INTRODUCTION:

Migraines are more common in women than in men. Women experience migraine attacks for longer periods of time. This chronic neurological disorder affects 10–12% of the population. The hallmark of migraine, a chronic pain condition, is excruciating pounding headaches. gastrointestinal issues, photophobia, and phonophobia, all of which reduce quality of life. Common comorbidities of migraine are Psychiatric disorders, like anxiety and depression, and patients with chronic migraine exhibit affective temperamental dysregulation and suicidal behaviours. Furthermore, the occurrence of migraine may be influenced by menarche, menstruation, pregnancy, menopause, and the use of oral contraceptives and hormone replacement therapy (HRT). Both sexes are equally affected by migraine. There is evidence to support the existence of gender differences in migraine, with the prevalence rate in females being almost twice that of males. Women witness the majority of related symptoms more frequently and with greater severity than males. Comorbid conditions are more common in female migraineurs, with psychiatric comorbidities being more prevalent. Migraine impairment may be caused by changes in estrogen levels in females. Migraines may affect from structural and functional differences in the brain between the sexes ¹. The most prevalent illnesses of the neurological system are headache disorders, which are illustrated by frequent headache episodes. The severe and incapacitating aspect of a few basic headache types, such as migraine, cluster headache, and tension type headache, is the headache itself. The most common, prevalent, incapacitating, and severe of these is the migraine headache. The most frequent headache-related and neurologic cause of impairment worldwide is migraine, which is also the second most prevalent cause of headaches. One of the most significant characteristics of the ailment is that, in many instances, the pain only affects half of the head. The word "migraine" comes from the Greek word "hemicrania," which translates to "half of the head." However, the pain can sometimes be felt on both sides, either in front of or behind the head, and in rare instances, it can spread to the entire body and face (a condition called "migrainous corpalgia"). Any movement of the head or body usually intensifies the pain, which is usually throbbing and occasionally pulsating in character. A prevalent chronic headache condition, migraine is characterized by recurring attacks that have a pulsing feel and last between four and seventy-two hours. The most frequent cause of headaches is migraine, which can range in severity from mild to severe and is exacerbated by any regular physical activity. Migraine is caused by the activation of meningeal perivascular pain fibers and also by enhanced sensitization of central pain neurons that process information from intrusions. Other linked symptoms of migraine include nausea, vomiting, photophobia, phonophobia, and others².

Migraine in Women’s (Defination of Migraine):

Participants' answers to the following standardized NHANES questionnaire item "Have you experienced a severe headache or migraine in the past three months?" were used to define migraine³.

Migraine and Women:

The woman’s reproductive cycle is governed by the hypothalamic-hypophyseal-ovarian axis through the release of hormones including oestrogen and progesterone. Variations in the amounts of hormones that control and regulate the menstrual cycle, pregnancy, puerperium, and menopause in every women’s life. 28 days make up the typical menstrual cycle. There are two stages to this: the luteal or ovulatory phase and the follicular or proliferative phase. The follicular phase is thought to begin on the first day of menstruation. The bleeding starts when the levels of progesterone and estrogen drop at the end of the preceding cycle. Pituitary follicular stimulating hormone (FSH) levels marginally rise during this period, which also promotes the growth of many ovarian follicles¹.

Signs and Symptoms:

Women are more likely to experience symptoms like phonophobia, photophobia, nausea, vomiting, and cutaneous allodynia. When comparing men and women, women experience headaches more frequently, for longer periods of time, and with greater severity. Men and women have similar levels of pain severity and attack frequency. Migraine is a complex neurological condition characterized by headache episodes. The adverse effects, which typically last 24 to 72 hours, include nausea, affectability to light, and loudness¹.

Role of Estrogens and Estrogen Receptors in the Pathophysiology of Migraine:

Estrogen Receptors and Estrogens Estrogens are lipophilic hormones that are mostly produced in the granulosa cells of the ovaries and are generated from cholesterol. Additionally, they originate from the aromatization of androgens in the brain and other peripheral tissues. E2, the traditional female sex steroid hormone, is the most significant endogenous estrogen. In addition to passively diffusing over the blood–brain barrier to reach the central nervous system (CNS), estrogens are either locally synthesized from cholesterol or transformed from aromatizable precursors by the brain enzyme aromatase, which results in their action as neurosteroids [19]. The three known kinds of estrogen receptors (ERs) that are activated by estrogens to produce physiological effects are estrogen receptor-α (ERα), estrogen receptor-β (ERβ), and the more recently discovered G proteincoupled estrogen receptor-1 (GPER/GPR30). The effects of estrogens on gene expression are mediated by two traditional nuclear receptors, ERα and ERβ. They are made up of four domains, including a DNA-binding domain and a ligand-binding domain, and are members of the nuclear receptor superfamily⁴.

