Migraine is a chronic neurological disorder characterized by recurrent moderate to severe headaches often in association with a number of autonomic nervous system symptoms.
Migraine is a predominantly female disorder. Menarche, menstruation, pregnancy, and menopause, and also the use of hormonal contraceptives and hormone replacement treatment may influence migraine occurrence. Migraine usually starts after menarche, occurs more frequently in the days just before or during menstruation, and ameliorates during pregnancy and menopause. Those variations are mediated by fluctuation of estrogen levels through their influence on cellular excitability or cerebral vasculature.
The prevalence of migraine before puberty is equal in boys and girls. After menarche and during women’s reproductive years, the gender ratio shows a two- to threefold preponderance of women, because the prevalence of migraine without aura increases much more in women than men. More than 50% of women with migraine report an association between menstruation and migraine.
Genetics of Menstrual Migraine: The Epidemiological Evidence, Russel MB et al. 2010
Throughout the reproductive years, menstruation is one of the most significant events related to the occurrence of migraine attacks. Compared with all other phases of the menstrual cycle, incidence of migraine without aura is greatest during a 5-day window that starts 2 days before the onset of menstruation and continues through the first 3 days of menstruation. The International Classification of Headache Disorders, II edition identifies in the Appendix:
- , which is migraine without aura that regularly occurs on or between days −2 to +3 of menstruation, with additional attacks of migraine with aura or migraine without aura at other times of the cycle
- , which is migraine without aura that occurs only on or between days −2 to +3, with no attacks at any other time of the cycle
Pure menstrual migraine is uncommon with respect to menstrually related migraine. Fewer than 10–20% of women report migraine exclusively with menstruation and at no other time of the month. Generally,the term menstrual migraine includes both types of those attacks. Menstrual migraine attacks occur almost invariably without aura even in migraine with aura patients. According to the majority of the available studies, compared with migraine at other times of the cycle, menstrual attacks last longer, are more severe, more likely to relapse, less responsive to treatment, and associated with greater disability.
The prevalence of pure menstrual migraine without aura varies between 7% and 14% among female migraineurs, while the prevalence of menstrually related migraine without aura varies from 10% to 71% among female migraineurs. Approximately one of every three to five female migraineurs has attacks of migraine without aura in relation to menstruation.
MECHANISMS LINKING SEX HORMONES AND MIGRAINE
Sex hormones may interfere with cellular excitability or cerebral vessels.Ovarian steroids cross the blood–brain barrier by passive diffusion, with brain levels mirroring blood levels and are also produced within the central nervous system.
Estrogen and progesterone can influence the pain-processing networks and the endothelium involved in the pathophysiology of migraine. Interrelationships between estrogens and brain neurotransmitters have been confirmed, including serotonin, norepinephrine, dopamine, and endorphins. In particular, estrogen has potent effects on the serotonergic system, increasing serotonergic tone.
Prostaglandins have also been implicated in menstrual migraine. In particular, entry of prostaglandins into the systemic circulation can trigger throbbing headache, nausea, and vomiting. Estrogen facilitates the glutaminergic system, potentially enhancing neural excitability. This effect is modulated by progesterone, which appears to activate GABAergic systems, suppressing neuronal reactivity. Induction of cortical spreading depression which is involved in the pathophysiology of migraine, depends on glutamatergic transmission. In addition, peak estrogen levels are associated with a significant decrease in serum Mg++ levels that could facilitate N-Methyl-D-Aspartate (NMDA) channel opening.
Estrogens may be involved in migraine pathophysiology also affecting the vasculature through stimulation of nitric oxide release. The estrogen receptor α increases NO synthase activity in the endothelium. Women with a history of menstrual migraine, with respect to women with migraine unrelated to the menstrual cycle or without migraine exhibit a heightened activation of the NO and L-arginine pathway and an increase in NO, especially during the luteal phase.
Mechanisms linking sex hormones and migraine, Simona Sacco et al. 2012
Recent studies show that hyponatriemia can lead to migraine .
Hyponatriemia leads to a dysfunction of Na+/H+ Exchanger One (HNE1) . The HNE-1 is one of the enzymes responsible for maintaining in normal range intracellular pH against acid attacks.
When natriemia goes down, this exchanger works worse, and so it does not eliminate enough well protons from cytoplasm towards extra cellular space. Cells are unable to tolerate the resulting trend to acidosis, so hyponatriemia can cause nausea and cephalea.
Nausea is due to a vagal nerve medieted response and cephalea depends on a depression of cerebral cortex cells. This depression is due to a decrease of methabolic and electric activity of the cell, probably caused by the dysfunction of ionic channels, like Na+/H+ exchanger and Na+/K+ Exchanger, inhibited also by estrogens and progesterone. In this depressed condition, the cerebral cell releases neuropeptides and originate vasodilation . The increase of blood flow in association with neuropeptides (substance P and CGRP) originate an inflammation of trigeminal nerve, that is the cause of headache's pain.
Migraine: Medication and Treatment
For the most part, abortive therapies are not specifically tailored to menstrual migraine. Treatments used in traditional migraine therapy are used for pure menstrual migraine and menstrually related migraine as well.These therapies include NSAIDs, triptans, ergotamine, dihydroergotamine, and opiates.
However, in recent years, randomized controlled trials or subsets of larger trials have focused on the use of triptans for abortive therapy for menstrual migraine.
Menstrual Migraine: Therapeutic Approaches, Macgregor EA et al. 2009
Management of Menstrual Migraine: A Review of Current Abortive and Prophylactic Therapies, Sullivan E. and Bushnell C. 2010