Migraine is an episodic, often debilitating condition that affects women more often than men. Twenty-eight million Americans suffer from migraine headaches—and nearly 75% of these are women.¹ Unlike other chronic pain conditions, migraine has its peak prevalence during the years of greatest productivity, when most women are juggling family responsibilities and careers.² Many women are particularly susceptible to migraine attacks just before and during menses. Currently, there is no accepted formal definition of “menstrual migraine.” Headaches that occur in association with menses are still classified as migraine with or without aura. Proposed definitions are “menstrually associated migraine” (MAM) and “true menstrual migraine.” Here, I will provide a brief overview of an array of treatment options— including lifestyle modifications, drug therapy, and “mini-prophylaxis”— that can markedly diminish the frequency and severity of menstrual migraine. WHAT IS MENSTRUAL MIGRAINE?
True menstrual migraine is defined as a headache that develops exclusively during the perimenstrual period (2 days before to 3 days after menses).³ It does not occur at any other time of the month. By these criteria, approximately 7% to 14% of female migraineurs can be said to have true menstrual migraine. Menstrually associated migraine (MAM) also begins 2 days before to 3 days after menses. Unlike true menstrual migraine, however, MAM also occurs at other times of the month. Approximately 60% of women migraineurs fit this definition; most note more frequent migraines during the perimenstrual period.⁴ These women have at least double the probability of suffering a migraine on the first 2 days of menstruation than on days 6 through 28 of their cycle. Pathophysiology. A simple pathophysiologic mechanism underlying hormonally associated migraines has not yet been discovered. While it is believed that fluctuations of estro-gen levels— particularly precipitousdrops— trigger MAM, studies have so far involved only a few patients, and data need to be reconfirmed. In his classic studies, Sommerville^5,6 concluded that it was the drop in levels of estrogen—not progesterone(Drug information on progesterone)— that triggered MAM. He injected premenstrual women with progesterone; this delayed the onset of menstruation but did not alter predictable MAM. He then injected these women with estrogen premenstrually, which delayed the usual drop in estrogen levels. Menstruation occurred at the usual time, but onset of MAM was delayed. Only 6 migraineurs were studied in Sommerville’s classic experiment, and his results have not been reproduced. Researchers have found no difference in the levels of reproductive hormones in women with and without migraine. There is speculation, however, that responses to normal hormonal fluctuations in the CNS differ in women who have migraine. Changes in neurotransmitter concentrations, receptor number, and/or sensitivities may be involved. Interestingly, nocturnal secretion of melatonin(Drug information on melatonin) (which is synthesized from serotonin) is decreased during the late luteal phase of the menstrual cycle. The clinical relevance of this finding is not yet known. Obviously, the mechanism of MAM is more complex than a simple relationship to estrogen concentrations. NONDRUG THERAPY
A comprehensive approach to therapy needs to be considered for patients with MAM. This involves:

• Patient education.
• Encouraging the patient to become an active participant in her care (for example, by keeping a headache diary).
• Employing nonpharmacologic measures, either alone or in conjunction with drug therapy.