Migraine during life:

Through the secretion of progesterone and estrogen, the hypothalamic-hypophyseal-ovarian axis controls a woman's reproductive cycle. The menstrual cycle, pregnancy, puerperium, and menopause are all regulated by changes in these hormones' levels and feedback regulation. The follicular or proliferative phase and the luteal or ovulatory phase are the two stages of a typical menstrual cycle, which lasts roughly 28 days. The follicular phase is thought to begin on the first day of menstruation, and bleeding happens when the levels of progesterone and estrogen drop at the end of the preceding cycle. The formation of many ovarian follicles is stimulated at this time by a modest increase in the pituitary follicular stimulating hormone (FSH) level. An egg is found in each follicle; only one follicle undergoes ovulation, generating elevated estrogen levels that cause a decrease in FSH production, inhibiting further follicle development, and stimulate the hypophysis to release luteinizing hormone (LH). With the exception of a slight increase right before ovulation, progesterone is low throughout the follicular period. A mature follicle bursts in reaction to an LH surge during ovulation, releasing a mature egg. The follicle, known as the corpus luteum, secretes progesterone and estrogen during the luteal phase, which begins shortly after ovulation. These hormones encourage the endometrium to create a dense layer of blood vessels in preparation for potential fertilization⁵.

PATHOPHYSIOLOGY MIGRAINE:

Migraine attacks are easily identified by their distinctive features, which include unilateral, pulsating pain that can be either throbbing or hammering, frequently accompanied by nausea or vomiting, phonophobia, or photophobia. It is moderate to severe in intensity and is typically made worse by regular activity, which restricts the everyday activities of persons who suffer from it. In addition to these symptoms, about one third of migraine sufferers may encounter reversible focal neurological symptoms, such as cortical disturbances, which are referred to as According to the International Headache Society's International Classification of Headache Disorders (ICHD), migraine encompasses a wide range of sensory system symptoms, including phonophobia (an aversion to sound) and photophobia (an aversion to light). touch (cutaneous allodynia), as well as symptoms that arise from the disruption of regular homeostatic function, like disturbed eating, sleeping, or mobility, all of which can occur during a migraine episode. The two types of migraine patients—those with aura and those without—have distinct profiles with regard to the risk factors for migraine comorbidities. The pathophysiology of migraine has been extensively researched, with a focus on neurological and vascular systems as potential primary triggers for attacks. The pathophysiological origin of migraine has been thoroughly investigated over several centuries, and its Over time, theories have evolved. Previously, it was believed to be a brain issue, a nerve force discharge. However, new theories were emerging that explained how migraines started with vasodilation. Subsequent research concluded that a vascular problem was the most likely cause of migraine. Numerous studies have used this vascular theory to demonstrate a connection between migraine attacks and the release of vasoactive peptides. such as the neurotransmitter nitric oxide (NO), the pituitary adenylate cyclase-activating polypeptide (PACAP-38), and the vasodilatory calcitonin gene-related peptide (CGRP), which are all potent vasodilators implicated in the pathophysiology of migrain. Preclinical research on NO triggered migraine has shown that practically all participants get an instant headache. Similar reactions to CGRP and PACA have been reporte ⁶.

Epidemiology:

According to estimates, 15% of the general population has migraines within a year, with a 3:1 female to male ratio. About 50% of people are impacted, and the frequency increases sharply during adolescence and the early stages of adulthood individuals who say that their migraines started before the age of 25. It is now widely recognized that migraines can occur in families, and that genetic factors are a significant contributor to the genesis of migraines. The lack of data and restrictions in population-based studies with varying case definitions and evaluation techniques are the main reasons why the prevalence of menstrual migraine is little recognized. 1181 women between the ages of 13 and 55 were selected from the general community for a Dutch study, which used a questionnaire to assess the presence of menstrual migraine. According to the poll, 3% of women said during the period between day −2 and day+2 of the menstrual cycle, 0.9% of women report having migraine attacks exclusively. In a populationbased study conducted in Norway, 3,514 women between the ages of 30 and 34 were screened for menstrual migraine using a questionnaire. To verify compliance with the ICHD-3β appendix criteria, prospective cases were contacted for a semi-structured interview. According to the findings, 0.8% of women in the general population between the ages of 30 and 34 suffer pure menstrual migraine without aura, and 0.1% have pure menstrual aura-accompanied migraine⁷.

