Mechanistic approach and therapeutic strategies in menstrual and non-menstrual migraine

Abstract

Migraine is a common condition that can cause intense headaches, often on one side of the head, along with symptoms like nausea and sensitivity to light and sound. These headaches can be triggered by various factors, including stress, changes in hormones, sleep disturbances, diet, and even gut health. Migraines are more frequent in women, particularly those under 45, and this may be linked to hormones. After age 45, this difference between men and women becomes less noticeable. Women tend to experience migraines that are more severe and last longer than men, with menstrual migraines affecting about 22% of women during nearly half of their menstrual cycles, and 7.6% of women with migraines. Treatments for migraines include medications, lifestyle changes, and alternative therapies, all of which aim to address the different ways migraines can affect people. This review explores these aspects in detail.

PLAIN LANGUAGE SUMMARY

Migraines are intense, one-sided headaches often accompanied by nausea and sensitivity to light and sound. They can be triggered by various factors, including stress, hormonal changes, sleep issues, gut health, and certain foods. Migraines are more common in women, especially those under 45, likely due to hormonal influences. Women also tend to have more severe and longer-lasting migraines, and some experience migraines related to their menstrual cycles. Treatments include pain relief medications, lifestyle adjustments, and alternative therapies like acupuncture. Since migraine can show up in different ways, diagnosis and treatments are personalized to fit each person’s needs. This review discusses these aspects in detail.

ARTICLE HIGHLIGHTS

1. Migraine and their phases: It encompasses a brief introduction explaining migraine and its various phases.

2. Mechanisms behind menstrual and non-menstrual migraines: This article highlights the numerous mechanisms that trigger menstrual and non-menstrual migraines.

3. Causes of menstrual and non-menstrual migraines: This review discusses the causes of both menstrual and non-menstrual migraines, which include hormonal imbalance, sleep, oxidative stress, gut microbiota and diet, and hereditary factors.

4. Clinical variations: menstrual vs. non-menstrual migraines: It additionally gives statistical data in case of clinical variations between menstruation and non-menstrual migraine.

5. Management: conventional and novel treatments: Both conventional and novel treatments have been briefly reviewed for managing both the two types.

1. Introduction

The physiological basis of migraine, a frequent episodic neurological condition, is complicated. Usually, it appears as recurring attacks of unilateral, usually severe, throbbing, painful headaches and specific ancillary symptoms like nausea, phonophobia and photophobia [1]. There are two main forms of migraine: migraine without aura (also called common migraine) and migraine with aura (also called classical/classic migraine), which is characterized by unique and fleeting focal neurological symptoms that can precede or coincide with the headache [2]. There are four overlapping phases to a migraine episode: the premonitory, aura, headache, and postdrome phases (Figure 1). The premonitory phase occurs hours or days before pain onset; the aura phase begins 30–60 minutes before pain onset; the headache phase is the period of persistent pain; and the postdrome phase is the one where the symptoms linger after the pain subsides. Yelling, mood swings, trouble focusing, a stiff neck, exhaustion, thirst, and increased frequency of urination are some premonitory signs [3]. The most prevalent variety of aura is visual, followed by brainstem, somatosensory, linguistic, motor, and retinal auras [4]. The trigeminal sensory pathways are what trigger headaches. Fatigue, drowsiness, and noise sensitivity are all postdrome symptoms [1]. Although postdromal symptoms in migraine seem to be reported quite frequently, the nature and frequency of these symptoms are not well-documented in the literature [5]. Over 1 billion people worldwide, representing all socioeconomic levels, regions, and cultures, are directly impacted by this chronic and frequently lifelong disease [6]. It involves genetic, environmental, and lifestyle elements [7]. The cause of the disease is multifactorial, with uncommon monogenic variants. The underlying headache-causing mechanism, trigeminal sensory activation, is most likely triggered by the spreading depolarization, which also most likely causes an aura [8]. The mechanisms of migraine may coincide with those of other disabling disorders like psychiatric disorders, stress-related disorders, hypertension, obesity and stroke. A better understanding of these shared mechanisms could inform the clinical management of diseases that cause a significant proportion of the world’s leading disabilities [9]. Women suffer from migraines two to three times more often than men do, and they also experience longer attacks, increased headache frequency, greater impairment, and longer recovery times [10].

Figure 1.

Phases of migraine. The different phases of migraine; migraine is divided into four main phases, namely, Prodrome –which includes symptoms like constipation, mood swings, neck stiffness, persisting for a duration of 3 hours to several days, Aura - which includes symptoms like speech difficulty, pins and needle sensation, face numbness, persisting for 5 to 60 minutes, Headache - includes symptoms like pain on one side of the head, light sensitivity, Postdrome - nausea and vomiting persisting for 4 to 72 hours, which include symptoms like feeling drained, confused, sudden head movement may cause headaches again.

