Considerations When Treating Migraines in Gender Diverse Patients Receiving Gender-Affirming Hormone Therapy

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Headache and migraine prevalence among transgender and gender diverse populations receiving gender-affirming hormone therapy is not significantly different than their cisgender (cis) counterparts, said Anna Pace, MD, assistant professor of neurology, director of the Headache Medicine Fellowship and Transgender Headache Medicine Program, Icahn School of Medicine, Mount Sinai, during a presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting in Denver, Colorado. However, hormones can influence the occurrence and severity of headaches and migraines in patients, regardless of whether they are transgender or cisgender, according to Pace.

Although data are limited on the subject, from an estrogen perspective, migraines are more common in ciswomen compared with cismen, most likely because of estrogen fluctuations or abrupt withdrawal. Specifically, ciswomen who experience menstrual cycles may see a relationship with an estrogen peak and a migraine attack, as a migraine attack may be triggered during the subsequent drop of hormone. Additionally, cismen who experience episodic migraines without aura are often found to have higher estrogen levels compared to controls. Based on existing data, Pace noted that estrogen is thought to be proinflammatory, and can facilitate cortical spreading depression and possibly increase the likelihood of aura.

Alternatively, cismen with chronic migraine were observed to have lower levels of testosterone compared to controls. In addition, a study that observed pre- and post-menopausal women with migraines who had implantable testosterone pellets found that there was an improvement in migraine attacks. Pace explained that based on this known data, testosterone is likely antinociceptive.

Further, 2 studies exist that look at the potential association between gender-affirming hormone therapy and migraines; however, Pace acknowledged that 1 study is from 2004 and the other is from 2007, making the data somewhat outdated. The studies support the idea that estrogen is a proinflammatory hormone, with 1 demonstrating that transgender women on estrogen experienced a similar prevalence of migraines to cisgender women, of which approximately 54% experienced aura; the other study showed that transgender women on estrogen had a worsening of chronic pain that included headache, musculoskeletal pain, and breast pain. Alternatively, the studies also found that transgender men on testosterone had improved chronic pain and headache. Pace noted that the studies may not be entirely accurate anymore, citing what she sees in her practice.

“I would say in my practice, it is not always like this, so take this with a grain of salt. [Additionally,] when looking at surgeries—for the most part—gender-affirming surgeries do not seem to affect headache frequency or severity. What I do want to mention [are] hysterectomies and oophorectomies—specifically oophorectomies,” said Pace during the presentation. “For cisgender individuals, we know that [for] those who have oophorectomy, because of a precipitous drop in estrogen--many will experience migraine. This is probably less relevant for those on gender-affirming hormone therapy because if they are already on hormones, you're not really getting that same precipitous drop. So just something to keep in mind. But for the most part, I don't typically see that these surgeries affect migraine in any negative way.”

Furthermore, Pace described secondary headaches and how they may be impacted by hormone and gender-affirming care. She noted that although they are relatively rare, it is important for health care providers to keep them in mind when treating patients, particularly if there is a noticeable pattern in headaches. Estrogen was associated with an increased risk of venous thromboembolism (VTE), and older formulations of estrogen—such as ethinyl estradiol and conjugated equine estrogens—were related to cases of cerebral venous sinus thrombosis; however, most prescribers no longer use these forms of estrogen in gender-affirming hormone therapy.

When treating migraines in transgender and gender diverse patients, Pace explained that treatment is nearly the same as treating cisgender individuals; however, she emphasized there are some factors that need to be taken into consideration. Individuals who are on estrogen should consider that topiramate induces CYP3A4, which reduces the free estrogen and progesterone in the body, while carbamazepine/oxcarbazepine can reduce the circulating estrogen levels. Additionally, individuals on testosterone should know that zonisamide may reduce testosterone levels, whereas valproic acid may increase levels.

"For the most part, anything that you can use that has the least likelihood of drug-drug interactions is what I would recommend. [For example,] in my practice, we typically use a lot of calcitonin gene-related peptide monoclonal antibodies [with or without] a botulinum toxin A [because there are] no drug interactions whatsoever. Patients are able to address their gender-affirming hormone treatments without fear of affecting their headaches because we have great preventive therapies on board,” said Pace during the session. “[There are also] patients with hypertension, you may want to think about candesartan if they're on testosterone…or those with concomitant mood disorders or other chronic overlapping pain conditions [may want to] consider selective serotonin reuptake inhibitors and other treatment considerations.”

In addition to medications, Pace also noted that lifestyle modifications—such as getting enough sleep, staying hydrated, maintaining a healthy diet, and exercising—can also help patients experience relief from their headaches and migraines. Further, other treatments can include nutraceuticals, neuromodulation, nerve blocks or trigger point injections, and physical therapy.

At the end of the session, Pace emphasized the importance of considering the proper treatments for transgender and gender diverse patients who are affected by headaches and migraines. Along with the correct treatment, secondary causes of headache should also be considered to identify any other potential red flags.

“[In addition, it is] really important to acknowledge patients' medical and psychiatric comorbidities, as well as their gender-affirming hormone therapy status,” said Pace at the presentation’s conclusion. "It is incredibly crucial to care for these patients, to be informed, and it's wonderful that you're all here... This is just the first step in helping to improve care for these individuals."

Reference

Speaker name. Neurologic Conditions in Transgender Patients: Neurological Care of Transgender and Gender Diverse Patients Part III. Presented at: American Academy of Neurology 2024 Annual Meeting; Denver, Colorado. April 13-18, 2024.