Terminology Menstrual cycle:

Menstrual cycle and concludes on day 14 with ovulation. The day following ovulation marks the start of the luteal phase, which concludes shortly before monthly bleeding. Variable Sex hormone levels, which include progesterone and estrogen, control the menstrual cycle. The concentration of estrogen is at its lowest during menstruation and then rises steadily throughout the follicular phase to peak the day before ovulation. A decline in estrogen levels then follows before a secondary smaller rise occurs during the mid-luteal phase. Menstruation begins as a result of a sharp decline in estrogen levels. An overview of the menstrual cycle and the related fluctuating levels of sex hormones are shown in⁷.

Relationship between migraine and hormones:

Women who suffer from migraines with aura have higher amounts of estradiol in their blood than those who do not. Migraines that happen during the luteal phases of the menstrual cycle may be lessened by progesterone metabolites. The pathophysiology of migraine is known to be influenced by feminine sex hormones. The drop in estrogen levels at the conclusion of the menstrual cycle in exogenous estrogen users and One important element in the pathophysiology of female headaches is the onset of the hormone-free phase. Both the menstrual cycle and genes are linked to migraine. One study suggests that the genetic foundation of migraine may be influenced by estrogen receptors 1 (ESR1) and 2 (ESR2).

Relationship between migraine and pregnancy and breastfeeding:

Migraines have long been believed to be an indication of pregnancy issues. Pregnancy and migraines are strongly correlated; studies show that 80% of women with a history of migraines can get them again during pregnancy. Breastfeeding was helpful and decreased the frequency of migraine return in the first week and the first month following delivery. The steady estrogen levels brought on by the lack of menstruation could may provide a protective effect during lactation. While nursing, taking sumatriptan for migrainesis also⁸.

Sex Hormone Fluctuation as A Trigger of Migraine:

Throughout a cisgender woman's life, migraines typically follow a traditional temporal pattern that aligns with changes in sex hormones during the female reproductive milestones. Sex hormone levels alter significantly during puberty, making it a crucial time. Intriguingly, the prevalence of migraine headaches in boys and girls is almost equal during childhood and adolescence but with puberty, the prevalence of migraines varies and is three to four times greater in women than in men. The beginning of menarche and the end of menopause are when this sex difference occurs. 18–25% of women with migraines experience migraine or headaches during their periods, and migraine symptoms can be associated with changes in the menstrual cycle (menstrual migraine). More frequent and severe migraine attacks, as well as a higher frequency of migraine-related symptoms, have been linked to menstrual migraine. When women with and without migraines are compared, it can be seen that those with migraines are distinguished by estrogen drop in the late luteal phase more quickly than in migraine-free women.

Which Sex Hormones Should Be The Target?:

Estrogen:

The effect of estrogen in migraine illness is complex. Although swings and decreases in estrogen are linked to migraine symptoms, each person experiences these effects differently due to differencein receptors, metabolites, and interactions with other hormones. The prevailing theory on the role of estrogen in shielding people from migraine symptoms is the estrogen withdrawal hypothesis, which describes what occurs when estrogen levels fall. According to this theory, decreases in plasma estrogen cause neuroinflammation and migraine attacks, which ultimately result in chronic sensitization.

Testosterone:

Many people think that estrogen is the female hormone and testosterone is the male hormone. This is oversimplified, though, because both testosterone and estrogen play significant roles in people of both sexes. For both men and women, The function of both reproductive and nonreproductive organs is influenced by the equilibrium between the production of estrogen and testosterone throughout life⁸. The androgen deficiency model of migraine is predicated on the idea that testosterone provides neuroprotection, as men with lower levels of androgen are more likely to experience cluster headaches. This idea is made more complex by discovering that testosterone stimulates neuroinflammation via microglial pathways, as opposed to estrogen, which does so through CGRP and other neuropeptides. Because of this, testosterone supplementation may prevent the development of chronic migraine in females, but it won't have the same impact in males because of their gender-specific physiology⁹.

