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- [00:00]
A
Hello, I'm Aaron Lohr, and this is the Endocrine News Podcast. We all know that stress leads to a number of negative outcomes. Today we're talking about how early life stress may influence youth substance use initiation and some endocrine factors that may be helping to drive that influence. Joining me today is Dr. Alexandra Donovan of the Charles R. Drew University of Medicine and Science. She recently published an abstract at Endo 2024 entitled Early Life Stress and Pubertal Predictors of Youth Substance Use Initiation. Does sex Moderate the Relationship between early life stress, puberty and Substance Use Initiation? Thank you for being here today, Dr. Donovan.
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B
Thank you for having me. This is going to be fun.
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A
It is going to be fun. I wish everybody came in here saying that. I know they think it, but it's nice to hear it being said. So your study looks at early life stress, pubertal status, and sex hormone levels as potential predictors of substance use initiation. First, let's talk a little bit about early life stress. What constitutes early life stress and how prevalent is it?
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B
So early life stress is negative experiences that span the range from abuse to neglect to family conflict. A family member goes to jail, lower socioeconomic status. You know, if you're struggling to pay the bills, it's going to be stress, and you'll get it through your parents and it comes out in the kit. So it's the experiences of stress that are extremely large or chronic as well, and it's fairly prevalent. The latest CDC figures that I looked up said about 61% of Americans have at least one factor. And considering that divorce is considered an early life stressor, we can kind of see how it's that common. About 17% have four or more early life stressors, and that tends to be the group that is suffering the most from the really programming impact that these early life stressors had on their body systems. And you start to see increased rates of heart disease, depression, substance use disorders. If you go to a treatment facility. There's been some literature reading that in the treatment facilities when they surveyed, there was a higher prevalence of early life stressors, multiple early life stressors, than in the general population. So you start to see some connections there, and we're starting to learn and understand that stress really affects everything.
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A
Also, one thing you looked at is a relationship between early life stress and puberty. Can you talk a little bit about how puberty enters into this conversation?
- [03:01]
B
Yes. So it's always exciting for me reading about the changes that occur in the brain and the body during puberty. And I think Back to when I was a teenager and I had no idea what was happening. But it totally explains everything I thought was happening at the time. The changes that occur in the transition from childhood to adulthood. We have these negative experiences that happen in childhood or up through adolescence. How does that translate to these detrimental factors that are still present in older adults? We have the transition period of adolescence where you have multiple body systems that are growing into being and you have the plasticity of the brain. You have your prefrontal cortex and your executive decision making areas that are growing and developing at that time. And part of that is connectivity to limbic systems and stress systems, the hypothalamic pituitary adrenal axis, the HPA axis that most people think of when I think of the stress axis that actually increases activity as they come into teens. So let's say that you grew up in a low resourced household and you dealt with domestic violence or situations of child abuse or even neighborhood violence. Let's say your family is supportive in there and that ameliorates some of the negative effect. But so you have this programming where there's constant stress, your body's constantly on alert and over time your body tries to compensate for the constant signal by reducing responsivity to that. So that sort of programs your body to respond to stress differently. And when you begin the process of puberty and you have the hypothalamic pituitary go natal axis starting to pump out sex hormones that is actually going to interact with the cortisol and your HPA system. So there's an HPA and HPG axis and they talk back and forth to one another. The literature states actually that in adulthood it's a direct activity of one, suppresses activity of the other, whereas in growing it's less clear. There's some where they sync up together and then as they begin to grow older and become more adult, then they start working more in opposition to each other. So a lot of studies have looked at these interactions and looked at the ratios, ratios of cortisol and testosterone, say. And there's some dysregulation there that is starting to explain some of the higher rates of depression and anxiety that you start to see around teens. Because that's really when some mental health disorders are starting to emerge. Which leads me to my point on sex differences, because that's really the other focus I want to look at. When you're talking about puberty, obviously you have these sex hormones coming in and growing the brain. And though there isn't Anything as concrete as a male brain and a female brain, you do have interactions of those sex hormones in these systems that are wiring together. You have a simplification of the brain systems that are growing together and your social interactions, your social brain is growing and you're learning how to deal with peers. And so there's a lot of stressors present on adolescents at the time. And you don't know it at the time because you're just going through it. That's just your day to day life. But if parents understand and if kids understand that there's a lot going on within you and you may feel like a big kid now, but you actually are still growing, you're still developing and you're not going to see some of the pitfalls and some of the bad decisions that you might make.