It is generally recognized that excessive or persistent emotional reactions can trigger migraines in vulnerably disposed individuals. Fatigue, intense or flickering light, slight transitory hypoglycemia, high altitude, changes in the weather, medications (vasodilators and reserpine), and hormonal imbalance during the menstrual cycle are additional attack-inducing factors [11]. Menstruation is the primary cause of migraines in a subset of female migraineurs [12]. Menstrual-related migraine without aura, in contrast to non-menstrual migraines, involves additional episodes of migraine during menstruating [13]. The frequency of migraine attacks in women changes substantially during adolescence, the menstrual cycle, pregnancy, the postpartum period, and menopause [14]. Prepubescent girls and boys experience migraines at roughly the same rate, nonetheless, this rate shifts following menarche and throughout the reproductive years, increasing the female-to-male ratio from 1:1 to 2–3:1 [15] In the general population, menstrual migraine without aura affects about 20% of female migraineurs [16]. Pure menstrual migraine and migraine associated with menstruation are two categories of menstrual migraine [12]. Diagnostic standards for menstrual migraine, migraine associated with menstruation, and pure menstrual migraine are listed in the International Classification of Headache Disorders appendix (Table 1) and are still primarily regarded as research standards that require validation [19]. It is believed that a significant drop in circulating estrogen was observed during the two to three days before the start of menstruation is the trigger for menstrual-associated migraine. About 50% of women are estimated to have an increased risk of experiencing migraines during the premenstrual phase due to decreasing estrogen levels [20].

Table 1.

IHS Diagnostic criteria for menstrual migraines.

Diagnosis	Description	Reference
Menstrually related migraine	Headaches meet the diagnostic criteria for migraine without aura. Attacks occur on day 1 ± 2 (i.e., days –2 to +3) of menstruation and at other times of the cycle.	[17]
Pure menstrual migraine	Headaches meet the diagnostic criteria for migraine without aura. Attacks occur exclusively on day 1 ± 2 (i.e., days –2 to +3) of menstruation and at no other times.	[18]
Diagnostic criteria A.	At least 5 attacks fulfilling criteria B–D	[16]
B. C.	Headache attacks lasting 4–72 hours (untreated or unsuccessfully treated) Headache has at least 2 of the following characteristics: (1) Unilateral location (2) Pulsating quality (3) Moderate or severe pain intensity (4) Aggravation by or causing avoidance of physical activity (e.g., walking or climbing stairs)	[16]
D.	During a headache, at least 1 of the following: (1) Nausea and/or vomiting (2) Photophobia and phonophobia	[18]
E.	Not attributed to another disorder	[17]

2. Clinical variations between menstrual migraine and non-menstrual migraine

Based on the headache history and a study of the diary cards, a migraine diagnosis and confirmation of the menstrual relationship are clinically determined [17]. Migraines afflict at least 50% of women’s menstrual cycles, 22% of all women, and 7.6% of migraine sufferers [10]. This study examined premenstrual, menstrual, and post-menstrual migraine attacks, in addition to the traits associated with migraine in those with menstrually connected migraine vs migraine without a menstrual association. According to the findings, the headache lasted longer and was accompanied by a greater number and variety of symptoms [18]. Menstrual migraine is distinguished from non-menstrual attacks by its severe intensity, protracted duration, resistance to pharmacological therapies, increased risk of recurrence, and work-related incapacity [21]. A type of migraine connected to the female reproductive cycle called menstrually-related migraine without aura is susceptible to rebound and less receptive to immediate therapy than non-menstrual migraine without aura [22]. Women with recurring, incapacitating headaches often suffer from migraines, but doctors must first rule out other headache conditions before making a diagnosis. Pharmacological and non-pharmacological treatments may be chosen to best meet the patient’s needs. This article discusses the distinctions between non-menstrual migraine, PMM, and MRM and identifies efficient therapy techniques for migraine brought on by hormonal changes [23]. 20–25% of women get menstrual migraines, which affects 22–70% of individuals who go to headache clinics. More incapacitating than non-menstrual attacks are perimenstrual migraine attacks [22]. A clinical history of migraine, a mental evaluation, electroencephalography, and a challenge involving food allergies can all be used to assess non-menstrual migraine. The challenge with particular food allergens was found to significantly correlate with the onset of migraine headaches, gastrointestinal discomfort, and favorable skin reactions [24]. In a study, the clinical characteristics of migraineurs with ictal osmophobia were compared to those without ictal osmophobia in order to better understand another kind of non menstrual migraine. According to the results, there are substantial disparities in pain, anxiety, and aura, indicating that ictal osmophobia is linked to a larger sensory hypersensitivity [25]. A substantial percentage of patients reported having headaches and sleep difficulties, and 38% of the patients reported sleeping an average of 6 hours per night. In 50% of patients, sleep disturbance was the cause of migraines, while 71% of patients experienced headaches upon awakening. With 85% of people choosing to sleep or rest and 75% being forced to, sleep was also a successful headache remedy. Patients with chronic migraine claimed to fall asleep for less hours each night than those with episodic migraine. They were also more likely to have problems falling asleep, keeping asleep, getting a headache when they tried to sleep, and opting to sleep rather than staying up. Short sleepers (i.e., those with an average sleep duration of six hours) displayed noticeably more frequent and severe headaches than those with longer sleep durations [26]. Both the Barany Society and the International Headache Society now acknowledges vestibular migraine as a separate diagnostic entity. Variability in the kind of vertigo, the existence or lack of clearly defined attacks, the length of attacks, and the temporal relationship between headache or other migrainous features and vestibular symptoms all present diagnostic challenges. Moreover, symptoms frequently coincide with those of other conditions that can produce vertigo, such as Ménière’s disease and BPPV [27]. Women experiencing menstrual migraines endure a debilitating condition characterized by headaches associated with menstruation. Fluctuations in hormone levels, particularly estrogen withdrawal, may play a role in the development of these migraines. Non menstrual migraines have a variety of treatment options, but early diagnosis and treatment can help control the condition [28].

