Hormone Disturbances in Migraine Disorder: A Meta-Analysis
Overview
Migraine, a prevalent cause of disability among young adults, displays a higher incidence in females and is often accompanied by stress-related disorders, hinting at a potential link with sex and stress-related hormonal mechanisms centered around the hypothalamus. Additionally, interactions with autonomic nervous system activity are suggested. To explore this connection, the present study conducted a meta-analysis of existing literature focusing on sex hormones (estrogen, progesterone, and testosterone), hypothalamic-pituitary-adrenal (HPA) axis cortisol responses, and heart rate variability (HRV) in individuals aged 13 to 65 years with migraines and control groups.
A systematic search of various databases yielded 29 studies for inclusion in the meta-analysis, encompassing a total of 719 migraine sufferers and 592 control participants, all of which adhered to predefined inclusion criteria and risk of bias assessment from the NHLBI. The analysis unveiled noteworthy findings:
- Estrogen Concentrations in Female Migraineurs: Female migraine sufferers exhibited reduced estrogen levels (effect size, g = -0.60, 95% CI [-0.91, -0.29], p < 0.001) during the luteal phase of their menstrual cycle compared to controls.
- Progesterone and Testosterone Levels: No significant variations were detected in overall progesterone levels among female migraineurs or testosterone levels in male migraineurs when compared to their respective control groups.
- Cortisol Dysregulation: Both female and male migraine sufferers displayed higher early diurnal cortisol concentrations (effect size, g = 0.32, 95% CI [0.00, 0.63], p = 0.036) relative to controls.
- Heart Rate Variability: No discernible distinctions emerged in HRV among female or male migraineurs compared to their respective control cohorts.
These findings point to disrupted estrogen levels in female migraineurs during the luteal phase, coupled with cortisol dysregulation observed in both female and male migraine sufferers. These trends underscore potential disturbances in hypothalamic function and highlight the intertwined relationship between migraine, stress, and neuroendocrine mechanisms. The study underscores the necessity for further rigorous investigations into hypothalamic neuroendocrine functions among migraine sufferers of both genders to advance our understanding of this intricate association.
Introduction
Migraine is a complex neurological disorder characterized by recurrent, debilitating headaches causing moderate to severe pain, commonly lasting between 4 to 72 hours. With a global prevalence of approximately 15%, it stands as a significant cause of disability for individuals under 50 years, imposing substantial healthcare costs. Females bear a higher burden, with 18.9% experiencing migraine compared to 9% of adult males. Remarkably, prepubescent males and females encounter the condition equally at 4%.
Migraine often coincides with poorer subjective sleep quality, and migraineurs are more prone to being diagnosed with major depressive and anxiety disorders. Distinctive neuroendocrine patterns have been noted among migraineurs, including elevated diurnal and nocturnal cortisol levels. This upregulation of the stress system appears to be orchestrated through the hypothalamic-pituitary-adrenal (HPA) axis. Furthermore, this study seeks to systematically review and analyze existing literature focusing on hypothalamic neuroendocrine function in migraine, particularly examining sex hormones linked to the hypothalamic-pituitary-gonadal (HPG) axis and stress hormone cortisol. These hormones’ intricate interplay could hold key insights into the underlying mechanisms of migraine and its connection to stress.
Migraine classification considers frequency, severity, and sensory symptomatology. It is categorized into chronic or episodic based on headache days per month, with further subgroups based on symptoms and environmental triggers like menstruation or stress. Menstrually-related migraines often occur during low progesterone and estradiol levels, typically in the luteal phase, whereas non-menstrual migraines can transpire at any point within the menstrual cycle.
The study emphasizes the interplay of sex hormones, including progesterone, estradiol, and testosterone, in the context of migraine. Migraineurs exhibit altered levels of these hormones, and the timing of hormonal fluctuations corresponds with different phases of the menstrual cycle. The connection between hormone changes and migraine incidence is complex and varies between genders.
Furthermore, the study examines the role of the HPA axis, which orchestrates the release of stress hormone cortisol. Migraineurs display heightened cortisol levels, suggesting HPA axis upregulation and its link to stress and pain anticipation. Moreover, these hormonal dysregulations influence the autonomic nervous system (ANS), resulting in altered heart rate variability (HRV). Sympathetic nervous system dominance is associated with reduced HRV, and this aspect appears perturbed in migraineurs.
To conclude, this comprehensive review aims to unravel the intricate interactions between sex hormones, stress hormones, and their effects on neuroendocrine function in migraine. By analyzing existing literature and synthesizing results, the study seeks to shed light on the underlying mechanisms of migraine and its association with hormonal and stress-related pathways. This exploration could offer valuable insights into more effective therapeutic strategies for managing this debilitating condition.
Method
This meta-analysis study, which was preregistered with PROSPERO under registration ID CRD42020188306, aimed to comprehensively analyze the existing literature on neuroendocrine factors in migraine. The study systematically searched and selected relevant research articles based on predefined criteria. The process of study selection, data extraction, and risk of bias assessment followed rigorous guidelines to ensure the robustness of the findings.
Inclusion Criteria
– Study abstracts and titles were screened based on predefined criteria to determine their relevance to the study’s objectives.
– Only studies involving human test subjects were considered.
– The language of the publications was limited to English.
– Studies reporting on sex hormones (estrogen, progesterone, testosterone), hypothalamic-pituitary-adrenal (HPA) axis cortisol responses, and heart rate variability (HRV) in relation to migraine were included.
– Full-text articles were assessed to determine their suitability for data extraction and analysis.
Exclusion Criteria
– Studies not available in English were excluded.
– Conference abstracts and non-peer-reviewed publications were not considered.
