This transcript has been edited for clarity.
Jessica Sparks Lilley, MD: Hi. I'm Dr Jessica Lilley, and I'm the director of pediatric endocrinology at the Mississippi Center for Advanced Medicine. I'm in Tupelo, Mississippi, the birthplace of Elvis, and I'm here for a fireside chat with the Taylor Swift of Pediatric Endocrinology, Dr Madhu Misra.
I want to let you introduce yourself and tell everybody what you have been up to in your area of expertise and why we are about to ask about anorexia nervosa and its manifestations to pediatric endocrinology.
Madhusmita Misra, MD, MPH: Thank you so much, Jessica. I'm Madhu Misra. I'm the chief of the Division of Pediatric Endocrinology at Massachusetts General Hospital and the Fritz Bradley Talbot and Nathan Bill Talbot Professor of Pediatrics at Harvard Medical School. I'm a physician-scientist, and much of my research has been in the field of neuroendocrine and bone alterations in conditions that span the weight spectrum, from anorexia nervosa to the female athlete with amenorrhea to, more recently, obesity.
Lilley: One thing we all noticed during the pandemic was the startling rise of disordered eating, especially with anorexia nervosa; there were more inpatient admissions and more sequelae. Now, we're all in the weeds trying to decide how to best take care of these teenagers and young adults. We know there's "ivory tower" medicine and we know there's "rubber hits the road" medicine. I think we represent both ends of the spectrum, all the way from Mass General to Tupelo, Mississippi.
When I have these young people come into my clinic, I'm noticing, especially with the young women, that we are faced with how to deal with the secondary amenorrhea. We are putting them on transdermal estrogen. We're cycling with progesterone and doing all the things we're supposed to do. Then what? That's where we're stuck. What are the things we need to think about when these young people come into our clinic?
Misra: Thank you for sharing that experience. These are conditions that are hard to live with. It's very hard to be a patient with functional hypothalamic amenorrhea, and it's very hard for the treating physician to know how best to help our patients.
The pitfalls are many, right? You can get fixated on weight regain and menstrual resumption. I think that is really, really important to emphasize, because the first step in managing functional hypothalamic amenorrhea is to address the low energy availability stage that characterizes these patients and work on optimizing energy availability. That can be a long process.
I'm not sure that a pediatric endocrinologist can do this on their own. We need help from dietitians with expertise in eating disorders, as well as psychologists and other therapists.
I talk to my patients about how, when the body is in a state of energy deficit, it's going to shut down its reproductive axis because it senses it's not the right time to bear a child. From an evolutionary perspective, this makes sense — that when you're in a state of energy deficit, you don't want to grow a baby inside you, so the reproductive axis shuts down. The best strategy to get the axis working again is to get the brain to know you are in a state of energy balance, at least, if not surplus.
The other component of functional hypothalamic amenorrhea that is less appreciated is the issue around chronic stress that also contributes. While we're talking about caloric intake, exercise, and energy expenditure, I think it's important to think about the stress these young women are going through and to be sure they have the psychological support they need to deal with that stress. In addition to the pediatric endocrinologist and the dietitian, a psychologist, therapist, or psychiatrist is critical.
We know there are certain measures that help. Cognitive-behavioral therapy helps; family-based therapies help. When it comes to our athletes with amenorrhea, the team extends to the coaches and athletic trainers because they have a big part in the athlete's life. It's important to have them be part of the team so they can contribute to the treatment plan and be supportive of the athletes. The parents must be part of the treatment plan. When you have that large team working together with the patient, then you start to make some inroads into helping the patients get better.
At the same time, I think we all know it's not enough. It's not always sure that a menses will return. That's when you start to get into, should we be starting transdermal estradiol with cyclic progestins? Why do we do that? What do we do before that?
Before we get to estrogen and progesterone replacement, I want to be sure that everybody is calcium and vitamin D replete. It would be silly to have a patient with a vitamin D level of 12 ng/mL that you start estrogen and progesterone in and don't treat the vitamin D deficiency first.
We know that getting calcium and vitamin D supplements is not sufficient to improve bone density and bone health, but it's important to optimize these nutrients to be able to mineralize bones. I have long conversations with my patients about the impact of functional hypothalamic amenorrhea and low energy availability on their bone health. It can be a wake-up call for a patient to realize there is impact on bone.