3. Migraine in adolescents and adults

Migraine is the world’s second leading cause of disability among all ages [14]. Those below the age group of 45 are more likely to experience it, with prevalence increasing during early adulthood, peaking in middle age, and gradually declining thereafter [29]. More than 53% of patients experienced their first migraine attack before reaching Adulthood [30]. Adolescents with migraines, compared to their peers, have a reduced quality of life, greater fatigue, more behavioral issues, higher school absences and lower capacity to function in class and participate in social activities [31]. Children and adolescents who experience migraines make up about 10% of the population which is caused by various reasons (Figure 2). They often go to their main healthcare provider with concerns about repeating, moderately to intensely painful headaches that persist for 2 to 72 hours [32]. Over the past decades, several studies have examined the potential alteration of intrinsic baseline brain activity caused by long-term episodes of migraine attacks in adults [33]. These studies demonstrate that between healthy controls and adult migraineurs, there are differences in brain connectivity at the level of pain processing networks, effective networks, default mode networks, executive control networks, silence networks, and visual networks [34]. According to another study, tension-type headaches (TTH) and H15+ were most common in people aged 20 to 64, regardless of gender, although the prevalence may vary within this age range depending on lifestyle, occupation and medical history. Certainly, the age span between 20 and 64 years is a fairly broad one, and this distinction just places adults aside from children, teenagers, and the old. Further research is needed to better understand the demographic patterns of these types of headaches [35]. As a result, compared to the elderly, people who suffer from migraines are exposed to higher levels of polypharmacy [36]. Polypharmacy is the use of multiple medications to treat different conditions, which can increase the risk of adverse drug reactions and interactions. Healthcare providers need to consider this when treating patients with migraines. The findings indicate that CM (chronic migraine) occurs less commonly in adolescents than in adults, adolescents are still significantly affected. Data show that there is an unmet medical need; nonetheless, developing effective criteria for diagnosing adolescents with CM is crucial to properly understand how medical requirements might be met in this complicated population [22].

Figure 2.

Different causes of migraine. The various causes of migraine which include hormonal imbalance, neurological and sensory mechanisms, sleep, gut microbes and diet, and genetic factors which are explained throughout the review.