- [06:59]
A
I doubt you'd know a better, you know, where your, your interests lie and what you really wanted to focus on. I wonder if you could take some time to tell us about the study that you're presenting here at Endo, why you wanted to do it and maybe what you did and then afterwards you could tell a little bit about what you found.
- [07:14]
B
Right? Yes. So what I'm presenting at Endo is the connections that I found so far. I have an overarching idea and you know, I'm not the first one to have the idea, but maybe to put it together, the background literature on all these topics is more of a mosaic than a pathway. My hypothesis is that the early life stress sets up this altered HPA axis function which then throws off the HPG axis function. And you have a difference in the way that the brain circuits are set up. And that difference leads to increase in mental health symptoms like rumination or anxiety symptoms. Don't know all of them off the top of my head. And that leads to substance use as a coping mechanism because that tends to be why people get into utilizing substances on a regular basis at that age. So my study looks at some of the connections. I have multiple sort of steps in that pathway that I'm building. But the first one is to establish that we have the measures that we need and we're looking at the right things in order to find the connections. So my particular study is looking at the relationship of early life stress and I've categorized it into about three sort of domains. There is resources which I call environmental. So that's looking at parental education. It's looking at divorce or separated or widowed relationships, status and neighborhood income to get a read on the resources available within the family Second domain is family, and it's looking at family history of psychopathology. It's looking at your family environmental conflict. So day to day, how does the family communicate? These are measures that are given in surveys and the parents and children are responding to it. So family history, that's a parental. But for example, the amount of conflict in the family environment. We asked the parents and the kids to get a full view of what that is. And I averaged those two scores together. There's a measure of how much emotional support the child feels. And then the final domain is traumatic events. And there is overlap across all of these domains. Yeah, but the traumatic events is specifically asking about instances of abuse, witnessing domestic violence in the home and witnessing violence in your neighborhood. So looking across those three spectrum, I wanted to see what are the relationships, Are some of them more salient to substance use likelihood than others? And does this vary across sexes? Sexes here meaning specifically biological sexes. So that was the way that we separated the population according to what they were assigned at birth. And so we took a look at the data that we pulled from the Adolescent Brain Cognitive Development Study, which is a fantastic study. ABCD multi site national longitudinal studies started with kids age 9, 10. And the plan is to follow them for 10 years and take a whole bunch of measures, some of which I'm using for making these stress scores. So utilizing that information, what I'm doing is creating a snapshot of the baseline activity, meaning when they were 9 and 10, what were the factors going into how stressful their life was at that time point? And then looking at substance use initiation, have they started to use substances by age 13? And it's still really low percentage, only about less than 5% have said, yes, I've had a full drink of alcohol or I've had more than just a puff of nicotine or marijuana. And with a young age I'm only considering those three substances. But the database contains many more and I'll potentially expand as the kids get older and 16 plus maybe there'd be more illicit substances. So looking at that interaction and I examined males and females together, I separated the data out into males only and females only and ran the analysis as well. And so we're looking at do these early life stressors, are they significantly associated with use of alcohol, nicotine, marijuana?
- [11:52]
A
Now that you've teed it up, we're all on the edge of our seats. Want to know what you found. And also, is there anything in your findings that maybe surprised you?