I will get a baseline bone density on my patients who have functional hypothalamic amenorrhea. I spend a good 30 minutes talking about the importance of the pubertal years in terms of bone accrual and the attainment of peak bone mass in the early 20s to the mid-20s, and how having a lower rate of bone accrual during puberty can lead to suboptimal peak bone mass and what that means in terms of future bone health.
I talk about the importance of the pubertal hormones, estradiol, and to some extent, testosterone also. That's important for bone health. I also discuss growth hormone and insulin-like growth factor 1 (IGF-1) and their impact on bone health. Growth hormone and IGF-1 are both anabolic; estradiol and testosterone are antiresorptive, but with some bone anabolic effects as well.
We talk about cortisol, which is made in excess and has multiple deleterious effects on bone. For many of my patients, when you talk about this in some detail, they start to get it and are curious about their bone health. Not that it always fixes the issue, but again, it's important to have those building blocks in place in developing that understanding of what these conditions can do to you.
Lilley: When you present all the future risk and all the things that can happen if we don't get the disease under better control, or if we don't get the care plan optimized, you are never sure what's going to resonate.
I love your analogy. You've written a wonderful article for Medscape about how these teenagers will come in with 70-year-old bones. I think it's a powerful metaphor that people can think about and say, gosh, that's not something I'd want, thinking about how this is going to impact their skeleton for the rest of their lives, thinking about impact on fertility and everything else they're dealing with. I think the bone health piece is much more powerful than we imagine it is.
Misra: I also talk about some of the newer data we have regarding the impact of estrogen deficiency and its replacement on neurocognitive measures and issues around emotion and mood. We've shown that estrogen replacement has an impact on anxiety measures, for example. There was one study that did show that girls with anorexia nervosa who received estrogen replacement had an improvement in trait anxiety, which is the tendency to be anxious over time.
We also showed that, with weight regain, when you didn't receive estrogen, there was an increase in anxiety. If you received estrogen with weight regain, you didn't have that increase in state anxiety or body dissatisfaction seen in the absence of estrogen. There actually seems to be an impact on eating behavior. The drive for thinness gets better and body dissatisfaction gets better with estrogen replacement. It seems that estrogen deficiency does the converse, where it's deleterious potentially to these measures.
Lilley: Estrogen is a powerful hormone. It's one of my very favorites of all the hormones. I think it can feel very overwhelming for those of us out here by ourselves. For me to send a patient to a sports nutritionist, it's at least an hour drive, and I have patients who are economically disadvantaged.
I think even accepting a diagnosis of an eating disorder is difficult for many patients in rural areas — it's a diagnosis around which there's denial, and so trying to realize we shouldn't try to do it alone is important.
Many times, these patients won't come with an eating disorder label on the referral. They'll come in with slightly abnormal thyroid function testing, or rapid weight loss. I think it's important for us to always keep it on our radar that this is something that can be present. We can even see some energy deficit and some malnutrition in children whose body mass indices (BMIs) aren't even that low. You're getting a good sense of that history — what kinds of nutritional measures are coming in, and what the quality of the caloric intake they're getting is. Any thoughts on that?
Misra: Jessica, you bring up a really good point. There is frank anorexia nervosa as we know it, associated with low weight and the eating behaviors associated with the condition. Then, there is atypical anorexia nervosa, which is very much part of the DSM-5 categorization of eating disorders.
Atypical anorexia nervosa refers to the kind of patients you just mentioned, who lose a large amount of weight but are still within the normal range for weight and BMI. You would think that because the BMI is OK, they're probably OK, but they're not. Actually, we just submitted a paper that shows that young women with atypical anorexia nervosa also have low bone density — not quite to the extent as in typical anorexia nervosa, but still low. A large proportion of them have low bone density Z-scores. It is important to pick up atypical anorexia nervosa, as much as it's really important to pick up anorexia nervosa that's typical.
Lilley: I'm becoming concerned. I rejoiced when the first American Academy of Pediatrics guidelines came out that urged use of glucagon-like peptide 1 receptor agonists in children with obesity. The number one state most years in pediatric obesity is Mississippi, and Medicaid has just made the decision — and I think it's really groundbreaking — to make sure that we cover with prior authorization and proper patient selection.
I'm excited about it. We finally have something that will work. But I'm [also] really worried about empowering clinicians to address disordered eating and malnutrition or poor nutrition, especially in places where you don't necessarily have a psychologist, a nutritionist, or someone else to help with this. I think we all need to bear that in mind. Do you share these concerns for these medications?
