Sex and Gender Considerations in Episodic Migraine

Abstract

Purpose of Review We seek to update readers on recent advances in our understanding of sex and gender in episodic migraine with a two part series. In part 1, we examine migraine epidemiology in the context of sex and gender, differences in symptomatology, and the influence of sex hormones on migraine pathophysiology (including CGRP). In part 2, we focus on practical clinical considerations for sex and gender in episodic migraine by addressing menstrual migraine and the controversial topic of hormone-containing therapies. We make note of data applicable to gender minority populations, when available, and summarize knowledge on gender affirming hormone therapy and migraine management in transgender individuals. Finally, we briefly address health disparities, socioeconomic considerations, and research bias. Recent Findings Migraine is known to be more prevalent, frequent, and disabling in women. There are also differences in migraine co-morbidities and symptomatology. For instance, women are likely to experience more migraine associated symptoms such as nausea, photophobia, and phonophobia. Migraine pathophysiology is influenced by sex hormones, e.g., estrogen withdrawal as a known trigger for migraine. Other hormones such as progesterone and testosterone are less well studied. Relationships between CGRP (the target of new acute and preventive migraine treatments) and sex hormones have been established with both animal and human model studies. The natural course of migraine throughout the lifetime suggests a contribution from hormonal changes, from puberty to pregnancy to menopause/post-menopause. Treatment of menstrual migraine and the use of hormone-containing therapies remains controversial. Re-evaluation of the data reveals that stroke risk is an estrogen dose- and aura frequency-dependent phenomenon. There are limited data on episodic migraine in gender minorities. Gender affirming hormone therapy may be associated with a change in migraine and unique risks (including ischemic stroke with high dose estrogen). Summary There are key differences in migraine epidemiology and symptomatology, thought to be driven at least in part by sex hormones which influence migraine pathophysiology and the natural course of migraine throughout the lifetime. More effective and specific treatments for menstrual migraine are needed. A careful examination of the data on estrogen and stroke risk suggests a nuanced approach to the issue of estrogen-containing contraception and hormone replacement therapy is warranted. Our understanding of sex and gender is evolving, with limited but growing research on the relationship between gender affirming therapy and migraine, and treatment considerations for transgender people with migraine.

Disease burden of migraine and tension-type headache in non-high-income East and Southeast Asia from 1990 to 2019

“…In addition, females were notably more susceptible and vulnerable than males to both migraine and TTH, suggesting that more resources and care should be focused on women to better prevent or manage their headaches in the future. This sex-related difference among patients with migraine and TTH detected by our research team was basically in line with the conclusions from several previous studies [ 6 – 10 ], yet specific proportions and values may vary. Unfortunately, the potential association of the headache burden with socioeconomic background was not fully discovered in this paper, which was not in line with the findings from previous studies [ 24 – 26 ].…”

“…According to the conclusions from the Global Burden of Disease (GBD) 2016 Headache Collaborators [ 4 ], approximately three billion individuals suffered from TTH and migraine worldwide in 2016, among which 1.89 billion suffered from TTH and 1.04 billion suffered from migraine. Notably, it has been widely observed that both of these diseases are more prevalent, frequent, and disabling among females [ 6 – 9 ]. Current sex-related discrepancies among patients might be associated with hormonal changes in women during the menstrual cycle and throughout their lifespan [ 10 , 11 ].…”

Endogenous inflammatory mediators produced by injury activate TRPV1 and TRPA1 nociceptors to induce sexually dimorphic cold pain that is dependent on TRPM8 and GFRα3

“…Our results also add to the increasing appreciation of the significant sex differences in pain (Mogil, 2020), in this case with evidence that CGRP and TLR4 mediate cold pain in females and males, respectively. For CGRP, the most well-characterized sex differences occur in migraine-related pain which is significantly more prominent in females compared to males (Ahmad and Rosendale, 2022). Intravenous CGRP triggers headaches in migraineurs (Lassen et al, 2002) and produces migraine-like pain only in female rodents when applied directly to the dura (Avona et al, 2019).…”

Neurological Health in Sexual and Gender Minority Individuals

“…66 Lastly, providers should be aware of possible secondary causes of headaches. 53 Masculinizing hormones are associated with increased risk of erythrocytosis and secondary polycythemia vera, 67 which can cause hyperviscosity and lead to headaches, blurry vision, paresthesias, and potentially strokes. Feminizing hormones may increase risk for venous thrombosis, 30 stroke, prolactinoma, 68 and meningioma, 69 which can also present as headaches.…”