Sex Hormones and Eating Disorders: An Evolving Relationship

CLINICAL CONVERSATIONS

Sex hormones are well established as factors that impact neurological and psychiatric development. Now researchers are investigating how sex hormones contribute to eating disorder pathology.¹ Psychiatric Times sat down with Tom Hildebrandt, PsyD, director of the Center of Excellence in Eating and Weight Disorders at Mount Sinai, to learn more about the biological and psychological mechanisms that contribute to eating disorders, as well as biomarkers and novel treatments.

Psychiatric Times: We know hormones can have a profound impact on the brain, and you have focused on this relationship with eating disorders. Can you elaborate on your research on the role of hormones in binge eating, specifically?

Tom Hildebrandt, PsyD: I have been studying hormones and their role in binge eating for about 15 years or so. The interest really came out of understanding how gonadal hormones, in particular androgens and estrogens, affect the brain in a way that creates a higher likelihood of disinhibition, but particularly in response to food cues. Binge eating is characterized predominantly by a loss of control over eating, which we can conceptualize as a response to eating cues that one is unable to inhibit themselves from following through on.² We thought, because there are sex differences in the expression of binge eating, that there are developmental differences in terms of when the onset of binge eating occurs, and it is a reasonable hypothesis that sex hormones were playing a role in that process. The more interesting details that have emerged are in both the timing of when this happens, as well as what kinds of roles androgens and estrogens are playing in the brain. For individuals who are at risk, they may have trouble remaining, we might say, immune to cues from the environment and from their body itself to limit eating when it is unnecessary.

PT: Can you expand on the role of hormones in other eating disorders, such as the role of estrogen and serotonin in the development of bulimia nervosa?

Hildebrandt: When I say binge eating, I really think of bulimia nervosa and binge eating disorder because the symptom of binge eating is observed across both diagnoses. We think the process is probably pretty similar, and particularly with bulimia nervosa, we think of a larger sex difference and maybe a wider range of impulse control comorbidity that happens in the context of the disorder. We started asking this question many years ago: What role, specifically, are sex hormones playing in the brain of those who go on to develop bulimia nervosa, particularly in adolescence? There were compelling data in the field coming out of Kelly Klump’s lab at Michigan State University.³ They started to tease apart this idea that there are differential risks between boys and girls as they develop into adolescence, and that the heritability risk from parents to children really seems stable prepuberty. But then it appears as though androgens are protective into adolescence, whereas they are kind of risk inducing for those born as females.

This idea led us to ask, what could be going on in the brain that might facilitate this process? Of course, there is the idea of programming that happens prenatally, where individuals’ brains are organized around sex hormones in the womb as the children are developing. There is this differential window in adolescence when the body starts producing its own hormones––the surge that comes from enough body fat stores that leads to what we call puberty, this onset and production of gonadal hormones. What was particularly interesting in the way we were thinking about it is that hormones have a metabolic pattern that is really governed by an enzyme or an enzymatic process, driven by aromatase. Aromatase is present all over the body, but it is particularly salient in the brain. We will call it localized regulation of sex hormones within the brain or sex hormone metabolism. Because estrogens are sort of created from testosterone, the argument that we were sort of following was, is there or are there aromatase differences in men and women, and who develops this problem to begin with, such that their brains are being exposed to less estrogen? Is that risk even more exacerbated among those born as boys?

PT: You noted the sex differences in hormone development. Have you found any other factors simultaneously influencing eating disorder development?

Hildebrandt: Some of the recent work that we just completed tells this story nicely. If we look at the amygdala, or if we look at the arousal circuit within the brain, and particularly the prefrontal cortex’s ability to prevent disinhibition, we see tons of aromatase differences between men and women; we see a greater exacerbation in folks who develop bulimia nervosa, relative to at least those healthy controls whom we initially evaluated. For us, it is very exciting because it shows this process is not governed necessarily just by the presence of the hormones themselves, but actually by the metabolism, and these metabolic differences can lead to very specific regional differences in the brain. In our case, this arousal circuit or this appetitive circuit that is very important for managing eating cues seems to have less estrogen exposure because of reduced aromatase availability, and we find that pretty compelling as a biomarker, if you will, for eating disorder risk. Of course, we have a lot more questions to ask and answer about how variability in the aromatase pathway leads to different individual differences and one’s ability to produce aromatase, as well as environmental or other influences that might affect aromatase along the way. But the translational work seems to show a pretty clear picture of estrogen’s role, particularly in those hypothalamic and arousal circuit areas of reducing appetitive drive. That sensitivity to appetite cues appears to underlie a lot of the dysregulation in bulimia and binge eating disorder.

PT: I am curious about the implications this will have for treatment. What do psychiatric clinicians need to know about this research?

Hildebrandt: It is a great question. You know, poking at hormones is hard to do, even with the best intentions in terms of thinking about interventions. I think for treatment, it might mean choices around birth control pills for women or that other types of birth control should be thought about carefully in terms of those at risk for binge eating or bulimia. For risk among men, looking for that kind of estrogen deprivation in the brain is going to be hard to do. Particularly, positron emission tomography studies are not easy to conduct in everyday populations, so we are going to have to get more creative about how we figure that out. In terms of treatment, if you think of the metabolic pathway for generating more estrogen and if you have a weak enzymatic or metabolic process driving the creation of estrogen, one way to increase the amount of estrogen is also to increase its precursor—to increase testosterone. Are there ways to do that safely? It would be great if we had a way of delivering it to the brain without the peripheral effects, and we could think creatively about how to do that.

We can also consider developmental windows and really being clear about how to prevent onset, prevent that triggering. If this is a vulnerability that acts more like a trait, one that we cannot manipulate so easily, are there developmental windows where we have to prioritize a different kind of intervention or environment that allows us to help that individual thrive, given that brain difference? If their brain is going to be more responsive to those kinds of cues in the environment, it would be great to find ways during those developmental windows or periods of time when they are at highest risk to help them through without developing a disorder.

PT: How might monitoring hormones play a broader role in psychiatry in the future?

Hildebrandt: Maybe the most compelling part of this work is that it has implications well beyond binge eating disorder and bulimia nervosa in the sense that it can help us understand a broad range of psychopathology where impulsivity or a difficulty responding to cues from the environment leads to less than optimal functioning or impairment in some cases. The understanding that maybe sex hormones play a role in this, either as a trait or potentially as a therapeutic target in the future, has a way of helping us understand this larger pattern in psychopathology, where sex differences have characterized it for many years.

PT: Thank you!

Dr Hildebrandt is a professor of psychiatry at Icahn School of Medicine at Mount Sinai in New York, New York. He is a clinical psychologist and director of the Center of Excellence in Eating and Weight Disorders at Mount Sinai.

References

1. Tsappis MW, Shrier LA. Sex hormones and psychiatry. J Am Acad Child Adolesc Psychiatry. 2022;61(suppl 10)S113.

2. Giel KE, Bulik CM, Fernandez-Aranda F, et al. Binge eating disorder. Nat Rev Dis Primers. 2022;8(1):16.

3. Rolan EP, Mikhail ME, Culbert KM, et al. Estrogen moderation of genetic influences on eating disorder symptoms during gonadarche in girls: specific effects on binge eating. Psychoneuroendocrinology. 2023;158:106384.