3.1. Neurological and sensory mechanisms

Headache is one of the most common neurological symptoms. In contrast to free times, plasma samples taken after attacks contained lower levels of the endogenous opioid peptide Even people who experience persistent headaches have considerably decreased beta-endorphin level. Although the exact cause of hypoendorphin anemia is unknown, it may be related to decreased amounts of the neuropeptide that regulates hedonic, nociception, and vegetative processes [37]. The four stages of migraine are aura, headache, postdrome, and premonitory symptoms. At this time, believed that a primary neuronal malfunction results in a chain reaction of intracranial and extracranial modifications that result in these abnormalities [38]. Aura is a gradually manifesting, an entirely reversible, focused neurological condition that can include visual, sensory, speech, and/or motor problems. It typically occurs before the headache phase. A substantial amount of research has established cortical spreading depression (CSD) as the primary mechanism underlying aura. Each aura symptom develops gradually and lasts no more than an hour. Positive and negative aura symptoms mean symptoms defined by presence (such as shimmering lines in the vision) and symptoms defined by absence (such as blind areas), and are completely reversible. The most frequent variety is visual aura, which is followed by sensory, aphasic, and motor symptoms. Exploration of brief ischemia events and prolonged phases that may or may not be auras should be done in an emergency [39]. The headache phase of a migraine episode is believed to start with the activation of nociceptors that innervate the pial, arachnoid, and dural blood vessels, as well as the major cerebral arteries and sinuses. When these structures are stimulated mechanically, electrically, or chemically (pro-inflammatory chemicals, blood, or infection), the result is a headache that is very comparable to migraine pain and its most prevalent accompanying symptoms: headache, photophobia and nausea [40]. Current research focuses on the general pattern of brain activation during migraine attacks as well as particular features including pain perception, photophobia, and osmophobia. There is evidence that ongoing attacks are changing the brain’s functionality and structure [41]. 50 patients experiencing common migraines had their visual (VEP) and brainstem auditory (BAEP) evoked potentials recorded. Differences in BAEP might represent signs of brainstem center dysfunction, possibly linked to serotonin or endorphin neurotransmission. Central migraine etiology may also be supported by left-sided asymmetry [42]. Significantly more infra-slow oscillatory power in migraineurs was present in the right V1, right V2, right V3, and left V3 regions at rest when 0.03–0.06 Hz power was compared. There were no discernible age or gender compositional differences [43].

3.2. Hormonal imbalance

Studies discovered an imbalance between ovarian and pituitary sex hormones that causes migraine seizures (Figure 3). As a consequence of a lack of adaptation, which is more common in women than in men, neuroendocrine events connected to reproductive stages and the menstrual cycle may cause a significant change in the clinical pattern of migraine over time. In fact, hormonal changes that naturally occur during the menstrual cycle and at the time of reproductive transitions affect each person’s threshold of vulnerability to exhibit migraine [44]. Research based on population studies suggests that symptoms experienced during perimenopause might worsen post-menopause. Studies on headache centers, however, demonstrate no improvement or deterioration. The etiology of menopause may have an impact on how migraines develop, with relief more likely to come after spontaneous menopause. Hormone replacement medication used after menopause has been linked to an increase in migraine frequency. Menopausal women with migraines are not advised to take any particular preventive precautions. To assess the burden of migraine after menopause and establish the connection between migraine and hormonal changes, more study is required [45]. The use of oral contraceptives affects the frequency and intensity of migraines and progesterone have a potent calming impact. Progesterone levels and progesterone-to-estradiol ratios are lower in migraine-prone women, while 17-beta-estradiol levels are greater in both ovarian stages. The premenstrual and menstrual phases are when menstrual misery is most severe, and estrogen levels during menarche, menstruation, pregnancy and menopause may have an impact on migraines (Figure 4) [46].

Figure 3.

Hormones playing a role in menstrual migraine. This figure shows the different genes like human Prostacyclin, Estrogen, Progesterone, Follicular Stimulating Hormone (FSH), Oxytocin, Prostaglandin and Luteinizing Hormone (LH) that plays a role in causing migraine.

Figure 4.

Prevalence of migraine in different phases of menstruation. This figure explains the fluctuation in the frequency and amplitude of migraine with changes in the estrogen and progesterone levels in the different phases of migraine, namely; menstrual phase, follicular phase, ovulatory phase, and luteal phase. Migraine is generally at its peak in the menstrual phase in people having menstrual migraine.

However, only a small number of studies have looked at the occurrence and features of migraine according to menopausal status. Data suggests that hormonal variables, notably estrogen levels, increase migraine activity. Population-based research has generally found that migraines get better after menopause, though perimenopause may make them worse. Yet, research conducted on people who visited headache clinics revealed no improvement or possibly a worsening of migraine symptoms. The etiology of menopause may influence the progression of migraine during the menopausal era, with migraine relief more likely to occur following spontaneous menopause than following surgical menopause. Observational population-based research has discovered a link between postmenopausal hormone replacement therapy and migraine exacerbation [45]. Menarche, pregnancy, the use of contraceptives, and frequently the use of sex hormone replacement therapy are all related to the regular female life cycle’s hormonal milestones (Silberstein 2001b). Pregnancy, birth control, menopause, and hormone replacement therapy (HRT) are just a few of the life cycles and hormonal treatments that can affect the frequency and severity of headaches [46]. The abnormal ratio of pituitary and ovarian sex hormones secreted is determined by urine excretion. They demonstrated that an elevated prolan output occurred before the migraine seizure, and they were able to cause headaches in these patients by administering prolan [47]. 185 migraine sufferers, including 70 married and unmarried women, were screened for the study. A total of 36 married women had undergone gynecological and obstetrical procedures. According to a study, women were more likely to experience migraines after procedures like D&C and hysterecto cesarean sections. According to the study, procedures should be avoided unless absolutely necessary, especially for people who have a migraine history [48].