- [11:59]
B
There was, yes. Yeah, and I can start there. So you May have heard me speaking a little bit on sex differences and the overall pathway I'm talking about and the depression and anxiety. We start to see sex differences right around the beginning of puberty. So before age 6, the rates of those mental health issues are very similar across sexes. You get into puberty and that's when you start to see more of a divergence. And there's multiple factors that go into that. It's not strictly biological. Of course we've got ideas about how society feels you should express yourself and what type of behaviors are reinforced. But it is interesting. And that sex difference continues in adulthood. You have more females that are coping with depression and anxiety than males. And that's a, you know, very popular in the literature to look into and dig into why some of those issues are. But these mental health issues are more likely in people with a history of early life stress. And so it seemed to me that adolescence was a good time point to dig into that. So I was surprised to find that males had more of a response to the trauma events, traumatic events of abuse and physical neglect or community violence. So I looked at how these incidents that happen when they're 9 and 10, whether they're associated with substance use, are they more likely to be using substances? And the answer varies by substance so far, which could be a factor of them being so young at age 13. In looking at the numbers, nicotine had the most effects and it was also the most used and that's nicotine, including cigarettes, including e cigarettes, including snus or chew tobacco, so any kind of nicotine. And we found that for males, they're more likely to use nicotine if they have more of a history of those traumatic events. So we found that connection and that wasn't the same in females. What was different in females, which we found across in our overall analysis of all substances and in the nicotine, was that they were more likely to use substances by age 13 if they came from a low resourced environment. So if they had a lot of what I termed environmental factors that were at play around age 9 and 10 and what was common between males and females. We saw this when we grouped them together and we saw it independently within each population, each sample group, male and female, was the family factors. And that really matched up with the literature because family psychopathology really impacts stress levels and it's very often found to be a significant factor in associated with later adult health issues and substance use. So that really tracked with the literature which helped us know that we were on the right track. We didn't get anything too bizarre. We also did an overall measure of just looking at. Okay, let's just say forget the domains. What about overall? And so both males and females had a response that overall. Yes, early life stress, the higher amount of early life stressors that you had, the increase in risk you had for starting any substance, which is what.
- [15:33]
A
That's the expected part. That's what she.
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B
Yes, but I was surprised a bit that it was already present so soon. It was a strong enough effect that we were able to detect it. We had about a little over 7,500 individual youths within the study that I was utilizing and even just 5% of that within that group, we were able to see who's connected and who used, who didn't use. And it's interesting because a lot of times other studies have looked at this question, but maybe within a higher risk subset. So, oh, we identified this family study and their low socioeconomic status status and they've got, you know, of history more deprived neighborhood. So we're going to track them and see how that plays out. This is a multi site, multinational study of all youths, the ABCD database. The study people worked very hard to match the population of the US in terms of the racial and ethnic profile of the sample, which is really important because, you know, minorities have been understudied in a lot of these studies. You'll take your population groups and it's predominantly white. So we want to see how these play out. Also as we're separating out these factors, there's a lot of really interesting papers coming out from that study as well. And if you're interested, you can go to the ABCD study website and you can see some of these publications that are coming out. So that helps with separating out. You know, you say there's maybe there's brain differences in volume, in race. Okay. But that's not because of the race. It's all these other factors that are present. And so it's really helping look holistically at some of the social determinants of health and some of these longer term aspects of how, let's say how trauma propagates forward across generations. You know, your parents don't know how to teach you good coping skills, you never pick up good coping skills. You have kids, you don't know how to teach them good coping skills. And cycles continues. The cycle continues. Yeah. And so that's what we found.
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A
Coming back to the part that was unexpected, is there anything in the literature that would help explain the differences you found between males and females? Or anything just from the data that you looked at in the database, is there any reason that we could look into to see? Well, maybe that's why it was different.