Misra: I think there are major concerns regarding the emphasis on weight loss in general. I think it's important to be worried about obesity and to think about how to manage it appropriately, but my psychology colleagues tell me that they are seeing many more eating disorders that happen in people with obesity losing weight suddenly.
I remember doing a plenary talk for one of the eating disorder societies. Many of the questions that I got were related to weight loss and obesity and the association with eating disorders.
My psychology colleagues tell me it's important to see whether we could loop in psychology when we're treating patients with obesity who are going on these very powerful medications that cause extended weight loss. I completely understand it's very hard to get behavioral therapy or psychology support in many parts of the country. We are really blessed, being here in Boston.
I wonder whether there's a way to engage other kinds of providers who can provide some support. Are there social workers who have an interest in the area who could be looped in to help with patients dealing with body image issues as they lose weight? It would be great if we could provide them with that support, but I don't want to presume that we can, because we're all so busy in our clinics and we have so little time for the patient visits. These are long conversations, and it takes a fair amount of skill to detect the emergence of eating disorders and to manage it appropriately.
Lilley: I think we have to keep our eyes and ears open as we're going into these encounters and realize that there are pitfalls and different things that we need to be aware of, rather than saying, "I can't do it; I don't have anywhere to send them. What am I going to do?" We need to make sure that we don't cause harm to patients when we're trying to help them.
Misra: One of my colleagues, who runs the obesity pharmacotherapeutics clinic, has been having some extensive conversations with my psychology colleagues. There are questionnaires you can have patients fill out on an ongoing basis that might be helpful, if you are by yourself, to help determine whether some of these behaviors are emerging that could be addressed early on.
Lilley: Before they become problematic. One thing that we also notice as we're taking care of patients who are in recovery, or after treatment for the eating disorders, is that other hormone axes are affected. Thyroid is one that we often see — almost like a sick euthyroid pattern at the beginning and then the thyroid-stimulating hormone (TSH) bump. What do you see as you follow these patients long-term? When do you start to worry? How quickly do you expect the thyroid to adapt to the improvement in BMI as they start to regain weight and restore a healthy body mass?
Misra: That's a really difficult question to answer because it's so variable from patient to patient. The rate of weight regain is variable. People can gain weight and lose it again; there can be remissions and exacerbations of the eating disorder. Everybody's thyroid axis is a little different in how that recovery occurs.
I think it's important to know that, if there are subtle abnormalities in the TSH levels or the thyroxine (T4) levels, it's important to think of a sick euthyroid picture first before jumping to any other conclusion. Now, if you have a slightly elevated TSH with a low free T4, that's unlikely to be primary hypothyroidism. You would expect the TSH to be quite elevated for the free T4 to be low.
If there is a patient you're really confused about, go ahead and get the antibodies. Buy yourself some time. If the TSH is just a little high and your free T4 is a little low, not treating for some time is not going to do any harm. Treating could do some harm for sure.
I'm always hesitant to think of these subtle thyroid hormone abnormalities or TSH abnormalities as anything more than a sick euthyroid syndrome in patients who have these eating disorders.
Lilley: If they're coming in worried about rapid weight loss, as we're trying to get to the bottom of the diagnosis, we're often screening for Addison disease, celiac disease, and other things that can cause sneaky weight loss. Is there anything else you're thinking of as an endocrinologist when you're seeing these patients?
You mentioned growth hormone deficiency. I know we're seeing younger patients who have eating disorders. Is there any kind of scenario in which you would treat with growth hormone, or would you focus on healing the eating disorder and restoring body mass?
Misra: I would really focus on treating the eating disorder and restoring body mass; they have a state of growth hormone resistance, and not so much deficiency, because they have low levels of IGF-1 and robust levels of growth hormone. Also, when you give growth hormone in pretty high concentrations to women with anorexia nervosa, it causes a little bit of a bump in IGF-1 levels that's not statistically significant. It's not helpful, at least from a bone standpoint.
We did a study where we gave supraphysiologic doses of growth hormone (five to six times replacement dosing) to adult women with anorexia nervosa. There was no significant increase in IGF-1 levels or in bone formation markers. What was really concerning in the study was that the women who received the high growth hormone doses lost fat mass. That makes sense because growth hormone is lipolytic, but it is certainly not what you want to see in the condition. They didn't have weight loss, but they had fat mass loss.