4. Sleep

One of the most prevalent neurological symptoms that affects patients’ life is headaches. Numerous types of headaches, including migraine, cluster headaches (CH), tension-type headaches (TTH), morning headaches, and hypnic headaches, have been linked to Obstructive Sleep Apnea (OSA) [49]. The relationship between migraine and sleep disorders significantly amplifies the impact of migraine. Migraine exhibits a clear correlation with various sleep-related disorders (Figure 5), with certain conditions like restless leg syndrome being supported by multiple studies, while the validity or consensus surrounding other associations is still unclear or subject to debate [50]. Each of the four to six cycles of sleep lasts 90 to 100 minutes and is divided into the following stages: light slow-wave sleep, deep slow-wave sleep, and rapid eye movement sleep. The average adult sleeps 7.5 hours every night, but some people, known as long sleepers require 9 to 10 hours of sleep, while others, known as short sleepers, require less than 6 hours of sleep per night. The tendency to fall asleep is controlled by homeostatic regulation during sleep [51]. Individuals with migraines usually encounter a change in their sleep pattern, as seen by their proportion of stage 3 and stage 4 NREM sleep increasing prior to a headache occurring and the percentage of REM sleep increasing when the individual awakens with a migraine. The brain’s inability to stop migraine attacks due to diminished wakefulness during REM sleep may be the cause of this, which in turn could explain why migraine episodes tend to happen during this stage of sleep [52] It has not yet been determined whether a headache is the primary cause of sleep disruption or if a headache is a primary event that triggers sleep. A lack of or an excess of sleep, poor sleep quality, or insufficient sleep duration are frequently mentioned as potential headache causes because headaches are known to occur while sleeping and are related to different stages of sleep [53].

Figure 5.

Migraine–sleep correlation. Difference between the various anatomical structures of the brain involved in sleep and migraine.

However, large-scale studies have now shown that snoring, insomnia, and a host of other sleep-disturbing conditions can all worsen and complicate migraine. One of the earlier and more compelling findings of research on the chronification of migraines was that sleep factors increase the risk of headaches going from episodic to chronic. The two sleep variables that were investigated were snoring and sleep disturbance and both were found to be important risk factors. There is substantial evidence linking poor sleep to a worse prognosis for chronic headaches, which calls for consideration in clinical settings [54]. The most frequent sleep issue among migraine sufferers is insomnia. According to Kim et al., individuals suffering from migraines were more likely to experience sleeplessness than those without headaches (25.9% vs. 15.1%). It has been hypothesized that it may make people more prone to migraine attacks, which may impact the trigeminal vascular system’s ability to process pain [55]. The pathogenic mechanism behind the migraine-insomnia connection is unknown A key factor in synchronizing the circadian sleep cycle is melatonin, which is primarily produced in the pineal gland and has a variety of biological activities, including anti-oxidative, anti-inflammatory, anti-apoptotic, endocrinologic, and behavioral effects. According to studies, melatonin acts as a modulator of ovarian and uterine functions and is also produced in the peripheral reproductive system (granulosa and placental cells) [56]. Follicle Stimulating Hormone (FSH) is secreted during sleep, but there are conflicting reports regarding how sleep affects FSH levels. According to a study done on 160 normally menstruating, reproductive-age women, there is a positive correlation between FSH and sleep duration that persists even after age and body mass index adjustments [57]. The effects of sleep deprivation on cognitive and emotion-processing tasks are most tolerable in women with elevated levels of progesterone [58]. According to the findings, poor sleep hygiene was substantially correlated with migraine severity in approximately two-thirds of migraine sufferers linked to a higher risk of migraine, especially in older female migraine sufferers. Inadequate sleep, recurrent sleep disruptions, and increased daytime somnolence were all observed in young women with migraines [59].

