Review Analyzes Estrogen’s Role in Migraine Pathogenesis

Results of a scoping review of 19 studies indicate estrogen likely plays a key role in migraine pathogenesis but affects patients in different ways depending on past medical history, age, and use of hormonal therapy. Findings were published in Systematic Reviews.

Because females exhibit higher prevalence of migraine worldwide (18% vs 6% in males) and the condition has been associated with menstruation, researchers hypothesized migraine may be hormonally mediated.

In addition, “It has been noted that puberty and menopause are the time periods most associated with migraines in women; up to 70% of female migraineurs notice menstrual association of their headaches,” authors wrote. A previous study also found prevalence of migraine in male-to-female transgender individuals taking estrogen therapy was similar to migraine prevalence in females.

However, the specific role of estrogen in migraine pathogenesis is not yet fully understood.

To investigate this challenge, and to offer providers and patients a better understanding of migraine pathology, treatment options, and areas of potential future research, authors conducted a literature search and scoping review to identify studies on estrogen and migraine headaches.

All included studies (n = 19) were published on PubMed or EMBASE in the English language, while 2 independent reviewers carried out data extraction. Of the studies included, 3 were randomized controlled trials, 3 were cross-sectional studies, 3 were prospective cohort studies, 2 were open-label clinical trials, 4 were crossover studies (of which 3 were double-blind placebo-controlled), and 4 were survey/diary-based studies.

A total of 37,139 patients were included in the review, of which 1646 were menstruating women, 35,394 were postmenopausal women, 50 were male-to-female transgender women, and 49 were pregnant women.

Overall, “The estrogen withdrawal hypothesis, discussed by 12 of the reviewed studies, is the most discussed theory about estrogen’s role in migraine physiology and describes the association of migraine onset with natural declines in estrogen levels, particularly when estrogen levels fall below 45–50 pg/mL after an extended period of priming,” authors explained.

Three studies found that hormone replacement therapy (HRT) in postmenopausal women with migraine yielded results varying by estradiol dosing, but that estrogen replacement increased the incidence of migraine in general.

Other studies suggested women with a history of migraine have an increased sensitivity to physiologic fluctuations in estradiol levels, and that migraine is associated with menstruation.

One study, which followed pregnant women with a history of migraine, revealed migraine frequency did not change significantly as pregnancy progressed.

Three studies included were assessed as high Grading of Recommendations, Assessment, Development and Evaluations (GRADE), 6 as moderate, 6 as low, and 4 as very low with lower rating due mainly to smaller sample size or the presence of confounding bias.

“It became apparent during our review that the pathophysiology of migraines is complex and not fully attributable to estrogen and its withdrawal alone,” researchers wrote, as “many studies focusing on postmenopausal women with migraines found that use of HRT actually increased the incidence of migraine.”

Future systematic reviews on the subject would help create a more holistic understanding of migraine pathology. In the current review, the majority of studies screened were confounded by the interplay between menstrual cycles and migraines, marking a limitation. Identifying the different subtypes of migraine (menstrual, postmenopausal, and non-hormonal) and independently studying each type will help minimize effects of confounding variables.

Researchers also excluded data reported in preclinical (animal) stages in the current review, which contained insight into the molecular interactions of estrogen with neuromodulators involved in nociception and vascular regulation. This phenomenon likely plays a role in migraine pathogenesis.

“We believe further study is warranted to differentiate the effects of estrogen on different study populations and also investigate what other hormones, neurotransmitters, and factors play into the pathogenesis of migraine” authors concluded.

Reference

Reddy N, Desai MN, Schoebrunner A, Schneeberger S, and Janis JE. The complex relationship between estrogen and migraines: a scoping review. Syst Rev. Published online March 10, 2021. doi:10.1186/s13643-021-01618-4