Research Needs Identified for Transgender, Gender-Diverse Patients With Headache


A narrative review was conducted to evaluate the relationship between gender-affirming hormone therapy and headache to advance care and improve resources for the transgender and gender-diverse population.

Jennifer A. Hranilovich, MD, assistant professor of pediatric neurology, University of Colorado

Jennifer A. Hranilovich, MD

Investigators found that a supportive environment for transgender and gender-diverse patients with headache was key to providing care, in addition to an understanding of gender-affirming hormone therapy (GAHT) and its potential effects on treatment, according to a new analysis. A narrative review was conducted of current best practices for these patients, as well as related research on headache in cisgender individuals. 

Reviewing clinical studies, investigators, led by corresponding author, Jennifer A. Hranilovich, MD, assistant professor of pediatric neurology, University of Colorado, found that transgender women receiving estrogen reported worsening headache, among other pain conditions, noting a similarity to cisgender women. Transgender women receiving higher doses of estrogen also had higher prevalence of aura.

Testosterone treatment in transgender boys was found to resolve both postural orthostatic tachycardia and related headache, according to a small case series of transmasculine youth. Suppression of endogenous estrogen with lynestrenol, a form of pubertal blockade, found headache to be an adverse effect. Although, headache was absent after 6 months, which investigators speculate may be due to estrogen withdrawal effect. 

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When looking into the effect of GAHT on secondary headache, investigators reviewed data from 2 recent studies that compared rates of venous thromboembolism (VTE) between trans- and cisgender patients. Investigators noted at least 3 cases of cerebral venous thrombosis in transgender individuals receiving estrogen therapy, but data is limited as to whether there is an increased risk of secondary headache. 

A cohort study reported increased rates of VTE in transgender women (standardized incidence ratio [SIR], 4.55 [95% CI, 3.59-5.69]), compared to cisgender men, and (SIR, 5.52 [95% CI, 4.36-6.90]) when compared to cisgender women. Another cohort study of electronic medical records found increased rate of VTE in transgender women with 2- and 8-year risk difference of 4.1 (95% CI, 1.6-6.7) and 16.7 (95% CI, 6.4-27.5) per 1000 person-years. This was then compared to cisgender men (3.4 [95% CI, 1.1-5.6]) and cisgender women (13.7 [95% CI, 4.1-22.7]). Higher rates of thromboembolism are associated with ethinyl estradiol, which is not prescribed for GAHT, but is often obtained without a prescription by patients who do not have access to care. Additionally, higher rates of smoking and human immunodeficiency virus (HIV) can also increase risk of VTE. 

The effect of hormones, particularly GAHT, should be evaluated as a potential independent risk factor for idiopathic intracranial hypertension, as it was reported by 2 transgender women and multiple transgender men in other studies. GAHT association with central nervous system tumors is another area identified as requiring additional research, according to investigators, following the report of 9 cases of meningioma in transgender women treated with estrogens and cyproterone acetate. New-onset or progressively worsening headache in patients with HIV should also necessitate screening for possible nervous system infections. 

Investigators further explored drug-drug interactions (DDIs) for transgender and gender-diverse patients who receive GAHT and antiretroviral therapies (ART) (TABLE). Toprimate, a cytochrome P450 inducer, was recommend in doses smaller than 200 mg for transgender women, with providers also monitoring estrogen levels, as the drug can lower levels of free estrogen and progesterone. Two anticonvulsants, carbamazepine and oxcarbazebine, showed significant reduction in estrogen levels for transgender women and could reduce testosterone levels in transgender men, suggesting they should be avoided in headache prevention therapy for this patient population. Although, investigators note that additional research is needed to identify clinically significant DDIs. 

TABLE. Transgender Care Drug-Drug Interactions. 
Click to enlarge.

TABLE. Transgender Care Drug-Drug Interactions.
Click to enlarge.

Despite rising numbers of transgender patients, the population remains underserved because of stigma and lack of support in the clinical environment. Research is also limited for gender minorities with headache, particularly when it comes to the effect GAHT may have on treatment. Investigators conducted the narrative review of best practices in treating transgender patients with headache; although, most research focused on cisgender individuals, namely cisgender women in looking at estrogen affects. 

Investigators note the importance of affirming patients’ gender identities and addressing barriers to care, particularly the lack of training in transgender medicine, stigma and discrimination, and inconsistent health insurance coverage for transgender patients. Helping patients identify the care that they need, particularly with providers experienced in treating transgender patients, is crucial, and patients can now identify these providers through a database with a searchable filter, created by the American Headache Society. 

“This kind of database could play a central role in surmounting the significant barriers to care identified…and demonstrating headache medicine's commitment to advancing the care for this underserved population,” Hranilovich et al wrote. “Further research in clinical outcomes of GAHT as it relates to headache pathophysiology, pharmacology, disability, and risk for secondary headache is key as well. Finally, improved education of headache providers on existing and emerging research in this area will be crucial in the coming years.”

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
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