriene Beltz 53:23

Yeah. A lot of folks think that and don't take the placebo pills. And so they'll just stack up their active pills, so that they don't bleed. And that has a lot of life benefits for a lot of folks. Not to have to deal with that. It's convenient. Yeah. And it's more comfortable. Some of the thought is that it really had to do with some of the marketing, right, this idea that it's mimicking a natural cycle, that folks will know they're not pregnant, if they're bleeding I see that provides some assurances, but there's no

Nick Jikomes 54:08

sort of deeper medical, biological reason there.

Adriene Beltz 54:14

Some folks might also argue that it's good to have a break from those exogenous hormones. But

Nick Jikomes 54:22

that's also interesting, because if it's good to have a break, that that brings up some other questions.

Adriene Beltz 54:28

Right. And I don't necessarily think that's well supported because in other forms of hormonal contraception, like the intrauterine device, for instance, there is no blank break. So in theater and device, there's an arm and plant. There's other what that what are called larks or long acting reversible contraceptives, and so in in things like that, including the IUD. The IUD does not contain a synthetic estradiol, it's progestin only and It's mechanistic action isn't necessarily ovarian hormone or ovarian function suppression, but changes to local morphology. So the presence of higher doses of exogenous progesterone. In the intro uterine space increases things like cervical mucus can change the the narrowing of the of the cervix and can make pregnancy rate less likely.

Nick Jikomes 55:33

I see so so it's it

Adriene Beltz 55:36

is different.

Nick Jikomes 55:36

I see. So with the IUD, it's there's no estradiol. It's just progestin. And the changes, it sounds like you said that there may or may not be some change to ovarian function. But there are also just just physical changes that basically provide a physical barrier to the sperm getting to where they need to go for fertilization to happen,

Adriene Beltz 55:59

at least at least early on. Right, the questions and there's also is most IUDs in the US are approved for up to five years. So after insertion, right there long acting, they can they can stay in place for up to five years. And then there might be some changes to ovarian function. There's also like endometrial thinning, and right many folks using IUDs. And stopping having a period, but they don't might, they might not necessarily because ovulation could still be occurring.

Nick Jikomes 56:38

So we've got multiple forms of contraception here for women, you've got oral hormonal contraceptives, you've got things like IUDs, a natural question is why a woman would choose one or the other. And I think that's tied to the question of why a woman might want to discontinue the use of one of these forms of contraception. So let's just say you're a hypothetical woman, you want contraception, hormonal contraception of some kind? Which former statistically you're most likely to get first? And what are the odds that that's going to work as intended without unwanted side effects? And if it does have side effects, what are the side effects likely to be? Yeah.

Adriene Beltz 57:18

It's such a loaded question, because there's lots of different reasons, folks might want to use hormonal contraception. And I think it's also important to acknowledge that there's a lot of folks who use hormonal contraception who don't identify as women, as well. So it's really a reproductive health measure. And which form is a good form? Depends can depend on the reason for you.

Nick Jikomes 57:45

Let's say it's a woman who is reproductively viable, and wants to be sexually active but does not want to get pregnant.

Adriene Beltz 58:00

I'm trying to think of the best way to answer this, I think a lot would depend on in the US. Right, the to directly answer your question where she goes for that source of contraception. And what her age is, you know, for instance, among a lot of younger folks, I IUDs are often offered, because they're long acting, you don't have to worry, you don't have to get a prescription refilled every month, you don't have to keep that prescription active. You don't have to worry about you know, forgetting or missing a day or something like this. And so these are some of the benefits of the of an IUD, for instance. But IUDs are progestin only. And some folks don't want to have right IUDs require an office visit to insert, you know, can be a pretty painful procedure. And some folks don't want to do that and are much more content with just taking a pill. So I think in in the US, and in a good scenario, there'd be a conversation between a physician and someone who wants to use you know, for that reason, and the their situation, can they refill a prescription? What's their comfort level with an office visit? It would really be these types of practicalities that drive the prescription decision. And the things that I mentioned about well, these are different contraceptive actions, they could be influencing the brain and behavior in unique ways for unique people. Those aren't as much part of this conversation. It's more about the efficacy for the contraceptive purpose if that's why if that's why somebody's taking,

Nick Jikomes 59:51

um, how common is it to discontinue the use of a contraceptive due to unintended had side effects or side effects that that aren't tolerated by by an individual. And what some of those tend to be. How common is that? And are there any clear patterns in terms of why women say that they're stopped? Did they want to discontinue use of say, the oral oral form of hormonal contraception or the IUD version of hormonal contraceptive?