5. Gut microbiota and diet

The frequency and severity of attacks can be reduced with pharmacological and lifestyle changes for migraine treatment. During clinical visits to treat migraine patients, a focus on lifestyle modifications, especially diet, is frequently discussed along with pharmacological interventions. The growing number of gastrointestinal conditions that have been linked to migraines suggests that the gut microbiota may be crucial in the development of migraines through the gut-brain axis. The community of bacteria, archaea, fungi, and viruses that inhabit the GI tract is known as the gut microbiome, while the term “gut-brain axis” refers to a two-way communication between the brain and the gastrointestinal (GI) system, in which the brain controls GI system operation and the GI system significantly influences brain function [60]. It is unclear how exactly the gut microbiota contributes to neurological disorders in general and migraine in particular, as human gut microbiota studies tend to be more correlative than causative in nature [61]. When compared to people without migraine, those with migraine have a higher prevalence of GI problems like diarrhea, constipation, dyspepsia, and gastroesophageal reflux. The ratio of human cells to bacteria varies by gender and is greater in females (2.2) than in males (1.3). During their menstrual cycle, healthy women of reproductive age suffer a cyclic alteration of the gastrointestinal (GI) system. The majority of healthy women also lament GI issues getting worse either during the menstrual or premenstrual phases [62]. In contrast, dietary intakes that can reduce estrogen activity have been demonstrated to be advantageous for menstruating women. Diets low in fat, high in fiber, or vegan may therefore be beneficial for some individuals, particularly those who suffer from menstrual migraine. Additionally, losing weight has been said to help with menstrual migraines [63]. In a pilot study that was issued in 2019, women with migraines were given a customized meal plan according to the dietary expert’s evaluation. The research was the initial study to offer proof that maintaining a healthy weight and practising good nutrition are crucial for treating menstrual migraines. The idea that migraines can be a response to reduced brain energy reserves or gratuitous oxidative stress has helped the ketogenic diet has regained popularity [64]. This dietary regimen might be employed to fix anomalies in glucose metabolism as an alternative form of energy because it works similarly to fasting, which leads to an increase in ketone bodies. A proof-of-concept study and other papers have shown the advantages of a ketogenic diet in lowering migraine frequency [65]. On the other hand, a recent article summarized probiotic therapies as a preventative method to treat migraines. Probiotics may lessen intestinal permeability and inflammation, which may reduce migraine attacks’ frequency and/or severity [66].

6. Genetic factors

Migraine is a complex neurovascular disorder that undeniably has a strong genetic component, classified primarily into two types: aura-related migraine (ARM) and migraine without aura (MO). Hemiplegic migraine, a rare variant, results from mutations in critical genes such as CACNA1A, ATP1A2, and SCN1A, which are essential for ion channel function and transport, and follows an autosomal dominant inheritance pattern. The connection between migraines and anxiety-related depression is significant and well-supported by genetic evidence [67]. First-degree relatives of individuals with migraine without aura face a 1.9-fold increased risk, while those with migraine with aura experience a staggering four-fold increased risk, highlighting the powerful genetic influence on the development of these conditions. Recent genome-wide association studies (GWAS) have decisively identified multiple genetic variants linked to migraine susceptibility, uncovering over 40 relevant SNPs and a wide range of implicated genes, including those that regulate estrogen and tumor necrosis factor [68]. It’s also essential to recognize MELAS syndrome, which arises from a mitochondrial mutation and manifests with migraine-like symptoms. As research advances, our understanding of the genetic underpinnings of migraines will continue to deepen, particularly through next-generation sequencing and explorations of gene regulation and epigenetics. With 47 known genetic loci affecting common migraine types, the field has made substantial progress, driven by GWAS that reveal critical associations between migraines and a host of other neuropsychiatric disorders [67].

