Importance of Headache Research for Transgender and Gender-Diverse Patients

Jennifer Hranilovich, MD

Research is limited for transgender and gender-diverse patients, as this patient population has been historically stigmatized and met with barriers to both care and insurance. Despite endeavors such as the establishment of the Sexual & Gender Minority Research Office by the National Institutes of Health in 2015 and the publishing of a guide on integrating transgender health education into medical schools’ curricula by the Association of American Medical Colleges in 2014, gender minorities remain a medically underserved population.

Jennifer Hranilovich, MD, assistant professor, pediatrics and neurology, Headache Program, University of Colorado School of Medicine/Children's Hospital Colorado, spoke on a recently published narrative review, which she and colleagues performed to evaluate research within this patient population, with a particular focus on the effects of gender affirming hormone therapy (GAHT) on headache, drug-drug interactions, and the epidemiology of headache disorders in sexual minorities. In doing so, the study further aimed to provide guidelines and resources for clinicians who may not be as familiar with caring for transgender or gender-diverse patients. 

According to Hranilovich, this area of study is of particular importance, as transgender and gender-diverse patients are interested in seeing research within their own population, particularly the effect of GAHT on new migraine, according to a study funded by the Patient-Centered Outcomes Research Institute. In conversation with NeurologyLive, Hranilovich outlined the narrative review, in addition to interesting findings, anticipated research efforts for this patient population, and the importance of creating welcoming, respectful environments in the health care space. 

NeurologyLive: What were the motivations behind the narrative review? How did you go about conducting it?

Jennifer Hranilovich, MD: I came to this area of research from kind of a unique perspective. I've been involved with research on the way that the brain’s exposure to sex steroids, like estrogen and testosterone, lead to sex differences in function for many years. And there's been a lot of preclinical research, such as animal research, in how pain is affected, in particular, by those hormones. So, I decided, once I realized during my medical training, that there was really a rising number of adolescents—because I'm a pediatric neurologist—being treated with what we call gender-affirming hormone therapy, that transgender individuals would be a unique population for study, with respect to hormone exposure.

We can see the effect of these hormones, independent of your genetic makeup of male and female assigned at birth [and] socialization, because men and women are socialized differently in terms of how they experience and report pain. Furthermore, the transgender population is just really understudied, in general. So that's the direction I came at this from. 

My coauthors are also interested in sexual and gender minorities and were interested in collaborating with me on this. We decided there's not really enough [research] out there to do a formal systematic review—we did what's called a narrative review—where we took our expertise and created a guide for individuals who aren't as familiar with transgender care, but who were familiar with neurology and headache in particular, on good resources [and] best practices for caring for this population.

Were any of the findings surprising?

I was a little surprised when I drilled down and tried to find, for instance, the epidemiology of transgender individuals, or particularly, the epidemiology of headache in that population. There really are no prospective population-based studies on headache prevalence in this population, and that is despite the Institute of Medicine, making it a priority. There are some big population-based prospective studies, like the European Network for the Investigation of Gender Incongruence, Trans Youth Research Network, but those don't ask about headache [and are] really missing that information. There was a Patient-Centered Outcomes Research Institute funded study that asked transgender patients, “What are you interested in seeing research in your own population?” One of the things that came up was development of new migraine during gender affirming hormone therapy. So, there's a lot of demand, but really nothing out there, which surprised me. 

We also tried to talk about research out there and summarize that. I was really surprised and interested to find that there have been prospective studies looking at testosterone treatment for cisgender women—those are women who are assigned a sex of female at birth, but then their gender identity remains female throughout their lifespan. Cisgender women who received testosterone were prospectively studied to see how that impacted headache as far back in the 1950s. It’s kind of surprising going through the literature and finding some of these studies as well, and that’s because there's so few studies on effects of hormone in the transgender population that we were also looking at studies on the effects of those hormones in cisgender individuals.

What are the key takeaways for clinicians? How can they ensure transgender and gender-diverse patients feel taken care of and provided for?

I think the key takeaway for clinicians is that they should become knowledgeable about this stuff, and by “this stuff,” I mean caring for the transgender population. One part of that would be to make a welcoming practice, for example, asking your patients what name you should use when speaking or communicating with them, and asking them, “Hey, what are your pronouns?” There are some modules in some of the electronic medical record systems out there where you can do sexual and gender identity information as a prominent part of the medical record to record that and make it easier for you and your staff to interact appropriately with patients. 

I think it also is incumbent upon neurologists to understand important drug-drug interactions in patients receiving gender affirming hormone therapy. I was surprised to find that, for example, carbamazepine oxcarbazepine, which are first line drugs for trigeminal neuralgia, can significantly reduce estrogen levels, and in theory should really be avoided for patients who have trigeminal neuralgia, and are transfeminine. Transfeminine here means patients who are assigned a sex of male at birth, but their gender identity is female, and that’s the population, when they're receiving estrogen, really have to think about that drug-drug interaction.

What are the next steps in migraine research for this population?

Broad brushstrokes, epidemiology, circling back to what I said earlier, it's really a missing piece to just start to frame an understanding of what's going on with headache in this population. And then I think it's also important to think about prospective trials—what is the effect of gender affirming hormone therapy, on headache frequency, headache painfulness, most bothersome symptom of headache, headache aura. We've got case series, retrospective chart review, things like that, but not as much information prospectively on the effects of gender affirming hormone therapy. 

There are some guidelines; there was a recent paper on the neurodevelopmental studies, so particularly gender affirming hormone therapy given to adolescents, on the effects of pubertal suppression. It kind of was a consensus paper from international experts on how to define and design these studies. There is some information out there about how we should be moving forward. My interest is in translational research, so I’m thinking in terms of functional and structural neuroimaging to kind of bridge the gap between the basic science research we have, and clinical stuff like the epidemiology to help us understand [questions such as], “If there is a difference between people who do and don't receive gender affirming hormone therapy, how does that work? What is the mechanism?”

What is the importance of research within this patient population?

The good news is that the National Institutes of Health, back in 2015, established the Sexual & Gender Minority Research Office, so they have made research in this area a priority. It doesn't have its own institute, so it doesn't have its own money, but they're coordinating [and] advertising resources through other institutes and trying to make applications that focus on this area of research higher priority in other institutes.

I think, given the stuff I talked about, where transgender individuals want to know more about the effects of gender affirming hormone therapy—which is relatively new, especially in the US—on their own health, so putting some more study into this understudied population is important. I think it's important to understand that transgender individuals have been stigmatized, and so even their clinical interaction with the medical profession has been somewhat limited by that, it's been disincentivized. Historically, being transgender [was] categorized as a form of mental illness, in Diagnostic and Statistical Manual, prior editions of it, so there's really been, clinically, and in terms of research, a lack of researchers who can kind of bridge that gap between the transgender population, which is interested in knowing more about the effects of gender affirming hormone therapy and researchers are interested in studying that. It’s kind of hard to bridge that gap when that sort of stigma exists. 

I think that the importance of the research is twofold. One, it's an intrinsically important population to study for the reasons that I just outlined. But I think it also is an area of study that can teach us a lot about the effect of hormones on everybody's brain, not just transgender individuals, so I think it's important for both those reasons.

Transcript edited for clarity.

REFERENCE

Hranilovich, JA, Kaiser, EA, Pace, A, Barber, M, Ziplow, J. Headache in transgender and gender-diverse patients: A narrative review. Headache. 2021;61:1040-1050. doi:10.1111/head.14171