Adriene Beltz 1:00:20

Yeah. There's so, so many different reasons and, you know, good and comprehensive data on this, you know, are challenging, especially, because, you know, we're talking here in the case where someone's using for contraceptive reasons, but 40 to 60% of folks are using hormonal contraception for other reasons. For endometriosis for PCOS for PMDD. Right.

Nick Jikomes 1:00:50

Yeah, briefly define each of those terms.

Adriene Beltz 1:00:52

Yeah, yeah, good, good point. polycystic ovary syndrome. So can have really a lot of pain in the reproductive area, sometimes high higher androgen levels, when they're cysts on the on the ovaries PMDD, we talked about you premenstrual dysphoric disorder. And so sometimes for some people, those natural sight cycle fluctuations we were talking about, can trigger some maybe negative mood, negative emotion, and other physical side effects as well. And so when folks will then use hormonal contraceptive, it kind of evens that out, right, because it's often the same dose of a given a given pill at a given time. dysmenorrhea is really painful, heavy, long periods of bleeding. So really intense episodes of bleeding, amen area would be when folks Stop, stop bleeding, and might want to kind of take that over exogenous ously endometriosis rate when endometrial tissue kind of grows outside. The places it should be can be very painful, can take folks out of work can be very hard to function. And so in a lot of these cases, and many others, having some exogenous form of ovarian hormone regulation can help even out these processes can help folks get back to work to get back to being themselves. So in a lot of cases, it's not just contraception, it's really a form of, you know, reproductive health management.

Nick Jikomes 1:02:38

Obviously, it's sounded like you said, something like, roughly half of the women using hormonal birth control are not primarily using it to avoid pregnancy. They're using it for one of these other reasons,

Adriene Beltz 1:02:49

at least in data from our group. So when we work with, you know, a large, young adult population, and we'll see about depending on the given study, and what our inclusion exclusion criteria are, we'll see about half Yep, who are saying that they're using for reproductive health purposes, or reproductive health purposes, right, and in combination with contraception.

Nick Jikomes 1:03:17

And so, you know, we've talked about all these sex hormones. Depending on the version of hormonal contraception one is using, it's going to be either estradiol together with progestin, or just the progestin, but in either case, you're gonna have at least one of those at elevated levels. So you're adding an exogenous sex hormone into the system, it's going to cross the blood brain barrier, I think, and is it fair to say that if you're on one of these hormonal contraceptives for any significant length of time, that it's definitely definitely going to lead to some kind of changes to the structure and function of the brain?

Adriene Beltz 1:03:53

I'm a scientist I can't say definitely. And, and we can't really, again, it's really, really hard in humans, because we can't compare those levels to what would be happening with a natural cycle, right? And to changes that might have occurred with those endogenous hormones, endogenous hormones as well. And you know, that that's, that's kind of the state of the science right now. We're working to try to refine like mass spectrometry with with some of these assessments to be able to understand different hormone different exogenous hormone levels in the blood, but even when we know what they are in the blood, we don't necessarily know in humans, these components of receptor density sensitivity and and whatnot. So so we know it's a player in the system. And we know for some people that there are behavioral side effects some good some intended if you have endometriosis, If you have PMDD, they're intended positive side effects. And for for some other folks, they have side effects that are less pleasant and that weren't intended. And so to get back to your question, and how many folks change or switch, I think these are very common, very common. And the changing and the switching doesn't always occur. Oh, I didn't like the pill. So I'm going to switch to the IUD, especially the pill comes in all different kinds of formulations as well. We I mentioned there's the synthetic estradiol, and usually ethanol estradiol. So there's, in most almost, this is changing slightly. But right now in the US, it's largely ethanol estradiol, but the progestins come in all kinds of different forms and generations. And the form and the generation is determined by the other synthetic hormones from which that particular progestin was derived. And so some progestogens have higher progestational activity than others, some have androgenic activity, some have no androgenic activity at all, meaning that the way that that synthetic progestin was derived, it can also have some receptor bind to some androgen receptors. And we have a little bit of a sense of what those activity levels are not active in an individual, but by looking at how those hormones work in other human or animal tissues. So we have a sense, like relatively, which ones are more progestational activity, which ones are somewhat androgenic. So some of those factors will be taken into consideration. If an individual says, I don't like how this one's making me feel, or it's not working for me, right. So if you if there's breakthrough bleeding, things like this suggests to breakthrough bleeding is when there's some bleeding or some spotting during the active pill phase. And so that means there is still some ovarian function. And that means that the the exogenous pill isn't completely controlling, right the ovarian function as is intended. So in those cases, there'll be probably a higher dose given or maybe consider a different type of progestin formulation. So in that way, it's like a lot of other medications. Okay, this is working a little bit, let's get the lowest effective dose. And, and if it's not working for you, either due to physiological or emotional side effects. Decisions will have to be made you tweak it a little like, I like the pill. So we're going to try a different pill or I don't like the pill at all. So you could try something different, like the IUD. And there's a lot of other options too. We didn't talk about right patches, shots, RMM plants?