- [18:16]
B
Certainly. And there are other factors that I could always pull into my next study and see if that is what the difference is. So with the overall connection between early life stress and later substance use use or depression, anxiety, mental health issues, there's this idea of males tend to go the externalizing pathway, which covers oppositional defiant disorder, conduct disorder, adhd, those are termed externalizing disorders. Whereas females go the internalizing pathway, which is depression, anxiety, rumination, turning more inwards on themselves and versus pointing the upset and stress and expressing it outwards. So that's a general trend that has been seen and is debated in the literature. So it may be that these externalizing symptoms, one of them is substance use. So breaking the rules and doing something that is against the rules is part of this externalizing. So it may be that we're seeing the males are using nicotine and it's part of this externalizing pathway that we see in males, but not in females. Now, the link for females is potentially through effects of puberty. So previous literature has found that in low resource environments there is a tendency for girls to go through puberty earlier. And that is looking at it in relation to their peers. When we're talking about early versus late. And there are some other health problems that happen with early puberty that increases the likelihood of depression symptoms, anxiety symptoms, it increases the likelihood also of substance use. So it may be that the link that we see for the females of the environmental factors is potentially tied to is this group actually going through puberty earlier relative to their peers. And that's the link that I'm actually picking up on in the study. So there's some clarification that can be done certainly to the study and those measures are present in the database. So I can go back in and see, okay, are you an early puberty or late puberty person? And stratify it and see if that is the factor that that's involved.
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A
And it sounds like to me you're going to continue pursuing this. So what's next for you?
- [20:48]
B
So next we started to, and actually we did a little bit of this just prior to the meeting. Still working on the plane here. We're incorporating salivary hormone levels. So I say, you know, I think the hormones are doing this, I think the hormones are doing that. Well, you know, put the money where your mouth is and see what the hormones are actually doing. So There are measures of DHEA, which most times works in opposition to cortisol. The database didn't take a cortisol measure. So DHEA is also a way of me looking at it and estradiol and testosterone. So I'm able to take a look at what those measures were at baseline, and they take them every year. So I'll be able to incorporate more data as that goes to see how those hormones are shifting. So I can see, is this a normal trajectory? Do we have extremely high levels? Is this, you know, only in the high testosterone group? And some of the first analysis I've done is to look and see if there's associations between baseline salivary hormones and whether or not they have used a substance by age 13. So we're no longer looking at time. We're not going to see, are you starting earlier than other people are starting? We're saying, did you do it at all? And looking at it that way, we were able to see that higher levels of testosterone within females was associated with using alcohol, and higher levels of estradiol within females was associated with using nicotine. And I did do this analysis together, apart all combinations and didn't have an effect for males. That could be because usually the timing of it, females go through puberty a little bit earlier than males do. So it may be that we just don't have males beginning that process yet because again, this is baseline data, age 9 to 10, and saying, yeah, followed up, yeah, but as I follow up, I can see, okay, is there an effect? So there's lots that can be done within this. And it's very exciting to be here. And the more I'm here at the ENDO conference, the more other things I think about and you know, inflammation, metabolism. It's really great to see the academic silos being broken down as people are incorporating a more holistic view of the body. Like metabolism affects everything, and we have to consider that. And thinking from the individual protein receptors up through systems up to behavior and social connections, that all fits together really well. And that's the kind of science I enjoy doing, really is. Is thinking from that and. Well, that's probably because that's my background.
- [23:36]
A
No, no, I love that. And I'm hoping that folks who are listening, if you've never been to an ENDO before, that this is the kind of thing that might pique your interest. This is kind of what coming together at the annual meeting is all about.
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B
And next year is going to be in San Francisco.
- [23:48]
A
That's right. We are just about out of time. So I'd like to thank Dr. Donovan for coming on the podcast and sharing her work with us. Thank you so much.
- [23:56]
B
Thank you very much for having me. This was fun.
- [24:00]
C
That's all for this episode. I hope you enjoyed hearing Dr. Donovan talk about her research. Do you ever wonder how I picked what to cover or who to invite on the podcast? Well, most times I'm looking through recent publications or meeting presentations trying to find find something important, interesting and current. And sometimes, like Today's episode with Dr. Donovan, it's from you, our amazing listeners. When I get a recommendation from you, I really take a look at it. So if you have an idea for the podcast, send it my way by emailing me@podcastocrine.org that's podcastndocrine.org we'll be back soon with another fantastic dive into the world of endocrinology. Until then, thanks for listening.
- [24:49]
A
Endocrine News Podcasts are a free service of the Endocrine Society. To learn more or to become a member, visit the society's website at www.endocrine.org.