1. The first day of menstruation is day 1 and the preceding day is day −1; there is no day 0.

2. For the purposes of this classification, menstruation is considered to be endometrial bleeding resulting from either the normal menstrual cycle or from the withdrawal of exogenous progestogens, as in the case of combined oral contraceptives and cyclical hormone replacement therapy.

1. The first day of menstruation is day 1 and the preceding day is day −1; there is no day 0.

2. For the purposes of this classification, menstruation is considered to be endometrial bleeding resulting from either the normal menstrual cycle or from the withdrawal of exogenous progestogens, as in the case of combined oral contraceptives and cyclical hormone replacement therapy.

Insufficient progesterone in the luteal phase was thought to be responsible for menstrual migraine on the basis of old studies that supported use of progesterone as a treatment (20,21). However, more recent studies dispute this (22,23) (Fig. 35-1).

There is evidence that menstrual attacks of migraine are associated, at least in some women, with falling levels or withdrawal of estrogen (24, 25, 26, 27). Somerville noted that a period of estrogen priming with several days of exposure to high estrogen levels is necessary for migraine to result from estrogen withdrawal, as occurs in the late luteal phase of the menstrual cycle (28, 29, 30). This explains why migraine is not associated with ovulation. MacGregor et al. noted that migraine was inversely associated with urinary estrogen levels across the menstrual cycle: attacks were significantly more likely to occur in association with falling estrogen in the late luteal/early follicular phase of the menstrual cycle and less likely to occur during the subsequent part of the follicular phase during which estrogen levels rose (22) (Fig. 35-2). If estrogen withdrawal is a trigger for migraine, averting the drop in estrogen using estrogen supplements should prevent attacks. Trials using estrogen supplements, usually started 48 hours before the earliest expected onset of menstrual attacks, confirm the efficacy of this approach (31, 32, 33). However, in some cases, treatment may only defer migraine until later in the cycle (28,31) (Fig. 35-3).

It is likely that menstrual cycle hormone changes trigger some alteration in activity of the hypothalamic-pituitary-adrenal axis, exposing susceptible women to a migraine attack. For example, estrogens are neurosteroids, known to raise levels of endorphins (34); aberrant opioid control of the hypothalamic-pituitary-adrenal axis has been reported in menstrual migraine (35). Close interrelationships between estrogens and other brain neurotransmitters have also been confirmed, especially the catecholamines, noradrenaline, serotonin, and dopamine (36). Fluctuating estrogen levels are associated with impaired glucose tolerance in the luteal phase of the menstrual cycle, which could trigger migraine (37,38). Other differences reported in menstrual migraine versus control groups include changes in aldosterone levels (39), intracellular magnesium (40), and platelet homeostasis (41).

Prostaglandins have also been implicated in menstrual migraine (42). In particular, entry of prostaglandins into the systemic circulation can trigger throbbing headache, nausea, and vomiting (43). In the uterus, prostaglandins are synthesized primarily by the endometrium. There is a threefold increase in prostaglandin levels in the uterine endometrium from the follicular to the luteal phase, with a further increase during menstruation (44). As a result of the withdrawal of estrogen and progesterone, the endometrium breaks down and prostaglandins are released. This causes vasoconstriction within the endometrium and disruption of endometrial cells, stimulating further prostaglandin synthesis. When an excessive amount of prostaglandins gains entrance to the circulation, other systemic symptoms occur that are characteristically associated with menorrhagia and/or dysmenorrhea such as headache and nausea (45,46). Plasma taken premenstrually from women with dysmenorrhea and then reinfused postmenstruation into the same women resulted in premenstrual symptoms, including headache (47). Therefore, prostaglandins may have a specific role in migraine associated with dysmenorrhea and menorrhagia. In support of this, prostaglandin inhibitors are effective for the prevention of menstrual attacks of migraine (48).

Some postmenopausal women, not taking hormonal treatments, continue to have regular monthly migraine attacks. Migraine attacks can also be cyclical in men, suggesting that some central phenomenon is responsible for these cycles (49).