Menstrual migraine appears to be an abnormal response to normal, rather than abnormal, hormonal fluctuations (Nagel-Leiby et al 1990; MacGregor 1997a). Estrogen can affect neuronal excitability by both genomic and nongenomic mechanisms (Eikermann-Haerter et al 2007). Plasma concentrations of follicle-stimulating hormone, luteinizing hormone, prolactin, and testosterone obtained throughout the menstrual cycle are normal (Epstein et al 1975). Somerville studied 14 women who had migraine exclusively related to menstruation and showed that migraine appeared to be triggered by falling levels of estrogen during the late luteal phase of the normal menstrual cycle. When migraine attacks were delayed by maintaining high plasma estradiol concentrations, endogenous progesterone levels fell as usual, resulting in menstruation that was not associated with a migraine attack. Only when plasma estradiol levels fell did an attack ensue (Somerville 1971; 1972; 1975a; 1975b). Once the migraine mechanism is activated by falling estrogen levels, subsequent estrogen administration does not influence the occurence of an attack. A study of 38 women with migraine without aura recorded migraine attack frequency and urinary levels of estrone-3-glucuronide and pregnanediol-3-glucuronide, metabolites of estradiol and progesterone, over 3 menstrual cycles. Migraine attacks were most likely to occur during the late luteal and early follicular phases, when estrogen levels were falling or low, and were least likely to occur when estrogen levels were rising (MacGregor et al 2006).
Additional evidence that menstrual migraine is due to estrogen withdrawal include the following: (1) some women who take combined oral contraceptives experience migraine during the pill-free week, when estrogen falls after 21 days of high levels; (2) migraine may improve during pregnancy, when estrogen levels rise gradually, but can reoccur immediately postpartum, when estrogen levels plummet; (3) some women have migraine during the week without estrogen replacement therapy in the old regimen of 21 days on and 7 days off treatment; (4) headache frequency increased when an estrogen preparation was followed by a nonestrogen preparation in a study of women with bilateral oophorectomies; and (5) migraine often improves after menopause, when the ovarian cycle ceases, estrogen levels remain low, and there is little fluctuation (MacGregor 1997a). A recent study showed that gene expression of pain-associated neuropeptides in the trigeminal ganglia of female mice is modulated by estrogen through estrogen receptor alpha (Puri et al 2005a). Estrogen also increases the production of calcitonin gene-related peptide (CGRP), a peptide well known to be implicated in pain perception, by the trigeminovascular system (Gangula et al 2001). A plethora of evidence also supports an estrogen-mediated increase in nitric oxide production, through activation of estrogen receptor a (ER-a). Despite its established vasodilatory and cardioprotective properties, the role of nitric oxide in migraine may be far more complicated because it has been shown to promote the production of proinflammatory mediators and activate trigeminal afferents (Kim et al 2008). Polymorphisms in the estrogen receptor and in the follicle stimulating hormone receptor (FSH-R) can also account for the variability in migraine propensity and clinical phenotype (Oterino et al 2008). Moreover, estrogen alters the expression of genes coding for proteins that may be involved in inflammatory pain, eg, extracellular signal-regulated protein kinase (Puri et al 2005b). Modulation of neurotransmission by estrogen within the trigeminal nucleus caudalis is another potential mechanism (Martin and Behbehani 2005). Polymorphisms of the progesterone receptor have been implicated as well (Colson et al 2005; Brandes 2006).
The high estrogen levels sustained during pregnancy are thought to be the basis for the headache relief that pregnant migraineurs often experience. It has also been suggested that the improvement might be related to changes in serotonin metabolism during pregnancy and increased endorphin concentrations during the last 2 trimesters (Sicuteri 1980). The rapidly falling concentrations of estrogen that follow childbirth are thought to be responsible for postpartum headaches.
Serotonergic pathways are certainly involved. A PET study showed that migraine patients had lower brain serotonin levels between attacks compared with controls and that those levels increased to the normal range during an attack (Sakai et al 2008). The study suggested that migraine may be associated with a low-serotonin state between attacks. Furthermore, there is evidence that serotonin synthesis is influenced by ovarian hormones (Bethea et al 2002). Data from primate experiments support the notion that the serotonergic tone is enhanced by estrogen (Martin and Behbehani 2006a; 2006b).
In general, ovarian steroid hormones regulate nociceptive pathways at multiple levels. The trigeminal vascular system is significantly modulated by estrogens and is probably the major determinant of sexual dimorphism observed in migraine (Gupta et al 2011). This relationship is well exemplified by the interaction between CGRP-ergic and serotoninergic pathways with estrogens (Gupta et al 2011).
Prostaglandins intensify nociception. This might provide a partial explanation for the commonly held view that menstrual migraine is generally more severe and less responsive to treatment compared with migraine not related to the menstrual cycle. However, there is little support for prostaglandins as primary mediators in migraine. Nattero and colleagues found that controls and migraineurs had similar prostaglandin levels during the cycle. However, migraineurs had significantly higher levels during a migraine attack than on any other day of their menstrual cycle (Nattero et al 1989). These results do not lend support to the idea that elevated prostaglandin levels per se trigger menstrual migraine. Because dysmenorrhea is clearly related to elevated prostaglandin levels (which intensify uterine contractions), one would expect that migraine and dysmenorrhea would correlate if prostaglandin levels played a primary role in menstrual migraine pathophysiology.
Mechanisms relating to dopamine and opioids have also been proposed for menstrual migraine, including reduction in serum dopamine beta-hydroxylase concentrations (Magos et al 1985), dysfunction of opioid control of the hypothalamic-pituitary-adrenal axis (Facchinetti et al 1990), reduced levels of magnesium (Facchinetti et al 1991b), and platelet dysfunction.
A multitude of other hormonal systems has more recently been implicated in the pathophysiology of migraine. Insulin resistance has been found in migraineurs compared with control subjects (Cavestro et al 2007), raising the question whether diabetes could be linked to migraine. Bosco and colleagues detected an increase in plasma prolactin levels during migraine attacks in migraineurs and tension-type headache patients with microprolactinoma--although the sample was small and did not include control subjects (Bosco et al 2008). Chronic migraine and chronic tension-type headache could be associated with abnormal sleep melatonin secretion (Bruera et al 2008). Whether this is the cause or the effect of chronic headache remains to be clarified. The orexin system has also been linked to migraine and medication overuse headache. In a study by Sarchielli and colleagues, CSF levels of corticotrophin releasing factor (CRF) and orexin-A were elevated in patients with chronic migraine and medication overuse headache (Sarchielli et al 2008).