There are some data out of France related to younger girls with anorexia nervosa who have an impact on height from being undernourished. They showed that giving growth hormone can help improve height outcomes. Now, when we look at height outcomes in our participants with anorexia nervosa in the study we did, we actually didn't find an impact on height, but that's probably because our patients were in the 12- to 18-year age range when they were diagnosed. Much of their growing had been done by the time they were diagnosed with the condition, as opposed to the cohort from France, where the girls were much younger and therefore there was an impact on height.
It was interesting that they responded to growth hormone.
Lilley: This is fascinating. You think you get one thing figured out, but there are many other cascades going on in the background.
Misra: There are all of the appetite-regulating hormones that are so interesting that go awry in these eating disorders. Some of them make sense, and some of those changes do not make a whole lot of sense.
Lilley: Some of them are kind of paradoxical in trying to unwind them and keep up. I know one of my biggest challenges is that I get the female athlete triad in my clinic often. We work on trying to get the calories up and get the activity down until we can get everything going.
While we're trying to restore menses — and we do start transdermal estrogen and progesterone — how long do you treat, and what measures do you use to be able to say, okay, let's withdraw this therapy and see if we're doing OK? Let's say that the [bone mineral density on] DXA has improved, we haven't had pathologic fractures, and we have a young woman who's on her way to healing. When do you feel comfortable withdrawing the supplemental estrogen and progesterone?
Misra: It depends on how the patient is doing in terms of recovery from the underlying condition. If a patient is able to bring her weight to a healthy point and keep it at this healthy point for several months, I think it's reasonable to give her a trial off transdermal estrogen and the cyclic progestin just to see whether they will resume menses on their own.
Even before we get to this, the one point I want to make is that as girls and young women regain their weight, there can be a lag period before they get their menses back. There was a study by Neville Golden's group from Stanford, where he showed that it can take several months of being at a healthy weight before menses resumes. Sometimes you might just want to be patient and give the patient a few months before you consider starting transdermal estrogen, particularly if she is on a good path toward optimal weight regain.
The other thing that Dr Golden showed in that study was that, on an average, the girls with anorexia nervosa who regained menses had a body weight at the time of menses recovery that was about 2 kg greater than that at which menses were lost. When you think about the target weight that you were aiming for, you need to think about what the weight was at the time that menses were lost.
Lilley: That's important to know. Having these parameters in mind is very helpful to us. I know many times these young women are at the age where they're starting to think about contraception. We might want to supply a contraceptive patch. Tell us why that's a bad idea or a suboptimal idea.
Misra: I'm going to first talk about the contraceptive pill and why that's a bad idea. One would think that, by this time, we all know that combined oral contraceptive pills do not improve bone density in young women with functional hypothalamic amenorrhea. I still get patients referred to me who are on the birth control pill for bone mass increases and not for contraception. That's problematic.
I think it's very important to recognize that being on a combined oral contraceptive pill can do two things. One, it doesn't help your bones. Two, it can take away the indicator of menstrual recovery, because it can be very reassuring to have regular menses on the birth control pill and to feel that you're probably doing OK for your reproductive axis. That's really important.
Transdermal estrogen is effective in improving bone health, whereas the combined oral contraceptive is not because of many reasons. One is because when estrogen is given orally — particularly as ethinyl estradiol, which is the kind of estrogen in the birth control pill — it suppresses IGF-1 because of hepatic first-pass effects. This does not happen with transdermal estrogen. Transdermal estrogen, which is actually transdermal 17-beta estradiol and what we use in hormone replacement therapy in this condition, will not increase sex hormone–binding globulin levels, whereas the combined oral contraceptive pill will quite dramatically. That would lead to a decrease in bioavailable gonadal steroids.
Other hormones are also affected by the route of estrogen administration, such as sclerostin and preadipocyte factor 1, and brain-derived neurotrophic factor, and they all have an impact on bone. It's important to recognize that the route of estrogen administration is important. In a woman who needs contraception, that is important. We need to think about what kind of contraception would work in this situation.
Combined oral contraceptives work, and if that's the only form of birth control that the patient is comfortable with, I would say do not withhold that. But it's important for them to recognize that this is only being given for contraception and that it's not going to have an impact on bone health; at least, it's not going to improve bone health.
With regard to the contraceptive patch, like the pill, it has ethinyl estradiol. It does not have 17-beta estradiol. We really do not have good studies at this point of time that tell us what transdermal ethinyl estradiol with progestin does to IGF-1 levels, to sex hormone–binding globulin levels, and to bone markers and bone health in general. We need those studies. It may be that they will be more effective than combined oral contraceptive pills. If I had to guess, I would say that the efficacy would probably lie between a combined oral contraceptive pill and the transdermal 17-beta estradiol patch in terms of bone efficacy.
