It appears that estrogen is very likely to play a key role in migraine pathogenesis, but seems to affect patients in different ways depending on their past medical history, age, and use of hormonal therapy. Further research is warranted to isolate the effects of estrogen in each unique patient population, and we believe that studies comparing menstruating women to postmenopausal women could help shed light in this area.
[PDF] Estrogeneration: How Estro
As migraines are more frequent among females, a variety of hormones have been implicated in their pathogenesis; specifically, prior research has repeatedly shown evidence linking estrogen to migraine headaches [5]. Pringsheim highlighted this association when they found that the prevalence of migraines in male-to-female transgender individuals taking estrogen therapy was similar to the prevalence of migraines in females, and far higher than that in males [6]. Although numerous studies have suggested that estrogen plays a leading role in migraine pathogenesis, its specific role has yet to be fully understood. The purpose of this review is to investigate the specific roles of estrogen in the pathophysiology of migraine headaches to give providers and patients a better understanding of migraine pathology, treatment options, and areas of potential future research.
In our literature search, our primary focus was to find studies that investigated the role of estrogen in the pathogenesis of migraine. We kept our search broad and utilized the inclusion and exclusion criteria below to narrow down search results in accordance with our predetermined PICO framework.
A scoping review was undertaken to identify studies pertaining to estrogen and migraine headaches. PupMed and EMBASE were searched for articles published in the English language using keywords and the respective MESH and PICO search engines. Our data collection and extraction is highlighted below in Table 1 and the PRISMA 2009 Flow Diagram.
The PICO engine of EMBASE was utilized in order to retrieve articles. Our search terms included [transformed migraine OR migraine], [estrogen], [chronic OR persistent OR recurrent] and were kept purposefully broad in order to return as many relevant papers as possible. Suggested synonyms for each term were selected to be included in the search. Papers were then screened in accordance with our PICO framework and inclusion/exclusion criteria to narrow down the search results.
General searches were also conducted on PUBMED using the keywords migraine, estrogen, sex hormones, menstrual migraine, menstrual-associated migraine, menstrual-related migraine, migraine and estrogens, migraine and sex hormones, estrogen and headaches, and sex hormones and headaches. Bibliographies of relevant articles were also examined in order to identify other potentially pertinent articles.
A total of 246 studies were imported for initial screening. Abstracts were initially screened by two blinded reviewers. Each reviewer screened each abstract, and studies that were agreed on by both reviewers advanced to full-text screening. Seventy-seven full-text studies were reviewed by the two blinded reviewers. Each reviewer screened each full-text article and studies deemed appropriate by both reviewers were included in the final review. After excluding any nonclinical studies as well as studies that did not directly study estrogen, 19 studies were included in the final review. This process is summarized in the PRISMA flow diagram in Fig. 1. A summary of findings can be seen in Table 2.
Three studies assessed the effects of hormone replacement therapy (HRT) on migraine in postmenopausal women with results varying by estradiol dosing, but generally concluding that estrogen replacement increased the incidence of migraine [8, 11, 23]. Three other studies found that women with a history of migraine had an increased sensitivity to physiologic fluctuations in estradiol levels [12, 16, 21]. Lastly, four survey/diary-based studies suggested that migraines most often occurred perimenstrually and were more common in male-to-female transgender patients on HRT when compared to the general population [6, 15, 17, 18]. These results suggest that estrogen is a major hormone implicated in migraine pathogenesis and that physiologic withdrawal of estrogen during menses likely plays a role in this condition. However, one study followed pregnant women with a history of migraine and found that migraine frequency did not change significantly as pregnancy progressed [20].