Nick Jikomes 1:08:11

What are what are some of the more common like side effects or risks? With the more common hormonal versions of birth control? The one that I hear about the most often that I can sort of remember from commercials and stuff? Is is blood clotting and blood issues? Is that is that is that in fact, the common one? And are there any others?

Adriene Beltz 1:08:32

Yeah, yeah, like, venous thrombosis is a big one my blood clotting. And it is linked with some types of progestins more than others. Right. So if that would be a risk for somebody stay away from that type of progestin. Yeah, so So that one's pretty common. You know, the the emotional, I'll say side effect there's a lot of conversation about right now is depression, and potential depression risk associated with some forms of hormonal contraception as well. And some people really have strong and intense reactions to two, maybe all hormones are exogenous hormone sensitivities broadly, or maybe to, you know, particular ones. And so, so that's another one that's really in the news, right?

Nick Jikomes 1:09:26

I see. So there are side by side effects that I guess we can call purely physiological. And there are some that are also related to mental health. Yeah,

Adriene Beltz 1:09:35

there seems to be some of the most compelling evidence comes from there have been several studies in in Europe, where they've been able to do population wide studies. There was one done in Denmark, where they tracked individuals as they were newly prescribed a hormonal contraceptive, contraceptive, and then they tracked them following up to six months and they found six months out, they they assessed um depression diagnoses as well as SSRI. So serotonin selective serotonin reuptake inhibitors. This is a common medication used for depression treatment. So they looked at depression diagnoses as well as SSRI prescriptions six months following, and they did see some on average increased risk. The risk was modulated though, for instance, younger folks, teens saw more risk than older folks. And it did seem like some of the risk was most likely to track with actually the progestin component of the contraceptives more than the estradiol component. And so

Nick Jikomes 1:10:53

that one's the more than that one's in all of them. Yeah, yep.

Adriene Beltz 1:11:00

Yep. But the generation really seems to matter. So what type of progestin really seems to matter? Right, the A tricky element of interpreting studies like this is like, yes, there, there does seem to be some increased risk at the population level. But the other piece of this study that's quite interesting is that when they kept tracking these folks, after four to seven years of hormonal contraceptive use, those individuals actually had reduced risk for depression. So there was some initial increase. And then, over time, there was actually some protective factors associated with it now. Right? We know that with all medications, if you have a negative side effect, you're not going to use it for four to seven years, most likely, right? Yes, yes, yes. If you're still using the pill, or the IUD, after four to seven years, or those didn't have negative,

Nick Jikomes 1:12:05

it could just be an artifact of the people who worked for didn't give him side effects. Stick around. Yeah.

Adriene Beltz 1:12:10

But the interesting thing, if you're talking about, like individual prescriptions, and individual level decisions, is that for all of those people in that study, it worked? Well, it did what it was supposed to do. And over time, you know, they had some reduced risk associated with it. But there was also a very meaningful subset of folks who saw some increased risk. And so both things can be true, Randy can really help some folks. And at least in the short term, it it can really, you know, pose some risk posed some risk for others. And, you know, where I think this all falls down is only an individual can really know, okay, why do I want to use this medication? And do those potential risks outweigh what I'm seeing as the potential benefits? And and that has to be an individual level decision, and an informed one, which is why we do the work we do in my group to try to help provide that information so folks can make the choice that's right for them.

Nick Jikomes 1:13:14

I want to ask you more about any sort of concerns or extra concerns one might have around when you start using hormonal contraceptives, in particular certainties some very, very early, right after the onset of puberty, say, versus waiting until, until full adulthood. You know, given everything that we talked about, you know, sensitive periods of development, some of these persistent changes that can be triggered, and then outlast the, you know, spike in hormone levels. Thinking about things like that. Is there any is there any extra concern about younger women who haven't maybe finished fully maturing and developing yet starting conscious hormonal contraception too early?

