New Treatments: Estrogen Patches

In the third in our series on novel treatments, Anorexia Myths chats to psychiatrist Dr Romi Goldschlager about a new trial looking at the effects of estrogen on anorexia nervosa 

AM: How did you become interested in the field of eating disorders?

RG: I first got interested in eating disorders work when I was a psychiatry trainee in 2018 and I worked for a year at the Royal Melbourne Hospital’s specialist eating disorders unit as part of my training. And it’s interesting that I came away from that wanting to do it because it was a really tricky job and very poorly resourced. I left work crying most days of the first six months of a one-year job. It was challenging, but I found the work interesting, and some of the consultants there inspired me with their compassion and their relentless hope for people who were in such a tricky situation. I think that’s what really called to me, that the kindness was probably the strongest thing that we had to fight against an eating disorder.

AM: I agree 100 per cent with that. They sound wonderful! And if everyone was like that, I think we’d have much better outcomes.

RG: But I thought it would also be really nice if we had a magic pill or recipe that would cure what’s an awful illness. And then I didn’t get the job that I wanted, so I ended up working in the general medical setting doing psychiatry work. That’s where you see people who are really medically unwell because of their eating disorder and not always, but often, very, very scared of getting better.

AM: How did you become interested in estrogen as a potential treatment for anorexia?

RG: The director of our centre, Professor Jayashri Kulkarni, has spent her life researching the role of women’s hormones in mental illness in general. And we know that women have twice the rate of all mental illnesses between the age of menarche to menopause. And pre-menarche and postmenopause your risk of mental illness goes back to that of men. We know that hormones play a big role. Also, we see debilitating mental illnesses like premenstrual dysphoric disorder and menopausal depression that often don’t get talked about but are really severe mental illnesses that have a very clear hormonal relationship. Part of Professor Kulkarni’s work is that she has been researching how to treat these illnesses with hormones, female hormones, and it’s found really good results for them.

The other thing that she’s done a lot of research on is the depressogenic effects of certain hormonal contraceptive pills. And she’s found that there’s one particular hormonal contraceptive pill called Zoely that is less likely to cause depression than others. The theory behind why is that the way the progesterone is synthesized more similarly resembles natural female hormones than in other contraceptive pills.

And in anorexia we also, for a long time, have thought that there’s a hormonal link. Its onset is often around the time of menarche, and there’s this big debate in the literature: does anorexia cause amenorrhea or does amenorrhea lead to anorexia. It’s not clear which way it goes, and there’s research to support both.

The other thing that’s really interesting is that there’s another peak risk for developing anorexia, which is in the perimenopausal period. This is not widely known about, and I think traditionally it was attributed to women going through menopause, maybe putting on a bit more weight and start getting more self-conscious. And it’s really been put down to this very superficial thing, but actually it could have an underlying hormonal cause. What we find is that it doesn’t matter if the menopause was surgically induced or naturally induced — the risk is the same. So, it’s kind of an obvious question: is there some relationship with estrogen?

And we also know that estrogen plays a big role in appetite, for kind of creating an equilibrium in your appetite. It influences a lot of the other hormones that manage appetite and weight management. And it’s also involved in a lot of mood regulation and cognition, a lot of the things that go off when someone has anorexia nervosa.

Estrogen is a really potent neurosteroid, or neurotransmitter, as well as being as a hormone, and it can also stimulate other brain receptors.

The other thing that we know is that physiological levels of estrogen, which is not what you get in the oral contraceptive pill but what you get from estrogen patches, do help bone mineral density.

So, we know that this treatment is helpful anyway for some of the physical effects of anorexia nervosa which are really debilitating — I had a patient once who broke her leg from dancing at a wedding and she was in her twenties. So, we thought, well, we know that it’s a helpful treatment in terms of bone density. Let’s do the research to see how it affects mood? How does it affect cognitions? How does it affect eating disorder behaviours?

So far we’ve had one patient who’s finished the study who was on active treatment, who was on estrogen. And the results in terms of the reduction in her eating disorder cognitions and behaviours, as well as kind of her mood and other symptoms, were profound. So, we’re really excited. It’s going to take another couple of years before we have enough people to draw significant conclusions from, but it’s certainly an exciting start.

AM: How is it hypothesised that the estrogen might work in a patient with anorexia?

RG: My sense is that it would work in a number of ways because estrogen plays such an important role both as a hormone and a neurotransmitter. I think it probably works in multiple areas of the brain simultaneously. Some of the existing research that’s looked at estrogen for people with anorexia has found that it helped manage the anxiety that people experience while they’re weight restoring and that it was easier for people to weight restore because they felt less anxious about it.

And we know that estrogen plays a role in the amygdala and areas of the brain that affect mood regulation and concentration. We also know that estrogen helps other areas of the brain to kind of regulate better, because it can stimulate other neuroreceptors. This stimulation allows them to upregulate or downregulate as needed. So, if you have a brain that isn’t firing properly or normally you may see those whole neurotransmitter systems being able to function better. If you think of train tracks with the signals, if the signals aren’t working properly, your train line is going to have chaos. But if you can get the signals for the train system working better, your trains will run smoothly.

AM: Have there been any previous trials with estrogen and anorexia?

RG: Not high-quality randomised controlled trials that have looked at the cognitive, emotional, behavioural and physical symptoms of anorexia. There have been some trials that looked at anxiety and anorexia nervosa and a whole lot of trials that have looked at bone mineral density and estrogen and anorexia nervosa. But there haven’t been trials like the one that we’re running where we’re really measuring on a whole lot of levels to see what elements of the eating disorder get better or worse or stay the same in a group of people who are on estrogen compared to a group who are on placebo.

