Dr. Pace is an Assistant Professor of Neurology at the Icahn School of Medicine at Mount Sinai, where she is Director of the Headache Medicine Fellowship Program, and Director of the Transgender Headache Medicine Program.
In the following Q&A, Dr. Pace discusses what is known about the causes and occurrence of headache, including migraine, in transgender individuals, and how her research is elucidating the epidemiology of primary and secondary headache syndromes in people on gender-affirming hormone therapy (GAHT).
Q. What do we currently know about the relationship between GAHT and headache?
Dr. Pace: Very little has been published in this area, and much of what we do know about hormones and migraine is derived from studies on cisgender individuals, or from animal models. I hope to shed some light on the relationship between GAHT and headache through my program’s ongoing research.
Q. What impact does estrogen have on headaches in transgender women who are on a steady regimen of the hormone?
Dr. Pace: One study from the early 2000s suggests that estrogen may worsen various types of pain in transgender women, including headache and musculoskeletal pain. In animal models, estrogen appears to induce cortical spreading depression, which is one of the proposed pathophysiologic processes involved in a migraine attack, so it’s thought that estrogen fluctuations may trigger migraine.
Conversely, for someone at a steady hormone level, migraine would not be expected to change. Alterations in dosing or administration of estrogen, however, could be a vulnerable time for the individual to experience a migraine attack.
Q. How about the effects of testosterone?
Dr. Pace: Testosterone has been postulated to be antinociceptive in animal models, and one study of postmenopausal cisgender women with migraine found improvement in their symptoms and migraine frequency after having testosterone pellets implanted. This would suggest testosterone may modulate pain processing, but it’s unclear from so small a study if the results would apply to transgender men on testosterone.
Q. Can GAHT lead to secondary headache disorders?
Dr. Pace: Some cases have been reported of transgender women on estrogen who develop cerebral venous sinus thrombosis. This is one diagnosis a physician does not want to miss when evaluating a patient on estrogen with new-onset headache, especially if it’s persistent and associated with vision changes, nausea and vomiting, or other red flags. Transgender women on estrogen may also have a higher rate of benign masses such as meningiomas and prolactinomas, which may present with headache.
Some cases have been reported of transgender women on estrogen who develop cerebral venous sinus thrombosis. This is one diagnosis a physician doesn’t want to miss when evaluating a patient on estrogen with new-onset headache.
There are a handful of case reports of transgender individuals on gonadotropin-releasing hormone (GnRH) agonists and transgender men on testosterone who developed idiopathic intracranial hypertension (IIH). While IIH is not thought of intuitively as a “secondary headache,” case reports suggest IIH develops as a result of hormones or GnRH agonism, leading to the assumption that testosterone or androgen excess may affect cerebrospinal fluid production.
As a result of these reports, the U.S. Food and Drug Administration updated its safety labeling for GnRH agonists in 2022. Further research is needed to investigate the prevalence of secondary headache disorders in this patient population, and whether hormones or other factors play a role.
Q. How does GAHT affect the risk for development of headaches in adolescents?
Dr. Pace: Unfortunately, this is an understudied area. We’re hopeful that future research will determine if the timing of GAHT matters in the development of migraine, or if a genetic predisposition to the condition supersedes any effects from administration of hormones/pubertal blockade, regardless of timing.
Many providers were never taught about transgender health during their medical training. Thus, almost half of all transgender patients report they have had to teach their own providers.
Q. What research does your program have underway that could shed light on headache pathophysiology?
Dr. Pace: Our program’s main goal is to provide culturally sensitive and competent gender-affirming medical care for headache. Our research is therefore aimed at determining the true epidemiology and pathophysiology of primary and secondary headache syndromes for individuals on GAHT to help improve quality of life and reduce disability in these individuals.
We also want to understand the prevalence and characteristics of aura in transgender individuals on GAHT and whether its presence confers an increased stroke risk. Future goals include assessing the efficacy of various new pharmacologic therapies for migraine in transgender and gender-diverse patients to determine what the safest and most effective treatments are that will not interact with hormone therapy.
“Our program’s main goal is to provide culturally sensitive and competent gender-affirming medical care for headache.”
– Anna Pace, MD
Q. What barriers exist for gender minorities attempting to access headache specialists?
Dr. Pace: Many sexual and gender minority individuals have experienced discrimination and unequal treatment in health care in the past, so they may be wary of seeking care from any health care professional.
There is also a professional knowledge gap when it comes to transgender health: Many providers were never taught about transgender health during their medical training. Thus, almost half of all transgender patients report they have had to teach their own providers about their care. Insurance coverage can also be an issue by preventing patients from general access to subspecialty care or to coverage for treatment and procedures.
Q. How can we improve access to care?
Dr. Pace: A database of gender-affirming providers could be helpful for patients to find the right providers based on their needs and help them feel more comfortable knowing those providers are well trained in transgender health and knowledgeable about safe and proper treatment options.
Other ways to address barriers include creating a welcoming, gender-affirming office environment with gender-neutral bathrooms, welcoming signage around the office, and office training for staff on using correct pronouns and gender-neutral language to avoid misgendering patients. Improving education in training and promoting advocacy are also ways to help address barriers to care.
To learn more, click on the following research papers published by Dr. Pace:
Headache in transgender and gender-diverse patients: A narrative review, Headache, July/August 2021
Gender Minority Stress, Psychiatric Comorbidities, and the Experience of Migraine in Transgender and Gender-Diverse Individuals: a Narrative Review, Current Pain and Headache Reports, December 2021
Update on underrepresented populations in headache medicine: What is known and care considerations, Practical Neurology, May/June 2023