Adriene Beltz 1:14:01

So when it comes to puberty, I'll start there. We were talking about earlier the there's a growth access to anarchy and gonad archy and how men archy. The first menstruation first period was part of gonad archy, or the maturation of the ovaries. Interestingly, and I don't know folks always widely realize this, but men are gay occurs very late in puberty. We said some of the first things that happened for girls are the growth in height and breast development, but menarche happens quite late in in puberty. And so it's unlikely that folks would be seeking out hormonal contraceptives for contraceptive reasons or for reproductive health reasons. Before menstruation has begun. Of course, it can happen, right? There's definitely you know, personal considerations but you I say that because often then folks are very close to or have completed puberty by the time they would be seeking out hormonal contraception. But to your point about things being early, if puberty is shifting for everyone to be quite early folks can have completed girls gonna have completed puberty, but you know, be 1314 years old, you know, even even younger than that, and looking into hormonal contraceptives. And, you know, from a brain development perspective, right, we know, brains continue to develop into early 20s. So we so that's a consideration. And a lot of the literature out there right now, on potential depression risk, for instance, there really does seem to be an age factor. You know, I mentioned the one study from Denmark that, you know, found heightened risk for, for younger folks. There's other data that shows something similar that the pattern really depends on age. And so I think this is a key consideration. You know, if we're talking about, you know, what I call the complex calculus of, you know, do I use hormonal contraceptives or not, that has to be a consideration for for younger folks. You know, if this meant, where you can, you could think of a million and a half reasons where the pros would outweigh the cons, or the potential risk and in a given scenario, and you can think of some reasons where maybe that wouldn't be the case, as well. But I think what we can do is, if there is a risk, be aware of it, and put supports in place, right, if there is a risk, it doesn't necessarily mean don't use hormonal contraception, it means be aware of what the risk is, and watch out for it, assess it, mitigate it through other means, you know, if, if, despite the rest, you know, there still seems to be, you know, a good reason or a choice for your for using that medication.

Nick Jikomes 1:17:08

Um, have there been any longitudinal studies looking at any links between hormonal birth control and psychiatric conditions?

Adriene Beltz 1:17:18

Longitudinal, so I mentioned the ones from the one in Denmark, there's been a similar one, there's been a couple coming out of Europe, and a lot of the results are consistent, there seems to be some elevated risk associated with age in many cases, and seem to be associated with that progestin component of contraception. In the US, we don't have as many of those longitudinal studies. And the ones we do have, they're not prospective. So even though they're longitudinal, they don't have information from folks before they use contraception when they start and then following. So that means we can't really rule out selection criteria, right? In in who chose to use and why and who stopped using and why. So it's really hard to interpret some of those data. And the perspective what some of those studies from Europe that I mentioned that our perspective, that's where some of the most compelling information comes from. The challenge with it, is that their population level so you see an increased effect broadly. But how does that translate to an individual? How does that play out in individual factors? Another thing that did come out of those studies that I should mention is that, you know, maybe some risk associated with age, and if folks have a previous history of, you know, mental health challenges, or high hormone sensitivities, right, then they're also at an increased risk. So this is information to be aware of. So those folks, you know, can can consider it and what's the best choice for them?

Nick Jikomes 1:19:22

I see. So, yeah, so history of mental health. That was relatively easy, because if you if you know, your family history, then then you'll know it. What is how does someone know their sensitivity to hormones?

Adriene Beltz 1:19:34

Yeah, sometimes through other medications that they may have taken. They'll know they had, like, oh, I tried, you know, this hormonal medication five years ago and did not feel good for me then. Yeah, probably a hormonal contraception, you know, could be in that kind of same set of experiences for you that

Nick Jikomes 1:19:55

I also want to ask you about, I know you've done some work on this. Just the effects of hormonal contraceptives are on cognition, generally speaking, what kind of effects have been looked at? And what do we know there?