– Studies that did not report on relevant neuroendocrine factors (sex hormones, cortisol, HRV) in relation to migraine were excluded.
The online databases MEDLINE, Embase, APA PsycINFO, PubMed, CINAHL, and Web of Science were thoroughly searched using specific terms outlined in Table 1. The final search was completed on 29 August 2022. Two independent assessors (E.B. and N.R.) screened abstracts and titles, followed by a full-text review to identify studies meeting the inclusion criteria. Discrepancies during this process were resolved through consensus among all authors.
The risk of bias assessment was conducted using the National Heart, Lung, and Blood Institute Quality Assessment of Case-Control Studies tool. This tool was employed to evaluate the risk of bias associated with comparing clinical and non-clinical populations. The assessors conducted the risk of bias assessment independently, and any disagreements were resolved through discussion and consensus among the authors.
Data extraction involved collecting relevant information from eligible studies, including demographic details, recruitment settings, migraine diagnosis criteria, sample size, mean and standard deviation (SD) of variables of interest for both migraine and control groups. Subgroup analyses were performed for various types of migraine, and effect sizes were calculated for each subgroup. In cases where data were presented as means and standard errors, conversions to SD were made. Additionally, an open-source program was used to extract data from figures when necessary.
It is noteworthy that the study also recognized the importance of including progesterone data alongside estrogen studies to enhance the interpretation of the estrogen-related findings.
By adhering to these stringent inclusion and exclusion criteria, the study aimed to ensure the reliability and validity of its findings, providing valuable insights into the intricate relationship between neuroendocrine factors and migraine.
Statistical Analysis
The analysis of the gathered data was carried out using a random-effects model with a restricted maximum likelihood estimator. This approach was implemented through JASP software to ensure robust results. The outcomes of the analysis were visually represented using forest plots, which included 95% confidence intervals, the weight percentage contributed by each study to the pooled effect size, the total number of participants, and measures of heterogeneity for each analysis.
Hedge’s g (Hedges, 1982) was utilized as the outcome measure to estimate the standardized mean difference. In this context, effect sizes of .20, .50, and .80 corresponded to small, medium, and large effect sizes, respectively. Heterogeneity among the studies was evaluated using the I² statistic, with values falling into categories such as minimal, moderate, substantial, and considerable heterogeneity (0–40%, 30–60%, 50–90%, and 75–100% respectively) (Higgins et al., 2020).
To assess potential publication bias, funnel plots were visually inspected. Further evaluation of funnel plot asymmetry was conducted using Egger’s regression test (*p* < .05) (Higgins et al., 2019). It is important to note that since many of the analyzed subsets comprised fewer than 10 studies, interpretation of publication bias results was approached cautiously (Sterne et al., 2011). As an additional measure, Rosenthal’s fail-safe *N* was also reported for significant analyses (*p* < .05) (Rosenthal, 1979). These steps were undertaken to ensure the reliability and validity of the analysis and to draw accurate conclusions from the gathered data.
Results
The initial search across electronic databases yielded a total of 4113 records. After removing duplicates (1092), the remaining 3021 studies underwent title and abstract screening. Among these, 2719 studies were deemed irrelevant and excluded. The remaining 302 studies underwent full-text review based on the defined criteria. Ultimately, 30 studies met the inclusion criteria for meta-analysis. However, one study was excluded due to risk of bias, resulting in 29 studies being included for analysis. The process of study selection, exclusion, and inclusion is depicted in Figure 3.
Quality Assurance and Risk of Bias Assessment
A comprehensive risk of bias assessment was carried out using the National Heart, Lung and Blood Institute Quality Assessment of Case–Control Studies tool. The assessment included 12 questions to evaluate potential biases associated with comparing clinical and non-clinical populations. One study was retained despite displaying high risk as it compared migraineurs to laboratory norms, and another study was excluded due to insufficient power and methodological issues. The remaining studies (totaling 1237 participants) were considered to have negligible risk of bias.
Sex Hormone Dysregulation and Clinical Manifestations
Estradiol, progesterone, and testosterone concentrations were analyzed among the included studies. For estradiol, no significant difference was observed in follicular concentrations between female migraineurs and controls. However, during the luteal phase, female migraineurs exhibited significantly lower estradiol concentrations compared to controls.
Progesterone concentrations during both the follicular and luteal phases showed no significant difference between female migraineurs and controls. Similarly, analysis of testosterone concentrations did not reveal significant disparities between male migraineurs and controls.
In terms of diurnal cortisol concentrations, meta-analysis indicated that migraineurs had significantly higher levels of cortisol compared to controls, albeit with a small effect size. No significant differences were found in heart rate variability (HRV) variables, such as LF, HF, LF:HF ratio, RMSSD, and SDNN, between migraineurs and controls.
Limitations and Implications
The study acknowledged limitations in terms of the lack of data for certain migraine subtypes and comorbid mental health disorders. Moreover, the skewed gender distribution with more female participants limited the generalizability of results to male migraine sufferers. The findings suggest sex hormone dysregulation and cortisol elevation as clinical manifestations of hypothalamic function in migraine, prompting further research into the intricate neuroendocrine mechanisms underlying this complex disorder.
Conclusions
The study’s findings support the notion that individuals with migraines tend to experience disturbances in sex and stress hormone regulation, particularly cortisol dysregulation. However, the presence of heterogeneity and some publication bias underscores the need for cautious interpretation. Moreover, the study suggested that hormonal and neuroendocrine disruptions might not solely stem from migraine itself, but could be linked to frequent painful episodes and chronic stress. This emphasizes the importance of comprehensive therapeutic approaches considering both neuroendocrine and neuropsychiatric factors in managing migraine.
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