Migraines at Various Phases of a Woman's Life:

A sharp drop in estrogen levels during the late luteal phase is usually the cause of the menstrual migraine, a subtype of migraine that closely relates to the menstrual cycle. It is distinguished by more severe, persistent, and resistant to therapy attacks in contrast to migraines that are not menstrual Up to 60% of female migraineurs reported a connection between their menstrual cycles and migraine attacks, according to epidemiological research, underscoring the important significance of hormone variations. There are period pure migraines which during the cycle, or two types of migraines: menstrual (PMMs) and only happen menstrual migraines that are specifically associated to the menstrual cycle (MRMs), which happen throughout the menstrual cycle but also at other periods of the month. Menstrual migraines are frequently treated with short-term preventative measures such as the use of nonsteroidal anti-inflammatory medicines (NSAIDs) to reduce pain during attacks and triptans, which are started a few days prior to the anticipated start of menstruation¹⁰.

Menstrual Migraine:

The International Classification of Headache Disorders (ICHD) provides clinical criteria that are used to diagnose migraine. Although it offered some commentary, the 1988 first version of the ICD lacked specific diagnostic standards for menstrual migraine. The classification committee recommended that When at least 90% of migraine attacks happen on day 1±2 (i.e., days −2 to +3) of menstruation, the condition is referred to as menstrual migraine⁷.

Migraine and hormanal contraption:

Depending on the type of contraception and the person's history of migraines, hormonal contraception can have a range of impacts on migraines. Both estrogen and progestin are used in combined hormonal contraceptives (CHCs), which may stabilize hormone fluctuations and may lower the incidence of menstrual migraines in some women by keeping their estrogen levels constant. However, classic combination contraceptive regimens' hormone-free interval might cause "estrogen withdrawal headaches," which in turn can cause migraines during this time.

Menopause and Postmenopausal Migraines:

Migraine patterns may change as a result of the menopausal transition, which is characterized by variable and diminishing estrogen levels. Hormonal instability during perimenopause frequently results in an increase in the frequency and intensity of migraine attacks. Particularly for people with MOs, migraine patterns may stabilize or improve during menopause. Particularly for women without auras, hormone replacement treatment (HRT) can help, minimize estrogen withdrawal headaches, and ease vasomotor symptoms¹⁰.

Treatment for Migraine:

Paracetamol is the drug of choice for acute treatment during pregnancy. According to one study, maternal hormones are essential for regulating the development of the embryonic brain. Acetaminophen or paracetamol use can cause neurotoxicity by causing oxidative stress, which can result in the death of neurons, or it can interfere with maternal hormones. Additionally, a study found that pregnant women who have children with hyperkinetic disorder (HKD) and characteristics like ADHD are more likely to take paracetamol. NSAIDs like ibuprofen and naproxen are secondchoice medications, but they shouldn't be used for prolonged periods of time or during the third trimester. Common acute treatments for expectant mothers include behavioral techniques, NSAIDs, opioids/barbiturates, triptans, dihydroergotamine, paracetamol/ acetaminophen, and nerve blocks. Less than 100mg of aspirin appears to be a safe dosage. Because of the Higher dosages in the third trimester should be avoided due to the risk of postpartum and neonatal hemorrhage, as well as the early closure of the ductus arteriosus⁸.

Estrogens in the Treatment of Menstrual Migraine:

The gender-dependent prevalence of migraine supports a close examination of reproductive stages and, ultimately, hormonal interventions, while the impact of reproductive hormones is still being studied. Some people get migraines primarily during their periods, with more severe clinical symptoms than during other times of the day of the menstrual cycle⁴.

CONCLUSION:

1. Prevalence and Sex Differences:

Migraine affects about 12% of people worldwide at any given time. Women are 2–3 times more likely than men to suffer from migraines, particularly after puberty. Before puberty, migraine prevalence is similar between boys and girls. Migraine is the leading cause of disability in women of reproductive age.

2. Clinical Features:

Migraine is a chronic neurological disorder with recurrent, moderate-to-severe headaches lasting 4–72 hours. Symptoms include pulsating headache, nausea, vomiting, photophobia, phonophobia, and sometimes cutaneous allodynia. Women experience more frequent, longer, and more severe migraine attacks compared to men.

3. Role of Female Hormones:

Estrogen fluctuations strongly influence migraine patterns. Migraine onset and severity are linked to menarche, menstrual cycle, pregnancy, oral contraceptive use, menopause, and hormone replacement therapy. Estrogen withdrawal (e.g., premenstrual drop in estradiol) can trigger migraine, particularly menstrual migraine. Stable or high estrogen levels (e.g., during pregnancy, especially 2nd–3rd trimester) often improve migraine symptoms.