Adriene Beltz 1:20:06

Yeah. On cognition, so we've focused in in our work and others as well, in terms of like verbal skills, and verbal memory skills, and then some spatial skills. And I think two sets of findings are beginning to emerge. One is that the extra dial, it seems like it's the extra dial component of like, would be of pills, right? Not IUDs, because they don't have that extra dial component, there seems to be some role for extra dial in verbal memory. Right. So remembering lists of words, anything you'd have to remember that has this kind of verbal or language element to it. That's also consistent with some of the rules we see for extra dial in like a menopausal hormone therapy, for instance. So this, this, you know, link between estradiol and verbal memory is, is not a new one. And it seems like there might be some evidence for it and hormonal contraception as well. It also seems like lower doses of estradiol might have some facilitative roles in spatial skills. So we focus a lot on a particularly difficult spatial tasks called three dimensional mental rotations. So it's basically imagine like a three dimensional like Tetris like object. And so basically, an object made out of a bunch of small cubes that go in kind of three dimensions. And then you'll see that object, and then you'll see four other objects that look like they could be that one, you have to indicate which of those four other objects is an accurate rotation.

Nick Jikomes 1:21:53

They're all in different orientations. And you got to match it. Yep.

Adriene Beltz 1:21:57

If span is a three dimensional space, which one of those objects matches you know, the target? This is actually a task that shows a very large gender difference, there might be some roles for androgen in this week. And and we see that may be lower doses of estradiol or folks using pills that contain that high androgen component the, in the progestin. So it's a highly androgenic progestin that they might do a little bit better on this particular task. But again, for these cognitive findings, we do, we are beginning to kind of see this story emerge. But just like when we were talking about with emotion earlier, there's a lot of things that matter for verbal memory, right? There's a lot of factors that contribute to spatial rotation. And so the effects we're seeing linked to hormones, these seem to be there, but they're small, on average, they might be big for some people, but on average, they're quite small, and they combined with a lot of other things.

Nick Jikomes 1:23:05

How do you? So we talked about hormonal IUDs? We talked about the hormonal pill. How do the non hormonal forms of contraception work?

Adriene Beltz 1:23:17

Yeah, so like, the copper IUD, for instance. Yeah. copper IUD is is one that's considered a lot in this space. Its mechanism of contraceptive action is also a bit unclear, but it like the hormonal IUD, it seems to work through kind of local morphology, that the presence of copper, intra uterine, for instance, in the contributor environment, increases local inflammation, right, and that local inflammation ends up thickening cervical mucus and providing some contraceptive action. So it's not interplaying with the the ovarian hormone levels, it's influencing the the local morphology.

Nick Jikomes 1:24:06

Does that have any, you know, potential negative consequences of chronic the sort of chronic local inflammation there?

Adriene Beltz 1:24:15

I'm honestly not sure. I can say that the copper IUD rates, right. So like everything we've talked about, some folks love it, but on average, it's not incredibly well tolerated. Pain, a lot of a lot of complaints of increased bleeding or, or longer bleeding. So there's huge individual differences in response to it.

Nick Jikomes 1:24:44

Well, we've covered a lot already, and I've already learned quite a bit. Is there anything that you think it's important to reiterate or or about anything that we talked about, or any sort of final thoughts on this general subject that you'd like to leave people with?

Adriene Beltz 1:24:56

Yeah, I think one thing we didn't really talk about But maybe indirectly, we've kind of referenced it. So it might be important to say directly is who we've talked indirectly about how go natural hormones and hormonal contraceptives, specifically, they obviously are working somehow in the human brain, right? How are they working, our best evidence comes from, you know, non human animal models where this can be done, experimentally, and, and, and manipulated in that way. But kind of as we've talked about influences on behavior and on cognition, we said, well, they're doing something in the brain. And then they influence behavior and cognition. The human neuroscience research on what exactly they're doing in the brain is really, really at its beginning stages. And so sometimes some of these studies come out and say, Ah, hormones change the brain, like, of course they do, right, the brain is an endocrine organ, obviously, you know, our brains have evolved to be changed by hormones. So, so some of those approaches are a bit obvious. And the, the science in this space is exciting, and it's emerging. But it is not conclusive yet, for for the, the good or the bad, if you will. And I think the important part to emphasize about all my work, and really why we're in this space, is to understand individuals, if we can figure out where risk is increased, and where hormones are having positive impacts for some people and, and identify factors that might matter for that relationship, then we can provide individuals with more information, the information they need to make the choices that are best for them, right, only they can weigh how the different pros and cons matter. So kind of wide sweeping, you know, this is good, or this is bad, isn't really helpful, in some ways, because there's individuals at all places of that decision pipeline, who have to make choices that are unique for them. And so I'm hoping some of the work we do just helps helps inform that so folks can be the healthiest versions of themselves possible.

Nick Jikomes 1:27:22

All right, Dr. Adrienne belts. Thank you for joining me.

Adriene Beltz 1:27:25

Yeah, thanks so much for having us.


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