The Initial Link Between Estrogen and Migraines: Estrogen Withdrawal Hypothesis
Estrogen’s association to migraines was first demonstrated by Somerville in 1972, providing for the first time an explanation for migraines, especially during menopause.7 Based on experimental observations in women with menstrual-related migraines (MRM), Somerville associated that the late luteal phase decline in estrogen levels triggered migraines and showed that migraines were postponed in women taking supplemental estrogen. When measuring plasma levels of estradiol and progesterone in a group of women with MRM, he found that the onset of migraines was associated with hormone withdrawal. In another group of women, Somerville administered plasma estradiol to women with MRM and found delays in migraine onset, with migraines again occurring with estrogen withdrawal. Somerville concluded that falling levels of estrogen play a significant role in the precipitation of menstrual migraines. Somerville’s work was limited by his small sample size; however, his theory in linking estrogen to migraine pathophysiology was universally accepted, and became the foundation of future research. This theory has led clinicians and scientists to examine how estrogen is associated with migraines in women of different physiological states, as estrogen levels fluctuate naturally throughout a woman’s lifespan.
Understanding the Mechanisms for Estrogen’s Role in Migraines: Biochemical Pain Pathways
While it is clear from Somerville’s work that estrogen is linked to migraines, the specific physiological mechanisms are complex and multifactorial. One mechanism by which estrogen affects migraines is through its role in pain processing and perception. Changes in estrogen levels have been shown to be associated with altering pain sensitivity.8 This has been thoroughly discussed by Cairns in his description of estrogen’s role in craniofacial nociception and pain processing2,9, which is bolstered by estrogen’s effects on neural inflammatory peptides.10 Estrogen can also directly affect the central nervous system, thus propagating migraines, which was highglighted by Fejes-Szabó et al. who showed that estrogen significantly influences nociception in the trigeminal system of the CNS in mouse models.11,12 In addition, several studies found that estrogen is linked to neuronal activation specific to migraines.13–16
The precise mechanisms through which estrogen propagates migraine headaches are still not fully understood, however these foundational studies have shown that estrogen has a profound range of physiological effects and these are linked to migraine headaches.
Estrogen’s Effects on Migraines in Menstruating Women
The influence of ovarian hormones on migraines during a women’s menstrual cycle was clearly identified in a comprehensive systematic review which analyzed self-reports from 1291 women suffering from migraines. These women reported that their migraines were more painful and occurred more frequently during menses or perimenstrually compared to other parts of the menstrual cycle.17 This relationship was further solidified when Brandes showed convincing evidence to support Somerville’s estrogen withdrawal hypothesis5 in a comprehensive metanalysis. In particular, he highlighted a rare randomized control trial whereby women undergoing in vitro fertilization were administered a gonadotropin-releasing hormone analog to down-regulate estrogen levels. Low 17ß-estradiol levels correlated with both a spike in migraine attacks and reported migraine severity. Brandes further developed this argument when he showed that women with histories of migraines being administered supplemental estrogen experienced worsening of migraine attacks upon withdrawal of that supplemental estrogen, directly contrasting with a control cohort of women. Brandes noted that these data supported Somerville’s hypothesis by showing drops in plasma estrogen concentration after prolonged exposure (estrogen withdrawal) had an increased risk of precipitating migraines.
Estrogen’s Effects on Migraines in Pregnant Women
Migraines have also been studied in pregnancy, when women’s estrogen levels dramatically increase. Researchers have hypothesized that the increase in estrogen during pregnancy should counteract estrogen withdrawal and lower both migraine incidence and severity in women. A 2006 systematic review by Martin and Behbehani showed that 70% of women experienced an improvement in their migraines during the course of their pregnancy (2nd and 3rd trimester).18 In 1999, a prospective study followed 49 pregnant women with migraines and recorded headache activity daily through three months postpartum. 19 Overall, headaches improved significantly for 41% of the women during pregnancy. They also noted that women reporting headache at the end of their first trimester continued to report headache throughout pregnancy and postpartum. While these results may support the estrogen withdrawal theory, they also give insight into the possibility of hormone replacement therapy in the treatment of estrogen-mediated migraine. However, further study is necessary to confirm these results.
Estrogen’s Effects on Migraines in Postmenopausal Women
As menopause is a natural state of hormone withdrawal, postmenopausal women have been studied to investigate the estrogen withdrawal hypothesis and estrogen’s effect on migraines. A 1996 study by Lichten et al. found that postmenopausal estrogen decline exacerbates migraines and noticed delayed migraines in women that were supplementally administered estrogen in comparison to control groups.20 The authors claimed this study to be confirmation of a biochemical marker for hormonal migraine in women. Brandes conducted a comprehensive systematic review investigating this topic and found that postmenopausal women who were artificially administered estrogen had a significantly increased risk of experiencing migraines compared to women not on hormone therapy (13–9%, p value = 0.001).5 In contrast to menstrual migraines, postmenopausal women receiving high or low doses of estrogen had a significantly higher risk of precipitating migraine headaches than women receiving intermediate doses. The mechanics behind this are unsolved and provide another example of the complexity of estrogen’s relationship with migraines.