4. Reproductive Life Events:

Menstrual migraine occurs perimenstrually and can be classified as pure menstrual migraine (PMM) or menstrually related migraine (MRM). Pregnancy: Many women experience improvement, but ~8% report worsening; migraine with aura may persist or appear anew. Menopause and hormonal therapies: Migraine patterns can change, often linked to estrogen fluctuations.

5. Neurobiological Mechanisms:

Estrogens act via nuclear (ERα, ERβ) and membrane (GPER) receptors, influencing both genomic and non-genomic pathways. These pathways affect gene transcription, neurotransmission, ion channel function, and neuronal excitability, explaining sex-specific differences in migraine susceptibility and presentation.

6. Comorbidities Migraine:

is often associated with psychiatric conditions (anxiety, depression), affective dysregulation, and suicidal behaviors. Female migraineurs show higher rates of comorbid conditions than males.

7. Overall Conclusion:

Migraines are sex-specific neurological disorders strongly influenced by estrogen and reproductive events. Understanding estrogen’s role helps in personalized management, including prevention and treatment strategies for menstrual and hormone-related migraines. Menstrual migraines are closely linked to hormonal fluctuations, particularly estrogen withdrawal around menstruation. Hormonal contraceptives and estrogen therapies can help prevent or reduce attacks by stabilizing hormone levels, though caution is needed in women with migraine with aura due to increased stroke risk. Non-hormonal strategies, including NSAIDs, acetaminophen, triptans, lifestyle modifications, and behavioral therapies, are important, especially during pregnancy and lactation when many medications are restricted. Migraine patterns also change across reproductive stages—improving during pregnancy, fluctuating in perimenopause, and sometimes stabilizing after menopause—highlighting the need for individualized treatment approaches based on hormonal status and migraine type.

REFERENCES:

1. Devika J. J., Lijolin V. S., Prasobh G. R.and Grace N. Raju. Role Of Hormones and Migraine Headache During Womens LIFE. World Journal of Pharmaceutical Research. 2021; 10(9):171-178.

2. Poojitha Mamindla., et al. A Review on Migraine. Acta Scientific Pharmaceutical Sciences. 2019; 3(1): 29-42.

3. Li, S., and Zhang, J. Association between magnesium intake and migraine among pre and Postmenopausal Women: A Cross-Sectional study. International Journal of Women S Health. 2025c; 17: 2747–275.

4. Nappi, R. E., Tiranini, L., Sacco, S., De Matteis, E., De Icco, R., and Tassorelli, C. Role of Estrogens in Menstrual Migraine. Cells. 2022; 11(8): 1355.

5. Sacco, S., Ricci, S., Degan, D., and Carolei, A. Migraine in women: the role of hormones and their impact on vascular diseases. The Journal of Headache and Pain. 2012; 13(3): 177–189.

6. Gomez, L. D. Exogenous and endogenous female sex hormones: Impact on women with migraine (Thesis). Lithuanian University of Health Sciences, Faculty of Medicine. 2022

7. Raffaelli, B., Phu, T., DO, Chaudhry, B. A., Ashina, M., Amin, F. M., and Ashina, H. Menstrual migraine is caused by estrogen withdrawal: revisiting the evidence. The Journal of Headache and Pain. 2023; 24(1).

8. Turankar, T., Sorte, A., Wanjari, M. B., Chakole, S., and Sawale, S. Relation and Treatment approach of migraine in pregnancy and breastfeeding. 2023

9. Godley, F., Meitzen, J., Nahman-Averbuch, H., O’Neal, M. A., Yeomans, D., Santoro, N., Riggins, N., and Edvinsson, L. How sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel review. Journal of Personalized Medicine. 2024b; 14(2): 184.

10. Barbanti, P., and Nappi, R. E. Framing and Management of Migraines in Women: An expert opinion on challenges, current approaches, and future multidisciplinary perspectives. Healthcare. 2025; 13(2): 164.

Received on 30.04.2026 Revised on 22.05.2026

Accepted on 06.06.2026 Published on 10.07.2026

Available online from July 14, 2026

Res.J. Pharmacology and Pharmacodynamics.2026;18(3):307-312.

DOI: 10.52711/2321-5836.2026.00042

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.