Having a placebo arm, as a researcher, is heartbreaking for me, for those participants. But from a scientific perspective, it is so important because you can’t underestimate the power of placebo. You need to be comparing people who think they’re on treatment to people who are really on treatment so that you actually know what is the benefit from the treatment rather than the benefit from believing that you’re in treatment and it’s going to work.

AM: Do the participants get any other kind of treatment, like a psychological treatment, in parallel, in both groups?

RG: We get them to continue their existing treatment. So, whether that’s regular checkups with their GP or engagement with their psychologist or their dietitian, whatever it was, we get them to continue that.

AM: And would the participants who don’t get the estrogen, get offered the estrogen treatment later if it’s successful?

RG: Yes, when patients are unblinded at the end of trial, and find out whether they were on treatment or not, we write a letter to their doctor explaining to them what they were on. If somebody was on estrogen and wants to continue it, and we’ve seen that it’s had beneficial effects for them, we can then tell the GP what they were on. And similarly for patients who were on the placebo. But we also offer patients who are on the placebo the opportunity to enrol in a different study.

AM: Where is the trial taking place, and do the participants need to be local?

RG: It is in Melbourne, Australia and they need to be living locally.

AM: And is it a non-invasive treatment? Simply a patch that participants wear?

RG: Yes.

AM: How will you be measuring the effectiveness of the trial?

RG: Our trial is a little bit different to a lot of previous research that’s happened in anorexia in that we’re not only enrolling people with DSM anorexia nervosa, which means that they have to be under a BMI of 18.5. We’re also enrolling people with atypical anorexia, or even people with anorexia nervosa in partial remission — that’s somebody who’s weight restored but still has ongoing cognitions and behaviours and might now be diagnosed with, say, bulimia nervosa but actually it’s just a continuation of their anorexia. So, while we’re looking at weight as an outcome measure, that’s not going to be applicable to everybody. We’re also doing rigorous studies looking at their eating disorder symptoms, depression scales, anxiety scales, OCD measures — a whole lot of other factors that we’ll look at to see whether they change with treatment.

The other thing that we hear so commonly is that people feel that they’re not sick enough to get into treatment because then their weight isn’t low enough. And the last thing we want to do is make people feel like they need to lose more weight.

AM: Do you expect estrogen to be a cure for anorexia?

RG: I’m really excited that of all of the six treatments we’re testing we will find a few treatments that are going to be helpful. I think it would be overstating it to say that we’re going to find the cure. And if we did it would be incredible! But I guess what I’m hoping is that we see a couple of signals that give us information for what could be helpful and then show us the next research paths to take till we do find the cure, or the cures. Maybe it’s a combination of a lot of things.

AM: Is this estrogen treatment safe and are there any downsides to the treatment as far as you know?

RG: Though it is safe, you don’t want to take unopposed estrogen for a long period of time because that can have negative impacts on your mental health. So, we’ve taken that into account in our protocol. There are some people for whom estrogen isn’t safe, and it’s a very small number, but people who get migraines with auras lasting over an hour or people who get migraines that are very complicated so they might get half of their face is paralyzed because of the migraine. It’s not recommended that they take estrogen because it can increase your risk of stroke in those patients. In somebody who has a history of estrogen positive cancer — breast cancer — you wouldn’t give them estrogen. As researchers we’re very cautious and don’t want to put anyone on to a treatment that is potentially dangerous, but it’s really just a small group of people for whom it isn’t safe. And what’s really exciting about our particular research projects is, because we’re trialling so many different medications, if you’re unsuitable for one of our trials because you have a history of estrogen-positive breast cancer you more than likely will be suitable for one of the other trials that we’re running.

AM: How long does the treatment take?

RG: Our trials run for three months. Then we follow up again at six months just to check in and make sure that people are safe.

AM: When do you expect to publish the results of the trial?

RG: We think that recruitment is probably going to take two or three years.

AM: As estrogen is a female hormone, what does this trial mean for men and boys with anorexia?

RG: For anybody who was assigned female at birth and now identifies as a transgender male or gender non-binary, if they were able to take estrogen we would be happy to enrol them in the trial. Regarding people who were assigned male at birth, I think if we found really strong results that there was a hormonal component to anorexia nervosa, or that it helped, I think we would need to re-look at the male physiology to think about what is going on in this population?

AM: Do you think it’s possible that there might be a different hormone that could be having a similar effect in a male body?

RG: Yes, I think you’d have to wonder.

AM: As well as the estrogen and TMS trials, you mentioned that there were four other anorexia trials occurring at the HER Centre. Could you tell us what they are?

RG: One is looking at an antipsychotic, as well as an anti-Alzheimers medication and a dietary supplement, zinc, comparing each of those medications against a placebo group. We also have another open-label study, which is looking at another dietary supplement that’s a kind of a short chain fatty acid to see if that can improve anxiety and anorexic behaviours. It reduces inflammation and increases the normal gut microbiome. We’re looking at the gut-brain access. Is that what’s going wrong in anorexia nervosa?

AM: Thank you for taking the time to answer these questions and for all the exciting work you are doing for people with anorexia nervosa.

Dr Romi Goldschlager is a psychiatrist specialising in eating disorders

If you are interested in taking part in the estrogen trial, or any of the other anorexia studies at the HER Centre, contact THRED, the Transformative Hub for Research into Eating Disorders: THRED@monash.edu