Hormone Replacement Therapy and Estrogen Administration
As migraines have been shown to be, in part, precipitated by estrogen withdrawal, researchers have studied how administering estrogen affects migraines. Though many studies have been published on this topic, there have been differing and inconsistent results. The first randomized controlled trial to investigate percutaneous estradiol in relation to migraine pathogenesis was conducted by de Liginieres et al. in 198621, which showed a signficiant improvement in migraine headaches in subjects given the hormone replacement therapy vs. controls. Calhoun and Ford performed a retrospective analysis of 229 consecutive women treated with HRT for MRM, and found4 resolution of MRM in 81% of subjects who were compliant with hormonal therapy, offering preliminary evidence that hormonal regimens may have a beneficial role in female migraines. Brandes’ meta-analysis found a 76% reduction in number of migraines/month in those taking 20 µg of ethinyl estradiol on days 1–21 of their respective menstrual cycles7.
On the contrary, MacGregor et al. published a double blind placebo-controlled crossover study investigating percutaneous estradiol gel in preventing migraines, and found a 22% reduction in the number of migraine days in gel-users, but a 40% increase in migraines in the five days after discontinuing the intervention, concluding that while perimenstrual percutaneous estradiol showed benefits, this was offset by deferred estrogen withdrawal which triggered migraine after the gel was stopped.22 A separate randomized control trial by Facchinetti et. al administered three different combinations of estrogen therapies to postmenopausal women and observed migraine outcomes—all three interventions showed a statistically significant increase in migraine attack frequency (2.2 vs 3.8) and severity when compared to control over the course of 6 months.23 The contradictory reports regarding HRT for migraine therapy is another example of estrogen’s complex and multifactorial influence in migraines.
Currently Accepted Treatments for Migraines
There are currently several modalities of migraine treatments, often varying based on a patient’s specific presentations, history, symptoms, triggers, and physiology. Pharmacotherapy is generally first line in the treatment of migraine disorders and is usually either acute (abortive) or preventative (prophylactic).24 Acute treatment can be specific (ergots and triptans), or non-specific (analgesics and antiemetics); preventative drug groups include ß-adrenergic blockers, tricyclic antidepressants, calcium-channel antagonists, serotonin antagonists, and anti-convulsants. Many clinicians also recommend psychotherapy and cognitive behavioral therapy as well.
Uncovering the precise role estrogen plays in the propagation of migraines is crucial as it can lead to profound impacts in how clinicians treat migraine patients. As stated above, estrogen’s withdrawl has been shown to propogate migraine headaches and shares a role in increasing both pain processing and perception. However, there is no definitive primary research which has provided evidence for a universal first-line therapy in treating hormonally mediated migarines.
The persistence of migraines following pharmacologic therapies has led to novel and alternate forms of migraine treatments. However, none have specifically shown to address hormone-related migraines. This includes the surgical treatment of migraines, which would not be expected to significantly improve headaches in this population of patients given that nerve decompression/ablation has no proven direct link to hormone level fluctuations.25–27 Hormonal control could, indirectly, help patients in this population, as migrainers with a nasal trigger site often have hormonal triggers—mucosal engorgement from hormone fluctuations can then, in turn, cause nerve impingement. This, however, has not been properly explored and should be a target for future, primary research.
Limitations:
The purpose of this study was to thoroughly review the literature as it relates to estrogen and its role in the pathophysiology of migraine headaches to better guide clinical decision making. While developing our inclusion and exlusion criteria for the scoping review, it became apparent that the pathophysiology of migraines is complex and not fully attributable to estrogen alone. Because our study primarily focused on only estrogen and not other variables involved in migraines, many valuable studies were excluded from our final analysis that could help shed light on potential triggers and therapeutic targets in migraine management. Further study and meta-analysis of studies like this one is warranted and would help create a more holistic understanding of migraine pathology and treatment. The other 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 inpendently to minimizine 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 far more preclinical studies than clinically validated trials to draw conclusions from. Many of the preclinical trials we excluded from our analysis contained significant insight into the molecular interactions of estrogen with neuromodulators involved in nociception and vascular regulation that are likely to play a significant role in migraine pathologenesis. A followup 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. Overall, addressing these limiations in future study would help better classify different types of migraines, understand various precipitating factors, guide clinical decision making, and reveal new therapeutic targets for medical, surgical, or behavioral intervention.