A headache diary is a vital tool in tracking headache frequency; a reliable record can help you accurately determine whether a consistent menstrual trigger exists. Predictable headaches in association with regular menses may help you develop an effective treatment plan. Counsel your patient that migraine has a neurobiologic basis. Let her know that there are many potential triggers for the disorder that are best recognized and—when possible—prevented, at least during times of greatest headache frequency. Chronobiology is especially important during periods of headache vulnerability. Advise your patient that consistency in her daily activities may reduce headache frequency. For example, encourage your patient to awake and eat at roughly the same time every day; to maintain adequate hydration; to avoid particular food triggers; and to practice stress reduction modalities, such as biofeedback or exercise. Unfortunately, some triggers (such as hormonal fluctuations) cannot always be prevented. Patients may fear that they are at the mercy of their hormones. Reassure such women that hormonal fluctuations are only one of many potential headache triggers. Emphasize the importance of identifying and addressing controllable triggers, and reassure your patient that most therapies for nonhormonal headaches also work quite well for MAM.⁷ DRUG THERAPY
First-line therapy for women with MAM is the same as that for other types of migraines. Triptans. In a stratified approach to care, migraine-specific agents, such as the triptans, are generally accepted as first-line therapy for moderate to severely disabling migraines.⁸ Most agonists that affect serotonin 5-HT_1B and 5-HT_1D receptor sites, including sumatriptan(Drug information on sumatriptan) (tablet or injectable form),⁹ zolmitriptan(Drug information on zolmitriptan) (tablet),¹⁰ and rizatriptan (tablet),¹¹ are significantly more effective than placebo. Alternatives to triptans. For patients with moderate to severe MAM, the ergots and ergot derivative, dihydroergotamine(Drug information on dihydroergotamine) (in tablet, sublingual, suppository, injectable, or nasal formulations), can be effective.¹² Unfortunately, ergots may cause nausea, and migraineurs may require additional anti-emetics with these medications. NSAIDs may be used as a firstline abortive therapy for women with mildly to moderately disabling MAM.¹³ These agents are especially appealing in this setting because they also have antiprostaglandin effects (the hormone is believed to play a role in MAM and dysmenorrhea). Combination analgesics that contain acetaminophen, aspirin(Drug information on aspirin), and caffeine(Drug information on caffeine) also offer effective pain relief for patients with MAM.¹⁴ In addition, anal- gesics, such as butalbital combinations or opioids, may be prescribed when other abortives are contraindicated or ineffective. Keep in mind that overuse of these agents may lead to rebound headaches or habituation—especially in patients with a history of substance abuse, frequent headaches, or comorbid anxiety. Generally, abortive medications should not be used more than 2 days per week. However, this rule may be extended for patients with prolonged migraines that occur exclusively during menses and at no other time of the month. In this setting, the risk of rebound headaches is acceptably low, even when analgesics are used for 4 or 5 consecutive days. Be sure to assess headache frequency and disability throughout the month, not just during menses. For women with frequent headaches, consider standard preventive agents, such as β-blockers, calcium channel block- ers, NSAIDs, antidepressants, anticonvulsants, or antiserotonin agents (ie, methysergide). For women who have severe headaches during menses, it is reasonable to increase drug dosages temporarily during the period of greatest headache vulnerability. HORMONAL MANIPULATION
This approach is usually reserved for MAM that is refractory to standard abortive and preventive measures. ^3,4,15,16 Results are still unpredictable, and theoretical benefits are unproven in well-controlled studies. Cyclic fluctuations in estrogen—as occur with menstruation, during the week of placebo tablets in oral contraceptive users, and with cyclic hormone replacement therapy during postmenopausal years—may unpredictably worsen migraines.¹⁵ Stable low estrogen levels during menopause or stable high levels during the last 2 trimesters of pregnancy often diminish the frequency of migraines. Therefore (at least in theory), migraineurs can be helped if their estrogen levels are stabilized, particularly if headaches have a hormonal trigger. How to stabilize estrogen levels? There are several approaches:

• For women already using oral contraceptives that contain monophasic estrogen and progesterone, consider continuous hormonal therapy.¹⁷ Have the patient skip the placebo week of pills and start on the next pack as week 4. This regimen is usually followed for 9 weeks to 12 weeks. It allows the patient to menstruate only 3 or 4 times a year, thereby reducing the frequency of MAM. Some women may still get unpredictable breakthrough spotting and headaches.
• Another approach is to add estrogen supplementation over the week of menstruation or during the placebo week of pills (days 22 to 28) for the patient who is already taking an oral contraceptive. Estrogen supplementation has been found to decrease headache frequency and severity. Supplementation may include a low-dose (20 μg of estradiol(Drug information on estradiol)) oral contraceptive; a 0.625- to 1.25-mg conjugated equine estrogen pill¹⁸; percutaneous estradiol gel¹⁹; or a transdermal estradiol 0.075- to 0.1-mg patch used on days 22 through 28 of a 28-day menstrual cycle.²⁰ Start with low doses of estrogen and increase as needed.¹⁸ Use hormones at bedtime to avoid a nadir of drug level coincident with the hours of most common onset of migraine (ie, in the early morning from 4 AM to 9 AM). Benefits of oral contraceptive use include regular cycling of menses (and perhaps at least predictable MAM), relief of dysmenorrhea, decreased blood loss with menses, reliable contraception, and decreased risk of ovarian cancer. Potential risks of hormonal manipulation among migraineurs are still controversial.^21,22 At issue is whether there is:
• Potential increased risk of ischemic stroke among female migraineurs younger than 45 years.
• A possible additive risk of ischemic stroke with oral contraceptive use.
Most studies that demonstrated increased relative risk involved women taking oral contraceptives in dosages rarely used today. Many experts believe that the risk of stroke is minimal for women taking low-dose oral contraceptives who have no other risk factors, such as smoking or prolonged migraine aura. ALTERNATIVE THERAPIES
One study found that magnesium therapy could help reduce the frequency of MAM.²³ The 20 women in the study were given placebo or oral magnesium pyrrolidone carboxylic acid in 3 divided doses totaling 360 mg/d on days 15 of the menstrual cycle to day of onset of menses for 2 months. The findings suggest that magnesium supplementation may offer effective migraine prophylaxis— and that a low migraine threshold could be related to a magnesium deficiency. Other alternative therapies found effective for migraines in general, such as feverfew and riboflavin(Drug information on riboflavin), have not been specifically studied in MAM.