7. Oxidative stress

Frequent migraine triggers include high rates of energy generation, toxicity, calcium overload, neuroinflammation, and activation of neuronal NADPH oxidase, all of which can result in oxidative stress. The varieties of migraine triggers found in clinical practise can all be attributed to oxidative stress, which may have significance for migraine attack prevention and comprehension [69]. This study examined the differences in oxidative stress status in migraine patients with or without an aura or attack. There were 56 patients (46 females and 10 males), while in the control group, there were 25 healthy participants. Patients in the migraine group had MDA levels that were noticeably greater than those in the control group. In comparison to the MWoA, the SOD activity was much higher in the MWA. Further understanding of this topic may help to understand the causes and side effects of migraines and may be crucial for the creation of therapeutic strategies. Due to either increased energy demand (hyperexcitable brain) or decreased energy supply, Migraineurs are more likely to have mitochondrial dysfunction, which is a deficiency in brain energy between attacks. However, it is ambiguous how this results in a serious attack. It has been alleged that oxidative stress is a major factor in this situation. The antioxidant defenses of neurons are primarily mediated by biologically synthesized NADPH (reduced nicotinamide adenine dinucleotide phosphate), and its concentrations are strongly associated with energy generation [69]. Here, we demonstrate that elevated oxidative stress increases the risk of migraine-related metabolic issues such as nitrosative stress, an atherogenic lipid profile, and hyperinsulinemia. Some findings imply that oxidative stress may be an important factor in the etiology of migraines and a promising treatment target. In comparison to the control group, plasma 8-OHdG levels were found to be considerably higher in migraine patients; this rise was more pronounced in cases of migraine without aura than in those with aura [70]. The findings revealed that migraine sufferers may have DNA damage related to oxidative stress [71]. Although the processes behind migraine pathophysiology are not fully understood, 31 P-nuclear magnetic resonance studies found that migraineurs lacks cognitive energy. Since glycolysis is the main way that the brain produces energy, mitochondria might have an enormous effect on migraine pathogenesis. Despite the fact that many migraineurs blame foods or foodstuffs for their attacks, nutrition is crucial to the pathophysiology of migraines [72]. One of the studies was to measure the levels of nitrosative and oxidative stress markers in the platelets of migraine sufferers both during headache-free and attack periods. The findings demonstrated that during migraine attacks, nitrate, nitrite, and MDA levels were considerably higher in migraineurs than in control patients. This shows that NO might modulate biological processes in some way. MDA and NO metabolites could be effective indicators of migraine patients’ heightened susceptibility to oxidative and nitrosative stress. The study looked at a novel oxidative stress parameter in migraine sufferers: dynamic thiol-disulfide homeostasis. There were 115 participants in total, including 63 migraine sufferers. Dynamic disulfide bond ratios were computed, and serum total thiol and native thiol levels were measured. The study discovered that, compared to healthy people, migraine patients had significantly higher levels of both total and native thiol. The ratios or amounts of dynamic disulfide bonds did not significantly differ. The amount of total thiol, native thiol, and dynamic disulfide bonds did not correlate with migraine type, attack frequency, or the severity of the pain, according to the study. A molecular alteration thought to be responsible for the pathogenesis of migraines is oxidative stress [73].

8. Treatment

To treat menorrhagia and/or dysmenorrhea, NSAIDs are the drug of choice. For cases without these symptoms, perimenstrual estrogen supplements, using percutaneous or transdermal estrogens, are recommended. Several randomized, placebo-controlled trials have evaluated the effectiveness of triptans—sumatriptan, naratriptan, zolmitriptan, and almotriptan—in treating menstrual migraines [22]. In women with menstruation-related migraines, frovatriptan has been found to significantly improve patient ratings of therapeutic effectiveness and tolerability [74]. Generic treatments for migraines include aspirin, paracetamol, NSAIDs, opiates, and combination analgesics. Specific migraine medications include ergotamine, dihydroergotamine, and triptans [23]. Menstrual migraines can be prevented or lessened in severity by taking prostaglandin inhibitors before the vulnerable period. Studies have shown that mefenamic acid, a prostaglandin production inhibitor, is both safe and effective for treating acute menstrual migraine. Additionally, over-the-counter combinations of paracetamol, aspirin, and caffeine have been shown to relieve the pain, impairment, and symptoms of both menstrual-associated and non-menstrual migraines. Oral zolmitriptan has proven to be successful and well-tolerated in the acute management of menstrual migraines. During pregnancy, paracetamol is the preferred treatment for acute migraines, but sumatriptan can be considered if paracetamol is ineffective [75]. Both pharmacological and non-pharmacological treatment options for menstrual migraines are summarized in Table 2. Some studies suggest that migraines may be caused by mitochondrial energy deficiencies or elevated homocysteine levels. Vitamins such as riboflavin, B6, B12, and folic acid, which help catalyze homocysteine, can reduce the intensity of migraines with aura. Elevated prostaglandin levels in the endometrium are linked to menstrual migraines, indicating that vitamin E could serve as an anti-prostaglandin treatment. Vitamin C may also help alleviate neurological inflammation in migraine sufferers. In clinical trials, vitamin E significantly improved pain, functional impairment, phonophobia, photophobia, and nausea compared to placebo [76]. Dietary interventions like low-sodium, deprivation, vegan, and ketogenic diets (KD) have also been suggested for migraine management, with the KD being particularly noteworthy [60]. In a study assessing REN (a non-pharmacological migraine abortive technique), most female migraine sufferers reported positive experiences. A REN (Remote Electrical Neuromodulation) device is a noninvasive, drug-free tool for migraine treatment. It delivers electrical pulses to the upper arm, stimulating peripheral nerves to help alleviate pain [77]. Therapies like biofeedback, relaxation, and stress management are effective across various age groups, including children, teens, and the elderly. Acupuncture, both real and sham, has been used frequently to treat migraines and their associated emotional symptoms [78]. Studies also reveal that caffeine withdrawal can trigger migraines in 2% to 30% of participants, although caffeine itself is effective for treating severe migraines when combined with other analgesics. It is important for migraine sufferers to regulate their caffeine intake to avoid withdrawal-induced headaches, as excessive caffeine can exacerbate migraines, while sudden withdrawal may trigger attacks. Rimegepant calcitonin gene-related peptides (CGRP) are emerging treatments for migraine prevention. Research shows that individuals with more frequent migraines and higher disability at baseline are less likely to respond to these anti-CGRP MAbs, highlighting the importance of early treatment to maximize the chances of success [79].