The phenomenon of estrogen withdrawal was later studied by Lichten in 1996 in 28 postmenopausal women taking HRT and with a history of severe menstrual migraines prior to menopause [19]. Lichten administered a one-time intramuscular injection of 5 mg depo-estradiol cypionate and serially tracked serum estradiol levels until all participants experienced a migraine. He found that all participants in the experimental group experienced a migraine 18 4 days after administration of the injection and that the average serum estradiol level at the time of migraine was between 45 and 50 pg/mL, as Somerville had found in his study. However, no participants in the control group (no prior history of migraine) experienced a migraine during the course of the study. Lichten concluded that is likely a genetic component in migraine pathogenesis and that a drop in estradiol levels to below 50 pg/mL after a period of priming with higher levels can be a trigger for migraine. Like the Somerville study, we assigned this study a very low GRADE score because of the limited sample size and confounding effects of ongoing HRT by participants.
The purpose of this study was to provide an updated review of the literature to better characterize the relationship between estrogen and migraines. While previous systematic and literature reviews on hormones and migraines have been conducted, our review focuses specifically on the effects of estrogen in isolation and includes more recent studies compared to prior reviews. The previous systematic review investigating this topic was conducted in 2006 and was impactful [5]; however, our paper advances the topic by including newer studies conducted in the last decade and also by greatly expanding on experiments that utilized hormone replacement therapies as a means for studying estrogen withdrawal. Our investigation also expanded the discussion in the population of post-menopausal women. We believe this provides greater evidence to the link between estrogen and migraines.
During our review, we identified 19 studies that met our inclusion criteria. Of these 19 studies, 12 studied the role of estrogen withdrawal in the precipitation of menstrual migraine. The remainder studied the role of hormone replacement therapy (HRT) in postmenopausal women, the effects of pregnancy, and the effects of fluctuating estrogen level on migraine activity. Overall, we found that many of the included studies fell into one of two categories: estrogen withdrawal migraines or migraines associated with fluctuations in estrogen. In general, nearly all studies concluded that estrogen withdrawal, in particular after a period of priming, significantly increased the likelihood of migraine. Various study designs and approaches have been used to support this theory. We believe that the topic of estrogen withdrawal migraine has been studied sufficiently; however, it became apparent during our review that the pathophysiology of migraines is complex and not fully attributable to estrogen and its withdrawal alone. In particular, many studies focusing on postmenopausal women with migraines found that use of HRT actually increased the incidence of migraine.
As our study primarily focused on only estrogen and not other variables involved in migraines, more general studies were excluded from our final analysis. Further broadened systematic reviews are warranted and would help create a more holistic understanding of migraine pathology. The major limitation in this study was that the majority of studies we screened were confounded by the interplay between menstrual cycles and migraines. While the menstrual migraine is one of the most common subtypes of migraines, the studies we reviewed suggest that the pathogenesis of migraines varies when comparing menstrual migraines, postmenopausal migraines, and non-hormonal migraines. These different subtypes must first be identified and then studied independently to minimizing the effects of confounding variables.
Lastly, a final limitation in our study design was that we focused on clinical research and excluded and studies with data only in the preclinical (animal) stages. Although migraines are extremely common in the population, there are a significant number of preclinical studies that could aid in understanding this disease. Many of the preclinical trials we excluded from our analysis contained insight into the molecular interactions of estrogen with neuromodulators involved in nociception and vascular regulation that are likely to play a role in migraine pathogenesis. A follow-up systematic review that is not constrained to only clinical research would help validate the results of clinical studies that have yet to find an explanation for their findings. In spite of the above limitations, we believe our study highlights the important and not fully understood role that estrogen plays in the pathogenesis of migraines. Further studies are needed to classify different types of migraines, understand various precipitating factors, guide clinical decision making, and reveal new therapeutic targets for medical, surgical, or behavioral intervention.
The pathophysiology of migraines has proven to be a complex phenomenon. Estrogen is implicated in migraine pathophysiology, but its roles are widespread and still not completely understood. Our scoping review found that most studies on the topic have agreed that the withdrawal of estrogen is a key factor in migraine pathogenesis. This has been extensively studied in both menstruating and postmenopausal women. However, we also found that the pathogenesis of migraines is more complex than can be attributed solely to the withdrawal of estrogen. 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. 2ff7e9595c
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