Lilley: Thinking about the young women who come in with polycystic ovary syndrome: When you're choosing the estrogen dose that you're putting in these combined contraceptive pills, do you tend to lean toward a higher estrogen dose, just thinking about bone health? Often, our general pediatrician colleagues will come in and pick the lowest estrogen dose they can. To me, that feels wrong.
I feel like when you're in that main period of bone accrual, I would tend to lean toward a higher estrogen dose — like maybe even more like a Sprintec rather than a Lo Loestrin — not to mention the breakthrough bleeding and everything else that we say with the lower doses. Is that something that matters to you as a bone expert?
Misra: I don't think the combined oral contraceptive pill does much at all because we have used the 30-µg combined oral contraceptive pill as one of the comparison arms in the studies looking at transdermal estrogen, and 30 µg of ethinyl estradiol did nothing. Catherine Gordon's group has looked at the 20-µg ethinyl estradiol pill, and that did not do anything either. It seems that there are different opinions regarding what dose of ethinyl estradiol may be good for bones in women with functional hypothalamic amenorrhea.
Like you mentioned, some people will think that maybe a higher dose is more effective. Then there are others who feel that maybe a higher dose is not more effective because there's a greater effect on IGF-1 and sex hormone–binding globulin levels. It's tricky. Overall, neither the 20-µg nor the 30-µg dose seems to work. We haven't used the 15-µg dose, for example, in functional hypothalamic amenorrhea. There are some comparative studies in normal-weight, healthy people, but those are difficult to extrapolate to this condition. I just say that they're not going to be effective.
Go with what you would do in a typical situation; I wouldn't expect the decision to be impactful to bone in any particular way. There was a study by Anne Klibanski many years ago, in adult women with anorexia nervosa, and in that study, she showed that the very, very low weight women did seem to have some benefit from being on a combined oral contraceptive pill. This was a post hoc analysis. In that study, there seemed to be some effect. In our studies, we've really not seen an effect even when we looked at weight status.
Lilley: That's helpful to know. Shifting gears to thinking about our young men: We are seeing young men come in with eating disorders, affecting their bones. They don't have the red flag of menses to let us know how things are happening for them. What are your concerns when you take care of young men with anorexia nervosa or other low-weight eating disorders?
Misra: You're so right. Without that biological indicator of menstrual status, it can be so difficult to have an early diagnosis and to know what's recovery. One of the differences in terms of males and females with eating disorders is that many times the boys with eating disorders may not be low weight. It's just that they have very low fat mass. We talk about the Drive for Muscularity Scale as something to assess in young men as opposed to the Drive for Thinness Score that we look for in young women with functional hypothalamic amenorrhea.
A second issue is that it seems to take much more of an energy deficit stage to lead to hypogonadism and low testosterone levels in young men with eating disorders than…in young women with eating disorders, in terms of the estradiol levels and menstrual function in general.
There's been much thought into what kind of testosterone levels do we think are concerning in young men whom we think have eating disorders? Are we looking for really low testosterone levels, which we can find in certain situations? But many will just have low-ish testosterone levels. That is also important to consider in the context of body composition.
The other issue I'd mentioned briefly before was that, as you work with these young men in terms of optimizing energy status and weight regain or fat mass regain, when do you know that you're at a safe place? We just published a study in male athletes who are runners. We found — and it was a small study, so you need much larger studies to really validate these findings — that a BMI of even 21 was a differentiator in terms of who had low bone density and who did not. That's not something that you would typically think of as you're demarcator in a sense, right? We're thinking of a BMI of 18.5 or such, but is that uniform across men and women?
There are many unknowns when it comes to how we diagnose eating disorders, how we manage them, and what are the indicators of recovery and adequate recovery in young men with eating disorders. They certainly can have low bone density. Young male runners who may be in a state of energy deficit are not affected to as great a level as those with frank anorexia nervosa.
Lilley: Every time I talk to you, I learn something new. I appreciate the light you're shining in our field on all these important issues and the way that you're encouraging others. I appreciate your time and your expertise. Thank you so much for your time.
Misra: My pleasure, Jessica. Thank you. Thank you for asking all these important questions.
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Cite this: 'Startling Rise' in Disordered Eating: Caring for These Patients - Medscape - Aug 21, 2023.