Table 2.

Pharmacological and non-pharmacological treatment of menstrual and non-menstrual migraine.

S.NO	Non-pharmacological treatment	Reference	Pharmacological treatment	Reference
1.	Caffeine	[75]	NSAIDS	[24]
2.	Vitamin B2, B6, B12, C, E	[76]	Triptans	[24]
3.	Folic acid	[60]	estrogen supplements	[24]
4.	Low sodium diet	[60]	Ergotamine	[24]
5.	Ketogenic diet	[60]	Prostaglandin	[75]
6.	Vegan diet	[60]	Anti-estrogen medication	[24]
7.	Acupuncture	[78]	Anti-CRGP monoclonal antibodies	[79]

9. Future perspectives

Our growing knowledge of menstrual migraines and the factors behind them is opening doors to groundbreaking improvements in how we treat and manage this condition. In the coming years, scientists are expected to explore genetic and hormonal connections more thoroughly, using advanced tools like genomics and proteomics to identify new treatment possibilities. For example, pinpointing mutations in genes related to estrogen, progesterone, and oxidative stress could lead to personalized therapies that cater to each person’s unique hormonal and genetic makeup. Artificial intelligence and machine learning could transform how we diagnose and address menstrual migraines, offering predictive models to detect early warning signs and implement preventive measures before a migraine strikes. At the same time, wearable devices might become a game-changer, tracking hormonal and physiological changes in real time to provide actionable tips for reducing migraine episodes. Given the risks of relying on multiple medications, future research will likely shift toward finding gentler, more natural solutions. For instance, a better understanding of how the gut and brain interact could inspire microbiome-focused treatments. Clinical trials may also confirm the benefits of vitamins and supplements like riboflavin, B6, B12, folic acid, and vitamin E, helping to refine their use for migraine relief. Ultimately, this growing body of research has the potential to deliver not only more effective treatments but also a better quality of life for individuals living with menstrual migraines.

10. Conclusion

Migraine, a neurological condition that affects more than 1 billion people worldwide, involving four phases: premonitory, aura, headache, and postdrome. Women suffer from migraines two to three times more often than men, experiencing longer attacks, increased headache frequency, greater impairment, and longer recovery times. Menstruation is the primary cause of migraines in a subset of female migraineurs. Menstrual migraines are more severe, protracted, and resistant to pharmacological therapies. Non-menstrual migraines, PMM and MRM, are characterized by longer headache lengths, more frequent and diverse symptoms, and resistance to pharmacological therapies. The second most common cause of impairment worldwide is migraine, which is more common in persons under the age of 45. Adolescents with migraines experience lower quality of life, sleep disturbances, school absences, and social activity issues compared to their peers. Migraine treatments are currently unavailable, leading to higher levels of polypharmacy, which can increase the risk of adverse drug reactions and interactions. Lifestyle changes, such as diet and pharmacological interventions, can help reduce migraine attacks. Migraine is linked to mutations in genes for estrogen, progesterone, insulin, MTHFR, angiotensin-converting enzyme, tumor necrosis factor, and low-density lipoprotein. Migraine triggers include high energy generation, toxicity, calcium overload, neuroinflammation, and activation of neuronal NADPH oxidase. A multidisciplinary approach is preferred for women with menstruation-associated migraines. Vitamins like riboflavin, B6, B12, and folic acid are essential for homocysteine catalysis, and vitamin E can be used as an anti-PG. Biofeedback, relaxation, and stress-coping techniques are useful for most migraine sufferers. However, more investigation is required to find long-term treatment for both menstrual and non-menstrual migraine.

Funding Statement

This article was not funded.

Author contributions

TM: Writing, investigation and resource. MM: Writing and investigation and data curation. RFB: Conceptualization, methodology and review. GH: Reviewing and editing. SM: Editing and Supervision.

Disclosure statement

No potential conflict of interest was reported by the authors.